NSAIDS for chronic pain relief in cats

 
A ginger cat looking at a bottle of NSAIDS for chronic pain relief in cats
 

In the UK, non-steroidal anti-inflammatory drugs (NSAIDs) are the only licensed products for treating chronic pain in cats. Many painful conditions such as osteoarthritis, periodontal disease and neoplasia may respond to NSAID therapy and treatment may be required to ensure good welfare and quality of life. However, there are concerns about using NSAIDs in cats, particularly older animals, because of potential adverse effects on kidney function (Monteiro et al 2019). Also, the Summary of Product Characteristics (SPCs) for some NSAIDs includes renal dysfunction as a contraindication of their use in cats (VMD product database). This module examines the evidence on the safety of using NSAIDs long-term in cats, particularly focusing on their impact on kidney function and use in cats with pre-existing renal disease. The module does not cover the evidence on efficacy of NSAIDs for treating chronic pain in cats.

 By doing this module you will:

  • Understand the mechanisms underlying the potential adverse effects of NSAIDs

  • Understand what is known about COX selectivity of NSAIDs in cats

  • Be aware of what is known about the adverse effects of NSAIDs in cats

  • Understand what is known about the comparative safety of meloxicam and robenacoxib 

  • Know the safety evidence on using NSAIDs in cats with chronic kidney disease  

  • Know how to monitor long-term NSAID therapy in cats

 Related modules:

Which NSAID

Post-operative pain in cats – meloxicam or robenacoxib

In the UK, two NSAIDs are authorised for the treatment of acute and chronic (specifically musculoskeletal) pain in cats. They are meloxicam oral suspension and robenacoxib tablets (VMD product database; VP 2018). Use of these for managing chronic pain other than that with a musculoskeletal cause is technically ‘off-licence’.

 
NSAIDs authorised for chronic pain management in cats
 

When cell membranes are damaged, short chain fatty acids (such as arachidonic acid) are released. The enzymes cyclooxygenase (COX) and lipoxygenase convert these substrates into inflammatory mediators such as prostaglandins, thromboxanes and leukotrienes. Prostaglandins enhance nociceptive stimuli produced by other inflammatory mediators, and act in synergy with histamine and bradykinin to increase vessel permeability. It is widely accepted that the main mechanism of action underlying the therapeutic and adverse effects of NSAIDs is inhibition of the enzyme COX. (Lees et al 2004).

In the kidney, all the major prostaglandins are synthesised as products of COX enzyme activity. Prostaglandin E2 is located in the nephrons, medullary interstitial cells and collecting tubules, where it functions as a vasodilator and has a major role in excretion of salt and water. Prostaglandin E2 and prostacyclin (PGI2) bind to prostaglandin E receptors and function as vasodilators (Harirforoosh et al 2013).  These prostaglandins are mediators of renal function and are thought to be especially important for protecting normal kidney function during periods of dehydration or hypovolaemia (Harris 2002). It follows that inhibition of prostaglandin effects by an NSAID could lead to reduced kidney function in susceptible patients. This includes animals that have chronic kidney disease (CKD) and also those under general anaesthesia, or which are hypotensive, dehydrated, or sodium-deficient. 

COX is known to exist in at least two isoforms (COX-1 and COX-2), with COX-3 also having been identified in the CNS of dogs (Chandrasekharan et al 2002). The analgesic and anti-inflammatory actions of NSAIDs were originally believed to depend mainly on their inhibition of COX-2, and the unwanted gastrointestinal and renal effects on their inhibition of COX-1. It followed, in theory, that NSAIDs that are more selective for COX-2 might be safer. However, the concept of COX-1 as ‘good’ and COX-2 as ‘bad’ is now known to be an oversimplification. For instance, as well as its pro-inflammatory actions, COX-2 also appears to contribute to the production of anti-inflammatory mediators: its activity results in inflammatory effects in the acute phase of injury and anti-inflammatory effects in the resolution phase (Lees et al 2004) but the relevance of this to the clinical effects of NSAIDs is not clear.

It is possible to determine the selectivity of a particular NSAID for either COX-1 or COX-2 in laboratory studies. However, selectivity can depend on animal species and the dose of the drug, and it is important to be aware that different methods for testing and calculating selectivity can give different values for any given NSAID (Lees et al 2004).

