Evaluation of the Clinical Use of Tepoxalin and Meloxicam in Cats

JFM15810.1177/1098612X12473994Journal of Feline Medicine and SurgeryCharlton et al 4739942013

Original Article

Journal of Feline Medicine and Surgery 15(8) 678 –690 Evaluation of the clinical use of © ISFM and AAFP 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav tepoxalin and meloxicam in cats DOI: 10.1177/1098612X12473994 jfms.com

Anna N Charlton1,*, Javier Benito1,*, Wendy Simpson2, Mila Freire1 and B Duncan X Lascelles1,3

Abstract Medical records where tepoxalin (Zubrin) or meloxicam (Metacam) were prescribed in cats were reviewed and data extracted. Comparisons were performed for exploring changes between pre- and post-non-steroidal anti- inflammatory drug course laboratory tests. Seventy-nine medical records fit the inclusion criteria (n = 57 and n = 22, tepoxalin and meloxicam, respectively). The median dosages administered were 13 and 0.029 mg/kg/day (tepoxalin and meloxicam, respectively). Median prescription durations were 11 (2–919) and 93 (4–1814) days for tepoxalin and meloxicam, respectively. Suspected adverse events were reported for tepoxalin (9%, 5/57 cats) and meloxicam (18%, 4/22 cats) a median of 774 and 448 days, respectively, after the prescription started. For cats prescribed meloxicam, there were several statistically significant changes for serum biochemistry and hematology parameters, but median values were within normal limits. These valuable clinical data suggest that tepoxalin and meloxicam are well tolerated in the clinical setting at the doses prescribed in this study.

Accepted: 15 December 2012

Introduction Recently, the International Society of Feline Medicine Tepoxalin (Zubrin) is a dual inhibitor [cyclooxyge- and American Association of Feline Practitioners pub- nase (COX) and lipoxygenase] approved for use in dogs lished guidelines on the long-term treatments of non- to treat osteoarthritic pain.13 Tepoxalin is a dual inhibitor steroidal anti-inflammatory drugs (NSAIDs) in cats.1 in the cat for the duration of its pharmacokinetic profile Despite these recommendations, data are still limited on (unlike the dog) and may show tissue selectivity. The the clinical use of NSAIDs in cats, dosages used, the cri- safety and effectiveness of tepoxalin have not been eval- teria for patient selection and clinical outcome following uated at any dose or for any indication in cats.13,14 their use. However, it’s relatively short half life (4.7 h) combined Long-term pain is associated with diseases such as with its dual inhibition makes it attractive for use in this cancer,2–5 trauma,1,6 gingivitis and stomatitis,7 idiopathic species. cystitis,8,9 uveitis, skin disease, slow healing wounds, Meloxicam (Metacam) is a COX enzyme inhibitor15 and diabetic neuropathy and degenerative joint disease it is one of the several NSAIDs, including robenocoxib,16,17 (DJD).6,10 It is becoming recognized that these diseases are common, as evidenced by two recent studies finding 1 Comparative Pain Research Laboratory, College of Veterinary that 60–90% of the feline population has radiographic Medicine, North Carolina State University, Raleigh, NC, USA evidence of DJD.11,12 The use of NSAIDs is a common 2Morrisville Cat Hospital, Morrisville, NC, USA means of pain management in other species owing to 3Center for Comparative Medicine and Translational Research, their relatively predictable efficacy across a wide range Department of Clinical Sciences, College of Veterinary Medicine, of pain conditions. In cats, only one NSAID (meloxicam) North Carolina State University, Raleigh, NC, USA *These authors made an equal contribution to this article is approved for long-term use, but only in certain countries and only for DJD-associated pain. The lack of Corresponding author: approved products, fears over side effects and lack of B Duncan X Lascelles BVSc, PhD, MRCVS, DSAS(ST), DECVS, knowledge regarding clinical tolerance of NSAIDs all DACVS, Comparative Pain Research Laboratory and Center for Comparative Medicine and Translational Research, Department combine to result in suspected under-treatment of of Clinical Sciences, College of Veterinary Medicine, North chronic pain in cats. More clinical data on NSAIDs in Carolina State University, Raleigh, NC, USA cats are needed. Email: [email protected]

