Sage Journals: Discover world-class research

Abstract

NSAIDs and cats Non-steroidal anti-inflammatory drugs (NSAIDs) are an important class of drug in feline medicine, having analgesic, anti-inflammatory and antipyretic activity. While most published data on their use in this species relate to short-term (often perioperative) therapy, there is increasing evidence of the value of these drugs in treating chronic pain in cats (for example, that associated with degenerative joint disease), and some NSAIDs have now become licensed for long-term use in cats in some geographies. Most of our knowledge of therapeutic mechanisms or adverse drug reactions associated with NSAIDs is extrapolated from work in other species, and there is a paucity of published data relating to cats.

Guidelines These guidelines have been drawn together by an expert panel, which have reviewed the current literature on long-term NSAID use in cats and other species, and developed guidance on their use based on this information. The aim is to provide practical information for veterinarians to encourage appropriate NSAID therapy whenever cats will benefit from the use of these drugs.

Introduction

Pain in cats has many negative effects, both physiological and emotional.^1,2 It is now accepted that there is no such thing as ‘good pain’ following surgery and during treatment for trauma or disease — eg, pain that inhibits potentially deleterious movement after surgery. Pain delays recovery, impacts negatively on a patient's wellbeing, and disturbs the bond with its owner and also the veterinary team.^1,3

Studies have looked at the use of non-steroidal anti-inflammatory drugs (NSAIDs) for acute, especially perioperative, pain in cats.^4–7 Surveys have shown clinicians were more likely to treat pain in dogs than cats,^8,9 as a result of difficulties in recognising pain, lack of knowledge concerning the use of analgesics, and fear of drug side effects in cats. Less has been published on the management of chronic pain in cats, but it is recognised that signs may be subtle and include withdrawing from attention, decreased mobility, reduced interactions with humans and other animals, poor appetite and aggression.^10–12

Chronic pain can be regarded as pain that has persisted for more than 2–3 weeks, often persists months or years, and may continue beyond the anticipated healing time. Importantly, chronic pain can become dissociated from the inciting cause and be maladaptive, such that the degree of pain does not necessarily correlate with the pathology observed or perceived by the individual, and is not associated with healing.¹² Multimodal analgesia is commonly advocated, but it is becoming evident that NSAIDs will play a key role in managing chronic feline pain, especially musculoskeletal pain, just as they do in humans and dogs.^10,13–16 Until quite recently, while many NSAIDs have been available to treat dogs with degenerative joint disease (DJD),¹⁷ only a restricted range has been licensed for short-term (up to a few days) use in cats. At the time of writing, at least one NSAID — meloxicam — has been licensed for long-term use in cats in many regions of the world, transforming our ability to manage pain in this species, and a second — robenacoxib — has been licensed for up to 6 days of therapy in cats (see Table 1, page 529). There is little doubt that others will become licensed for long-term use in the future, due to the recognition of the need and value for such NSAID therapy in this species.^{10,11,13–15,18}

TABLE 1

NSAIDs licensed for systemic use in cats (NB not all drugs are licensed in all regions and veterinarians should refer to local information and regulations)

Pain delays recovery, impacts negatively on a patient's wellbeing, and disturbs the bond with its owner an also the veterinary team.

Clinicians are aware of their duty to promote animal welfare and relieve suffering, but are also often reminded of Hippocrates' advice to ‘first do no harm’. This is often rightly used to question whether an intervention will actually do more harm than good, and to withhold that intervention when doubts exist. However, we need also to recognise that withholding treatments such as analgesics can sometimes cause the greater harm, because we are no longer addressing the pain and suffering the animal is enduring. In drawing up these guidelines, the international panel of experts' purpose has been to review the current literature on long-term NSAID use in cats, and to provide practical guidance on their use. The overarching aim is to encourage more widespread and appropriate NSAID therapy, when cats will benefit from the use of these drugs. However, most of our knowledge of therapeutic mechanisms or adverse drug reactions is extrapolated from work in other species, as there is a paucity of published data relating to cats.

Common causes of chronic pain and inflammation in cats

One of the difficulties in managing pain in cats is its initial recognition. It is important, therefore, to be aware of common causes of pain and to have a high index of suspicion for signs and behaviours potentially related to pain. If something is painful to us, it is likely to be painful to a cat.

Degenerative joint disease

The most common cause of chronic feline pain is thought to be DJD, and this has been the subject of a number of important studies in the past 10 years.^{11,15,16,18–24} From these studies, it is clear that DJD is very common, with radio graphic changes affecting up to 60–90% of cats (Figs 1 and 2),^18,24 that it affects both the spine and the appendicular joints, and that it occurs especially commonly in older patients.^18,24 The hips, stifle, shoulder, elbow, tarsus and spine are the most common sites affected, although other joints can also be involved. Studies based on radiographic findings have limitations, though, as the changes observed do not necessarily correspond to clinical disease, or the severity of clinical disease and pain. Nevertheless, where clinical disease is present many owners may simply assume a cat is ‘getting old’, and even educated and attentive owners may not necessarily appreciate suffering associated with DJD without veterinary observation and insight.

FIG 1

(a,b) Degenerative joint disease of the elbow in a feline patient

FIG 2

Anteroposterior (a) and lateral (b) radiographs of the hock of a Scottish fold cat with severe osteochondrodysplasia, showing destruction of joint spaces and extensive plantar exostosis. Courtesy of Kim Kendall

In the absence of medical intervention, many cats with DJD suffer pain and discomfort for years, greatly affecting their quality of life and the human/feline bond. It is vital that examinations of the older feline patient should specifically address whether DJD is present, through history and physical examination and, where necessary, radiology and therapeutic trials. Control of bodyweight, exercise and environmental modifications may help cats with DJD, as may other medical therapies. However, the dramatic responses reported to NSAIDs^13,21,23 indicate that there is a huge scope for safe, effective long-term NSAID therapy in the large cohort of aged cats with DJD (Fig 3).

FIG 3

Watson, a DJD sufferer, enjoying the benefits of daily NSAID treatment

Other diseases

There are many other feline diseases where control of protracted inflammation and pain is important. These include various cancers (Fig 4a), particularly where definitive treatment is not possible, or in some cases for the anti-neoplastic effect NSAIDs may offer.^25–28 Other common conditions associated with chronic pain where NSAIDs may form part of therapy include trauma, lymphoplasmacytic gingivostomatitis (Fig 5),²⁹ idiopathic cystitis,^30,31 skin disease and uveitis (Fig 6). In the last, both topical and/or systemic NSAID therapy may be valuable.³² Through their antipyretic effect, control of fever with NSAIDs may also be valuable in some situations. A short therapeutic trial of an NSAID without a definitive diagnosis may sometimes be appropriate, using the response to treatment as a guide to diagnosis and further therapy. Informed client consent and close monitoring of the patient is mandatory, especially in such cases.

FIG 4

Transitional carcinoma of the bladder (a) and multifocal osteomyelitic bone lesions (b) in two feline patients. The tumour in the first cat was debulked surgically and the cat then received piroxicam; the second cat was given meloxicam in addition to antibiotics. Courtesy of Randolph Baral (a) and Emma Hughes (b)

FIG 5

(a-c) Severe and painful ulcerative and proliferative gingivostomatitis in three cats. (c) Courtesy of Alberto Barneto

FIG 6

Uveitis in a cat with toxoplasmosis. Courtesy of Carolyn O'Brien

If something is painful to us, it is likely to be painful to a cat.

NSAIDs and cyclo-oxygenase/lipoxygenase inhibition

The therapeutic benefits of NSAIDs include their antipyretic, analgesic and anti-inflammatory actions. They exert these effects mostly through inhibiting the production of prostaglandins (PGs) and leukotrienes (LTs) by the cyclo-oxygenase (COX) and 5-lipoxygenase (5-LOX) enzymes, respectively.^33–35 Most NSAIDs primarily inhibit the activity of COX enzymes. Although some also inhibit LOX enzymes, for currently licensed feline drugs this is generally short-lived in comparison with COX inhibition, and evidence of additional clinical efficacy from this is lacking. More effective dual COX/LOX inhibitors may become available in the future.^36–38

Two distinct COX isoforms (COX-1 and COX-2) have been identified as being responsible for the production of prostaglandins (Fig 7).³⁵ A third isoform has also been identified, initially known as COX-3, now described as a splice-variant of COX-1, which seems to have a role in the central control of pain.³⁸ Phospholipase A₂ is the rate-limiting enzyme that initiates the COX pathway by liberating arachidonic acid (AA) from membrane-bound phospholipids. Both COX isoforms are then responsible for converting AA to PGG₂ and PGH₂ via identical enzymatic reactions. Following these initial steps, PGH₂ functions as an intermediate substrate for the biosynthesis, by specific synthases and isomerases, of prostaglandins, prostacyclin and throm-boxanes. COX-1 converts AA to a range of molecules, including thromboxanes (TX), such as thromboxane A₂ (TXA₂), and prostaglandins, such as PGD₂, PGE₂ and PGF₂, and prostacyclin (PGI₂). COX-2 activity produces a narrower spectrum of prostaglandins, specifically PGE₂, and prostacyclin.