A study designed to determine the relative selectivity of meloxicam and robenacoxib for COX-2 in the cat, under the same laboratory conditions, indicated that robenacoxib has high selectivity for COX-2 whereas meloxicam has low selectivity (Schmid et al 2009).  However, we cannot assume that COX-selectivity data for specific drugs will translate into the expected clinical effects (either beneficial or harmful), so it is important to look for evidence of clinical efficacy and safety.

For more information on the pharmacology, pharmacodynamics and pharmacokinetics of NSAIDs see the Which NSAID? module (VP 2018).

Chronic kidney disease (CKD) in cats is characterised by the irreversible loss of kidney function over a prolonged period. It is common and increases in prevalence with age. It has been shown to affect approximately 40% of cats aged over 10 years, and 80% of cats aged over 15 years (Marino et al 2014). It is a progressive disease and the cause is often unclear (Marino et al 2014; Sparkes et al. 2016). Evidence-based guidelines on diagnosing, staging, and treating this complex disease in cats are available (Sparkes et al 2016). 

Acute kidney injury is an abrupt deterioration in kidney function characterised by a raised serum creatinine concentration, acute uraemia, and changes in urine volume (Legatti et al 2018). Causes include a compromised blood supply, infection, lily poisoning, ethylene glycol toxicity, urinary tract obstruction and nephrotoxic drugs including NSAIDs (Legatti et al 2018). Outcome following acute kidney injury in cats is variable ranging from full recovery of renal function, to incomplete recovery resulting in CKD, to complete non-recovery needing permanent renal replacement therapy or euthanasia. Mortality rates in cats from acute kidney injury may be as high as 53% (Legatti et al 2018). 

It is now thought that chronic kidney disease is a risk factor for acute kidney injury and vice versa, rather than them being distinct diseases. Acute kidney injury may exacerbate pre-existing CKD and accelerate its progression (Cowgill et al 2016).

In general, the adverse effects of NSAIDs have been less well studied in cats than in dogs (VP 2018).  There has been an analysis of NSAID adverse effects in cats spontaneously reported to the Veterinary Medicines Directorate (VMD) (Hunt et al 2015). Overall, there were 190 adverse events reported in cats from 60 million doses of oral NSAIDs administered. The six most common adverse events shared by oral robenacoxib and meloxicam, in descending order, were: emesis, anorexia, lethargy, death, renal insufficiency and dehydration. From these data, the predicted number of reports of renal insufficiency resulting from every million NSAID doses sold is 110 for oral meloxicam and 133 for oral robenacoxib. The data do not provide information on the nature of the renal adverse effects. In dogs and cats combined, the frequency of emesis, renal insufficiency and death were significantly higher for injectable compared to oral NSAIDs (p=0.043). This is potentially due to the circumstances in which they are administered, with injectable NSAIDs more likely to be used peri-operatively. Under these conditions, patients would be at a higher risk of hypovolaemia and the adverse effects seen could be confounded by the general risks of anaesthesia and surgery. Overall, the frequency of reported adverse effects to NSAIDs was considered by the study’s authors to be low (when related to the total number of doses sold) and similar for the different NSAIDs. The study’s authors acknowledge that adverse events are likely to be under-reported to the VMD (Hunt et al 2015).

The SPCs for meloxicam products state that renal failure is reported occasionally, whereas the SPC for robenacoxib does not mention any renal adverse effects. 

Several published studies have examined the tolerance of cats to longer-term use of meloxicam and robenacoxib. However, to our knowledge there are no published trials directly comparing long-term use of these two NSAIDs.