Downloaded from jfm.sagepub.com at ISFM on May 11, 2015 Charlton et al 679 tolfenamic acid,18,19 carprofen19,20 and ketoprofen,16,17,19,21 Data collected licensed for use in cats in various countries. Meloxicam Information was gathered on sex, breed, age, weight, has been shown to be an effective analgesic in cats when diagnosis and reason for treatment, NSAID prescrip- used perioperatively,22 when administered for short peri- tions (total dose administered, average dose per kilo- ods of time for acute musculoskeletal pain21,23,24 and is gram per day, duration of prescription), pre-existing licensed in Europe for long-term administration for mus- diseases and clinical signs, concurrent treatments, rea- culoskeletal pain. son for stopping treatment, pre- and post-treatment The purpose of this retrospective study was to review values for serum biochemistry, hematology, urinaly- the clinical use of tepoxalin and meloxicam in a single sis, T4 test values and if ADEs occurred. Duration of feline-only practice, and to evaluate the clinical tolerance treatment was considered to be the first day of treat- of tepoxalin and meloxicam. This review was performed ment to last day of treatment, or to date of the final to add to our knowledge of the clinical tolerance of clinical chemistry test — whichever came first. ADEs NSAIDs in cats, and to determine if there was any sup- were defined as adverse events considered by the port for the further experimental and clinical evaluation attending veterinarian to be due to the NSAID treat- of tepoxalin in cats. ment and directly stated as such by the veterinarian in Our hypothesis was that the use of tepoxalin and the record. They were dichotomized into two catego- meloxicam would be well tolerated clinically (tolerated ries — cats that suffered an ADE during treatment by 90% of treated cats) and that there would be no sig- which caused the treatment to be stopped perma- nificant effect of tepoxalin or meloxicam on serum bio- nently, and cats that suffered an ADE episode during chemistry, urinalysis and hematological values over the treatment but treatment was not stopped or was re- duration of treatment courses. initiated after a few days. If, during the treatment The aims of this study were, first, to review all the period, any additional oral doses of NSAID were medical records from a single practice and extract perti- administered these were recorded. nent information from records on the prescription and clinical use of tepoxalin or meloxicam; second, to deter- Statistical analysis mine the number of cats in which the NSAID medication All data were entered in the database (Microsoft Excel) was stopped owing to adverse drug events (ADEs); and and analyzed using software (GraphPad Prism version last, to evaluate whether there were any significant 5.02 and JMP 10). Descriptive statistics were used to effects on hematological and clinical chemistry parame- describe the data set and appropriate statistical tests ters in cats receiving tepoxalin or meloxicam. (Fisher’s exact, Mann–Whitney, 2) used to compare the characteristics of the cats treated with the two different Materials and methods NSAIDs. A Wilcoxon sign-ranked test was used to test The database of a feline-only practice in North Carolina, for significant changes between initial versus final lab- Morrisville Cat Hospital (Morrisville, NC, USA), was oratory tests within each treatment group. No adjust- searched for all cases (2003–2012) in which cats had been ment was made for multiple comparisons in order to prescribed either tepoxalin or meloxicam. A total of 332 maximize the chance of detecting potential changes records fulfilled the criteria, and these were searched for induced over the course of the prescription. Mean, cases where either NSAID had been prescribed, and median, range and SD were also calculated and com- serum biochemistry and/or urinalysis and/or hematol- pared to reference intervals. Comparisons between ogy had been collected prior to the course of NSAID (ini- subgroups of cats with and without ADEs were evalu- tial test) and at the end of the course of treatment (final ated using the Mann–Whitney test. The critical P-value test). This retrospective study was performed on the was set at 0.05. basis of an ‘intent to treat’ approach — it was assumed, unless otherwise stated, that the prescriptions given to Results owners were administered to the cat. Each medical Demographic data record was reviewed carefully and included if they fit A total of 79 cases were included in this study. Fifty- the inclusion parameters. seven clinical cases were prescribed tepoxalin and 22 were prescribed meloxicam. The painful conditions for Inclusion criteria which the NSAIDs were prescribed were classified as Cases were included if clinical chemistry and/or hema- musculoskeletal (eg, arthritis, lack of movement, stiff- tology tests were performed less than 60 days before the ness, lameness), urinary tract (eg, stranguria, cystitis, start of NSAID treatment and less than 60 days after the hematuria, urinary tract infection, crystals), surgical pro- NSAID treatment finished. If cats were prescribed both cedures and constipation (see supplementary data). The tepoxalin and meloxicam then there had to be a washout majority of cats prescribed tepoxalin were prescribed the period of at least 60 days between treatments. drug for urinary tract discomfort (82.5%) and the

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majority of cats prescribed meloxicam were prescribed in the average daily and total dose calculations. One cat meloxicam for musculoskeletal discomfort (68.2%). prescribed tepoxalin also received a dose of meloxicam; Demographic data and conditions treated are summa- this was not included in any dose calculations. rized in Table 1. Cats treated with meloxicam were older (P <0.001) and were treated for longer (P <0.001). The Pre-existing diseases conditions for which the NSAIDs were being used were Pre-existing diseases were classified as suspected or doc- significantly different between the groups (P <0.001). umented renal impairment, suspected or documented cardiovascular disease, hepatomegaly, gastrointestinal Exceptions to inclusion criteria disease, hyperthyroidism, pancreatitis, seizures, dehy- Some cats were included in the study despite not meet- dration, lower urinary tract disease, suspected or docu- ing the inclusion criteria precisely. Eight of the 57 cats mented respiratory disease, obesity, dermatological prescribed tepoxalin had an initial test that occurred 1–3 disease, deafness, dental disease, ocular disease, miscel- days after starting the NSAID prescription. One of the 22 laneous and no pre-existing diseases noted. The miscel- cats prescribed meloxicam had an initial test that laneous category included diseases, such as retro peritoneal occurred 4 days after starting the NSAID prescription. effusion and unidentified masses. For cats treated with One of the 57 cats prescribed tepoxalin had a washout tepoxalin the majority of reported pre-existing diseases period of only 9 days between meloxicam and tepoxalin, and one cat was on a low dose of meloxicam before starting tepoxalin and had no washout period.