FIG 7

Overview of the role of COX and LOX in prostanoid production

The prostaglandins play a major role in many aspects of normal physiology, including vascular homeostasis, gastroprotection, renal development and blood flow, blood clotting, reproduction, bone metabolism, wound healing, nerve development and growth, and immune responses. They are also involved in pathophysiological processes, including pain and inflammation, and cancer progression. However, much of our knowledge is extrapolated from other species, as there is a paucity of feline-specific data.

Expression of COX enzymes

Both COX-1 and COX-2 are enzymes that are constitutively expressed (normally present in tissues and at fairly constant concentrations), as well as induced (appear and/or increase in concentration in response to an inciting factor, often associated with inflammation). COX-1 is considered as predominantly constitutive, being expressed in almost all tissues, and involved in the production of prostaglandins responsible for ‘house-keeping’ functions, such as the cytoprotective effects in the gastric mucosa, normal platelet function and maintenance of renal perfusion.³⁹ Constitutive expression of COX-2 appears to be more restricted,^39,40 although it is present, along with COX-1, in the central nervous system, kidney, vascular endothelium, reproductive tract and gastrointestinal (GI) tract — sites where COX-2 activity contributes to homeostatic functions.^35,41 It appears that COX-2 has an important role in healing damaged mucosa in the GI tract, and although COX-2 has been shown to be constitutively expressed in the canine GI tract,^42,43 information on cats is lacking.

While COX-1 is the predominant constitutively produced enzyme, COX-2 is predominantly inducible and its production is dramatically upregulated during inflammation, in which it plays a central role.⁴⁴ The expression of COX-2 may also be upregulated in certain neoplasms, and in cats variable expression has been reported in transitional cell carcinomas, squamous cell carcinomas, mammary carcinomas and pancreatic carcinomas.^{25–28,45–47} However, just as COX-2 has some constitutive expression, COX-1 expression also has a role to play in the inflammatory response.^39,40

COX and LOX selectivity, and NSAID adverse effects

Inhibition of COX-1, the enzyme predominantly associated with homeostatic functions, is reported to be the cause of most NSAID-induced side effects such as gastric ulcers and blood dyscrasias. In an attempt to avoid this, NSAIDs with a greater propensity to suppress COX-2 than COX-1, so-called ‘COX-2 preferential’ (or ‘COX-1 sparing’) NSAIDs, have been developed. Drugs that have negligible effect on COX-1 have been termed ‘COX-2 selective’ rather than ‘preferential’, although there is no recognised precise definition of these terms.⁴⁸

However, it rapidly became evident from human studies that COX-2 preferential or selective NSAIDs, while reducing some of the side effects classically associated with COX-1 inhibition, still caused adverse events such as acute renal failure, thromboembolic disease and gastric ulceration,^49,50 consistent with a physiological role for COX-2 in a number of tissues. For example, both COX-1 and COX-2 are expressed in mammalian kidneys. They are found within different cells of the kidney (macula densa, cortical ascending tubule, medullary interstitial cells), and play different roles, but both are important to preserve renal function during hypovolaemia.⁵⁰ Additionally, the inhibition of COX has been postulated to be associated with an increase in LOX activity, which can result in adverse effects on the GI mucosa. Furthermore, it has been suggested that dual inhibitors may be associated with fewer GI adverse effects than COX-1 or COX-2 inhibitors.

Although the COX/LOX selectivity of an NSAID may be important, this does not negate all potential side effects, and indeed evaluation of COX/LOX selectivity is not the only factor to consider when trying to predict the safety of an NSAID.

There are several other issues to consider. Firstly, the risks of adverse events can be affected by tissue concentrations of the drug — where the extracellular fluid is of a lower pH than the intracellular fluid, ‘ion trapping’ of weakly acidic drugs, such as most NSAIDs, can occur with accumulation of the drug within cells (eg, the gastric mucosa).⁵¹ The extent to which this occurs will vary between drugs but this local accumulation can affect the prevalence of side effects.

Secondly, differences are recognised between species in both the expression and distribution of the COX enzymes.^52–55 Very little feline-specific data are available, but there could be differences in susceptibility to adverse events as a result of such differences in cats.

Thirdly, there are substantial variations in the reported COX selectivity of an NSAID based on the type of in vitro assay used to measure COX-1 and COX-2 activity. These results vary depending on the species used to source the material for the assay; and, even when the assay is performed in tissue from the target species, different assays yield different results.^36,38,56 Additionally, differences in metabolism of drugs between species can result in differing selectivity. In the dog, tepoxalin is a dual inhibitor for a short period of time only; but, in the cat, tepoxalin pharmacokinetics indicate it is potentially a balanced COX and LOX inhibitor throughout its kinetic profile.³⁸

Other factors also affect the risk of adverse events — for example, age. Older humans are recognised to be at greatest risk of GI ulceration; and in human medicine pre-existing renal insufficiency, cardiovascular disease and hepatic disease are all relative contraindications for use of NSAIDs. However, management of pain in the geriatric patient becomes critical to quality of life. Therefore, careful selection of NSAIDs and their dose, and the use of adjunctive therapies (such as proton pump inhibitors to assist gastroprotection, other analgesics to modulate other parts of the pain pathway and reduce the required NSAID dose, and fluid therapy to minimise effects of hypovolaemia), must be considered rather than simply avoiding addressing pain in both humans^57–60 and veterinary species.⁶¹ Patient selection, dose titration and ongoing monitoring for the early signs of toxicity are essential.^62,63

Panel recommendations

COX-2 selectivity

In keeping with other species, studies of NSAIDs in cats suggest no difference in anti-inflammatory or analgesic efficacy between COX non-selective drugs and variably COX-2 selective inhibitors.

It is presumed, as in other species, that using drugs with a greater COX-2 selectivity in cats will help avoid some of the potential adverse effects associated with COX-1 suppression, such as GI irritation/ulceration and platelet inhibition. However, selective COX-2 inhibition will not completely negate the possibility of adverse effects and may not confer any renoprotective effect in comparison with a non-selective inhibitor.

It is presumed that dual inhibition of COX and LOX may be associated with reduced GI adverse effects over COX inhibition alone. However, it is unlikely that dual inhibition will completely negate the possibility of adverse effects.

What does this mean for cats?

Because of species differences in expression of COX enzymes and in the in vitro COX selectivity assays, it is imprudent to generalise results from any single study.⁶⁴ With all these variables, it is not surprising that there is no simple answer to the question of whether a COX selective or a dual COX/LOX inhibitor is better, and indeed what the ‘ideal’ COX/LOX selectivity and profile of an NSAID is in the cat. It may indeed depend on the disease process and the individual being treated. Despite these caveats, and given the paucity of feline-specific data at present, we can only cautiously extrapolate knowledge based on data from other species.

Practical NSAID therapy in cats

Beyond the question of COX selectivity, many other factors are also important in choosing and using NSAIDs for long-term therapy in cats.

Compliance

Administering medication to cats can be challenging for owners, yet adequate therapy relies on good owner compliance. Along with NSAIDs, many cats will be receiving other medications and the ‘administration burden’ may be daunting for owners, leading to inconsistent dosing. To help long-term use, a drug should ideally be highly palatable and taken voluntarily by the cat — for example, in food or as a treat — and veterinary pharmaceutical companies undertake much research into this.⁶⁵ Published studies suggest meloxicam liquid is highly palatable in cats,^13,16 with one study suggesting it was significantly more palatable than ketoprofen tablets.¹⁶ Other drugs may be compounded in specific flavours that are appealing to individual cats. However, it is important to follow all regulations and compliance policies for drug com-pounding,⁶⁶ which are different throughout the world, and to consider the potential effect of compounding on bioavailability and stability/shelf-life.

