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.
Introduction
Recently, the International Society of Feline Medicine and American Association of Feline Practitioners published guidelines on the long-term treatments of non-steroidal anti-inflammatory drugs (NSAIDs) in cats. 1 Despite these recommendations, data are still limited on the clinical use of NSAIDs in cats, dosages used, the criteria for patient selection and clinical outcome following their use.
Long-term pain is associated with diseases such as cancer,2 –5 trauma,1,6 gingivitis and stomatitis, 7 idiopathic cystitis,8,9 uveitis, skin disease, slow healing wounds, diabetic neuropathy and degenerative joint disease (DJD).6,10 It is becoming recognized that these diseases are common, as evidenced by two recent studies finding that 60–90% of the feline population has radiographic evidence of DJD.11,12 The use of NSAIDs is a common means of pain management in other species owing to their relatively predictable efficacy across a wide range of pain conditions. In cats, only one NSAID (meloxicam) is approved for long-term use, but only in certain countries and only for DJD-associated pain. The lack of approved products, fears over side effects and lack of knowledge regarding clinical tolerance of NSAIDs all combine to result in suspected under-treatment of chronic pain in cats. More clinical data on NSAIDs in cats are needed.
Tepoxalin (Zubrin) is a dual inhibitor [cyclooxygenase (COX) and lipoxygenase] approved for use in dogs to treat osteoarthritic pain. 13 Tepoxalin is a dual inhibitor in the cat for the duration of its pharmacokinetic profile (unlike the dog) and may show tissue selectivity. The safety and effectiveness of tepoxalin have not been evaluated at any dose or for any indication in cats.13,14 However, it’s relatively short half life (4.7 h) combined with its dual inhibition makes it attractive for use in this species.
Meloxicam (Metacam) is a COX enzyme inhibitor 15 and it is one of the several NSAIDs, including robenocoxib,16,17 tolfenamic acid,18,19 carprofen19,20 and ketoprofen,16,17,19,21 licensed for use in cats in various countries. Meloxicam has been shown to be an effective analgesic in cats when used perioperatively, 22 when administered for short periods of time for acute musculoskeletal pain21,23,24 and is licensed in Europe for long-term administration for musculoskeletal pain.
The purpose of this retrospective study was to review the clinical use of tepoxalin and meloxicam in a single feline-only practice, and to evaluate the clinical tolerance of tepoxalin and meloxicam. This review was performed to add to our knowledge of the clinical tolerance of NSAIDs in cats, and to determine if there was any support for the further experimental and clinical evaluation of tepoxalin in cats.
Our hypothesis was that the use of tepoxalin and meloxicam would be well tolerated clinically (tolerated by 90% of treated cats) and that there would be no significant effect of tepoxalin or meloxicam on serum biochemistry, urinalysis and hematological values over the duration of treatment courses.
The aims of this study were, first, to review all the medical records from a single practice and extract pertinent information from records on the prescription and clinical use of tepoxalin or meloxicam; second, to determine the number of cats in which the NSAID medication was stopped owing to adverse drug events (ADEs); and last, to evaluate whether there were any significant effects on hematological and clinical chemistry parameters in cats receiving tepoxalin or meloxicam.
Materials and methods
The database of a feline-only practice in North Carolina, Morrisville Cat Hospital (Morrisville, NC, USA), was searched for all cases (2003–2012) in which cats had been prescribed either tepoxalin or meloxicam. A total of 332 records fulfilled the criteria, and these were searched for cases where either NSAID had been prescribed, and serum biochemistry and/or urinalysis and/or hematology had been collected prior to the course of NSAID (initial test) and at the end of the course of treatment (final test). This retrospective study was performed on the basis of an ‘intent to treat’ approach — it was assumed, unless otherwise stated, that the prescriptions given to owners were administered to the cat. Each medical record was reviewed carefully and included if they fit the inclusion parameters.
Inclusion criteria
Cases were included if clinical chemistry and/or hematology tests were performed less than 60 days before the start of NSAID treatment and less than 60 days after the NSAID treatment finished. If cats were prescribed both tepoxalin and meloxicam then there had to be a washout period of at least 60 days between treatments.