Prescription duration and doses The 1.5 mg/ml concentration suspension of meloxicam and 50 mg tepoxalin tablets were dispensed. The median (range) dosages of the prescribed NSAIDs were 13 (2–22) mg/kg/day for tepoxalin and 0.029 (0.019–0.072) mg/ kg/day for meloxicam. The median duration of the prescriptions were 11 (2–919) days for tepoxalin and 93 (4– 1814) days for meloxicam. Prescription information is summarized in Table 2. Of cats prescribed meloxicam, seven received additional single doses of oral meloxicam during the treatment period for pain associated with receiving an injectable vac- cine. Six of these cats only received one additional dose of meloxicam, while one cat received three during the prescribed treatment period, and these doses were included Charlton et al 681

Table 2 Prescription characteristics for tepoxalin and meloxicam

Tepoxalin Meloxicam

(n = 57) (n = 22) Dose (mg/kg/day) Mean (SD) 12 (5) 0.034 (0.012) Median (range) 13 (2–22) 0.029 (0.019–0.072) Duration (days) Mean (SD) 73 (197) 327 (513) Median (range) 11 (2–919) 93 (4–1814) Cats without ADEs (n) (%) (n = 52) (91%) (n = 18) (82%) Dose (mg/kg/day) Mean (SD) 12 (5) 0.035 (0.013) Median (range) 13 (2–22) 0.031 (0.019–0.072) Duration (days) Mean (SD) 31 (84) 247 (408) Median (range) 10 (2–504) 81 (4–1426) Cats with ADEs (n) (%) (n = 5) (9%) (n = 4) (18%) Dose (mg/kg/day) Mean (SD) 11 (1) 0.027 (0.001) Median (range) 11 (9–12) 0.026 (0.026–0.029) Duration (days) Mean (SD) 509 (438) 688 (831) Median (range) 774 (4–919) 448 (41–1814) Cats with ADEs that resulted in treatment stopping (n) (%) (n = 1) (2%) (n = 3) (14%) Dose (mg/kg/day) Mean (SD) 11 (– ) 0.027 (0.001) Median (range) 11 (– ) 0.026 (0.026–0.029) Duration (days) Mean (SD) 4 (– ) 645 (1012) Median (range) 4 (– ) 81 (41–1814) Cats with ADEs that did not result in treatment being (n) (%) (n = 4) (7%) (n = 1) (5%) stopped Dose (mg/kg/day) Mean (SD) 10 (1) 0.026 (– ) Median (range) 10 (9–12) 0.026 (– ) Duration (days) Mean (SD) 635 (388) 815 (– ) Median (range) 779 (62–919) 815 (– ) Days between treatment and clinical tests Initial test to treatment Mean (SD) 4 (10) 10 (13) Median (range) 0 (0–51) 4 (0–44) Last treatment day to final test Mean (SD) 12 (13) 5 (13) Median (range) 9 (0–53) 0 (0–48)

ADE = adverse drug event tepoxalin, 24/57 (42%) of cats were prescribed a concurrent were reported as vomiting with excessive salivation and medication for cardiovascular support and systemic antibi- diarrhea. The average dose per day for both tepoxalin otics were used in 21/57 (37%) of cats. Of the cats prescribed (P = 0.89) and meloxicam (P = 0.81) prescribed for cats with meloxicam, nutritional supplements were used in 12/22 ADEs did not differ from those not experiencing ADEs (55%) of cats and systemic antibiotics were used in 10/22 (Table 2). The median duration of treatment prior to an (46%) of cats. Table 3 summarizes concurrent treatments ADE occurring was 774 days for tepoxalin and 448 days and a list of how medications and supplements were classi- for meloxicam (Table 2). There was no difference between fied is provided in the supplementary data. the drugs in this respect, although numbers of cats were small (n = 5 and n = 4, tepoxalin and meloxicam, respec- ADEs tively). The median duration of treatment prior to an ADE ADEs were reported in the medical records of five cats that resulted in the treatment being stopped was 4 days (n (8.8%) prescribed tepoxalin and four cats (18.2%) pre- = 1) for tepoxalin, and 81 days (n = 3) for meloxicam. scribed meloxicam. There was no difference between the groups with respect to the number of ADEs (P = 0.19). Blood and urine tests Vomiting was the primary ADE, but diarrhea, drooling, The median number of days between first day of treat- elevated blood urea nitrogen (BUN) and lack of appetite ment and initial serum biochemistry, urinalysis and hema- were also reported. In the tepoxalin group, treatment was tology tests were 0 (0–51) and 4 (0–44) days for tepoxalin stopped owing to an ADE (vomiting) in one cat (1.75%). In and meloxicam, respectively. The median number of days the meloxicam group, ADEs resulted in treatment being between the last day of treatment and the final clinical tests stopped in three cats (13.63%). The ADEs for these cats performed were 9 (0–53) and 0 (0–48) days for tepoxalin

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Table 3 Concurrent treatments and medications

‘Tepoxalin’ cats (n = 57) ‘Meloxicam’ cats (n = 22)

Flea/tick, n (%) 20 (35%) 6 (27%) Subcutaneous fluids, n (%) 10 (18%) 11 (50%) Anesthesia,* n (%) 6 (11%)† 6 (27%) Nutritional supplements, n (%) 13 (23%) 12 (55%) Gastrointestinal support, n (%) 11 (19%) 8 (36%) Systemic antibiotics, n (%) 21 (37%) 8 (36%) Additional systemic analgesics, n (%) 20 (35) 10 (46%) Topical steroids, n (%) 2 (4%) 0 (0%) Cardiovascular support, n (%) 24 (42%) 3 (14%) Other, n (%) 12 (21%) 7 (32%)

*Unrelated to the conditions being treated †One cat anesthetized twice and meloxicam, respectively. A total of 11 paired chemistry normal range. Several parameters were altered signifi- panel results (initial and final) for tepoxalin and 12 paired cantly in the meloxicam group: red blood cells panel results for meloxicam were available for analysis. (P = 0.014), hemoglobin (P = 0.037) and hematocrit (P = For complete blood count (CBC), a total of eight paired 0.006) all decreased significantly, and mean corpuscular panel results for tepoxalin and 10 paired panel results for hemoglobin (P = 0.028) and neutrophil count (P = 0.02) meloxicam were available for analysis. A total of 53 paired increased significantly. However, these values were still urinalysis results for tepoxalin and 16 paired results for within the normal range (Table 5). meloxicam were available for analysis. Similarly, eight and