Additionally, owners must be consistent and remember to administer the drug. Based on the long duration of action of many NSAIDs in cats, this should be at a set time on treatment days. Creative reminder systems may help ensure cats receive medication on the correct day(s), at the correct time(s) and at the correct dose. Giving medication along with a daily food ration (which should also be done for safety) can provide a built-in reminder system for owners, and encourage owner involvement in the monitoring process.

Dosing — intervals, frequency, timing and the ‘lowest effective dose’

Short-term pharmacokinetic data are available for a number of NSAIDs in cats, which form a basis for dosing intervals. While many NSAIDs are metabolised via glucuronidation in the liver, and the relative deficiency of glucuronyl transferase enzymes in cats may lead to a prolonged half-life for some of these drugs,^37,56 others, such as piroxicam and meloxicam,^56,67 are metabolised by oxidation. Single doses of many approved/licensed NSAIDs for acute pain in cats seem to have a duration of action of around 18–20 h.⁵⁶ However, it is not known if such prolonged pharmacokinetics are necessary for appropriate efficacy. For example, meloxicam and robenacoxib have a serum half-life of approximately 24 and 2 h, respectively,^68,69 yet both have been shown to be effective for daily treatment of musculoskeletal pain in cats by virtue of their European licences.

For most of the NSAIDs used in cats, it is not known if repeated long-term dosing alters the pharmacokinetics or pharmacodynamics of the drug. In one study, the administration of flunixin daily for 7 days appeared to result in more rapid metabolism of the drug after 7 days and decreased pharmacodynamic effects,⁷⁰ although the same did not appear to be evident during daily administration of meloxicam for 7 days.⁶⁸ Additionally, information on the apparent efficacy of daily versus every-other-day or less frequent dosing is anecdotal, with no controlled studies yet published. Daily dosing of meloxicam at less than the labelled dose for a mean of 5.8 months was considered to be clinically effective and associated with minimal adverse effects in one non-blinded study,¹³ although efficacy was not measured objectively or with a validated assessment system. However, due to the inter-cat variability of pharmacokinetics with administration of a variety of NSAIDs, it is likely that daily dosing may be appropriate for some cats, while longer intervals might be appropriate for others.

Unfortunately there is no practical way to determine which cats might be ‘fast’ metabolisers and which slower. Additionally, probably as a result of their high protein-binding, which may enable NSAIDs to persist in inflamed tissue sites for longer than in plasma, the anti-inflammatory and analgesic activity of these drugs often persists longer than would be predicted from their serum half-life. This may enable daily dosing even for drugs with a relatively short half-life.^38,69 Indeed persistence at the site of inflammation has been demonstrated in an experimental study of robenacoxib in cats.⁶⁷ It is, therefore, unlikely that a set mg/kg dose and dosing schedule will work equally well for all cats; furthermore, variations in the level of pain may alter the cat's needs over time.

Very little attention has been given to the best time of day to administer NSAIDs to cats to achieve the most beneficial effect, a concept termed chronotherapy.⁷¹ Theoretically, long-term dosing may result in a pharmacokinetic and pharmacodynamic steady-state. However, ‘peaks and troughs’ may still occur. If the peak beneficial effect on lameness occurs at say 5 h after dosing, treatment may be tailored to achieve maximum clinical effect when the cat is most active. The timing, therefore, may depend on a cat's lifestyle. Alternatively, an owner may find that at ‘peak effect’ the cat is more comfortable, it rests for longer and may choose to administer the drug to promote resting and sleeping at the most suitable time for the household.

Panel recommendations

Dosing frequency

To avoid potential side effects, owners should be encouraged to work on titrating to the ‘lowest effective dose’ that works for their cat, with the understanding that this may change over time. This dose may often be less than the labelled dose.^13,14,21

In overweight or obese cats, it is prudent to calculate initial doses for NSAIDs according to their lean or ideal bodyweight.

When attempting to reduce the overall dose of an NSAID, it would seem prudent to reduce the label dose but maintain the label frequency, where possible.

The panel recognise that intermittent therapy, for example 2–3 times weekly rather than daily, is better than no therapy at all, and anecdotally appears efficacious in some cats. However, there may be a risk of significant periods of time when no effective therapy, or suboptimal therapy, is being achieved.

Intermittent drug withdrawal, a reduced frequency of dosing, or a reduction of the dose may all help owners to assess drug efficacy.

The panel see little rationale for pulse therapy with NSAIDs unless the underlying disease process varies sufficiently in severity that it does not require consistent analgesic/anti-inflammatory therapy.

Dosing — accuracy

Dosing accuracy will depend on the formulation of the drug. Liquids are more easily measured, and can be delivered in small volumes. Thus incremental increases or decreases in dose are potentially more readily achieved. However, differing dispensing methods can potentially result in wide variations in doses. Tablets or caplets are not always easy to divide and therefore delivering a small dose may be problematic and inaccurate. Intact tablets will provide a different dose to cats of different weights, which may not be a problem when the drug is licensed for a dose range, as for example robenacoxib, but may be a problem if a very precise target dose is required. Repeat subcutaneous injections may be another option in some cats and with some owners, although no NSAIDs are currently licensed for long-term use by this route.

Treatment may be tailored to achieve maximum clinical effect when the cat is most active. Alternatively, an owner may choose to administer the drug to promote resting and sleeping at the most suitable time for the household.

Panel recommendations

Dosing accuracy X

Liquid formulations will provide for the most accurate dosing and dose adjustment of NSAIDs in cats; and manufacturers are encouraged to explore this route of delivery.

The use of a dedicated and clearly marked syringe for administration of the liquid (Fig 8) should be encouraged to prevent accidental administration of excess drug when it is administered directly from a storage container.

FIG 8

Use of a dedicated dosing syringe is advisable

Dosing — switching drugs

There is little objective data available on the best way to transition therapy from one NSAID to another, and feline-specific information is lacking. There is concern about changing from aspirin to another NSAID in other species due to COX-2 dependent adaptive mechanisms that may occur during therapy.^38,61 However, there is uncertainty about the need for or timing of any ‘washout’ period with other NSAIDs.^38,61

Panel recommendations

Switching between NSAIDs

As a precaution, a ‘washout’ period of approximately 7–10 days should be used when switching from aspirin to another NSAID.

A sensible precaution may be to allow a washout period of 3–5 days when switching between other NSAIDs, and potentially longer if the previous NSAID had a prolonged half-life. Additional adjuvant therapy with other analgesics should be considered if required during this time.

Monitoring efficacy

There is no validated assessment tool for acute or chronic feline pain, although studies are ongoing.⁷² In studies evaluating the efficacy of NSAIDs in cats with musculoskeletal pain, improved mobility, and in particular the willingness to jump and the height of the jump, have been the most obvious signs of improvement,^13,21 and another study found increases in mobility with administration of an NSAID.¹⁵ One key feature of chronic pain assessment is owner involvement and observation, especially as pain may manifest in different ways in individual cats.^56,73 It has been postulated that four behavioural domains — mobility, activity, grooming and temperament — are particularly useful to both clinicians and owners in assessing chronic musculoskeletal pain and monitoring the response to therapy.²³

When treating animals with long-term diseases, an overall assessment of ‘quality of life’ may be beneficial; this includes, but is not limited to, pain. An assessment tool may need to be individually designed since what is important to each patient will be different: can the cat climb trees, hunt, play with other pets in the household, and so on?¹⁵ This was the thinking behind the use of client-specific outcome measures in a recent study.¹⁵ Owners should keep a regular journal or diary of the cat's activities, as changes in mobility and behaviour may be subtle and occur slowly. The owner is the best person to judge and track the cat's behaviour and demeanour. It may only be obvious from consulting the ‘diary’ that a change in treatment is needed.

A key feature of chronic pain assessment is owner involvement and observation.