Meloxicam

prospective case-control study assessed the safety, palatability and efficacy of oral meloxicam for a mean of 5.8 months (Gunew et al 2008). The study enrolled 46 cats with osteoarthritis and matched them to control cats with no clinical evidence of osteoarthritis and not receiving meloxicam. The cats with osteoarthritis received meloxicam at a dose of 0.1mg/kg daily for 4 days, then a dose range of 0.01–0.03mg/kg once daily. This dose is lower than the licensed dose (0.05 mg/kg once daily). There were no statistically significant differences between the two groups in the overall number of illnesses reported during the trial, or in the number of gastrointestinal upsets recorded (4 cases in the meloxicam group vs. 2 in the control group, p=0.438). One treated cat and one control cat died during the study due to pre-existing CKD. There was no statistically significant change in serum creatinine concentration in the meloxicam group between baseline and the end of the study (p=0.66). The study’s authors concluded that long-term administration of meloxicam is safe, but that supportive evidence was needed from larger studies. 

retrospective, case-control study examined the long term (>6 months) use of meloxicam in the treatment of degenerative joint disease in 38 cats that were aged over 7 years (Gowan et al 2011). In all, 22 of the included cats had pre-existing kidney disease and 16 had no diagnosed kidney disease. The study aimed to assess the effect of meloxicam on renal function. Control cats that had not received meloxicam were matched to cats in the study based on their renal disease status and age. The median starting dose of meloxicam was 0.05mg/kg but owners were encouraged to reduce this to the lowest effective dose (the median dose throughout the study was 0.02mg/kg daily). In the cats with no pre-existing kidney disease, meloxicam had no significant effect on serum creatinine concentrations, urine specific gravity measurements or body condition scores.

These studies on meloxicam have provided information on the safety of longer-term use of NSAIDs in cats, however they do have substantial limitations. Lower than licensed doses of meloxicam were used with minimal assessment of whether pain was adequately controlled. There was no justification of the sample sizes used in these studies, and the number of cats was relatively low. While case-control studies can be an effective way of assessing relatively rare events they are inherently prone to a higher level of bias, so their results are less reliable than well conducted, adequately-powered randomised controlled trials.

Robenacoxib

In one multicentre blinded randomised controlled trial, 193 cats with osteoarthritis received robenacoxib (1.0–2.4 mg/kg) or placebo once daily for 28 days (King et al 2016). In all, 102 adverse events were reported in 70 cats receiving either robenacoxib or placebo with no difference between the groups in the rate of any adverse event. Vomiting was the most frequently reported adverse event in both groups (in 20% of cats on robenacoxib vs. 21% on placebo). There were no deaths or cases of euthanasia reported during the study, and no significant differences in change from baseline between groups in biochemical parameters. It is worth noting that this study was designed to assess efficacy and was not powered to detect adverse events. The study duration of 28 days gives limited information about long-term use.

A few studies have examined the effects of NSAIDs in cats with pre-existing CKD.

Meloxicam

The retrospective case-control study described above that examined the long term (>6 months) use of meloxicam in cats with degenerative joint disease included a subgroup of 22 cats with CKD (International Renal Interest Society [IRIS] stage 1–3). These were matched with control cats that were not treated with meloxicam (Gowan et al 2011). All cats were over 7 years old. In the CKD subgroup, meloxicam had no detectable negative effect on kidney function. Urine specific gravity and body condition scores decreased over time in all cats with CKD in the study, with no significant differences between the meloxicam and not treated groups for either parameter. Median serum creatinine concentrations actually increased more slowly in the cats with CKD that were treated with meloxicam compared to those not receiving meloxicam. Possible explanations for this could be increased comfort and mobility leading to increased food and water intake in the treated cats, or an anti-inflammatory effect of meloxicam on the kidneys (Gowan et al 2011; Monteiro et al 2019). The results suggest that a long-term maintenance dose of 0.02 mg/kg of meloxicam once daily can be safely administered to cats aged over 7 years, even if they have CKD, provided their overall clinical status is ‘stable’. However, as mentioned above, this study used a meloxicam dose that is lower than the licensed dose (0.05mg/kg daily), and we cannot be certain that all cats received appropriate analgesia. There was also no sample size justification and small group sizes.

Another study examined survival rates of cats on long-term meloxicam (Gowan et al 2012). It included 82 cats which were over 7 years old and had been treated with meloxicam for more than 6 months (median dose of 0.02mg/kg daily). In all, 47 of the included cats had CKD diagnosed before meloxicam therapy was started (renal group); the remaining 35 cats had no overt CKD (non-renal group). In the non-renal group, 25 cats developed overt CKD during the study; this is explained by the fact that a lot of older cats could have had subclinical CKD when recruited. All cats in the study were treated with meloxicam (there was no control group not treated with meloxicam). Median longevity for the renal group was 18.6 years compared to 22.0 years for the non-renal group (it is not stated if this is a statistically significant difference) and the median survival time after CKD diagnosis was 1,608 days. The study’s authors interpret this as indicating that meloxicam therapy does not reduce longevity on the basis that the cats with CKD that were treated with meloxicam in this study had similar survival times to those reported in other studies of cats with CKD not treated with meloxicam (Gowan et al 2012). However, drawing conclusions about longevity is unreliable when the groups are not compared within the same study.