11 paired panel results for T4 were available for analysis in Urinalysis panel In cats prescribed tepoxalin, urinary the tepoxalin and meloxicam groups, respectively. protein decreased significantly over the course of the prescription (P = 0.0004). Proteinuria was present in both Serum biochemistry panel For cats prescribed tepoxa- initial and final urinalysis, but final median values were lin there were no statistically significant changes in lower (0.5 mg/dl) than initial median values (2 mg/dl). blood clinical chemistry between the initial and final There were no statistically altered parameters for cats tests. Several parameters were significantly altered in the prescribed meloxicam (Table 6). meloxicam-treated group over the duration of treatment: alanine aminotransferase and total protein values T4 test panel There were no significant differences decreased after the treatment with meloxicam (P = 0.043 between initial and final T4 test results for tepoxalin and and P = 0.031, respectively). However, these values were meloxicam (Table 7). still within the normal range. Initial and final BUN and serum creatinine concentrations were not significantly Discussion different for cats prescribed meloxicam or cats prescribed Overall, there is a paucity of information on the conse- tepoxalin (Table 4). In the meloxicam treated cats, 6/12 quences of medium- and long-term administration of cats had increases in creatinine, with one cat going from NSAIDs in feline clinical cases. This retrospective study within (1.8 mg/dl) to outside the normal range (2.8 mg/ gives insight into the clinical use and tolerance of tepoxalin dl; normal range: 0.8–2.3 mg/dl). In the tepoxalin-treated and meloxicam in cats under the care of a primary, feline- cats, 7/11 cats had increases in creatinine, with none only practice. Results suggest that both tepoxalin and going from within to outside the normal range. No cats meloxicam are well tolerated. The majority of ADEs had a 1.5 times (suggestive of risk) or greater increase in included the clinical signs of vomiting, which stopped serum creatinine. In the meloxicam-treated cats, 6/12 when the drug was discontinued. In dogs, vomiting is rec- cats had increases in BUN (mean: 17.3 mg/dl), with four ognized as the most common clinical sign associated with cats going from within to outside the normal range. In gastrointestinal side effects.25 Meloxicam and tepoxalin the tepoxalin-treated cats, four out of 11 cats had were used for different conditions, and treatment with increases in BUN (mean: 16 mg/dl), with 2 going from tepoxalin was of shorter duration than meloxicam. The within to outside the normal range. data suggests that ADEs resulting in the drug being stopped occurred later with tepoxalin. However, the popu- Hematology (CBC) panel For cats prescribed tepoxa- lations being prescribed the two NSAIDs were very differ- lin, hemoglobin value was significantly lower (P = 0.014) ent and the numbers of ADEs relatively small, and it is not at the final test; however, median values were within the known if the doses are ‘equi-analgesic’, and so true

Downloaded from jfm.sagepub.com at ISFM on May 11, 2015 Charlton et al 683 (Continued) 0.043* 0.148 0.074 0.067 0.071 0.031* 0.387 0.850 0.388 0.148 Initial vs final P-value 0.275 0.831 114 (77–30,540) 99 (18–345) 29 (12) 27 (14–53) 65 (54) 63 (119) 27 (14–421) 2889 (9171) 2 (2) 2 (0–5) 1320 (542) 1113 (828–2601) 131 (100) 3.3 (0.3) 3.4 (2.9–3.6) 7.1 (0.5) 7.2 (6.0–7.6) 3.7 (0.5) 3.9 (2.9–4.5) 0.1 (0.1) 0.1 (0.0–0.4) 40 (20) 37 (15–82)

50 (34–226) Final

157 (78–16,950) 95 (21–310) (n = 11) (n = 11) (n = 11) (n = 11) (n = 12) (n = 12) [n=11] (n = 12) (n = 12) (n = 11) (n = 11) (n = 12) (n = 11) 37 (15) 35 (14–59) 72 (31) 53 (65) 35 (18–247) 1706 (5057) 4 (2) 5 (0–5) 1075 (301) 1101 (633–1546) 137 (102) 3.6 (0.4) 3.6 (2.8–4.5) 7.5 (0.8) 7.4 (6.4–9.2) 3.9 (0.5) 3.8 (3.4–4.7) 0.1 (0.1) 0.1 (0.1–0.2) 34 (14) 30 (19–69) ‘Meloxicam’ cats (n = 22) 61 (42–158) Initial

1.00 0.109 0.742 0.098 0.547 0.483 0.441 1.00 0.594 1.00 0.756 Initial vs final P-value 0.426 46 (23–1000) 40 (23) 38 (17–96) 156 (317) 24 (7) 24 (17–38) 213 (117) 204 (85–365) 2 (2) 2 (0–5) 1554 (932) 1168 (931–3731) 93 (61) 83 (16–172) 3.3 (0.4) 3.3 (2.5–3.9) 7.2 (0.8) 7.2 (6.1–8.8) 4.1 (0.6) 4.1 (3.1–4.9) 0.1 (0.1) 0.1 (0.0–0.2) 40 (15) 36 (24–77)

