Canine parvovirus type 2c infection in a kitten associated with intracranial abscess and convulsions

Abstract

The aim of this study was to evaluate the efficacy and palatability of meloxicam 0.5 mg/ml oral suspension, compared to ketoprofen tablets in cats suffering from painful acute locomotor disorders. This single blinded, positively-controlled, randomised, multicentre trial involved 121 client owned cats. Cats received either meloxicam (0.5 mg/ml oral suspension) at 0.1 mg/kg on day 1 followed by 0.05 mg/kg q 24 h on days 2–5, or ketoprofen 5 mg tablets at 1.0 mg/kg q 24 h for 5 days. The efficacy of the two treatments was assessed subjectively by clinicians on day 6 using a clinical sum score (CSS). Palatability and accuracy of dosing were also assessed. The baseline CSS was not significantly different between the groups, and after 5 days of treatment the CSS had decreased to a similar extent, reflecting a reduction in pain. There were no significant differences between the CSS of each group at day 6. Both treatments were well tolerated. Meloxicam was significantly more palatable than ketoprofen, and allowed for more accurate dosing. Meloxicam and ketoprofen are a safe and efficacious treatment for acute locomotor disorders in cats. Meloxicam (Metacam) may be associated with superior compliance in clinical practice due to the higher palatability, which results in better ease of administration.

Painful acute locomotor disorders, not requiring surgery, are a common presentation of cats in general practice, ranging from soft tissue injuries such as cat bites and contusions, sprains, muscular bruising, and other ligamentous injury, to joint pathology, such as arthritis, luxating patella and thoracolumbar or lumbar pain. However, few drugs are licensed for the control of pain in cats for more than 24 h duration, potentially leaving feline patients in unrelieved pain for several days thereafter. In addition, there are other issues, such as a lack of recognition of pain, leading to the probable under-use of analgesics in cats for acute pain. ¹ Cats are able to modify their level of exercise, or just show subtle changes in behaviour ² and are not taken for walks as dogs are, making the diagnosis of locomotor disorders in cats more challenging. Owners have difficulty administering medication to cats and clinicians are often concerned about the potential for side effects with non-steroidal anti-inflammatory drug (NSAID) use.

Ketoprofen (Ketofen 5 mg tablets; Merial) is an NSAID licensed in several European countries for the relief of acute pain and inflammation associated with musculoskeletal and other painful disorders in cats at a dose of 1.0 mg/kg bodyweight, administered orally for up to 5 days. Ketoprofen has been demonstrated to provide good postoperative analgesia in cats undergoing both soft tissue and orthopaedic surgery (at a single dose of 2 mg/kg given subcutaneously). ^3–5 Meloxicam (Metacam; Boehringer Ingelheim Vetmedica) has also been well established as an effective analgesic in cats used pre-operatively (at 0.2 to 0.3 mg/kg subcutaneously, as a single dose) again, for both soft tissue and orthopaedic procedures. ^3,6–8 For a more sustainable postoperative pain relief, an initial subcutaneous dose of 0.2 mg/kg followed by an oral dose of 0.05 mg/kg for up to four additional days demonstrated efficacy and is licensed in Europe. ⁹ None of the currently published studies have found any significant differences in analgesic efficacy between the different NSAIDs, used pre- or postoperatively. A 5-day study ¹ in cats with painful locomotor disorders used orally administered meloxicam at 0.3 mg/kg on day 1 followed by 0.1 mg/kg daily for four more consecutive days. This group of cats was compared to a second group that received ketoprofen tablets at 1.0 mg/kg daily for 5 days. The study found no significant difference in efficacy or safety between the two NSAIDs. However, meloxicam was found to be significantly more palatable than ketoprofen. More recently, Metacam 0.5 mg/ml oral suspension for cats has been specifically licensed in the EU in cats for the alleviation of pain and inflammation in chronic musculoskeletal disorders. It has been developed as a palatable ‘syrup’ and is dispensed in drop form or with a weight graduated syringe to provide accurate dosing. Safety and efficacy of the 0.5 mg/ml suspension have already been demonstrated in a long-term study looking at cats with chronic osteoarthritic pain at a range of doses. ¹⁰

