Hot Literature: Long-term NSAID use in cats

The International Society of Feline Medicine (ISFM) and the American Association of Feline Practitioners (AAFP) recently published a set of guidelines for the long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) in cats. The guidelines, based on the most current research and the panel members' knowledge and experience, identify several key points. The guidelines were compiled and published for the benefit of practitioners and their feline patients. To download a PDF of the guidelines, visit http://www.isfm.net/toolbox/info_sheets/NSAIDs_guidelines.pdf.

INDICATIONS AND OBSTACLES

Pain becomes chronic when it lasts longer than two to three weeks-frequently continuing beyond expected healing and often existing independent of the original cause. As in dogs, cats experience chronic pain associated with various conditions.

Common Causes of Chronic Pain in Cats

• Degenerative joint disease
• Various cancers
• Trauma
• Lymphoplasmacytic gingivostomatitis
• Idiopathic cystitis
• Skin disease
• Uveitis

Signs of Chronic Pain in Cats

• Withdrawing from attention
• Decreased interaction with people and other pets
• Decreased appetite
• Aggression

It is important to look for evidence of chronic pain and manage it appropriately. The signs may be subtle in cats and are most often expressed as changes in behavior rather than as an overt inability to perform usual physical exercises.

The notion that some pain is acceptable or even necessary to reduce movement after surgery or with other medical conditions is outdated. No form of pain is considered good. Any cat experiencing perioperative or chronic pain should be treated and may be an excellent candidate for NSAID use.

The use of NSAIDs in cats has been limited, largely because of concerns over possible complications, difficulty with treatment administration, and, perhaps most important, a failure by both veterinarians and owners to recognize the existence of pain. As the panel notes, there is no question that medicating cats can present insurmountable challenges. Inconsistent dosing is a common result of multiple-drug and frequent-dosing protocols. Compliance can be improved by providing palatable medications, encouraging consistent dose timing, and reducing dose frequency. Several palatable formulations of NSAIDs are currently available, and the long duration of many of these drugs can greatly improve client compliance.

Not a lot of feline-specific data is available on the use of NSAIDs, but the panel was able to infer much from other species and clinical experience. Being effective anti-inflammatory and analgesic agents as well as having significant antipyretic activity, NSAIDs should not be excluded from the choices of feline pain therapies. For the benefit of feline patients, the guidelines urge more appropriate use of NSAIDs.Most NSAIDs work by inhibiting the activity of cyclooxygenase (COX), thereby reducing prostaglandin production. Prostaglandins exert their effects on many areas necessary for normal physiologic function.

Effects of Prostaglandins on Normal Physiologic Functions

• Vascular homeostasis
• Gastroprotection
• Renal development

• Blood flow

• Blood clotting
• Reproduction

• Bone metabolism

• Wound healing

• Nerve development

• Growth

• Immune responses

Effects of Prostaglandins on Pathophysiologic Processes

• Pain

• Inflammation

• Cancer progression

Two main types of COX are responsible for prostaglandin production-COX-1 and COX-2. These enzymes are present in a variety of tissues and will increase in response to inflammation. COX-2 is thought to play a major role in the inflammatory response.

Since COX-1 inhibition is thought to be the cause of most NSAID-related side effects, such as gastric ulceration and blood dyscrasias, it is generally considered desirable to choose NSAIDs with greater COX-2 effects. These drugs are referred to as COX-2 preferential or, for those with virtually no COX-1 effects, COX-2 selective. Still, this group of NSAIDs can cause adverse effects. Other factors contribute to the risk of developing adverse effects, including advanced age and concurrent disease processes. Choosing the appropriate pain management should be based on the disease process being treated and the individual patient. There is no ideal NSAID.

MINIMIZING ADVERSE REACTIONS

Veterinarians often avoid using NSAIDs to treat chronic pain in cats largely because of fears of deleterious side effects. In fact, the panel emphasizes that the risk of these undesirable effects can be minimized with thoughtful patient selection, dose titration, and ongoing monitoring.

There are recognized differences in local tissue accumulation of NSAIDs based on a variety of factors including tissue pH, rate of drug metabolism, and the specific pharmacokinetics of the particular NSAID given. Consequently, these factors alter the risk in individual patients for developing adverse side effects. Given its effect on prostaglandin production in a variety of tissues, NSAID administration can result in acute renal failure, thromboembolic disease, or, more commonly, gastrointestinal (GI) bleeding. Prostaglandins influence many normal physiologic functions in numerous tissues throughout the body, so many organ systems can be affected by alterations in prostaglandin production with the administration of NSAIDs.

Several NSAIDs are metabolized through glucuronidation in the liver. Since cats have a relative deficiency of glucuronyl transferase, these drugs can have a prolonged effect. This should be taken into account when determining dose timing and frequency to reduce the risk of adverse effects. However, other NSAIDs such as piroxicam and meloxicam are metabolized by oxidation. Single doses of currently licensed NSAIDs in cats have a duration of action of about 18 to 20 hours, which is not directly related to drug half-life or dose. There is marked individual cat variation in the effects and duration of these drugs, and, unfortunately, it is not possible to identify fast vs. slow metabolizers before treatment. Other factors besides basic pharmacokinetics are also at work. NSAIDs can persist longer in inflamed tissues, allowing for daily dosing even with shorter-acting drugs. Variations in pain level will also affect a cat’s need for analgesia over time.

GI bleeding associated with NSAID administration is the most common side effect of these drugs. Adverse GI effects appear to be associated with individual NSAIDs, higher doses, advanced age, previous NSAID-related GI disease, liver disease, existing GI ulcers, or concurrent anticoagulant or glucocorticoid administration. To reduce the likelihood of developing GI bleeding in higher-risk cats, using COX-1-sparing drugs and combining treatment with a mucosal protectant are suggested.

