Nonsteroidal Antiinflammatory Drug (NSAID) Toxicity in Dogs and Cats: Pathophysiology, Diagnosis and Monitoring

Jamie Totten, DVM; Holly M. Brown, DVM, Bruce E. LeRoy, DVM, PhD

Class of 2006, College of Veterinary Medicine, University of Georgia, Athens, GA 30602; Goochland Animal Clinic, Maidens, VA (Totten) and Department of Pathology (Brown, LeRoy) College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Introduction

Non-steroidal anti-inflammatory agents (NSAIDs) are a class of drugs commonly used in both human and veterinary medicine for treatment of a wide range of conditions such as osteoarthritis, cancer, balanced anesthesia, and perioperative analgesia. NSAIDs provide a cost-effective and convenient strategy for analgesia in painful acute and chronic disease states and procedures. These characteristics have increased the use of NSAIDs for pain control in companion animals. However, the judicious use of NSAIDs must include a balance between relief of symptoms and side effects. The most common NSAID-associated toxicities in companion animals are renal toxicity and gastrointestinal ulceration. Other less common but potentially life-threatening side effects include hepatotoxicity, platelet dysfunction and bleeding, aplastic anemia, and - with long-term use - possibly decreased bone healing and increased cartilage degradation.^{2, 3, 6}

Pathophysiology of Common Side Effects

NSAIDs provide analgesia by inhibiting enzymes that produce pro-inflammatory mediators known as prostaglandins [Figure 1]. There are two major classes of NSAIDs commonly used in veterinary medicine:  COXIBS (which selectively inhibit COX-2 isoform while ideally sparing the “cytoprotective” COX-1 isoform) and traditional NSAIDs which inhibit both the COX-1 and COX-2 enzymes. Examples of “traditional” NSAIDS include: ibuprofen, naproxen, ketoprofen, carprofen, and etodolac. Examples of COXIBs are: celecoxib, rofecoxib, deracoxib, meloxicam, and previcoxib.¹

Figure 1. Metabolic pathway of arachadonic acid and examples of some target tissues of the prostanoids and leukotrienes. PLA2 = phospholipase A2, COX = cyclooxygenase, 5-LOX = 5-lipoxygenase, TXA2 = thromboxane A2, PGE2 = prostaglandin E2, PGI2 = prostaglandin I2, LT= leukotriene (A4, B4, C4, D4, E4), VSMC = vascular smooth muscle cells, CNS = central nervous system, VEGF = vascular endothelial growth factor, MO = macrophages

Both the COX-1 and COX-2 enzymes serve important homeostatic roles in many body systems. The inhibition of these enzymes produces the therapeutic benefits as well as the toxicities associated with NSAIDs. COX-1 is a constitutive enzyme that plays an important role in maintaining renal and gastrointestinal blood flow as well as ensuring platelet integrity. COX-2 has traditionally been thought to be an inducible enzyme that is upregulated in inflammatory disease, however, constitutive COX-2 expression has recently been shown in the renal and central nervous systems.² 

Gastrointestinal side effects:
NSAIDs may cause ulceration of the gastrointestinal (GI) tract by inhibiting the synthesis of prostaglandins (via blockade of the COX-1 enzyme) which serve as a component of the protective layer of the gastric mucosa. All NSAIDs have the potential to cause GI side effects ranging from gastric ulceration to erosion. COX-1 sparing NSAIDs are associated with 50% less GI ulceration in humans and animal studies have yielded similar results.²  Animals at an increased risk of having gastrointestinal side effects include geriatric animals, animals receiving multiple NSAIDs, as well as animals receiving concurrent glucocorticoid therapy. However, it should be noted that it is not recommended for animals to receive multiple NSAIDs or glucocorticoids in addition to NSAIDs.⁷

Renal side effects:
NSAIDs should be used judiciously in patients who are dehydrated or who are at risk for developing hypotension for any reason (hypoadrenocorticism, anesthetic-related hypotension, hypovolemic shock, etc.).^2,4 This is because COX-2-mediated production of prostaglandin E2 (PGE2) is an important factor normally produced in response to hypovolemia. PGE2 helps maintain renal perfusion by its vasodilatory effects. Blockade of COX-2 and the resulting decrease in PGE2 production in hypovolemic individuals may lead to acute renal failure due to renal ischemia.⁸

Hepatic side effects:
Idiosyncratic drug reactions resulting in fulminant acute hepatic necrosis following NSAIDs administration has been reported.⁹ Affected dogs were receiving a therapeutic dose of carprofen for musculoskeletal pain. Labrador retrievers were overrepresented. The toxicity usually occurs within the first 3 weeks of administration.⁴ The mechanism of action of the hepatotoxicity is unknown but has been postulated to be due to “an immunologic response to reactive metabolites or to a difference in carprofen metabolism.”⁶

Platelet dysfunction / Bleeding:
NSAIDS produce a reversible inhibition of the COX-1 enzyme and thereby decrease production of thromboxane A2, which is necessary for platelet aggregation. NSAIDS should be used judiciously in thromobocytopenic animals or those with coagulopathies like von Willebrand’s disease.³

Aplastic anemia:
This side effect is associated with phenylbutazone. Phenylbutazone may exhibit selective toxicity towards hematopoietic stem cells of the bone marrow. This toxicity generally occurs after long-term treatment, is not dependent on the dose administered and it occurs sporadically.³ It may or may not resolve following discontinuation of the drug.