The objective of the study reported here was to evaluate the efficacy and palatability of meloxicam 0.5 mg/ml oral suspension, in comparison to a positive control, ketoprofen tablets as a short-term analgesic under ‘field conditions’. Meloxicam was used at lower doses than previously reported, ¹ ie, the dose of 0.1 mg/kg on day 1, followed by 0.05 mg/kg on each of the following 4 days, in cats suffering from painful acute locomotor disorders.

Materials and methods

Work in the UK was performed under an Animal Test Certificate from the Veterinary Medicines Directorate and with approval of the local authorities in Germany and France. A total of 121 client owned cats were recruited into this multicentre study. All the cats were diagnosed with a painful acute locomotor disorder from the history, clinical examination and, in approximately half of the cases, by radiography. Included cats had to be greater than 6 weeks of age, weigh between 1.5 kg and 10 kg bodyweight, and had to have had signs of an acute locomotor disorder for no more than 14 days. All cats included in the study had a clinical sum score (CSS) composed of the sum of scores for posture, lameness and pain on manipulation of greater than or equal to 6 (see Table 1). Informed owner consent was granted for all cases selected for inclusion in the study. The conditions diagnosed fell into four types. The first three types involved the limbs and were classified as soft tissue injuries (such as contusions, cat bites, and sprains), joint diseases (such as osteoarthritis, luxations and ligament damage) or other limb problems (such as fractures). The fourth type of locomotor disorder was classified as diseases of the spine such as spondylosis and intervertebral disc disease.

Table 1.

SDS scoring system used to evaluate the general clinical parameters and the locomotive system on days 1 and 6.

General clinical parameters	Score	Description
Feed intake	1	Unchanged (normal)
	2	Up to one-third reduced
	3	Between one and two-thirds reduced
4	More than two-thirds reduced
General behaviour	1	Unchanged (normal)
	2	Slightly disturbed
	3	Moderately disturbed
4	Markedly disturbed
Locomotive system
Standing posture (at rest)*	1	Sound – normal weight bearing on all limbs
	2	Slightly modified – all feet are placed down but weight shifting
	3	Moderately modified – occasional lifting up of a limb
4	Markedly modified – permanent lifting up of a limb
Lameness (in motion)*	1	Sound – no sign of lameness
	2	Slight lameness – noticeable lame, but weight bearing on all limbs
	3	Moderate lameness – only occasional weight bearing on a limb
4	Marked lameness – non-weight bearing on a limb
Pain on manipulation*	1	None – no signs of pain
	2	Slight pain – after intensive palpation, extension and/or flexion only
	3	Moderate pain – after moderate palpation, extension and/or flexion
4	Marked pain – after gentle palpation, extension and/or flexion

^*The scores assigned of each these parameters were added together, resulting in a cumulative sum score (CSS).

Cats that had received other analgesics or corticosteroids in the 2 weeks prior to the study, cats that had received long-acting corticosteroids within the previous 2 months, cats with hypovolaemia or a known history of renal, hepatic or gastrointestinal disorder, pregnant or lactating cats, and cats with an abscess causing the lameness were all excluded from the study. Recruited cats were examined and then randomised to one of two treatment groups on day 1, using a SAS software package to generate a randomisation list. Investigators were blinded to the treatment received by each case, and gave each owner identical treatment packages (containing medication instructions) that were only opened by the owner at home. Blinding was ensured by the use of sealed outer packaging, which was identical in both appearance and weight, and by the use of additional internal wrapping to prevent the noise of the contents moving if the packaging was shaken.