Robenacoxib

In the tolerability study described above (King et al 2016), a subgroup of 40 cats (out of 193) had concomitant CKD (mainly IRIS stage 2; one stage 3 cat in the placebo group). The cats were treated with robenacoxib or placebo and monitored for 1 month; none received concurrent treatment for renal disease. During the study there was no statistically significant change in body weight in either group. There were also no statistically significant differences between groups in changes in serum creatinine, urea nitrogen or urine specific gravity. Kidney function worsened in one cat on robenacoxib during the study (from IRIS stage 2 to stage 3) but improved in one cat on robenacoxib and in three cats on placebo by the end of the study (i.e. they moved to a lower IRIS stage). Of the 40 cats in this subgroup, adverse events were reported in 6 in the robenacoxib group vs. 7 in the placebo group. However, as mentioned above, the study was not powered to detect adverse events.

For meloxicam, there is some evidence from a few retrospective studies that a dose lower than the authorised dose can be used for around 6 months and longer in cats with no kidney disease or mild–moderate CKD (IRIS 1–3) without causing adverse effects on the kidney. However, we cannot be certain that the doses used in the studies provided adequate pain relief or that the lower doses are safer than authorised doses.

For robenacoxib, there is limited evidence from one randomised efficacy trial (that included a small number of cats with CKD; mainly IRIS stage 2) that the drug can be used at the authorised dose for 28 days without increasing the likelihood of adverse effects on the kidney in cats with or without CKD. However, a high-quality study powered to detect such adverse events is needed to assess this fully.

  • As for all species, an NSAID should only be prescribed if necessary, and used alongside appropriate lifestyle or management changes that could alleviate the underlying painful condition. If an NSAID is needed for a cat (especially an older one) to manage pain long-term, kidney function should be appropriately assessed before starting. Ideally, evaluation of haematocrit, hepatic parameters and blood pressure would also be assessed (Sparkes et al 2010; Sparkes et al 2016).

  • The available evidence suggests that meloxicam (at a lower dose than authorised) and robenacoxib can be safely administered to cats with ‘stable’ CKD (IRIS stage 1–3) provided adequate management of CKD is in place and appropriate monitoring is employed (Monteiro et al 2019). ‘Stable’ CKD is defined as minimal changes in bodyweight and creatinine over a period of at least 2 months and controlled concurrent conditions including hypertension (Monteiro et al 2019).

  • The safety of using NSAIDs in cats with advanced disease (IRIS stage 4) is not known and is less certain for cats with stage 3 disease than for stages 1–2.

  • The general advice for all species is to use the lowest effective dose of an NSAID (Sparkes et al 2010; Monteiro et al 2019). However, it is important to assess efficacy alongside any dose reduction and there is currently no evidence that lower than authorised doses result in fewer adverse effects in cats. It has been suggested that for overweight or obese cats, initial drug doses should be based on their ideal, or lean, weight (Sparkes et al 2010).

  • In keeping with the general management of CKD, the cat should have free access to fresh water, which should be provided at various locations around the house. Wet food also helps to increase water intake (Sparkes et al 2016; Monteiro et al 2019). 

  • NSAIDs should not be administered alongside other NSAIDs (including aspirin) or corticosteroids. 

  • Additional renal risk factors should be avoided in cats on NSAIDs, including hypotension, dehydration, anaesthesia and the use of nephrotoxic drugs (e.g. aminoglycosides). 

  • Anticoagulants and other substances with high protein binding may compete for binding and lead to toxic effects (VMD product database). Concurrent use of highly protein bound drugs with a low margin of safety (e.g. warfarin, digoxin, anti-convulsants such as phenobarbitone and chemotherapeutic agents should be done with great care), if at all (Sparkes et al 2010).