Final

(n = 9) (n = 8) (n = 8) (n = 8) (n = 11) (n = 10) (n = 8) (n = 11) (n = 11) (n = 7) (n = 8) (n = 10) (n = 9) 33 (12) 35 (14–52) 69 (40) 58 (26–149) 32 (13) 34 (19–57) 367 (343) 261 (70–1031) 1 (1) 0 (0–2) 1478 (1026) 1110 (860–3903) 93 (56) 79 (23–174) 3.2 (0.3) 3.2 (2.8–3.6) 7.0 (0.9) 7.2 (5.6–8.1) 3.9 (0.8) 4.1 (2.8–5.2) 0.1 (0.1) 0.1 (0.0–0.2) 39 (8) 39 (24–53) ‘Tepoxalin’ cats ‘Tepoxalin’ (n = 57) Initial Chemistry panel — initial and final results summary. Normal range and units are shown for each measured parameter Normalshown for each measured range and units are Chemistry summary. panel — initial and final results

Alanine aminotransferase (10–100 U/l) Creatine kinase (56–529 U/l) Amylase (100–1200 U/l) Lipase (0–205 U/l) Total protein (5.2–8.8 g/dl) Globulin (2.3–5.3 g/dl) Total bilirubin (0.1–0.4 mg/dl) Blood urea nitrogen (BUN) (14–36 mg/dl) Creatinine (0.6–2.4 mg/dl) Aspartate aminotrasnferase (10–100 U/l) Gamma-glutamyl transferase (1–10 U/l) Albumin (2.5–3.9 g/dl) Alkaline phosphatase (6–102 U/l) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Table 4 Table

Downloaded from jfm.sagepub.com at ISFM on May 11, 2015 684 Journal of Feline Medicine and Surgery 15(8) 0.327 0.622 0.109 0.554 0.054 0.365 0.511 0.339 0.182 0.824 Initial vs final P-value 0.423 96 (75–198) 2.0 (0.8) 1.8 (1.0–3.3) 206 (95) 180 (97–386) 105 (37) 10.2 (0.6) 4.5 (1.1) 4.8 (2.4–5.7) 119 (4) 120 (111–123) 4.3 (0.6) 4.2 (3.2–5.5) 154 (3) 154 (151–159) 0.89 (0.16) 0.90 (0.60–1.20) 20.49 (8.29) 18.00 (12.50–37.00) 37.09 (5.36) 36.84 (28.00–48.00)

10.0 (9.3–11.2) Final

(n = 12) (n = 11) (n = 12) (n = 12) (n = 12) (n = 12) (n = 12) (n=12) (n = 12) (n = 12) 1.8 (0.5) 1.7 (1.2–2.8) 211 (77) 212 (108–384) 113 (30) 111 (69–148) 10.1 (0.6) 4.1 (0.9) 4.2 (2.2–5.5) 120 (5) 121 (109–130) 4.7 (0.7) 4.7 (3.0–5.5) 156 (4) 156 (150–162) 0.93 (0.12) 0.95 (0.80–1.10) 18.66 (6.15) 16.15 (13.00–34.00) 34.07 (6.07) 33.36 (27.00–50.67) ‘Meloxicam’ cats (n = 22) 10.1 (9.3–11.5) Initial

0.307 0.922 0.074 0.506 0.833 0.681 0.721 0.588 0.413 0.575 Initial vs final P-value 0.878 9.7 (8.5–12.8) 2.0 (0.8) 1.8 (1.2–3.8) 222 (105) 194 (155–511) 104 (17) 104 (78–129) 10.0 (1.1) 4.5 (0.7) 4.7 (2.6–5.1) 119 (3) 119 (116–124) 4.5 (0.5) 4.5 (3.6–5.3) 153 (2) 153 (150–157) 0.80 (0.15) 0.80 (0.50–1.00) 20.00 (4.84) 19.00 (13.89–29.20) 34.16 (4.18) 34.00 (28.00–43.00)

Final

9.8 (8.9–12.3) (n = 10) (n = 9) (n = 10) (n = 10) (n = 10) (n = 10) (n = 11) (n = 10) (n = 10) (n = 10) 1.9 (0.6) 1.7 (1.1–2.9) 216 (64) 225 (124–362) 128 (47) 114 (62–207) 10.1 (1.1) 4.7 (0.6) 4.8 (3.6–5.8) 119 (3) 119 (115–124) 4.4 (0.4) 4.5 (3.5–4.9) 154 (3) 153 (151–160) 0.85 (0.18) 0.80 (0.60–1.20) 21.30 (4.78) 21.82 (13.50–30.00) 34.93 (3.93) 35.15 (31.00–43.00) ‘Tepoxalin’ cats ‘Tepoxalin’ (n = 57) Initial Continued

Cholesterol (75–220 mg/dl) Glucose (64–170 mg/dl) Chloride (104–128 mEq/l) Potassium (3.4–5.6 mEq/l) Sodium (145–158 mEq/l) Albumin/globulin ratio BUN/creatinine ratio Sodium/potassium ratio Phosphorus (2.4–8.2 mg/dl) Calcium (8.2–10.8 mg/dl) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Table 4 Table *Statistically significant

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Initial vs final P 0.131 0.014* 0.037* 0.006* 0.918 0.028* 0.059 0.020* 0.059 0.167 0.905 Final 7.5 (2.5) 7.0 (4.3–11.9) 7.6 (0.7) 7.4 (6.5–8.6) 12.1 (1.1) 12.1 (10.7–13.9) 35.7 (3.4) 34.9 (31.0–41.6) 47.4 (3.9) 47.0 (41.0–53.0) 15.8 (1.5) 15.5 (14.3–18.9) 34.0 (2.0) 33.4 (31.8–38.5) 75 (7) 75 (68–86) 15 (6) 15 (7–25) 3 (2) 3 (0–6) 7 (4) 8 (2–13)

