In cats which treatment, meloxicam or prednisolone, most quickly reduces clinical signs of feline interstitial cystitis?

a Knowledge Summary by

Thomas Smith-Uchotski BSc (Hons) BVSc MRCVS ^1*

¹Wherry Veterinary Group, Bungay, Suffolk, NR35 1RX
^*Corresponding Author (smith.uchotski@gmail.com)

Clinical scenario

Feline interstitial cystitis (FIC), also known as feline idiopathic cystitis and historically as idiopathic feline lower urinary tract disease (FLUTD), is one of the most commonly diagnosed lower urinary tract diseases of cats. As a clinician, you are aware that the clinical signs brought about by the condition are caused by an inflammatory reaction. Commonly, anti-inflammatory treatments are a staple of treatment for this condition. Both meloxicam and prednisolone offer anti-inflammatory action; you wonder which is the most efficacious treatment in reducing the clinical signs of FIC.

The evidence

Unfortunately, no studies directly comparing the effectiveness of meloxicam against prednisolone as treatments of FIC were uncovered. Two studies which partially answered the PICO question were uncovered. One was a double-blinded randomised controlled trial comparing meloxicam against a placebo (Dorsch et al., 2016). The other was a double-blinded randomised controlled trial comparing prednisolone against a placebo (Osborne et al., 1996). Two studies were omitted from assessment due to being inaccessible.

The first paper, by Dorsch et al. (2016), comparing meloxicam against a placebo, concluded that there was no statistical significance in the reduction of clinical signs when comparing the two study groups. While the number of participants in the study was relatively substantial (n = 37), no power calculations were performed to assess if the number of participants was sufficient to provide viable evidence. Additionally, the responsibility of data recording was passed from the researchers to animal owners, which could introduce a high degree of variability in the quality of data recording, potentially skewing the data.

The second paper, by Osborne et al. (1996), comparing prednisolone against a placebo, also concluded that there was no statistical significance in the reduction of clinical signs when comparing the two study groups.

Summary of the evidence

Appraisal, application and reflection

The most relevant, available evidence excavated were two double-blinded randomised controlled trials. Both explored the time to reduction of clinical signs of cats with feline interstitial cystitis (FIC). One study evaluated the efficacy of meloxicam as a treatment when contrasted with a placebo (Dorsch et al., 2016), where the other evaluated the efficacy of prednisolone as a treatment when contrasted against a placebo (Osborne et al., 1996). Both studies only partially answered the PICO question, as neither directly contrasted meloxicam against prednisolone as therapy modalities.

The study by Dorsch et al., 2016, concluded that there was no statistical significance between the use of meloxicam and the use of a placebo as treatments for FIC, as well as the likelihood of recurrent urethral obstruction (rUO). The main outcome of the study was the time to development of rUO, with the clinical signs being used as indicative measures for when this occurred. The cats in this study all were obstructed at the start of the study (Dorsch et al., 2016).

Superficially, as a double-blinded randomised controlled trial, the study by Dorsch et al., 2016, stands to potentially provide good clinical evidence. While randomised controlled trials are traditionally regarded as strong evidence, the experimental design is the true factor which determines how reliable the evidence generated is (RCVS Knowledge, 2015). Unfortunately, several factors in the study design potentially weaken the study’s overall evidential strength.

All animals were initially treated with buprenorphine (in addition to meloxicam or the placebo). The effects of buprenorphine, in addition to the meloxicam or placebo, were not part of the intended study outcome and as a consequence, overlap of the treatments with buprenorphine and meloxicam (or the placebo) could confound the data which was gathered for day 1 of treatment with meloxicam and/or the placebo. Additionally, recording of data was passed from hospital assessors to a multitude of up to 37 different owners. Owners were expected to assess their animals via a survey devised by the researchers, which removes all of the objective parameters measured in the hospital such as heart rate and respiration rate. As the survey omits many of the previously measured parameters and is purely subjective with up to 37 different and potentially untrained assessors, this could introduce a lot of variability in the data recorded during this portion of the study.