NSAIDs and concomitant disease

Renal disease

Prostaglandins play an important role in mammalian renal physiology, helping to autoregulate vascular tone, glomerular filtration rate (GFR), renin production and sodium/water balance. When renal haemodynamics are normal, prostaglandins appear to have a minimal role. In keeping with this, a recent study evaluating the effect of 5-day therapy with meloxicam in healthy adult cats showed no alteration in GFR based on iohexol clearance studies,⁷⁴ and similarly in healthy cats undergoing anaesthesia there is evidence of its safety when standard care is taken to avoid hypovolaemia and hypotension.⁵ Under conditions of low effective renal blood flow, however, prostaglandins become crucial in maintaining renal function and GFR. Prostaglandin inhibition by NSAIDs may reduce renal blood flow and GFR and can result in the potential complication of acute kidney failure (AKF) in humans.⁷⁵

Both COX-1 and COX-2 enzymes appear to be important in maintaining renal function, but their relative importance and physiological role may differ between species;^56,74 for example, a recent immunohistochemistry study demonstrated greater COX-2 expression in the kidneys of dogs with chronic renal disease than in cats.⁵⁵ These observations suggest that the propensity for NSAIDs to cause AKF may vary between species. In humans, the risk of AKF is regarded as low, and can occur with both non-selective and COX-2 selective NSAIDs, although the risk may vary between individual agents.^50,75–79 In general, the risks for NSAID-induced AKF in humans are higher with conditions causing renal hypoperfusion (eg, dehydration, hypovolaemia, congestive heart failure), with old age (occult renal disease) and pre-existing renal disease, with concomitant drug therapy (eg, diuretics, angiotensin converting enzyme inhibitors [ACEIs]) and with higher doses of NSAIDs. The resultant AKF is usually reversible, provided it is detected in time.^{50,63,76,77,79–81} The use of NSAIDs also carries a small risk of inducing hyperkalaemia in human patients, which is higher in those with existing renal disease and those on potassium supplements.^50,57,75

In human medicine, the role of NSAIDs in chronic kidney disease (CKD) is much less clear. While some studies have suggested that NSAIDs may be a risk factor for developing CKD (so-called ‘analgesic nephropathy’),^82–84 or in the progression of existing CKD,⁸⁵ others have found no evidence of a causal association,^86,87 and the difficulties in interpreting trial data have been highlighted.⁸⁸ Where studies have suggested a link between CKD and NSAID use, the risk appears to be low, and may be exacerbated by heavy use of one or more NSAIDs.^85,88,89

Two retrospective studies evaluated the safety of NSAIDs in a total of 76 older cats, including some cats with stable CKD. In both studies, cats received oral meloxicam (approximately 0.02 mg/kg/day) on a long-term basis for osteoarthritis. One study included three cats with International Renal Interest Society (IRIS) stage 3 CKD⁹⁰ and an additional 10 cats without CKD that had serum creatinine concentrations monitored,¹³ and the other included 22 cats with IRIS stage 1–3 CKD.¹⁴ Neither study showed any significant difference in the development or progression of renal dysfunction in treated cats, compared with age- and disease-matched controls, over an average period of 6 months¹³ or more than 1 year.¹⁴ Another study evaluated 73 cats that received oral piroxicam at an average dose of 0.2–0.3 mg/kg/day for between 1 and 38 months. In that study, no significant changes were seen in serum renal or hepatic parameters within the first month of therapy in 43 cats that had follow-up samples collected.⁹¹ During prolonged therapy, five cases of renal insufficiency were detected in 58 cats receiving piroxicam, but as other therapies were being received, as the cats had underlying neoplasia, and as they were an older population without any controls, it was impossible to know if any of these were related directly to piroxicam therapy.⁹¹ It has been demonstrated that cats with CKD have higher circulating levels of gastrin⁹² and, as such, these cats may be at increased risk of GI adverse effects when NSAIDs are used.

Panel recommendations

Renal disease

Based on data from cats and other species, the risk of AKF developing during appropriate therapeutic NSAID use in cats is low and not abrogated by the use of COX-selective agents.

Monitoring serum renal analytes and urine parameters before and after commencement of NSAID therapy is highly recommended as a precaution, in an attempt to recognise AKF at an early stage should it occur (see section on monitoring).

Risk factors for renal toxicity in humans are presumed to apply to cats. Where an increased risk of renal toxicity is anticipated the lowest effective dose should always be administered (which may be facilitated by the use of adjuvant analgesic therapy) and increased monitoring is prudent.

NSAIDs should be administered with food, and therapy withheld if food is not eaten — see recommendations for GI disease. In cats predisposed to dehydration, such as with CKD, using a wet rather than dry diet is a sensible precaution to optimise water intake.

Specific risk factors, such as dehydration and hypovolaemia, should always be addressed before therapy is administered, and if analgesia is required in the interim period an alternative such as an opioid can be utilised. Care should be taken to ensure good renal perfusion is also maintained if anaesthesia is required during therapy.

Current data suggest that at least some NSAIDs can be used safely in cats with stable CKD at judicious doses, and that this should not be a reason for withholding analgesic therapy when it is indicated. Further data, particularly in cats with advanced renal disease, would be valuable and such pharmacovigilance studies are vital.

The combination of cardiac disease and renal disease is problematic — care is urged with the use of NSAIDs in this situation due to the increased risks of AKF. The exploration of analgesic options other than NSAIDs may be prudent, but the potential risks of exacerbating these diseases should not restrict the use of analgesic therapy where it is needed.

As there is a risk of hyperkalaemia developing during NSAID therapy in other species, especially in the face of renal failure or potassium supplementation, potassium monitoring is recommended during therapy.

Gastrointestinal disease

Because of the physiological role of COX in maintaining the normal gastric mucosal barrier, upper GI bleeding has been the most common serious complication associated with NSAID use in humans. Indeed, the GI tract has been considered the major site for NSAID toxicity in both humans and animals, including cats.^{13,16,21,48,57,93} In one study of the long-term use of piroxicam in 73 cats with neoplasia,⁹¹ vomiting was the most commonly reported adverse effect (occurring in 16% in the first month), although there was evidence that other therapies (eg, chemotherapeutic agents) contributed to the reported prevalence. During long-term use of oral meloxicam at a dose of 0.1 mg/cat, vomiting was reported in 2/46 cats (4%).¹⁴ Direct topical injury to the GI mucosa may also occur and contribute to adverse GI effects.^38,59 Although studies in cats are lacking, in humans and other species, COX-1 has a major role in maintaining the mucosal integrity. However, COX-2 expression is also thought to be important, especially for repair of injured mucosa.^48,49,94,95

Factors that have been recognised as increasing the risks of GI adverse events in humans include higher doses of NSAIDs, the specific NSAID used, increased age, previous NSAID-associated GI disease, liver disease, pre-existing GI ulcers, and concurrent anti coagulant or glucocorticoid use.^57,59,63,77 Some of these risk factors have also been noted in dogs.³⁸ In humans, the two main strategies to prevent GI adverse events with NSAIDs are to use COX-1 sparing drugs, and/or a combination of an NSAID and a mucosal protectant such as a prostaglandin analogue (eg, misoprostol) or a proton-pump inhibitor (eg, omeprazole).^{49,57,59,62,63,77} In cats, NSAID-associated gastric and intestinal ulceration and perforation is recognised and, in the current absence of species-specific studies, data from humans are considered relevant.⁵⁶

Panel recommendations.

Cardiovascular disease

The risks of NSAID therapy in feline cardiovascular disease are unknown.

The panel recommend that, based on human studies, hypertensive cats receiving NSAID therapy should have their blood pressure monitored regularly. Patients with congestive heart failure should also be monitored carefully, and the NSAID use should be titrated to the lowest effective dose.

Given the relatively high prevalence of thromboembolic disease in cats, whether long-term use of highly selective COX-2 inhibitors might increase this risk, as has been recognised in humans, deserves further investigation.

Panel recommendations

Gastrointestinal disease

It is assumed that, as in other species, COX-1 sparing NSAIDs may have a better safety profile than non-selective agents. As GI pain and discomfort may be difficult to detect clinically, the panel recommend the routine use of COX-1 sparing NSAIDs for long-term therapy in cats.

NSAIDs should routinely be given with, or after, food in cats. Inappetence or anorexia may be an early sign of adverse GI events; hence withholding therapy in an inappetent patient is prudent. Furthermore, inappetent or anorexic cats are far more likely to become dehydrated, which would increase the risks of renal adverse events if therapy were to be continued.

Cardiovascular disease

Inhibition of COX activity by NSAIDs can have a number of potential adverse cardiovascular effects in humans. These are uncommon or rare, but include occasional exacerbation of congestive heart failure (CHF) and/or hypertension due to water and salt retention mediated by COX-1 and COX-2 suppression in the kidneys; reduced platelet aggregation and bleeding as a result of inhibition of COX-1 mediated platelet thromboxane production; and thromboembolic disease due to inhibition of COX-2 mediated endothelial prostacyclin production.^77,96–98 While ex vivo inhibition of platelet thromboxane has been demonstrated for a number of NSAIDs in cats, studies have not been able to demonstrate a clinically beneficial effect in preventing thromboembolic disease, or in promoting unwanted bleeding.^56,99 Currently, there are no data on the potential effects of NSAID therapy on blood pressure or CHF in cats, or on whether COX-2 selective agents may have a prothrombotic effect in certain individuals, such as those with a propensity to develop thromboembolism.