(n = 100 (n = 10) ‘Meloxicam’ cats (n = 22) 5.8 (2.2) 5.7 (3.1–9.9) 8.9 (1.2) 9.1 (6.5–10.9) 13.5 (1.2) 13.7 (11.9–15.2) 41.3 (3.6) 42.4 (35.6–46.7) 47.1 (4.6) 47.0 (40.0–56.0) 15.4 (1.4) 15.0 (13.9–18.4) 32.8 (1.1) 33.0 (30.4–34.9) 66 (7) 64 (58–81) 21 (6) 22 (11–30) 5 (2) 6 (2–8) 8 (3) 8 (5–17) Initial (n = 10) (n = 10) (n = 10) (n = 10) (n = 10) (n = 10) (n = 10) (n = 10) (n = 10) -value Initial vs final P 0.250 0.195 0.014* 0.109 1.00 0.195 0.441 0.498 1.00 0.242 0.395 Final 9.2 (4.5) 8.4 (4.9–19.0) 7.32 (1.30) 7.50 (5.43–8.92) 11.1 (1.7) 10.9 (8.8–13.8) 33.4 (6.7) 32.8 (25.8–44.9) 45.6 (4.7) 46.5 (39.0–51.1) 15.3 (1.3) 15.5 (13.4–17.3) 33.5 (2.0) 33.7 (30.7–36.9) 81 (7) 79 (70–92) 11 (7) 10 (2–20) 3 (1) 3 (1–4) 5 (3) 6 (0–10)

(n = 8) (n = 8) Initial ‘Tepoxalin’ cats ‘Tepoxalin’ (n = 57) 10.9 (5.0) 10.8 (5.7–20.9) 7.74 (1.02) 7.78 (5.87–9.35) 12.4 (1.8) 11.8 (10.9–15.5) 35.7 (4.8) 34.8 (31.0–46.2) 46.0 (3.8) 45.1 (42.0–53.0) 16.1 (1.5) 15.8 (14.5–18.6) 34.8 (2.5) 34.4 (31.5–40.4) 83 (5) 83 (76–89) 11 (4) 12 (6–16) 2 (1) 2 (1–4) 4 (3) 3 (0–9) (n = 8) (n = 8) (n = 8) (n = 8) (n = 8) (n = 7) (n = 7) (n = 7) (n = 7) /Ul) 6 /Ul) 3 Hematology (complete blood count) panel summary

WBC (3.5–16 10 Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) RBC (5.52–9.93 10 Hemoglobin (9.3–15.9 g/dl) Hematocrit (29–48%) MCV (37–61 fl) MCH (11–21 pg) MCHC (30–38 g/dl) Neutrophils (35–75%) Lymphocytes (20–45%) Monocytes (1–4%) Eosinophils (2–12%) Table 5 Table

Downloaded from jfm.sagepub.com at ISFM on May 11, 2015 686 Journal of Feline Medicine and Surgery 15(8) -value Initial vs final P 0.773 0.164 0.065 0.695 1.00 0.846 1.00 Final 0.1(0.3) 0 (0–1) 149 (167) 94 (38–574) 5.670 (1.945) 5.501 (2.924–9.401) 1.125 (0.675) 0.962 (0.392–2.750) 0.258 (0.209) 0.234 (0.0–0.714) 0.470 (0.224) 0.445 (0.238–0.923) 0.007 (0.002) 0.000 (0.000–0.069)

(n = 9) (n = 10) (n = 10) (n = 10) (n = 10) (n = 10) ‘Meloxicam’ cats (n = 22) (n = 10) 0.2 (0.4) 0 (0–1) 151 (48) 141 (92–225) 3.805 (1.408) 3.448 (2.232–6.039) 1.242 (0.667) 1.243 (0.372–2.376) 0.273 (0.151) 0.274 (0.09–0.594) 0.481 (0.235) 0.430 (0.185–0.891) 0.009 (0.020) 0.000 (0.000–0.058) Initial -value Initial vs final P – 0.799 0.109 0.461 0.461 0.641 1.00 Final 0 (0) 0 (0–0) 262 (242) 228 (37–760) 7.393 (4.522) 6.582 (3.392–17.480) 1.127 (0.748) 0.930 (0.380–2.638) 0.272 (0.212) 0.224 (0.117–0.760) 0.373 (0.260) 0.307 (0.000–0.880) 0.016 (0.045) 0.000 (0.000–0.128)

(n = 7) (n = 8) (n = 8) (n = 8) (n = 8) (n = 8) ‘Tepoxalin’ cats ‘Tepoxalin’ (n = 57) Initial (n = 7) 0 (0) 0 (0–0) 182 (111) 165 (69–393) 9.077 (4.580) 8.573 (4.332–18.601) 1.125 (0.496) 1.172 (0.360–1.840) 0.239 (0.169) 0.186 (0.115–0.627) 0.419 (0.326) 0.391 (0.000–0.900) 0.007 (0.020) 0.000 (0.000–0.057) /Ul) 3 /Ul) 3 /Ul) /Ul) /Ul) 3 3 3 /Ul) 3 (Continued)