All cats were weighed accurately prior to treatment on day 1 and the investigators calculated and informed the owner of the dose rates of both medications. Owners of cats receiving meloxicam administered the initial dose of 0.1 mg/kg on day 1, followed by 0.05 mg/kg on days 2 to 5. The meloxicam was either given directly into the mouth of the cat using the syringe provided or with a small amount of food which was immediately eaten by the cat. Ketoprofen 5 mg tablets were administered by owners, at a dose of 1.0 mg/kg orally from day 1 to day 5 according to the label. Both drugs were given once daily. No concomitant treatments with other analgesics or corticosteroids were allowed during the treatment period. Alpha-2-agonists were permissible if the investigator needed to perform anaesthesia during the study period, eg, to take radiographs.

Full clinical examinations by the investigating veterinary surgeons were carried out on days 1 and 6, ie, 1 day after the end of the treatment period. If the exact timing of the second examination was not possible, the cat was seen on day 5. Thus, the predefined treatment period was 4–5 days. The clinical examinations comprised scoring of all the cats on simple descriptive scales (SDS). Data was recorded for general clinical parameters (rectal temperature, feed intake, and general behaviour) and specific parameters of the locomotive system (posture at rest, lameness in motion and pain on manipulation) as detailed in Table 1. In addition the two treatments were assessed on day 6, using an overall clinical efficacy score, and in conjunction with the owner, a palatability score as shown in Table 2.

Table 2.

Scoring system used to evaluate overall clinical efficacy and palatability of each drug.

Overall clinical efficacy score	Description
1 – Excellent	Clinical condition greatly improved. The clinical signs observed during the first examination have disappeared.
2 – Good	Clinical condition satisfactorily improved. There is clear improvement of the signs.
3 – Moderate	Clinical condition sufficiently improved. Clinical improvement is seen, however, the cat has responded only slightly to treatment.
4 – Poor	Clinical condition remained the same or deteriorated. The clinical signs of the cat have not changed or have deteriorated under the course of treatment.
Palatability
1 – Excellent	Immediate voluntary reception
2 – Good	Hesitating voluntary reception
3 – Moderate	Occasional reluctant reception
4 – Poor	Permanent reluctant reception

Cats were withdrawn from the study if they received non-permitted concomitant treatment, if there was significant violation of the study protocol, owner non-compliance or if an adverse event prevented continuation of the treatment. The administration of any permitted concomitant drugs during the study was recorded by the investigator.

Concerning statistical analysis, the primary variable for the evaluation of the efficacy of each drug was the change in the ‘clinical sum score’ (CSS) from before treatment and after treatment. This comprised the sum of the assigned scores for posture, lameness and pain on manipulation (taken from the locomotive system examination) and was recorded on days 1 and 6. If the exact timing of the second examination was not possible, the cat was seen on day 5. The CSS could range from 6 or 3 to 12 before or after treatment.

The change in the CSS was statistically analysed by comparing the difference between the two CSS scores (day 1 score and day 6 score) between the two treatment groups. Meloxicam was tested for non-inferiority and superiority to ketoprofen, using changes in CSS scores. The non-inferiority was significant if the upper limit of the two-sided 95% confidence interval of the difference between the test group (one-sided, P≤0.025) and the reference group did not exceed the clinical equivalence limit of 1.0 score point. Following proven non-inferiority the test group was tested on superiority by a one-sided t-test (P≤0.025) without exceeding the global type 1 error of 2.5%. Single scores of posture, lameness and pain on manipulation, feed intake, general behaviour, overall efficacy and palatability were evaluated by frequency tables, and descriptive statistics and were tested on differences between treatment groups using the Wilcoxon–Mann–Whitney test. Results were considered statistically significant only if P≤0.05. The data on population parameters, ie, sex distribution, breeds, age and bodyweight were summarised descriptively. All the statistical analyses were performed using SAS software release 8.2 (SAS, Cary, USA/North Carolina, SAS Institute).