Liver disease

In humans, NSAID-induced hepatotoxicity is an uncommon or rare event. It is regarded as an idiosyncratic reaction mediated by hyper-sensitivity or a metabolic aberration, possibly as a result of genetic polymorphism, although with salicylates it has a predictable dose-dependent occurrence.^77,100,101 The risk of this may be higher in patients receiving other potentially hepatotoxic drugs and varies between different NSAIDs, with toxicity usually developing within the first 6–12 weeks of therapy.^100–102 Idiosyncratic hepatotoxicity has also been reported in dogs receiving NSAIDs.¹⁰³

Severe hepatotoxicity following clinical use of NSAIDs has not been reported in cats, although this may simply reflect the lower prevalence of NSAID prescribing in this species.⁵⁶ Although NSAIDs are metabolised by the liver, pre-existing liver disease does not appear to predispose to NSAID-induced hepatotoxicity.³⁸ As drug metabolising pathways are often well preserved in liver disease, withholding NSAID therapy in such patients may not necessarily be required without evidence of significant liver dysfunction,³⁸ although reducing doses in severe/advanced liver disease is recommended in humans.¹⁰⁴ In humans, pre-existing advanced liver disease may be a risk factor for NSAID-associated renal and GI adverse events.^63,81

NSAIDs and concomitant drug therapy

Glucocorticoids

Concomitant use of glucocorticoids and NSAIDs carries a well-characterised increased risk for adverse GI events in humans and dogs,^38,56 with an estimated 2- to 15-fold greater risk for peptic ulcer disease in humans.^59,63

Panel recommendations

Concurrent drug therapy

The panel recommend that concurrent use of NSAIDs and glucocorticoids should be avoided whenever possible. For short-acting glucocorticoids, a ‘washout’ period of around 5 days may be appropriate before starting an NSAID,⁶¹ but longer times should be given when long-acting steroids have been used.

Because NSAIDs are highly protein-bound and have the potential to displace other protein-bound drugs, concurrent use of protein-bound drugs with a low margin of safety, such as warfarin, digoxin, anticonvulsants such as phenobarbitone, and chemotherapeutic agents, should be pursued with great care, if at all.

Based on data from other species, it is likely that the concomitant use of ACEIs and/or diuretics with NSAIDs will increase the risk of renal adverse effects. Appropriate care is needed if using such combinations, with increased monitoring and the use of the lowest effective NSAID dose. The use of analgesics such as opioids should be explored as alternatives to NSAIDs, or to help minimise the dose of NSAIDs required.

Panel recommendations

Liver disease

Due to the rare potential for NSAIDs to cause hepatotoxicity in other species, routine biochemical monitoring, including liver enzymes, of cats receiving long-term NSAID therapy is recommended.

Dose-reduction (titration) should be considered in cats with pre-existing liver disease. In the presence of severe liver dysfunction (eg, as evidenced by moderate to severely elevated bile acids), and/or hypoalbuminaemia (of any cause), NSAIDs should be used with extreme caution, if at all.

Angiotensin converting enzyme inhibitors and diuretics

The use of ACEIs (and/or angiotensin receptor antagonists) and/or diuretics along with an NSAID carries a well-recognised risk for development of acute NSAID-associated renal adverse events in humans,^63,75,81,105 and there is evidence of a higher risk when all three drugs are used together.¹⁰⁵ Both ACEIs and NSAIDs may individually result in altered renal haemodynamics and reduced GFR, thus together the risk may be compounded, and the use of diuretics may lead to volume depletion and a greater renal dependence on prostaglandins to maintain GFR.¹⁰⁵

Anticoagulants

Although COX-1 inhibiting NSAIDs may suppress platelet thromboxane production and reduce platelet aggregation, clinically significant bleeding as a result of this is rare in humans and, to date, has not been reported in cats.^56,61,63 However, NSAIDs may appreciably potentiate the effect of warfarin, and other highly protein-bound drugs, through competitive protein binding⁶³ and the use of these drugs together should be avoided.

Monitoring cats receiving long-term NSAID therapy

Adverse drug events (ADEs) related to NSAID use most commonly affect the GI system, liver, kidneys and platelet function, but lessons learned from the long-term use of these agents in dogs suggest that this class of drug is often used inappropriately and without screening and monitoring.¹⁰⁶

While the need for, and benefit of, NSAID therapy in many situations is clear, screening and monitoring is important for the clinician, owner and patient, to help minimise the likelihood of ADEs occurring. Until further data become available, especially from pharmacovigilance studies, suggested protocols for screening and monitoring cats on long-term NSAID therapy have to be based on a knowledge of the use of these drugs in both animals and humans, and it is important that protocols are adapted to the individual needs of the patient.

Testing and screening before treatment

Thorough patient evaluation before commencing therapy is crucial, with a view to identifying concurrent conditions or therapies that may impact on NSAID administration, and allowing informed client consent to be obtained.

Panel recommendations

Screening before therapy

A thorough history and physical examination is mandatory in all cats prior to commencement of NSAID therapy, paying particular attention to conditions and therapies that may impact on NSAID therapy. Wherever possible this should include blood pressure measurement (Fig 9).

Ideally, the physical examination should be accompanied by laboratory testing. Laboratory evaluation should focus on the renal and hepatic systems, along with plasma proteins and haematocrit (see Table 2). The latter parameters may be surrogate markers of GI bleeding and/or mucosal damage. This aids in identifying potential problems and establishes a baseline for later comparison.

Abnormalities identified in the clinical examination and on laboratory testing do not necessarily preclude the use of NSAIDs, but the risks and benefits of embarking on therapy must be discussed with the owner, and concurrent diseases may affect subsequent monitoring recommendations.

FIG 9

Blood pressure measurement should ideally be performed as a screening measure before NSAID therapy in cats

Screening during treatment

In dogs, most NSAID-related ADEs occur between 14 and 30 days (range 3–90) after the start of treatment.¹⁰⁷ However, it is recognised that the time for an ADE to develop is extremely variable, probably being dependent on the individual drug, the dose and the individual patient. In humans, hepatotoxicity is usually reported within the first 6 months of therapy, with more than 60% of cases reported in the first 3 months,¹⁰² whereas acute renal failure is usually reported early, often within the first few days or weeks of commencing drug administration.⁷⁸

Based on appropriate use of NSAIDs in other species, the prevalence of ADEs is low in healthy patients. However, the frequency of certain ADEs increases in some patient groups, and these can therefore be classified as having a ‘higher’ or ‘lower’ risk. This approach enables treatment and monitoring plans to be adjusted according to perceived risks.^{57,59,60,62,63,81} Critically, ADEs are typically reversible with prompt recognition and intervention. Categorising patients as having a higher or lower risk of ADEs has clear benefits and should be equally applicable to cats, although at present this has to be based largely on knowledge of ADEs in other species, due to the lack of feline-specific data.

Adverse drug effects are typically reversible with prompt recognition and intervention.

Panel recommendations

Classification of patients

Clinical recognition of patients that may have an increased risk of an ADE relating to NSAID therapy is important — not necessarily to avoid therapy, but to encourage more cautious dosing and increased relevant monitoring. Based primarily on experience in human medicine, the panel cautiously suggest that more vigilant monitoring may be required in the following situations:

An increased risk of renal ADEs may be anticipated in cats with functional volume depletion (renal hypoperfusion, including that associated with hypotension during anaesthesia); older cats (eg, >8–10 years of age); cats with concurrent cardiovascular, renal or hepatic disease; and cats receiving concurrent therapy with ACEIs, diuretics and β-blockers. As in humans, there may be a greater risk of NSAID-induced hyperkalaemia in patients receiving potassium supplements.

An increased risk of GI ADEs may be anticipated in cats that are older; have had a previous history of NSAID-induced GI signs; have renal disease; are receiving glucocorticoid or anticoagulant therapy; have a history of GI disease; or have concurrent liver or other serious disease.

An increased risk of hepatic ADEs may be anticipated in cats that are older; have renal disease; or are receiving multiple drug therapies.

An increased risk of cardiovascular ADEs may be anticipated in cats that are older; have hypertension; or have pre-existing renal or cardiac disease. Particular care should be taken with unstable disease such as congestive heart failure or thromboembolic disease.

The panel recommend that, where NSAIDs are used in patients with perceived higher risks of developing ADEs, greater care is taken, efforts are made to use the lowest effective dose, and increased monitoring is undertaken (see Table 2).