The study quoted a P-value of 0.049 when comparing day 0’s results for macroscopic haematuria when comparing the meloxicam group against the placebo group, implying a statistically significant difference between the two groups. As one group had statistically significantly worse clinical signs than the other, it could mean that the meloxicam group was more severely affected than the other, which could have affected the time to resolution of clinical signs, being in a more progressed state from the outset. However, as no interventions had been administered at the time of this measurement, this is potentially an irrelevant observation when comparing meloxicam to a placebo, since neither therapy had been initiated. Additionally, P-value calculations for each subsequent day showed no significant difference between the two groups following the admission of both interventions, so it could still be concluded that there is no statistically significant difference between either protocol.

The double-blinded randomised controlled study by Osborne et al. (1996), compared the efficacy of prednisolone against a placebo in reducing the clinical signs caused by idiopathic FLUTD. Similarly, this study also found that there was no statistically significant difference between the different treatment modalities. The main outcome of this study was the time to reduction of clinical signs (Osborne et al., 1996).

Similarly to the study by Dorsch et al. (2016), the study design also stands to potentially provide strong evidence as a double-blinded randomised controlled trial. However, there are also factors of this study's individual design which cast some shade over the strength of the study. The study sometimes proves to be a little sparse with its reporting of data; despite urine samples being taken daily from animals, only those from days 0, 5 and 10 are included in the study. Additionally, it is not explicitly mentioned how urine specific gravity is measured. These omissions weaken the overall trust in the study, especially as urine specific gravity has both subjective (Dipstix) and objective (refractometry) measures of being assessed. Additionally, the sample size of the study is very small, where n = 12, and as such the study group may be too small to provide sufficient power. Lastly, no calculations to quantify statistical significance were quoted, which throws doubt over whether the evidence provided actually shows statistical significance or not.

One other single-blinded randomised controlled trial by Nivy et al. (2019), assessed the recurrence rates of FIC and rUO in cats. While this study did not answer the PICO question, the study itself does provide some interesting food for thought. This study compared the use of phenoxybenzamine and alprazolam with or without low dose meloxicam (0.025 mg/kg, q24h, PO) as a treatment for cats with FIC. 51 males with urethral obstruction and FIC were allocated one of the treatment protocols in a single-blind fashion. The study drew the conclusion that the addition of low-dose meloxicam to phenoxybenzamine and alprazolam treatment did not make a significant difference in the return to urethral obstruction and/or FIC compared with cats only treated with phenoxybenzamine and alprazolam (Nivy, et al., 2019).

While the reduction in clinical signs was not measured in this study, it is interesting to note that the addition of meloxicam did not provide any clinical benefit for the assessed parameters. Another study, examining cats with experimentally induced synovitis, showed that low-dose meloxicam of 0.025 mg/kg q24h PO did not make a significant in the reduction of pain signs in comparison to a placebo. However, higher dose rates of 0.05 mg/kg and 0.075 mg/kg with the same dosing interval showed a statistically significant reduction in pain parameters (Carroll et al., 2011). It could therefore be possible that the dose rate chosen by Nivy et al. (2019), was not high enough to be efficacious.

Taking into account all papers cited, it is key to note that the populations of animals studied are slightly different. Both studies which used meloxicam in their treatment protocols – Dorsch et al. (2016), and Nivy et al. (2019), – used cats with obstructive FIC as their populations. By comparison, the paper by Osborne et al. (1996) used animals with non-obstructive FIC as their study population. While all cats had FIC by definition, those with obstructive FIC present with a much more severe clinical syndrome than those with non-obstructive FIC, which raises the question as to whether these populations are truly comparable. As such, it may be good to be more specific with the population and contrast animals exclusively with non-obstructive or obstructive FIC. That being said, it may only be possible to compare these therapies in non-obstructed animals as prednisolone is often contraindicated when an indwelling catheter is present (Osborne et al., 1984).