Data collected
Information was gathered on sex, breed, age, weight, diagnosis and reason for treatment, NSAID prescriptions (total dose administered, average dose per kilogram per day, duration of prescription), pre-existing diseases and clinical signs, concurrent treatments, reason for stopping treatment, pre- and post-treatment values for serum biochemistry, hematology, urinalysis, T4 test values and if ADEs occurred. Duration of treatment was considered to be the first day of treatment to last day of treatment, or to date of the final clinical chemistry test — whichever came first. ADEs were defined as adverse events considered by the attending veterinarian to be due to the NSAID treatment and directly stated as such by the veterinarian in the record. They were dichotomized into two categories — cats that suffered an ADE during treatment which caused the treatment to be stopped permanently, and cats that suffered an ADE episode during treatment but treatment was not stopped or was re-initiated after a few days. If, during the treatment period, any additional oral doses of NSAID were administered these were recorded.
Statistical analysis
All data were entered in the database (Microsoft Excel) and analyzed using software (GraphPad Prism version 5.02 and JMP 10). Descriptive statistics were used to describe the data set and appropriate statistical tests (Fisher’s exact, Mann–Whitney, χ2) used to compare the characteristics of the cats treated with the two different NSAIDs. A Wilcoxon sign-ranked test was used to test for significant changes between initial versus final laboratory tests within each treatment group. No adjustment was made for multiple comparisons in order to maximize the chance of detecting potential changes induced over the course of the prescription. Mean, median, range and SD were also calculated and compared to reference intervals. Comparisons between subgroups of cats with and without ADEs were evaluated using the Mann–Whitney test. The critical P-value was set at 0.05.
Results
Demographic data
A total of 79 cases were included in this study. Fifty-seven clinical cases were prescribed tepoxalin and 22 were prescribed meloxicam. The painful conditions for which the NSAIDs were prescribed were classified as musculoskeletal (eg, arthritis, lack of movement, stiffness, lameness), urinary tract (eg, stranguria, cystitis, hematuria, urinary tract infection, crystals), surgical procedures and constipation (see supplementary data). The majority of cats prescribed tepoxalin were prescribed the drug for urinary tract discomfort (82.5%) and the majority of cats prescribed meloxicam were prescribed meloxicam for musculoskeletal discomfort (68.2%). Demographic data and conditions treated are summarized in Table 1. Cats treated with meloxicam were older (P <0.001) and were treated for longer (P <0.001). The conditions for which the NSAIDs were being used were significantly different between the groups (P <0.001).
Demographic data of cats included in the study, and conditions being treated
M = male; MC = male castrated; F = female; FS = female spayed
Statistically significant
Exceptions to inclusion criteria
Some cats were included in the study despite not meeting the inclusion criteria precisely. Eight of the 57 cats prescribed tepoxalin had an initial test that occurred 1–3 days after starting the NSAID prescription. One of the 22 cats prescribed meloxicam had an initial test that occurred 4 days after starting the NSAID prescription. One of the 57 cats prescribed tepoxalin had a washout 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.
Prescription characteristics for tepoxalin and meloxicam
ADE = adverse drug event
Of cats prescribed meloxicam, seven received additional single doses of oral meloxicam during the treatment period for pain associated with receiving an injectable vaccine. 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 in the average daily and total dose calculations. One cat prescribed tepoxalin also received a dose of meloxicam; this was not included in any dose calculations.
Pre-existing diseases
Pre-existing diseases were classified as suspected or documented renal impairment, suspected or documented cardiovascular disease, hepatomegaly, gastrointestinal disease, hyperthyroidism, pancreatitis, seizures, dehydration, lower urinary tract disease, suspected or documented respiratory disease, obesity, dermatological disease, deafness, dental disease, ocular disease, miscellaneous and no pre-existing diseases noted. The miscellaneous category included diseases, such as retroperitoneal effusion and unidentified masses. For cats treated with tepoxalin the majority of reported pre-existing diseases and clinical signs fell into the dental disease category. For cats prescribed meloxicam, the majority of pre-existing diseases and clinical signs fell into the oral and cardiovascular categories (See supplementary data).
Concurrent treatments
Concurrent treatments included flea and tick treatments, subcutaneous fluids and concurrent medications. Concurrent medications were divided into seven groups as follows: nutritional supplements, gastrointestinal support, systemic antibiotics, additional systemic analgesics, topical steroids, cardiac support drugs and other. The ‘other’ category included all medications not included elsewhere, such as, anti-anxiety, anti-nausea and seizure medications. For cats prescribed either meloxicam or tepoxalin, >25% of cats received flea and tick medication. General anesthesia (not related to the condition being treated with the NSAID) was performed in 6/57 (11%) cats prescribed tepoxalin and 6/22 (27%) cats prescribed meloxicam. In cats prescribed tepoxalin, 24/57 (42%) of cats were prescribed a concurrent medication for cardiovascular support and systemic antibiotics were used in 21/57 (37%) of cats. Of the cats prescribed meloxicam, nutritional supplements were used in 12/22 (55%) of cats and systemic antibiotics were used in 10/22 (46%) of cats. Table 3 summarizes concurrent treatments and a list of how medications and supplements were classified is provided in the supplementary data.