TABLE 2

Suggested monitoring of cats on long-term NSAID therapy

Parameter		Always required	Suggested minimum	Ideal if possible
Review history with owner		✓	✓	✓
Full clinical examination (including blood pressure measurement wherever possible)		✓	✓	✓
Haematology	Haematocrit		✓
	Complete blood count		✓
Serum chemistry	Total protein, albumin		✓
	Urea		✓	✓
	Creatinine		✓	✓
	ALT, ALP		✓	✓
	AST, GGT, bile acids			✓
	Na, K			✓
Urinalysis	Specific gravity		✓	✓
	‘Dipstick’ biochemisty		✓	✓
	Protein:creatinine ratio			✓
	Sediment analysis			✓

Panel recommendations

Monitoring during therapy

Monitoring should take place routinely while cats are on NSAID therapy (Table 2), but the panel recognise that the extent of monitoring will be affected by many factors, including the presumed risk for the individual patient, financial constraints and owner compliance. Furthermore, multiple visits to the veterinary clinic can be stressful for some cats. Any recommendations have to be adjusted to individual situations.

Involvement of owners in monitoring therapy is crucial. Owners need to be made aware of signs that should prompt cessation of therapy and/or the need for veterinary advice. Ideally a client leaflet, such as the one that accompanies these guidelines (Fig 10), or one supplied by the drug manufacturer, should be used to reinforce such information.

To reduce the potential for ADEs, the panel suggest that NSAID therapy is always given with or after food. If the cat does not eat then therapy should be withheld.

An initial reassessment of all cats is recommended after the first 5–7 days of therapy, and sooner if there is concern. Although rare, acute renal failure can be life threatening and can be seen within the first few days of therapy. In some cases a telephone conversation with the owner may suffice.

A routine re-evaluation of all cats (Table 2) is recommended after the first 2–4 weeks of NSAID therapy. Thereafter, the frequency of re-evaluation should be based on perceived risks and patient characteristics.

For ‘lower risk’ patients, the panel recommend that a re-evaluation (Table 2) should generally take place at least every 6 months.

For ‘higher risk’ patients, the panel recommend that re-evaluation (Table 2) should generally take place every 2–6 months, depending on the perceived risks.

The potential risk of ADEs is a dynamic process, and at each visit the veterinarian should reassess the patient status based on the history, physical examination ± laboratory data and determine the most appropriate ongoing monitoring.

FIG 10

Client leaflet advising on safe use of NSAIDs. The leaflet may be downloaded from www.isfm.net/toolbox and www.catvets.com/professionals/guidelines/publications

Adverse events and adverse event reporting (pharmacovigilance)

If ADEs are encountered or undesirable effects are seen, these should be managed as appropriate. If adverse GI events are observed, NSAID therapy should be withheld, and appropriate supportive therapy introduced, until any mucosal lesions have healed. If therapy is re-instituted, it should be done so at the lowest effective dose with consideration given to the concomitant use of omeprazole (0.7–1.0 mg/kg PO q24h) or misoprostol (5.0 μg/kg PO q8h),^99,108 and/or a different NSAID where licensing permits.

Hepatotoxicity or acute renal failure are usually reversible in other species on drug withdrawal and appropriate supportive therapy, providing they are detected early enough — this emphasises the importance of patient monitoring and of ensuring clients are involved in this process. In humans, it is recommended that a three-fold increase in ALT should lead to cessation of NSAID therapy. Milder increases may prompt more attentive monitoring, with further investigations being warranted if the ALT fails to return to baseline concentrations.⁵⁷ Re-institution of alternative NSAID therapy after hepatotoxicity or acute renal failure should be done very cautiously. Increases in blood pressure have been documented in other species with NSAID therapy, and this should be monitored in cats — antihypertensive therapy or more intense antihypertensive therapy should be used as appropriate.

All ADEs should be reported to the relevant pharmaceutical company and regulatory board to help the patient and enable accurate collation of information so that we can learn more about when and why they occur.

Acknowledgements

Boehringer Ingelheim Animal Health GmbH generously provided an educational grant to help facilitate the development of these guidelines.

SUMMARY POINTS

It is only recently that NSAIDs have become licensed for long-term use in cats in some countries.

The panel believe that these drugs have a major role to play in the management of chronic pain in cats, but at present only limited feline-specific data are available.

To date, published studies of the medium- to long-term use of the COX-1 sparing drug meloxicam in older cats and cats with chronic kidney disease provide encouraging data that these drugs can be used safely and should be used to relieve pain when needed.

While further data are needed, and would undoubtedly lead to refinement of the guidelines presented here, the panel hope that these recommendations will encourage rational and safe long-term use of NSAIDs in cats, thereby improving patients' quality of life in the face of painful disease conditions.

References

Hellyer

Rodan

Brunt

AAHA/AAFP pain management guidelines for dogs and cats. J Feline Med Surg 2007; 9: 466–80.

ACVA. American College of Veterinary Anesthesiologists' position paper on the treatment of pain in animals. J Am Vet Med Assoc 1998; 213: 628–30.

Mathews

.Pain assessment and general approach to management. Vet Clin North Am Small Anim Pract 2000; 30: 729–55, v.

Slingsby

Waterman-Pearson

Postoperative analgesia in the cat after ovariohysterectomy by use of carprofen, ketoprofen, meloxicam or tolfenamic acid. J Small Anim Pract 2000; 41: 447–50.

Carroll

Howe

Peterson

Analgesic efficacy of preoperative administration of meloxicam or butorphanol in onychectomized cats. J Am Vet Med Assoc 2005; 226: 913–19.

Taylor

Robertson

Dixon

Evaluation of the use of thermal thresholds to investigate NSAID analgesia in a model of inflammatory pain in cats. J Feline Med Surg 2007; 9: 313–18.

Benito-De-La-Vibora

Lascelles

Garcia-Fernandez

Efficacy of tolfenamic acid and meloxicam in the control of postoperative pain following ovariohysterectomy in the cat. Vet Anaesth Analg 2008; 35: 501–10.

Lascelles

Capner

Waterman-Pearson

Current British veterinary attitudes to perioperative analgesia for cats and small mammals. Vet Rec 1999; 145: 601–4.

Hugonnard

Leblond

Keroack

Attitudes and concerns of French veterinarians towards pain and analgesia in dogs and cats. Vet Anaesth Analg 2004; 31: 154–63.

10.

Robertson

Managing pain in feline patients. Vet Clin North Am Small Anim Pract 2008; 38: 1267–90.

11.

Lascelles

Robertson

DJD-associated pain in cats: what can we do to promote patient comfort?

J Feline Med Surg 2010; 12: 200–12.

12.

Robertson

Lascelles

Long-term pain in cats: how much do we know about this important welfare issue?

J Feline Med Surg 2010; 12: 188–99.

13.

Gunew

Menrath

Marshall

Long-term safety, efficacy and palatability of oral meloxicam at 0.01–0.03 mg/kg for treatment of osteoarthritic pain in cats. J Feline Med Surg 2008; 10: 235–41.

14.

Gowan

Retrospective analysis of the long-term use of meloxicam in aged cats with musculoskeletal disorders and the effect on renal function [abstract]. J Vet Intern Med 2009; 23: 1347.

15.

Lascelles

Hansen

Roe

Evaluation of client-specific outcome measures and activity monitoring to measure pain relief in cats with osteoarthritis. J Vet Intern Med 2007; 21: 410–16.

16.

Lascelles

Henderson

Hackett

Evaluation of the clinical efficacy of meloxicam in cats with painful locomotor disorders. J Small Anim Pract 2001; 42: 587–93.

17.

Beale

Use of nutraceuticals and chondroprotectants in osteoarthritic dogs and cats. Vet Clin North Am Small Anim Pract 2004; 34: 271–89.

18.

Lascelles

Feline degenerative joint disease. Vet Surg 2010; 39: 2–13.

19.

Allan

Radiographic features of feline joint diseases. Vet Clin North Am Small Anim Pract 2000; 30: 281–302.

20.

Hardie

Roe

Martin

Radiographic evidence of degenerative joint disease in geriatric cats: 100 cases (1994–1997). J Am Vet Med Assoc 2002; 220: 628–32.

21.

Clarke

Bennett

Feline osteoarthritis: a prospective study of 28 cases. J Small Anim Pract 2006; 47: 439–45.

22.

Clarke

Mellor

Clements

Prevalence of radiographic signs of degenerative joint disease in a hospital population of cats. Vet Rec 2005; 157: 793–99.