One other thing to note as well is that steroids and NSAIDs are not the only treatments which are available for treatment of FIC in cats. Many other treatment modalities including amitriptyline, tolfenamic acid, polysulphated glycosaminoglycans and pentosan polysulphate which were not explored in this Knowledge Summary are available and may be worth further consideration and evaluation in another Knowledge Summary. One paper noted that ketoprofen was often the choice NSAID for use in Canada for managing pain associated with musculoskeletal disease, and is often used in treatment of FIC (Dowling, 2000).

In summary, no studies directly comparing the efficacy of meloxicam against prednisolone as a means of reducing the clinical signs of cats with FIC could be identified. At an even more specific level, no studies exist comparing these treatments in populations of cats exclusively with non-obstructive or obstructive FIC. The studies uncovered, all of which were randomised controlled trials, had flaws in their experimental design or, possessed sufficient limitations which weaken their strength as valid evidence. It could be hypothesised that, since both relevant studies found no significant difference between the use of a placebo or a treatment (either meloxicam or prednisolone), there would be no significant difference between using prednisolone and meloxicam. However, the study examining meloxicam used only cats which were obstructed (Dorsch et al., 2016) whereas the study examining prednisolone only used unobstructed cats (Osborne et al., 1996) and as such, these studies are not necessarily directly comparable. Two papers were also inaccessible for evaluation.

At present, there is insufficient evidence to prove absolutely whether meloxicam or prednisolone is the superior therapeutic agent for the treatment of FIC with respect to the reduction of clinical signs. The fact that two papers were also unavailable for assessment may also make these findings spurious, as these may offer strong evidence which answers the PICO question. Further studies comparing the efficacy of meloxicam and prednisolone as treatments for FIC may be required in order to answer the PICO question. Finally, it would be worth broadening the horizon of this question to include other commonly used and available therapies for treating FIC, since one of these treatments may prove effective where meloxicam and prednisolone may not.

Methodology

Search Strategy
Databases searched and dates covered:	CAB Abstracts on Ovid Platform; 1973–2021 Week 14. PubMed on NCBI interface; 1920–April 2021.
Search strategy:	CAB Abstracts: (cat or cats or feline* or felid* or queen* or tom* or DSH* or DLH* or (domestic long?hair* or short?hair*))).mp. ((feline and (interstitial or idiopathic) and cystitis) or ((interstitial or idiopathic or sterile) and cystitis) or ((pandora or feline urologic) and syndrome*) or (FIC not "fractional inhibitory concentration") or FUS or FLUTD or "feline lower urinary tract disease").mp. (melox* or "loxicom" or "metacam" or "inflacam" or "rheumocam" or NSAID* or non?steroidal anti?inflammatory drug* or non?steroidal nati?inflammator* or anti?inflammator*).mp. (steroid* or glucocorticoid* or corticosteroid* or predni* or "prednicortone" or "prednicare" or prednisolone* or anti?inflammator*).mp. (resol* or reduc* or improve* or recover* or symptom* or treat* or therap* or clinical sign* or haematuria* or hematuria* or dysuria* or stranguria* or pollakiuria* or periuria* or void* or bladder inflammation or inappropriate* void* or voids inappropriate*).mp. 1 and 2 and 3 and 4 and 5 (9) 1 and 2 and 3 and 4 (9) 1 and 2 and 3 (12) 1 and 2 and 4 (17) 1 and 2 and 3 and 5 (12) 1 and 2 and 4 and 5 (16) 6 or 7 or 8 or 9 or 10 or 11 (20)   PubMed: (cat or cats or feline or felid or queen or tom or DSH or DLH or (domestic and (long hair or longhair or short hair or shorthair))) feline interstitial cystitis or feline idiopathic cystitis or pandora urologic syndrome or feline urologic syndrome or FIC or FUS or FLUTD or feline lower urinary tract disease meloxicam or loxicom or metacam or inflacam or rheumocam or orocam or NSAID or non-steroidal anti-inflammatory drug or non-steroidal anti-inflammatory or anti inflammatory steroid or glucocorticoid or corticosteroid or prednisone or prednicortone or prednicare or prednisolone or anti inflammatory 1 and 2 and 3 and 4 (22)
Dates searches performed:	12 Apr 2021