  • The use of ACE inhibitors and diuretics alongside NSAIDs is likely to increase the risk of renal adverse effects and careful monitoring and dose adjustments may be required (Sparkes et al 2010; VMD product database). 

The SPCs for meloxicam specifically state not to use the drug in cats with impaired renal function. Therefore, use in cats with CKD is unlicensed and must be under the Cascade. This makes robenacoxib the logical first choice, even though there is no clinical evidence that robenacoxib is a safer choice than meloxicam. However, given that the two drugs are available in different formulations, choice might be determined by the practicality of administering the drug, because compliance is crucial for effective treatment. If one NSAID is not effective or causes mild adverse effects, it is worth switching to another, after the appropriate washout period. Washout periods should be based on pharmacokinetics of the previously prescribed drug. Use of any NSAID other than meloxicam or robenacoxib for the treatment of chronic pain in cats is ‘off licence’. 

  • The SPCs for both meloxicam and robenacoxib state that the response to long-term therapy should be monitored at regular intervals by a veterinary surgeon; although they do not indicate what form the monitoring should take.

  • Ideally, the efficacy of NSAID treatment should be monitored using a validated chronic pain assessment or quality-of-life tool for cats, such as Vetmetrica.  For osteoarthritis, response to therapy includes increased level of activity and ability to perform activities (such as jumping, grooming, using the litter box), improved demeanour and socialisation. 

  • Owners should look out for adverse events and report any concerns to their veterinary surgeon. Especially careful monitoring is required by owners of cats with CKD (e.g. monitoring fluid intake closely).

  • Monitoring on a regular basis by clinical examination, body weight, haematology, assessment of hepatic and renal parameters, urinalysis and blood pressure measurement is advised but this may not be practical in some cats. There is no evidence or consensus to guide the frequency of monitoring and it will depend on individual circumstances and perceived risk level of the patient (Sparkes et al 2010; Monteiro 2019). 

  • Some guidelines have suggested evaluation 5–7 days after starting treatment (although some cats may take longer to respond), followed by a 2–4 week review and subsequent follow up at 6-monthly intervals (Sparkes et al 2010). 

  • Monitoring of body weight is important to ensure the correct dose of drug is being administered. 

  • If acute kidney injury develops during NSAID therapy, the drug should be discontinued, appropriate treatment started, and alternative analgesia used.

The risks and benefits of administering NSAIDs to cats should be discussed with owners before prescribing and owner consent obtained for any off-licence use. The owner should understand that NSAID treatment is being used in order to maintain or improve quality of life by relieving pain but that there is a risk (thought to be rare) of the treatment having a detrimental effect on kidney function. Owners should be given guidance on how to monitor treatment efficacy at home, be made aware of the known side effects to look out for (including vomiting, diarrhoea, not eating and lethargy), and signs of kidney dysfunction (including urinating and drinking more than usual and weight loss). They should be warned to stop the product and contact their veterinary surgeon if their cat is unwell. Owners should ensure there is plenty of access to fresh water at home to avoid potential dehydration. 

Osteoarthritis, or other causes of chronic pain, might necessitate the use of NSAIDs to improve quality of life in cats.The NSAIDs meloxicam and robenacoxib are a first line therapy, and the only authorised option for treating chronic (musculoskeletal) pain in cats. The first choice of NSAID in cats with renal dysfunction is robenacoxib because the SPCs contraindicate the use of meloxicam, although we do not know if robenacoxib is any less likely to cause adverse effects. However, in some cases, meloxicam (which is in liquid form) might be preferred because of dosing convenience or ease of administration, or if robenacoxib has not been effective or is not tolerated. The risks and benefits of administering NSAIDs should be considered and discussed with owners before prescribing. Regular monitoring of both response to treatment and adverse events by the owner and veterinary surgeon are necessary. The most common reported adverse event is vomiting and more serious adverse events, such as renal dysfunction, are thought to be rare. NSAID therapy may be started in cats with stable CKD with additional monitoring. Larger, and longer duration, prospective studies are needed to help determine the true incidence and nature of rarer adverse events, including those affecting the kidneys.