Results

Animal data

A total of 112 cats were included in the final data analysis. Nine cats were withdrawn during the study period (six treated with meloxicam and three treated with ketoprofen) due to deviations from the protocol (eight cats) or adverse events (one cat treated with ketoprofen). All these nine cats were excluded from the efficacy evaluation but were still included in the adverse events data for safety evaluation.

Of the 112 cats eligible for evaluation, 54 were treated with meloxicam and 58 were treated with ketoprofen. The mean age (± standard deviation) was 7.1 (5.4) years for the meloxicam treated group and 4.0 (4.0) years for the ketoprofen group. Both treatment groups had an average bodyweight of 4.3 (1.2) kg. Sixty-one percent of the meloxicam group was males, 39% females. In the ketoprofen group, 55% of the cats were male and 45% were female. Approximately 55% of cats were spayed or castrated and the majority of cats (83% in both groups) were classified as European Shorthair.

CSS

On day 1, before the start of treatment, the median CSS was 9 in both the meloxicam and the ketoprofen group (Fig 1). The difference at baseline was not significant (t-test, P>0.05) between groups. The CSS decreased to a similar extent in both treatment groups, reflecting a reduction in pain during the median treatment period of 5 days [mean/SD: 4.51/± 0.57 (meloxicam group), 4.75/± 0.70 (ketoprofen group)]. At the end of treatment the median CSS was 4 in the meloxicam group versus 4.5 in the ketoprofen group. The improvement in the CSS score within the meloxicam group between the start and end of treatment was found to be significantly non-inferior (P≤0.025) to the change in CSS score seen in the ketoprofen treated group. There was no significant superiority between the treatments over the study period (P≥0.025).

Fig 1.

CSS before and after treatment.

The single parameters of the CSS were also evaluated. There were no significant differences between the treatment groups at day 1 or at day 6 for any of the variables. Median scores for each parameter decreased to a similar extent in both treatment groups and there were no significant differences in the degree of improvement seen in each parameter between treatment groups (Table 3).

Table 3.

Parameters used to evaluate the locomotive system, and differences between groups.

Day	Parameter	Median score for meloxicam group (min–max)	Median score for ketoprofen group (min–max)	P
1	Posture	3 (1 to 4)	3 (1 to 4)	0.45 ns
6	Posture	1 (1 to 4)	1 (1 to 4)	0.45 ns
1–6	Posture	−2 (−3 to 1)	−2 (−3 to 0)	0.81 ns
1	Lameness	3 (1 to 4)	3 (2 to 4)	0.54 ns
6	Lameness	1 (1 to 4)	2 (1 to 4)	0.24 ns
1–6	Lameness	−1 (−3 to 2)	−1 (−3 to 0)	0.74 ns
1	Pain on manipulation	3 (1 to 4)	3 (1 to 4)	0.23 ns
6	Pain on manipulation	1 (1 to 3)	1 (1 to 4)	0.99 ns
1–6	Pain on manipulation	−2 (−3 to 1)	−2 (−3 to 0)	0.52 ns

P=P value of the Wilcoxon–Mann–Whitney test on differences between groups, ns = not significant, P>0.05.

Secondary variables

At day 1 and day 6 the mean rectal temperatures of both groups of cats were comparable, and within the normal range, ie, mean temperature 38.6°C (meloxicam and ketoprofen) on day 1 and 38.4°C/38.5°C (meloxicam/ketoprofen) on day 6. There were no significant differences between the groups for feed intake or general behaviour (Table 4).

Table 4.

Parameters used to evaluate the general condition and differences between groups.

Day	Parameter	Median score for meloxicam group (min–max)	Median score for ketoprofen group (min–max)	P
1	Feed intake	1.5 (1 to 4)	1 (1 to 4)	0.48 ns
6	Feed intake	1 (1 to 3)	1 (1 to 2)	0.89 ns
1–6	Feed intake	0 (−3 to 0)	0 (−3 to 1)	0.47 ns
1	General behaviour	2.5 (1 to 4)	2 (1 to 4)	0.24 ns
6	General behaviour	1 (1 to 3)	1 (1 to 4)	0.65 ns
1–6	General behaviour	−1 (−3 to 0)	−1 (−3 to 1)	0.15 ns

ns=not significant.