Exclusion / Inclusion criteria
Inclusion and exclusion criteria were predetermined in order to assess the most suitable and powerful evidence for appraisal. Full texts to all relevant articles were then obtained and thoroughly examined where possible.
Exclusion:	Non-English language, popular press articles, conference abstracts, book chapters, opinion articles, conference papers.
Inclusion:	Studies comparing the time to resolution or improvement of clinical signs in cats with FIC when comparing meloxicam or prednisolone. Studies examining the efficacy of meloxicam in reducing the clinical signs of cats with FIC when compared to another treatment or placebo. Studies examining the efficacy of prednisolone in reducing the clinical signs of cats with FIC when compared to another treatment or placebo.

Search outcome
Database	Number of results	Excluded – Duplicates	Excluded – Non-English	Excluded – Conference paper and/or book chapter	Excluded – Entire journal issue*	Excluded – Did not answer PICO question	Total relevant papers
CAB Abstracts	20	0	1	6	1	10	2
Medline	22	5	0	0	0	17	0
Total relevant papers when duplicates removed							2

*The individual articles within the journal issue were evaluated and deemed as either not relevant to the PICO question or, had already been included in the search results elsewhere.

The author declares no conflicts of interest.

The author would like to extend thanks to Bridget Sheppard, Clare Boulton and the remainder of the staff at RCVS Knowledge for their guidance throughout the process of writing the Knowledge Summary and support with the literature searches, as well as Sarah O'Shaughnessy at the University of Bristol for informing them of the ability to submit Knowledge Summaries through the Veterinary Evidence website.

1. Carroll, G.L., Narbe, R., Kerwin, S.C., Taylor, L., Peterson, K. & Hartsfield, S.M. (2011). Dose range finding study for the efficacy of meloxicam administered prior to sodium urate-induced synovitis in cats. Veterinary Anaesthesia and Analgesia. 38(4), 394–406. DOI: https://doi.org/10.1111/j.1467-2995.2011.00621.x
2. Dorsch, R., Zellner, F. & Schulz, B. (2016). Evaluation of meloxicam for the treatment of obstructive feline idiopathic cystitis. Journal of Feline Medicine and Surgery. 18(11), 925–933. DOI: http://dx.doi.org/10.1177/1098612X15621603
3. Dowling, P.M. (2000). Potential therapies for recurrent idiopathic cystitis in cats. Veterinary Medicine. 95(7), 512–515.
4. Nivy, R., Segev, G., Rimer, D., Bruchim, Y., Aroch, I. & Mazaki-Tovi, M. (2019). A prospective randomized study of efficacy of 2 treatment protocols in preventing recurrence of clinical signs in 51 male cats with obstructive idiopathic cystitis. Journal of Veterinary Internal Medicine. 33(5), 2117–2123. DOI: https://doi.org/10.1111/jvim.15594
5. Osborne, C.A., Kruger, J.M., Lulich, J.P., Johnston, G.R., Polzin, D.J., Ulrich, L.K. & Sanna, J. (1996). Prednisolone therapy of idiopathic feline lower urinary tract disease. A double-blind clinical study. Veterinary Clinics of North America, Small Animal Practice. 26(3), 563–569. DOI: https://doi.org/10.1016/S0195-5616(96)50085-9
6. Osborne, C.A., Polzin, D.J., Klausner, J.S. & Kruger, J.M. (1984). Medical management of male and female cats with nonobstructive lower urinary tract disease. Veterinary Clinics of North America: Small Animal Practice. 14(3), 617–640. DOI: https://doi.org/10.1016/S0195-5616(84)50067-9
7. RCVS Knowledge. (2015). EBVM Toolkit 3 - Introduction to "Levels of evidence" and Study Design. [online] Available at: https://knowledge.rcvs.org.uk/document-library/ebvm-toolkit-3-introduction-to-levels-of-evidence-and-study/ [Accessed 28 Apr 2020].