PODCAST

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NSAIDS-for-chronic-pain-relief-in-cats-test-your-knowledge.jpg

How we produced this module

Our modules start with a detailed outline and electronic literature search. We commission a collaborating author, who is a specialist in the module topic, to write a draft module. The collaborating author on this module was Matthew Gurney, RCVS and EBVS European Specialist in Veterinary Anaesthesia and Analgesia. The draft is circulated unsigned to a wide range of commentators, include practising first-opinion vets, other topic specialists, the companies that market any mentioned drugs and other organisations and individuals, as appropriate. They can raise points about the interpretation of evidence, ask questions that are important to clinical practice, and present alternative viewpoints. There is a rigorous editing and checking process and the result is a module that is evidence-based, impartial and relevant to clinical practice. The final module is unsigned because it is the result of collaboration. 

Searches

We searched RCVS Knowledge Discovery Service (including PubMed) and VetMed Resource (CAB Abstracts) on 19 May 2019 using the terms: (cat OR cats OR feline OR felines OR felis) AND (nonsteroidal OR non steroidal OR nonsteroidals OR non steroidals OR NSAID OR NSAIDs OR meloxicam OR Metacam* OR inflacam* OR loxicom* OR melosus* OR meloxaid* OR meloxidyl* OR meloxoral* OR ketoprofen OR ketofen* OR robenacoxib OR onsior*) AND (kidney OR kidneys OR renal).

References

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Cowgill LD et al. (2016) Is progressive chronic kidney disease a slow acute kidney injury? Vet Clin North Amer:Sm Anim Pract 46: 995-1013

Gowan RA et al. (2011) Retrospective case-control study of the effects of long-term dosing with meloxicam on renal function in aged cats with degenerative joint disease. J Fel Med Surg 13: 752-61

Gowan RA et al. (2012) A retrospective analysis of the effects of meloxicam on the longevity of aged cats with and without overt chronic kidney disease. J Fel Med Surg 14: 876-81

Gunew MN et al. (2008) Long-term safety, efficacy and palatability of oral meloxicam at 0.01–0.03 mg/kg for treatment of osteoarthritic pain in cats . J Fel Med Surg 10: 235-41 

Harirforoosh S et al. (2013) Adverse Effects of Nonsteroidal Antiinflammatory Drugs: An Update of Gastrointestinal, Cardiovascular and Renal Complications.  J Pharm Pharm Sci 16: 821-47

Harris RC. (2002) Cyclooxygenase-2 inhibition and renal physiology. Am J Cardiol 89:10D-17D.

Hunt JR et al. (2015) An analysis of the relative frequencies of reported adverse events associated with NSAID administration in dogs and cats in the United Kingdom. Vet J 206: 183-90

International Renal Interest Society. IRIS staging of CKD (modified 2017) [online]. Available: http://www.iris-kidney.com/pdf/IRIS_2017_Staging_of_CKD_09May18.pdf.

King JN et al. (2016) Clinical safety of robenacoxib in feline osteoarthritis: results of a randomized, blinded, placebo- controlled clinical trial. J Fel Med Surg 18: 632–42 

Lees P et al. (2004) Pharmacodynamics and pharmacokinetics of nonsteroidal anti-inflammatory drugs in species of veterinary interest. J Vet Pharmacol Ther 27: 479–90

Legatti SAM et al. (2018) Acute kidney injury in cats and dogs: A proportional meta-analysis of case series studies. PLoSONE 13(1): e0190772

Marino et al. (2014) The prevalence and classification of chronic kidney disease in cats randomly selected within four age groups and in cats recruited for degenerative joint disease studies. J Fel Med Surg 16: 465–72 

Monteiro B et al. (2019) Long-term use of non-steroidal anti-inflammatory drugs in cats with chronic kidney disease: from controversy to optimism. J Small Anim Pract. doi:10.1111/jsap.13012 

Schmid VB et al. (2009) In vitro and ex vivo inhibition of COX isoforms by robenacoxib in the cat: a comparative study. J Vet Pharmacol Therap 33: 444–52

Sparkes AH et al. (2010) ISFM and AAFP Consensus Guidelines Long term use of NSAIDs in cats. J Fel Med Surg 12: 521–38

Sparkes AH et al. (2016) ISFM Consensus guidelines on the diagnosis and management of feline chronic kidney disease. J Fel Med Surg 18: 219–39

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Which NSAID? Veterinary Prescriber, August 2018.