Concomitant diseases must be taken into account when you administer NSAIDs in cats. Within the kidney, prostaglandins help regulate vascular tone and glomerular filtration rate and are involved in renin production and in maintaining sodium and water balance. Their role is magnified when there are decreases in renal blood flow. While the risk for NSAID-induced acute renal failure in cats is low, it appears to be highest for patients with preexisting conditions that decrease renal perfusion.

Conditions Resulting in Decreased Renal Perfusion

• Dehydration

• Hypovolemia

• Congestive heart failure

• Old age

• Preexisting renal disease

• Other drug therapies: diuretics, angiotensin-converting enzyme inhibitors

• High doses of NSAIDs

This form of acute renal failure is generally reversible when detected early, and the risk of developing NSAID-induced chronic renal failure appears to be extremely low.

Cardiovascular effects and the development of hepatotoxicosis associated with NSAID administration are not well-documented and are considered rare. Still, patients with hypertension, congestive heart failure, or liver disease should be closely monitored for changes or progression of disease when treated with NSAIDs.

Concurrent treatment with certain medications should be avoided or approached with care if they are likely to increase the risk for adverse reactions.

Medications to Avoid During NSAID Therapy

• Glucocorticoids
• Protein-bound medications-warfarin, digoxin, anticonvulsants (phenobarbital), chemotherapeutic agents
• Angiotensin-converting enzyme inhibitors and diuretics

In some cases, these medications may be discontinued before NSAID administration but can require a washout period to eliminate the additional risk associated with their actions.

Management of pain can be critical to quality of life even in geriatric patients or those with underlying conditions such as renal disease, cardiovascular compromise, or liver disease. For these patients, careful selection of drug and dose and the addition of adjunctive therapies such as gastroprotectants can minimize the risk and allow for early detection and reversal of any harmful conditions.

DOSING RECOMMENDATIONS

To avoid potential complications with NSAID therapy, veterinarians and owners should work together to achieve the lowest effective dose, recognizing that this dose is likely to change. Achieving this may require temporary withdrawal of the drug or reduced frequency of administration to best assess efficacy. However, reducing the daily dose while following the manufacturer's recommended dose frequency is encouraged.

Dose timing can be important, too. Encourage owners to observe their cats to determine the drug's period of peak effect. This way, treatment can be tailored to provide maximum benefit when the patient needs it most. To achieve the best treatment for each individual patient, switching between NSAIDs may be necessary. The panel recommends a seven- to 10-day washout period when transitioning from aspirin to any other NSAID and a minimum of three to five days between other drugs in this class.

Obviously, to be effective, drugs need to be given and the appropriate dose administered. Accuracy can be largely based on the drug’s formulation. Liquid medications can be simple to measure, making small dosing changes easier to accomplish. Tablets or caplets cannot be divided easily, which can make appropriate or accurate dosing difficult. All oral NSAID formulations should be given with food, and therapy should be withheld if food is not eaten. If hydration is a concern, wet food may be a good choice to improve water intake. Subcutaneous injections are an attractive alternative, but currently no injectable NSAIDs are licensed for long-term treatment in cats.

For cats with underlying disease processes that may increase their risk for developing adverse reactions, the panel gives some additional recommendations. Patients with renal disease, hypertension, congestive heart failure, or liver disease should always be given the lowest effective dose, and adjunctive analgesia should be considered in some cases to further reduce the NSAID dose. COX-2 preferential or selective NSAIDs may be less likely to cause GI complications, so this type of NSAID is preferred for long-term therapy. Cats with renal failure or receiving potassium supplementation should also be monitored for the development of hyperkalemia. And while cats with stable chronic renal failure are candidates for NSAID analgesia, patients with combined cardiac and renal disease are better managed with other analgesics.

MONITORING THERAPY

Monitoring patients during treatment is critical to avoid or detect adverse reactions and to achieve optimal drug effect. For patients with musculoskeletal pain, evidence of successful pain management will be seen most readily in the cat's behavior. A willingness to jump up is a good sign of improved mobility, but changes in other areas such as activity, grooming, and temperament are equally telling. Owner observation is critical to assessing pain, and an overall estimation of quality of life is valuable in the long-term treatment of chronic diseases. The guidelines recommend encouraging owners to keep a journal of their cats' activities to better detect subtle behavior or activity changes.

Before you initiate long-term NSAID therapy, all cats should be thoroughly evaluated. This includes taking a complete medical history and reviewing it with the owner. A comprehensive physical examination including blood pressure measurement is necessary, and recommended laboratory work should include a complete blood cell count, serum chemistry profile, and urinalysis. The guidelines suggest a follow-up evaluation at five to seven days to detect early signs of renal failure. This may be accomplished through a phone consultation. A complete evaluation should be scheduled for two to fours weeks after initiation of therapy for all patients, during which the examinations and laboratory work should be repeated. Throughout NSAID therapy, for uncomplicated, low-risk cases, reevaluation every six months may be adequate. Cats at increased risk for adverse effects should be seen every two to six months. The response of individual cats to NSAID therapy and the results of reassessments should be the overriding guide to ongoing treatment and monitoring.

SUMMARY

Licensure of NSAIDs for long-term therapy in cats is still in its infancy (see a complete table of available NSAIDs licensed for systemic use in cats in the guidelines). However, the panel members think that these drugs can be safe and effective in managing chronic pain in cats. The most current research shows promising results for the use of the COX-2 preferential NSAID, meloxicam, even in older cats and cats with chronic kidney disease.

Sparkes AH, Heiene R, Lascelles BDX, et al. ISFM and AAFP consensus guidelines: long-term use of NSAIDs in cats. J Feline Med Surg 2010;12(7):521-538.

To download the guidelines, click here.