Concurrent treatments and medications
Unrelated to the conditions being treated
One cat anesthetized twice
ADEs
ADEs were reported in the medical records of five cats (8.8%) prescribed tepoxalin and four cats (18.2%) prescribed meloxicam. There was no difference between the groups with respect to the number of ADEs (P = 0.19). Vomiting was the primary ADE, but diarrhea, drooling, elevated blood urea nitrogen (BUN) and lack of appetite were also reported. In the tepoxalin group, treatment was stopped owing to an ADE (vomiting) in one cat (1.75%). In the meloxicam group, ADEs resulted in treatment being stopped in three cats (13.63%). The ADEs for these cats were reported as vomiting with excessive salivation and diarrhea. The average dose per day for both tepoxalin (P = 0.89) and meloxicam (P = 0.81) prescribed for cats with ADEs did not differ from those not experiencing ADEs (Table 2). The median duration of treatment prior to an ADE occurring was 774 days for tepoxalin and 448 days for meloxicam (Table 2). There was no difference between the drugs in this respect, although numbers of cats were small (n = 5 and n = 4, tepoxalin and meloxicam, respectively). The median duration of treatment prior to an ADE that resulted in the treatment being stopped was 4 days (n = 1) for tepoxalin, and 81 days (n = 3) for meloxicam.
Blood and urine tests
The median number of days between first day of treatment and initial serum biochemistry, urinalysis and hematology tests were 0 (0–51) and 4 (0–44) days for tepoxalin and meloxicam, respectively. The median number of days between the last day of treatment and the final clinical tests performed were 9 (0–53) and 0 (0–48) days for tepoxalin and meloxicam, respectively. A total of 11 paired chemistry panel results (initial and final) for tepoxalin and 12 paired panel results for meloxicam were available for analysis. For complete blood count (CBC), a total of eight paired panel results for tepoxalin and 10 paired panel results for meloxicam were available for analysis. A total of 53 paired urinalysis results for tepoxalin and 16 paired results for meloxicam were available for analysis. Similarly, eight and 11 paired panel results for T4 were available for analysis in the tepoxalin and meloxicam groups, respectively.
Serum biochemistry panel
For cats prescribed tepoxalin there were no statistically significant changes in blood clinical chemistry between the initial and final tests. Several parameters were significantly altered in the meloxicam-treated group over the duration of treatment: alanine aminotransferase and total protein values decreased after the treatment with meloxicam (P = 0.043 and P = 0.031, respectively). However, these values were still within the normal range. Initial and final BUN and serum creatinine concentrations were not significantly different for cats prescribed meloxicam or cats prescribed tepoxalin (Table 4). In the meloxicam treated cats, 6/12 cats had increases in creatinine, with one cat going from within (1.8 mg/dl) to outside the normal range (2.8 mg/dl; normal range: 0.8–2.3 mg/dl). In the tepoxalin-treated cats, 7/11 cats had increases in creatinine, with none going from within to outside the normal range. No cats had a 1.5 times (suggestive of risk) or greater increase in serum creatinine. In the meloxicam-treated cats, 6/12 cats had increases in BUN (mean: 17.3 mg/dl), with four cats going from within to outside the normal range. In the tepoxalin-treated cats, four out of 11 cats had increases in BUN (mean: 16 mg/dl), with 2 going from within to outside the normal range.
Chemistry panel — initial and final results summary. Normal range and units are shown for each measured parameter
Statistically significant
Hematology (CBC) panel
For cats prescribed tepoxalin, hemoglobin value was significantly lower (P = 0.014) at the final test; however, median values were within the normal range. Several parameters were altered significantly in the meloxicam group: red blood cells (P = 0.014), hemoglobin (P = 0.037) and hematocrit (P = 0.006) all decreased significantly, and mean corpuscular hemoglobin (P = 0.028) and neutrophil count (P = 0.02) increased significantly. However, these values were still within the normal range (Table 5).
Hematology (complete blood count) panel summary
Statistically significant
WBC = white blood cells; RBC = red blood cells; MCV = mean corpuscular volume; MCH = mean corpuscular hemoglobin; MCHC: mean corpuscular hemoglobin concentration
Urinalysis panel
In cats prescribed tepoxalin, urinary protein decreased significantly over the course of the prescription (P = 0.0004). Proteinuria was present in both initial and final urinalysis, but final median values were lower (0.5 mg/dl) than initial median values (2 mg/dl). There were no statistically altered parameters for cats prescribed meloxicam (Table 6).