The median score for overall efficacy was 2 in the meloxicam group and in the ketoprofen group, and was not significantly different (Wilcoxon–Mann–Whitney test, P>0.05). The palatability of meloxicam was found to be significantly better than for ketoprofen (Wilcoxon–Mann–Whitney test, P<0.001). The median palatability score for meloxicam was 1, compared to 2 for the ketoprofen group. The palatability was judged as good to excellent in 87% of the cats treated with meloxicam versus 72.4% of the cats treated with ketoprofen. Fifty-two percent of owners reported meloxicam palatability to be excellent, with the cat immediately and voluntarily taking the medication, compared to only 21% in the ketoprofen group (Fig 2).

Fig 2.

Frequency of palatability scores.

Dosing accuracy

Dosing accuracy was calculated taking into account the determined bodyweight on day 1 and the prescribed and administered dose volume (meloxicam) or number of tablets (ketoprofen).

For the cats included in the efficacy evaluation, the dosing accuracy of meloxicam ranged between 97% and 122%. The dosage accuracy of ketoprofen ranged between 71% and 167%. The wide range was due to the tablet formulation and the fact that the Veterinary Medicine Directorate (VMD) did not allow the splitting of tablets into quarters for the cats included in the UK.

Adverse events

Investigators reported adverse events for six cats; three cats in the meloxicam group and three cats in the ketoprofen group. In the meloxicam group, two of these cats were found to no longer meet the inclusion criteria. One developed an abscess at the site of the initial lameness and the CSS of another cat had been miscalculated at day 1. The CSS was actually less than 6 and so it should not have been included in the study. A third cat developed hind-limb palsy and was removed from the study to be treated with corticosteroids.

Two cats in the ketoprofen group developed vomiting during the study period and were subsequently withdrawn. A third cat was withdrawn after it developed signs including loss of appetite, weakness, persistence of pain and anaemia.

Discussion

The safety and efficacy of meloxicam for the long-term treatment of osteoarthritis have been demonstrated in several studies. ^10,11 This study demonstrated that the efficacy of oral meloxicam at an initial dose of 0.1 mg/kg followed by 0.05 mg/kg for up to four additional days, ie, at a lower dose rate used in a previous study, ¹ was comparable, ie, statistically non-inferior, ¹² to that of ketoprofen when used at the registered dose. However, ketoprofen is sometimes also administered at higher doses of 2 mg/kg/day subcutaneously. ¹³

A non-inferiority margin of 1.0 score point was chosen as this was the minimal unit for differentiation of efficacy in each individual animals and considered reasonable for detecting relevant treatment differences taking into account an initial CSS≥6. In general, the wider the proposed difference representing equivalence, the greater the difficulty in agreeing that it is clinically unimportant. ¹² This study assessed the efficacy of meloxicam in client owned cats suffering from 19 different types of acute locomotor disorder (including six disorders associated with the spine). It would have been preferable if all the cats recruited had undergone further diagnostic procedures to confirm the diagnosis and cause of the locomotor disorders (only 46/121 cases in the study underwent radiography). However, this would not have affected the assessment of pain in the cats which was based on clinical examination, and this limitation of the study also reflects the situation in general practice.

Currently, there is no robustly tested or validated pain scoring system for cats. ¹⁴ Common pain scales for pain assessment in animals are SDS, numerical rating scales (NRS), visual analogue scales (VAS) and multi-factorial pain scales (MFPS). ¹⁵