23.

Bennett

Morton

A study of owner observed behavioural and lifestyle changes in cats with musculoskeletal disease before and after analgesic therapy. J Feline Med Surg 2009; 11: 997–1004.

24.

Slingerland

Hazewinkel

Meij

Cross-sectional study of the prevalence and clinical features of osteoarthritis in 100 cats. Vet J. In press, 2010. doi: 10.1016/j.tvjl.2009.12.014.

25.

Beam

Rassnick

Moore

An immunohistochemical study of cyclooxygenase-2 expression in various feline neoplasms. Vet Pathol 2003; 40: 496–500.

26.

Dibernardi

Dore

Davis

Study of feline oral squamous cell carcinoma: potential target for cyclooxygenase inhibitor treatment. Prostaglandins Leukot Essent Fatty Acids 2007; 76: 245–50.

27.

Hayes

Scase

Miller

COX-1 and COX-2 expression in feline oral squamous cell carcinoma. J Comp Pathol 2006; 135: 93–99.

28.

Hayes

Adams

Scase

Survival of 54 cats with oral squamous cell carcinoma in United Kingdom general practice. J Small Anim Pract 2007; 48: 394–99.

29.

Healey

Dawson

Burrow

Prevalence of feline chronic gingivo-stomatitis in first opinion veterinary practice. J Feline Med Surg 2007; 9: 373–81.

30.

Buffington

Westropp

Chew

Clinical evaluation of multimodal environmental modification (MEMO) in the management of cats with idiopathic cystitis. J Feline Med Surg 2006; 8: 261–68.

31.

Gerber

Boretti

Kley

Evaluation of clinical signs and causes of lower urinary tract disease in European cats. J Small Anim Pract 2005; 46: 571–77.

32.

Giuliano

Nonsteroidal anti-inflammatory drugs in veterinary ophthalmology. Vet Clin North Am Small Anim Pract 2004; 34: 707–23.

33.

Lees

Giraudel

Landoni

PK-PD integration and PK-PD modelling of nonsteroidal anti-inflammatory drugs: principles and applications in veterinary pharmacology. J Vet Pharmacol Ther 2004; 27: 491–502.

34.

Lees

Landoni

Giraudel

Pharmacodynamics and pharmacokinetics of nonsteroidal anti-inflammatory drugs in species of veterinary interest. J Vet Pharmacol Ther 2004; 27: 479–90.

35.

Warner

Mitchell

Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J 2004; 18: 790–804.

36.

Clark

The clinical pharmacology of cyclooxygenase-2-selective and dual inhibitors. Vet Clin North Am Small Anim Pract 2006; 36: 1061–85.

37.

Maddison

Cats and NSAIDs — what are the issues?

Ir Vet J 2007; 60: 174–78.

38.

Papich

An update on nonsteroidal anti-inflammatory drugs (NSAIDs) in small animals. Vet Clin North Am Small Anim Pract 2008; 38: 1243–66.

39.

Crofford

.COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol 1997; 49 (suppl): 15–19.

40.

Wallace

.Distribution and expression of cyclooxygenase (COX) isoenzymes, their physiological roles, and the categorization of nonsteroidal anti-inflammatory drugs (NSAIDs). Am J Med 1999; 107: 11S–16S; discussion 16S–17S.

41.

Ito

Okuda-Ashitaka

Minami

Central and peripheral roles of prostaglandins in pain and their interactions with novel neuropeptides nociceptin and nocistatin. Neurosci Res 2001; 41: 299–332.

42.

Wooten

Blikslager

Marks

Effect of nonsteroidal anti-inflammatory drugs with varied cyclooxygenase-2 selectivity on cyclooxygenase protein and prostanoid concentrations in pyloric and duodenal mucosa of dogs. Am J Vet Res 2009; 70: 1243–49.

43.

Wooten

Blikslager

Ryan

Cyclooxygenase expression and prostanoid production in pyloric and duodenal mucosae in dogs after administration of nonsteroidal anti-inflammatory drugs. Am J Vet Res 2008; 69: 457–64.

44.

Claria

Romano

Pharmacological intervention of cyclooxygenase-2 and 5-lipoxygenase pathways. Impact on inflammation and cancer. Curr Pharm Des 2005; 11: 3431–47.

45.

Landolfi

Terio

Transitional cell carcinoma in fishing cats (Prionailurus viverrinus): pathology and expression of cyclooxyge-nase-1, −2, and p53. Vet Pathol 2006; 43: 674–81.

46.

Millanta

Citi

Della Santa

COX-2 expression in canine and feline invasive mammary carcinomas: correlation with clini-copathological features and prognostic molecular markers. Breast Cancer Res Treat 2006; 98: 115–20.

47.

Newman

Mrkonjich

Cyclooxygenase-2 expression in feline pancreatic adenocarcinomas. J Vet Diagn Invest 2006; 18: 590–93.

48.

Bergh

Budsberg

The coxib NSAIDs: potential clinical and pharmacologic importance in veterinary medicine. J Vet Intern Med 2005; 19: 633–43.

49.

Coruzzi

Venturi

Spaggiari

Gastrointestinal safety of novel nonsteroidal antiinflammatory drugs: selective COX-2 inhibitors and beyond. Acta Biomed 2007; 78: 96–110.

50.

Harris

Cyclooxygenase-2 inhibition and renal physiology. Am J Cardiol 2002; 89: 10D–17D.

51.

Ellis

Blake

Why are non-steroidal anti-inflammatory drugs so variable in their efficacy? A description of ion trapping. Ann Rheum Dis 1993; 52: 241–43.

52.

Radi

Pathophysiology of cyclooxygenase inhibition in animal models. Toxicol Pathol 2009; 37: 34–46.

53.

Khan

Venturini

Bunch

Interspecies differences in renal localization of cyclooxygenase isoforms: implications in nonsteroidal antiinflammatory drug-related nephrotoxicity. Toxicol Pathol 1998; 26: 612–20.

54.

Sellers

Senese

Khan

Interspecies differences in the nephrotoxic response to cyclooxygenase inhibition. Drug Chem Toxicol 2004; 27: 111–22.

55.

Yabuki

Endo

Fujiki

Expression of cyclooxygenase-2 and nitric oxide synthase-1 in kidneys of dogs and cats with renal failure. Bulletin of the Faculty of Agriculture-Kagoshima University (Japan). 2007.

56.

Lascelles

Court

Hardie

Nonsteroidal anti-inflammatory drugs in cats: a review. Vet Anaesth Analg 2007; 34: 228–50.

57.

Bush

Shlotzhauer

Imai

Nonsteroidal anti-inflammatory drugs. Proposed guidelines for monitoring toxicity. West J Med 1991; 155: 39–42.

58.

Savage

. Cyclo-oxygenase-2 inhibitors: when should they be used in the elderly? Drugs Aging 2005; 22: 185–200.

59.

Schoenfeld

Kimmey

Scheiman

Review article: non-steroidal anti-inflammatory drug-associated gastrointestinal complications — guidelines for prevention and treatment. Aliment Pharmacol Ther 1999; 13: 1273–85.

60.

Dubois

Melmed

Henning

Guidelines for the appropriate use of non-steroidal anti-inflammatory drugs, cyclo-oxyge-nase-2-specific inhibitors and proton pump inhibitors in patients requiring chronic anti-inflammatory therapy. Aliment Pharmacol Ther 2004; 19: 197–208.

61.

Lascelles

Mcfarland

Swann

Guidelines for safe and effective use of NSAIDs in dogs. Vet Ther 2005; 6: 237–51.

62.

Rostom

Moayyedi

Hunt

Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks. Aliment Pharmacol Ther 2009; 29: 481–96.

63.

Tannenbaum

Davis

Russell

An evidence-based approach to prescribing NSAIDs in musculoskeletal disease: a Canadian consensus. Canadian NSAID Consensus Participants. CMAJ 1996; 155: 77–88.

64.

Livingston

. Mechanism of action of nonsteroidal anti-inflammatory drugs. Vet Clin North Am Small Anim Pract 2000; 30: 773–81.

65.

Thombre

Oral delivery of medications to companion animals: palatability considerations. Adv Drug Deliv Rev 2004; 56: 1399–1413.

66.

Papich

Drug compounding for veterinary patients. AAPS J 2005; 7: E281–87.

67.

Thoulon

Narbe

Johnston

Metabolism and excretion of oral meloxicam in the cat [abstract]. J Vet Intern Med 2009; 23: 695.