Basophils (0–1%) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Mean (SD) Median (range) Platelets (200–500 10 Absolute neutrophils (2.5–8.5 10 Absolute lymphocytes (1.2–8.0 10 Absolute monocytes (0–6.0 10 Absolute eosinophils (0–1.0 10 Absolute basophils (0–0.15 10 Table 5 Table *Statistically significant blood cells; MCV = mean corpuscular volume; MCH hemoglobin; MCHC: hemoglobin concentration WBC = white blood cells; RBC red

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Table 6 Table 688 Journal of Feline Medicine and Surgery 15(8) comparison of these drugs will require further study with without ADEs. This might suggest that the incidence of greater numbers of cats. Additionally, our analysis is essen- ADEs in cats bears some relationship to the length of tially an ‘intent to treat’ approach and therefore it is unclear treatment; however, the number of cats with ADEs was if either drug was actually given as prescribed, that is the relatively low and the data may be skewed, and so firm findings reported here may not reflect the consequences of conclusions cannot be drawn. Additionally, one might actual administration of the drug. This may be even more be tempted to draw comparisons between the two treat- true of the longer prescriptions, but this is speculation. ment groups when evaluating ADEs. This should not be Tepoxalin is approved for use in dogs for control of done as the groups were treated for different conditions pain and inflammation associated with arthritis in the and, probably most importantly, the cats treated with USA, and in Europe for relief of pain caused by muscu- meloxicam were significantly older than those treated loskeletal disorders.26 Tepoxalin has not been tested for with tepoxalin. From a clinical perspective it would clinical efficacy in cats.27 Following the interest of one appear as if the ADE rate for tepoxalin was acceptable investigator (BDXL) in NSAIDs with shorter half-lives (less than 10%), but unacceptable for meloxicam (>10%); and discussions with another investigator (WS) about owing to the differences between cats in each group the NSAID options in cats requiring pain relief, Morrisville ADE rate is not directly comparable. The higher rate of Cat Hospital began using tepoxalin in 2003 for feline ADEs in the meloxicam-treated cats may well be owing pain associated with urinary tract clinical signs. to the older age of these cats. There was nothing about Tepoxalin was prescribed at a median dose of 13 mg/ the cats with ADEs that appeared different from the cats kg/day. Pharmacokinetic studies suggested that both that did not suffer ADEs, but the number of cats was the parent drug and metabolite would allow for safe small. More information is needed to better understand dosing at 10 mg/kg27 (http://aavpt.affiniscape.com/ the risks associated with using NSAIDs in older cats. associations/12658/files/tepoxalin.pdf). However, a We hypothesized that there would be no significant recent experimental study used a lower dose of tepoxa- effects of tepoxalin or meloxicam on serum biochemistry, lin (5.0 mg/kg, PO, q12h), suggesting this dose was rec- urinalysis and hematology test values over the duration ommended by the manufacturer.13 The dose reported in of treatment courses. However, several parameters were this study (13 mg/kg) should not be considered suffi- altered significantly. In some instances, the significant ciently safe until further toxicity studies are performed. changes were likely positive, such as the decrease in uri- Meloxicam was used primarily for pain related to the nary protein in the cats treated with tepoxalin. This was musculoskeletal system. Mean prescribed dosages for likely related to a decrease in urinary tract inflammation meloxicam in this study (0.034 mg/kg/day) are similar as the condition resolved. In the meloxicam cats, the to previously reported and suggested doses for long- changes in packed cell volume and total protein may well term oral administration (0.01–0.03 mg/kg)28 and very have been related to an improvement in hydration status, similar to a recent retrospective study (0.03 mg/kg).29 rather than any loss of blood/protein via gastrointestinal Meloxicam is registered for chronic use in cats in Europe bleeding. However, more detailed data would be required at a dose of 0.05 mg/kg/day, a dose reported to be suffi- to ascertain this. In cats prescribed meloxicam or tepoxa- ciently safe14,30 and described to be the lowest efficacious lin, there were no significant differences between initial dose in a feline model of synovitis.31 A recent study in and final BUN and serum creatinine concentrations in cats with transitional cell carcinoma of the urinary blad- this retrospective study. For meloxicam, these results der5 reported a mean dose of meloxicam of 0.04 mg/kg agree with a previous prospective study28 and a retro- for 311 days. It is not known if doses lower than 0.05mg/ spective case-controlled study.29 Our data are the first kg are efficacious and further studies assessing pain relief available on the effect of tepoxalin on clinical chemistry produced by these doses need to be performed in order values. The data we present here are a paired analysis to validate this approach for long-term treatment of pain. approach, reporting overall group effects and means. After dogs, cats are the species most reported to have Despite the fact that all group means remained within the ADEs involving exposure to NSAIDs,32 both in the US normal range, it is clear from the data that individual cats and in the UK.33 We hypothesized that the use of tepoxa- in both groups did have chemistry values outside of the lin or meloxicam would be well tolerated clinically (tol- normal range. Additionally, closer inspection of the data erated by 90% of treated cats). We found that for cats confirmed that there were few clinically significant prescribed tepoxalin, 91% did not experience ADEs, but changes in individual cats. For example, creatinine that only 82% of cats prescribed meloxicam did not expe- increased from within to outside the normal range only rience ADEs. Currently-available data for dogs suggests in one cat that received meloxicam. In approximately half that longer courses of NSAIDs do not lead to an increase of all cats creatinine increased, and in approximately half in the incidence of adverse events.34 However, in cats it stayed the same or decreased. Cause and effect cannot treated with tepoxalin or meloxicam, the duration of be ascertained from our data, but it underscores the need treatment was longer in cats with ADEs versus cats to evaluate patients individually.