SDS were used for each efficacy parameter, the scores of which were then added together to give a total CSS. Although the SDS is considered a basic pain scale, and not particularly sensitive to small differences in pain intensity (compared to a VAS or NRS) it is probably the easiest of the systems to use in large clinical studies in general practice. This is because it does not require specific training of observers and there is a limited scope for inter-observer variability. ¹⁶ These advantages are particularly relevant in studies involving many different investigators, such as this one. The SDS has already been used successfully in the subjective pain scoring of cats with painful locomotor disorders. ^1,10 The CSS is an MFPS as it is a combination of a number of SDS values (ie, posture, lameness, pain on palpation). The idea of this pain scale is to gain a broader and possibly a more accurate view of the patient's pain by examining a number of factors. ¹⁵ In addition, the t-test was used to analyse the CSS, as it is robust with respect to deviations from normal distribution. However, a more sensitive method of pain scoring, such as collar mounted activity monitors, ¹¹ may have been advantageous, especially towards the end of treatment periods when pain intensity is expected to be relatively mild.

Before the start of the study both groups had comparable bodyweights, sex distribution, duration and severity of clinical signs. The meloxicam group did have a higher mean age than the ketoprofen group, 7 years rather than 4 years.

The per protocol variable duration of the treatment period (ie. 4–5 days) could potentially have biased the study if there had been an unequal duration of treatment period between the treatment groups. However, the actual duration of the treatment period was equally balanced [mean/SD: 4.51/± 0.57 (meloxicam group), 4.75/± 0.70 (ketoprofen group)].

There was no significant difference in the number of adverse events seen in the two treatment groups in the study. None of the three cats with adverse events in the meloxicam group displayed signs typically associated with NSAID intolerance. Two of the three cats in the ketoprofen group with adverse events were withdrawn due to vomiting which is a recognised side effect of NSAID administration. However, no further diagnostic tests were performed to determine whether the vomiting in these cats was related to therapy, or to a different underlying cause. It would have been useful to have a control group to compare rates of suspect adverse reactions in untreated cats with the two NSAID treated groups to see if there were any significant differences.

The liquid formulation of the meloxicam (Metacam 0.5 mg/ml oral suspension) allowed for much more accurate dosing than the ketoprofen tablets, between 97% and 122% compared with 71% to 167%, respectively. This dosing accuracy may be a factor in any difference seen in NSAID-associated side effects. However, it is also important to use an NSAID with a wide margin of safety and use the minimum effective dose in clinical practice. Previous studies have demonstrated the safety of ketoprofen (1 mg/kg q 24 h for 5 days) and meloxicam administered to cats at three times the recommended dose on day 1, followed by a double dose, q 24 h over 5 days. ^1,2 In addition, the efficacy of meloxicam has been demonstrated at a dose range of 0.01–0.03 mg/kg once daily over several months in cats with osteoarthritic pain. ¹⁰ Assessing pain in cats, is notoriously difficult as it often relies on recognising subtle behavioural and lifestyle changes. ^2,17

Overall the palatability of meloxicam was better than ketoprofen, (87% vs 72.4% judged good to excellent) but 52% of owners reported the palatability of meloxicam to be excellent, compared to only 21% of owners administering ketoprofen to their cats. Palatability is recognised as a major factor in determining compliance in both veterinary medicine. ^18,19 A study investigating the efficacy and palatability of pradofloxacin concluded that the palatability of the liquid formulation optimised owner compliance. ¹⁹ In turn, compliance can strongly predict treatment success. ¹⁸ Therefore, the importance of having a palatable formulation available for the treatment of cats should not be underestimated, particularly when untrained owners are the caregivers.

Conclusion

In this study meloxicam demonstrated significant non-inferiority for efficacy (ie, similar efficacy) compared to the positive-control ketoprofen, when administered to cats. Metacam 0.5 mg/ml oral suspension had significantly better palatability than ketoprofen 5 mg tablets and also allowed the administration of a more accurate dose. Treatment with meloxicam suspension at a dosage of 0.1 mg/kg once on the first day of treatment followed by 0.05 mg/kg q 24 h for four subsequent days is safe and efficacious in painful acute locomotor disorders in cats.

Conflict of interest

Laura Johnston and Rüdiger Narbe are employees of Boehringer Ingelheim GmbH.