Urinalysis panel summary
Statistically significant
Urinary protein (0.5 = <100 mg/dl; 1 = 100–200 mg/dl; 2 = 200–300 mg/dl; 3 = 300–500 mg/dl; 4 = >500 mg/dl)
Casts (1 = positive; 0 = none seen)
USG = urine specific gravity; HPF = high powered field
T4 test panel
There were no significant differences between initial and final T4 test results for tepoxalin and meloxicam (Table 7).
T4 test summary
Discussion
Overall, there is a paucity of information on the consequences of medium- and long-term administration of NSAIDs in feline clinical cases. This retrospective study gives insight into the clinical use and tolerance of tepoxalin and meloxicam in cats under the care of a primary, feline-only practice. Results suggest that both tepoxalin and meloxicam are well tolerated. The majority of ADEs included the clinical signs of vomiting, which stopped when the drug was discontinued. In dogs, vomiting is recognized as the most common clinical sign associated with gastrointestinal side effects. 25 Meloxicam and tepoxalin were used for different conditions, and treatment with tepoxalin was of shorter duration than meloxicam. The data suggests that ADEs resulting in the drug being stopped occurred later with tepoxalin. However, the populations being prescribed the two NSAIDs were very different and the numbers of ADEs relatively small, and it is not known if the doses are ‘equi-analgesic’, and so true comparison of these drugs will require further study with greater numbers of cats. Additionally, our analysis is essentially an ‘intent to treat’ approach and therefore it is unclear if either drug was actually given as prescribed, that is the findings reported here may not reflect the consequences of actual administration of the drug. This may be even more true of the longer prescriptions, but this is speculation.
Tepoxalin is approved for use in dogs for control of pain and inflammation associated with arthritis in the USA, and in Europe for relief of pain caused by musculoskeletal disorders. 26 Tepoxalin has not been tested for clinical efficacy in cats. 27 Following the interest of one investigator (BDXL) in NSAIDs with shorter half-lives and discussions with another investigator (WS) about NSAID options in cats requiring pain relief, Morrisville Cat Hospital began using tepoxalin in 2003 for feline pain associated with urinary tract clinical signs. Tepoxalin was prescribed at a median dose of 13 mg/kg/day. Pharmacokinetic studies suggested that both the parent drug and metabolite would allow for safe dosing at 10 mg/kg 27 (http://aavpt.affiniscape.com/associations/12658/files/tepoxalin.pdf). However, a recent experimental study used a lower dose of tepoxalin (5.0 mg/kg, PO, q12h), suggesting this dose was recommended by the manufacturer. 13 The dose reported in this study (13 mg/kg) should not be considered sufficiently safe until further toxicity studies are performed.
Meloxicam was used primarily for pain related to the musculoskeletal system. Mean prescribed dosages for meloxicam in this study (0.034 mg/kg/day) are similar to previously reported and suggested doses for long-term oral administration (0.01–0.03 mg/kg) 28 and very similar to a recent retrospective study (0.03 mg/kg). 29 Meloxicam is registered for chronic use in cats in Europe at a dose of 0.05 mg/kg/day, a dose reported to be sufficiently safe14,30 and described to be the lowest efficacious dose in a feline model of synovitis. 31 A recent study in cats with transitional cell carcinoma of the urinary bladder 5 reported a mean dose of meloxicam of 0.04 mg/kg for 311 days. It is not known if doses lower than 0.05mg/kg are efficacious and further studies assessing pain relief produced by these doses need to be performed in order to validate this approach for long-term treatment of pain.
After dogs, cats are the species most reported to have ADEs involving exposure to NSAIDs, 32 both in the US and in the UK. 33 We hypothesized that the use of tepoxalin or meloxicam would be well tolerated clinically (tolerated by 90% of treated cats). We found that for cats prescribed tepoxalin, 91% did not experience ADEs, but that only 82% of cats prescribed meloxicam did not experience ADEs. Currently-available data for dogs suggests that longer courses of NSAIDs do not lead to an increase in the incidence of adverse events. 34 However, in cats treated with tepoxalin or meloxicam, the duration of treatment was longer in cats with ADEs versus cats without ADEs. This might suggest that the incidence of ADEs in cats bears some relationship to the length of treatment; however, the number of cats with ADEs was relatively low and the data may be skewed, and so firm conclusions cannot be drawn. Additionally, one might be tempted to draw comparisons between the two treatment groups when evaluating ADEs. This should not be done as the groups were treated for different conditions and, probably most importantly, the cats treated with meloxicam were significantly older than those treated with tepoxalin. From a clinical perspective it would appear as if the ADE rate for tepoxalin was acceptable (less than 10%), but unacceptable for meloxicam (>10%); owing to the differences between cats in each group the ADE rate is not directly comparable. The higher rate of ADEs in the meloxicam-treated cats may well be owing to the older age of these cats. There was nothing about the cats with ADEs that appeared different from the cats that did not suffer ADEs, but the number of cats was small. More information is needed to better understand the risks associated with using NSAIDs in older cats.