68.

Lher

Narbe

Jons

.Population pharmacokinetic modelling and simulation of single and multiple dose administration of meloxicam in cats. J Vet Pharmacol Ther 2009; 33: doi: 10.1111/j.1365–2885.2009.01134.x.

69.

Giraudel

King

Jeunesse

Use of a pharmacokinetic/pharmacodynamic approach in the cat to determine a dosage regimen for the COX-2 selective drug robenacoxib. J Vet Pharmacol Ther 2009; 32: 18–30.

70.

Taylor

Lees

Reynoldson

Pharmacodynamics and pharmacokinetics of flunixin in the cat: a preliminary study. Vet Rec 1991; 128: 258.

71.

Smolensky

Peppas

Chronobiology, drug delivery, and chronotherapeutics. Adv Drug Deliv Rev 2007; 59: 828–51.

72.

Zamprogno

Hansen

Bondell

Development of a questionnaire to assess degenerative joint disease associated-pain in cats: item generation and questionnaire format. Am J Vet Res. In Press, 2010.

73.

Lascelles

Hansen

Thomson

Evaluation of a digitally integrated accelerometer-based activity monitor for the measurement of activity in cats. Vet Anaesth Analg 2008; 35: 173–83.

74.

Goodman

Brown

Torres

Effects of meloxicam on plasma iohexol clearance as a marker of glomerular filtration rate in conscious healthy cats. Am J Vet Res 2009; 70: 826–30.

75.

Weir

.Renal effects of nonselective NSAIDs and coxibs. Cleve Clin J Med 2002; 69 (suppl 1): SI53–58.

76.

Griffin

Yared

Ray

Nonsteroidal antiinflammatory drugs and acute renal failure in elderly persons. Am J Epidemiol 2000; 151: 488–96.

77.

Laine

White

Rostom

COX-2 selective inhibitors in the treatment of osteoarthritis. Semin Arthritis Rheum 2008; 38: 165–87.

78.

Patzer

Nephrotoxicity as a cause of acute kidney injury in children. Pediatr Nephrol 2008; 23: 2159–73.

79.

Winkelmayer

Waikar

Mogun

Nonselective and cyclooxygenase-2-selective NSAIDs and acute kidney injury. Am J Med 2008; 121: 1092–98.

80.

Juhlin

Jonsson

Hoglund

Renal effects of aspirin are clearly dose-dependent and are of clinical importance from a dose of 160 mg. Eur J Heart Fail 2008; 10: 892–98.

81.

Lelorier

Bombardier

Burgess

Practical considerations for the use of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors in hypertension and kidney disease. Can J Cardiol 2002; 18: 1301–8.

82.

Morlans

Laporte

Vidal

End-stage renal disease and non-narcotic analgesics: a case-control study. Br J Clin Pharmacol 1990; 30: 717–23.

83.

Perneger

Whelton

Klag

Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs. N Engl J Med 1994; 331: 1675–79.

84.

Rexrode

Buring

Glynn

Analgesic use and renal function in men. JAMA 2001; 286: 315–21.

85.

Gooch

Culleton

Manns

NSAID use and progression of chronic kidney disease. Am J Med 2007; 120: 280.e1–280.e7.

86.

Baigent

Landray

Leaper

First United Kingdom Heart and Renal Protection (UK-HARP-I) study: biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease. Am J Kidney Dis 2005; 45: 473–84.

87.

Van Der Woude

Heinemann

Graf

Analgesics use and ESRD in younger age: a case-control study. BMC Nephrol 2007; 8: 15.

88.

Mclaughlin

Management of chronic osteoarthritic pain. Vet Clin North Am Small Anim Pract 2000; 30: 933–49.

89.

Fored

Ejerblad

Lindblad

Acetaminophen, aspirin, and chronic renal failure. N Engl J Med 2001; 345: 1801–8.

90.

IRIS International Renal Interest Society — Staging of CKD. http://wwwiris-kidneycom/pdf/IRIS2009_Staging_CKDpdf. Accessed May 2010.

91.

Bulman-Fleming

Turner

Rosenberg

Evaluation of adverse events in cats receiving long-term piroxicam therapy for various neoplasms. J Feline Med Surg 2010; 12: 262–68.

92.

Goldstein

Marks

Kass

Gastrin concentrations in plasma of cats with chronic renal failure. J Am Vet Med Assoc 1998; 213: 826–28.

93.

Cariou

Halfacree

Lee

Successful surgical management of spontaneous gastric perforations in three cats. J Feline Med Surg 2010; 12: 36–41.

94.

Jones

Budsberg

Physiologic characteristics and clinical importance of the cyclooxygenase isoforms in dogs and cats. J Am Vet Med Assoc 2000; 217: 721–29.

95.

Tomlinson

Blikslager

Role of nonsteroidal anti-inflammatory drugs in gastrointestinal tract injury and repair. J Am Vet Med Assoc 2003; 222: 946–51.

96.

Antman

Bennett

Daugherty

Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation 2007; 115: 1634–42.

97.

Gluszko

Bielinska

Non-steroidal anti-inflammatory drugs and the risk of cardiovascular diseases: are we going to see the revival of cyclooxygenase-2 selective inhibitors?

Pol Arch Med Wewn 2009; 119: 231–35.

98.

Moodley

Review of the cardiovascular safety of COXIBs compared to NSAIDS. Cardiovasc J Afr 2008; 19: 102–7.

99.

Carroll

Simonson

Recent developments in nonsteroidal antiinflammatory drugs in cats. J Am Anim Hosp Assoc 2005; 41: 347–54.

100.

Aithal

Day

Nonsteroidal anti-inflammatory drug-induced hepatotoxicity. Clin Liver Dis 2007; 11: 563–75.

101.

Rubenstein

Laine

Systematic review: the hepatotoxicity of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther 2004; 20: 373–80.

102.

O'Connor

Dargan

Jones

Hepatocellular damage from non-steroidal anti-inflammatory drugs. QJM 2003; 96: 787–91.

103.

Macphail

Lappin

Meyer

Hepatocellular toxicosis associated with administration of carprofen in 21 dogs. J Am Vet Med Assoc 1998; 212: 1895–1901.

104.

Verbeeck

Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol 2008; 64: 1147–61.

105.

Loboz

Shenfield

Drug combinations and impaired renal function — the ‘triple whammy’. Br J Clin Pharmacol 2005; 59: 239–43.

106.

Lascelles

Blikslager

Fox

Gastrointestinal tract perforation in dogs treated with a selective cyclooxygenase-2 inhibitor: 29 cases (2002–2003). J Am Vet Med Assoc 2005; 227: 1112–17.

107.

Hampshire

Doddy

Post

Adverse drug event reports at the United States Food and Drug Administration Center for Veterinary Medicine. J Am Vet Med Assoc 2004; 225: 533–36.

108.

Kuehn

North American Companion Animal Formulary. North American Compendiums, Inc; 2008.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

2.12 MB

1.52 MB

2.15 MB

0.00 MB

ISFM and AAFP Consensus Guidelines: Long-Term use of NSAIDs in Cats

Abstract

Introduction

Common causes of chronic pain and inflammation in cats

Degenerative joint disease

Other diseases

NSAIDs and cyclo-oxygenase/lipoxygenase inhibition

Expression of COX enzymes

COX and LOX selectivity, and NSAID adverse effects

Panel recommendations

COX-2 selectivity

What does this mean for cats?

Practical NSAID therapy in cats

Compliance

Dosing — intervals, frequency, timing and the ‘lowest effective dose’

Panel recommendations

Dosing frequency

Dosing — accuracy

Panel recommendations

Dosing accuracy X

Dosing — switching drugs

Panel recommendations

Switching between NSAIDs

Monitoring efficacy

NSAIDs and concomitant disease

Renal disease

Panel recommendations

Renal disease

Gastrointestinal disease

Panel recommendations.

Panel recommendations

Cardiovascular disease

Liver disease

NSAIDs and concomitant drug therapy

Glucocorticoids

Panel recommendations

Concurrent drug therapy

Panel recommendations

Liver disease

Angiotensin converting enzyme inhibitors and diuretics

Anticoagulants

Monitoring cats receiving long-term NSAID therapy

Testing and screening before treatment

Panel recommendations

Screening before therapy

Screening during treatment

Panel recommendations

Classification of patients

Panel recommendations

Monitoring during therapy

Adverse events and adverse event reporting (pharmacovigilance)

Acknowledgements

SUMMARY POINTS

References

Supplementary Material