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For cats treated with tepoxalin, the initial and final was receiving salary support from Novartis Animal Health, median values for urinary protein were both outside of both as part of other projects. normal limits. However, the final median value was lower, and closer to normal limits, than initial median Conflict of interest BDXL has received research funding value. This probably reflects the fact that the majority of from both Schering-Plough (now Merck Animal Health) and cats prescribed tepoxalin were being treated for urinary Boehringer-Ingelheim. BDXL has also acted as a consult for both companies and received honoraria for continuing educa- tract inflammatory pain conditions. tion lectures. This retrospective study has several limitations. We assumed the prescriptions were administered following the attending clinician recommendations. In a recent References clinical study run in our institution where we monitored 1 Sparkes AH, Heiene R, Lascelles BD, Malik R, Sampietro the amount of medication used, a mean of 120% of the LR, Robertson S, et al. ISFM and AAFP consensus guide- target dose of a liquid medication was administered by lines: long-term use of NSAIDs in cats. J Feline Med Surg owners, with a range of 20–190% of the target dose. In 2010; 12: 521–538. the present study, there was no way of knowing if either 2 DiBernardi L, Dore M, Davis JA, Owens JG, Mohammed SI, Guptill CF, et al. Study of feline oral squamous cell carci- medication was actually administered. A second limita- noma: potential target for cyclooxygenase inhibitor treat- tion is that we did not include controls (age- and disease- ment. Prostaglandins Leukot Essent Fatty Acids 2007; 76: 245–250. matched cats) that were not receiving medication. It is 3 Hayes A, Scase T, Miller J, Murphy S, Sparkes A and Adams not easy to accurately match treated and control cats in V. COX-1 and COX-2 expression in feline oral squamous retrospective studies, as demonstrated by the study by cell carcinoma. J Comp Pathol 2006; 135: 93–99. Gowen et al,29 where, despite the attempt to case-match, 4 Hayes AM, Adams VJ, Scase TJ and Murphy S. Survival of the control group was not accurately matched to the 54 cats with oral squamous cell carcinoma in United King- treated group. An important limitation of our study is dom general practice. J Small Anim Pract. 2007; 48: 394–399. that the reason for the prescription of the NSAID was 5 Bommer NX, Hayes AM, Scase TJ and Gunn-Moore D. different for the two drugs evaluated. While we did not Clinical features, survival times and COX-1 and COX-2 intend to statistically compare the changes in clinical expression in cats with transitional cell carcinoma of the urinary bladder treated with meloxicam. J Feline Med Surg chemistry in the two populations, it is, inevitably, going 2012; 14: 527–533. to be performed, and, when doing this, is it important to 6 Sparkes AH. A summary of the ISFM and AAFP consen- note the very different indications and populations. Our sus guidelines on the long-term use of NSAIDS in cats. study should not be considered a comprehensive evalu- Tijdschr Diergeneeskd 2011; 136: 804–806. ation of safety and tolerability. Further work is needed to 7 Healey KA, Dawson S, Burrow R, Cripps P, Gaskell CJ, Hart investigate this fully, and to determine if the doses of CA, et al. Prevalence of feline chronic gingivo-stomatitis meloxicam and teploxalin used in this study have any in first opinion veterinary practice. J Feline Med Surg 2007; pain-relieving effects. 9: 373–381. 8 Buffington CA, Westropp JL, Chew DJ and Bolus RR. Clini- Conclusions cal evaluation of multimodal environmental modification (MEMO) in the management of cats with idiopathic cysti- This study confirms other reports that low-dose meloxi- tis. J Feline Med Surg 2006; 8: 261–268. cam can be used for an extensive period of time in cats. 9 Gerber B, Boretti FS, Kley S, Laluha P, Müller C, Sieber A commonly reported adverse event was vomiting, N, et al. Evaluation of clinical signs and causes of lower increased salivation and diarrhea, which occurred in cats urinary tract disease in European cats. J Small Anim Pract administered meloxicam or tepoxalin, but to a lesser 2005; 46: 571–577. degree with tepoxalin. Further studies as to safety and 10 Robertson SA and Lascelles BD. Long-term pain in cats: efficacy of tepoxalin in cats are warranted. how much do we know about this important welfare issue? J Feline Med Surg 2010; 12: 188–199. Supplementary data List of reasons for prescription of 11 Lascelles BD, Henry JB 3rd, Brown J, Robertson I, Sum- NSAIDs, list of pre-existing diseases and classification of con- rell AT, Simpson W, et al. Cross-sectional study of the current medications and supplements. prevalence of radiographic degenerative joint disease in domesticated cats. Vet Surg 2010; 39: 535–544. Acknowledgements We would like to specially thank the 12 Slingerland LI, Hazewinkel HA, Meij BP, Picavet P and staff at Morrisville Cat Hospital for their help in the collection Voorhout G. Cross-sectional study of the prevalence and of medical records. clinical features of osteoarthritis in 100 cats. Vet J. 2011; 187: 304–309. Funding This study (ANC salary) was funded by the Com- 13 Goodman LA, Torres BT, Reynolds LR and Budsberg SC. parative Pain Research Laboratory, at the College of Veterinary Effects of firocoxib, meloxicam, and tepoxalin administra- Medicine (North Carolina State University). JB was receiving tion on eicosanoid production in target tissues of healthy salary support from the Morris Animal Foundation and MF cats. Am J Vet Res 2010; 71: 1067–1073.

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