We hypothesized that there would be no significant effects of tepoxalin or meloxicam on serum biochemistry, urinalysis and hematology test values over the duration of treatment courses. However, several parameters were altered significantly. In some instances, the significant changes were likely positive, such as the decrease in urinary protein in the cats treated with tepoxalin. This was likely related to a decrease in urinary tract inflammation as the condition resolved. In the meloxicam cats, the changes in packed cell volume and total protein may well have been related to an improvement in hydration status, rather than any loss of blood/protein via gastrointestinal bleeding. However, more detailed data would be required to ascertain this. In cats prescribed meloxicam or tepoxalin, there were no significant differences between initial and final BUN and serum creatinine concentrations in this retrospective study. For meloxicam, these results agree with a previous prospective study 28 and a retrospective case-controlled study. 29 Our data are the first available on the effect of tepoxalin on clinical chemistry values. The data we present here are a paired analysis approach, reporting overall group effects and means. Despite the fact that all group means remained within the normal range, it is clear from the data that individual cats in both groups did have chemistry values outside of the normal range. Additionally, closer inspection of the data confirmed that there were few clinically significant changes in individual cats. For example, creatinine increased from within to outside the normal range only in one cat that received meloxicam. In approximately half of all cats creatinine increased, and in approximately half it stayed the same or decreased. Cause and effect cannot be ascertained from our data, but it underscores the need to evaluate patients individually.
For cats treated with tepoxalin, the initial and final median values for urinary protein were both outside of normal limits. However, the final median value was lower, and closer to normal limits, than initial median value. This probably reflects the fact that the majority of cats prescribed tepoxalin were being treated for urinary tract inflammatory pain conditions.
This retrospective study has several limitations. We assumed the prescriptions were administered following the attending clinician recommendations. In a recent clinical study run in our institution where we monitored the amount of medication used, a mean of 120% of the target dose of a liquid medication was administered by owners, with a range of 20–190% of the target dose. In the present study, there was no way of knowing if either medication was actually administered. A second limitation is that we did not include controls (age- and disease-matched cats) that were not receiving medication. It is not easy to accurately match treated and control cats in retrospective studies, as demonstrated by the study by Gowen et al, 29 where, despite the attempt to case-match, the control group was not accurately matched to the treated group. An important limitation of our study is that the reason for the prescription of the NSAID was different for the two drugs evaluated. While we did not intend to statistically compare the changes in clinical chemistry in the two populations, it is, inevitably, going to be performed, and, when doing this, is it important to note the very different indications and populations. Our study should not be considered a comprehensive evaluation of safety and tolerability. Further work is needed to investigate this fully, and to determine if the doses of meloxicam and teploxalin used in this study have any pain-relieving effects.
Conclusions
This study confirms other reports that low-dose meloxicam can be used for an extensive period of time in cats. A commonly reported adverse event was vomiting, increased salivation and diarrhea, which occurred in cats administered meloxicam or tepoxalin, but to a lesser degree with tepoxalin. Further studies as to safety and efficacy of tepoxalin in cats are warranted.
Supplemental Material
Click here for Supplementary Appendix
List of reasons for prescription of NSAIDs, list of pre-existing diseases and classification of concurrent medications and supplements
Footnotes
Acknowledgements
We would like to specially thank the staff at Morrisville Cat Hospital for their help in the collection of medical records.
Supplementary data
List of reasons for prescription of NSAIDs, list of pre-existing diseases and classification of concurrent medications and supplements.
Funding
This study (ANC salary) was funded by the Comparative Pain Research Laboratory, at the College of Veterinary Medicine (North Carolina State University). JB was receiving salary support from the Morris Animal Foundation and MF was receiving salary support from Novartis Animal Health, both as part of other projects.
Conflict of interest
BDXL has received research funding from both Schering-Plough (now Merck Animal Health) and Boehringer-Ingelheim. BDXL has also acted as a consult for both companies and received honoraria for continuing education lectures.
References
Supplementary Material
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