Decreased bone healing:
COXIBs may delay the early stages of bone healing and potentially lead to non-unions of healing fractures (via inhibition of prostaglandins E and F). This effect appears reversible with short-term administration of the COXIB.²

Clinical Signs associated with NSAIDs Toxicity

GI toxicity:
1. Vomiting
2. Diarrhea
3. Nausea
4. Darkened stools (melena)
5. Inappetance or anorexia
6. Lethargy
7. Hematochezia
8. Depression
9. Abdominal tensing

Nephrotoxicity:
1. Polyuria and polydypsia
2. Vomiting and anorexia (as a result of uremic toxin production)
3. Oliguria or anuria
4. Other signs of chronic or acute renal failure

Hepatotoxicity (idiosyncratic reactions and acute overdoses):
1. Icterus
2. Lethargy
3. Vomiting
4. Weight loss
5. Hepatic encephalopathy

Aplastic anemia:
1. Pale mucous membranes
2. Lethargy
3. Dyspnea

Platelet dysfunction:
1. Prolonged bleeding at venipucture sites
2. Excessive bleeding during minor surgical procedures

Histopathological findings

Kidney:
Renal papillary necrosis as a consequence of ischemic tubular and interstitial necrosis. Renal tubular obstruction, calculus formation, and pyelonephritis may also occasionally be present.

Liver:
Acute, fulminant hepatic necrosis⁷

GI:
Mucosal ulcers
Partial thickness erosions
Full thickness erosions
Hematochezia
Melena

Clinical Laboratory findings

GI Ulceration:
1. Decreased hematocrit and total protein, increased blood urea nitrogen (BUN) due to gastrointestinal hemorrhage
2. Elevated leukocyte count ⁴

Renal toxicity:
1. Increased BUN, Creatinine
2. Decreased urine specific gravity (best to review serial USGs)
3. Cast formation
4. Proteinuria

Hepatotoxicity:
1. Increased alanine aminotransferase (ALT)
2. Increased aspartate aminotransferase (AST)
3. Increased alkaline phosphatase (ALP)¹
4. +/- hyperbilirubinemia
5. +/- hypoalbuminemia⁶

Treatment

Supportive care is used to treat NSAID toxicity. Due to the serious complications of NSAIDs toxicity, it is prudent to attempt to prevent toxicity rather than treat it. Veterinarians should educate clients about early signs of toxicity and instruct them to discontinue the medication if these appear. This strategy will likely help to prevent the development of the more severe complications of NSAIDs toxicity. Consideration of other less toxic therapies of pain control - weight loss, opioids, chondroprotective agents, and physical therapy - may allow a reduction in the dose and/or frequency of NSAID administration, which will inherently reduce the likelihood of toxicity.⁴  However, idiosyncratic reactions to NSAIDs may still occur even at reduced doses. Careful patient selection followed by close monitoring and sound clinical judgment will aid the clinician in the prevention of these toxicities.

Clinical Laboratory Monitoring

At this time, there is no consensus protocol for appropriate monitoring of patients receiving chronic NSAID therapy. Some manufacturers of NSAIDs recommend a baseline CBC and biochemical profile followed by another CBC and profile 2 weeks after initiation of therapy. Thereafter individual clinicians should determine appropriate monitoring based on clinical judgment.⁴  

One author recommends the following tests as part of a baseline examination:

1. Complete blood count

2. Biochemical profile including:  BUN, creatinine, ALT, ALP, albumin, and total protein. Some commercial reference laboratories offer an NSAID panel which includes these tests (with the exception of TP) in a bundled package.⁵

3. Compete urinalysis (including a sediment examination and urine specific gravity on a refractometer), urine protein:creatinine ratio or assessment of microalbuminuria to qualify, quantify and monitor the presence or development of proteinuria during the course of NSAID therapy.

Summary

NSAIDs are effective medications that afford many veterinary patients a significant amount of relief from pain associated with both chronic disease states and acute inflammatory events.  However, before initiating NSAID therapy, it is prudent for veterinarians to educate clients on signs of toxicity and to exercise sound clinical judgment in patient selection based on physical examination findings, concurrent drug therapy and preexisting diseases. Adjunctive methods such as weight loss and chondroprotective agents may help reduce untoward side effects of NSAIDs. During therapy, early recognition of signs of toxicity, both through routine clinicopathological monitoring and keen client based observations, are essential for safe NSAID therapy for veterinary patients.

References

1. Albretsen JC. Oral Medications. Veterinary Clinics of North America: Small Animal Practice 32 (2):421-422, 2002.

2. Bergh MS, Budsberg SC. The COXIB NSAIDS: potential clinical and pharmacologic importance in veterinary medicine. Journal of Veterinary Internal Medicine 19(5):633-43, 2005.

3. Feldman B, Zinkl J, Jain N (eds):  Veterinary Hematology, 5th Ed. Philadelphia, Lippincott Williams and Wilkins, 2000, pp 213, 496.

4. Lascelles BD, McFarland JM, Swann H. Guidelines for Safe and Effective Use of NSAIDs in Dogs.Veterinary Therapeutics 6(3):237-51, 2005.

5. Press Release:  NSAID Panel Leads IDEXX Laboratories Additions to Growing Vet Test^® Chemistry Analyzer Lineup. http://www.idexx.com/aboutidexx/pressroom/releases/20051128pr.jsp  (4/17/2006).

6. Trepanier L. Mechanisms of Drug Associated Hepatotoxicity in the Dog and Cat. ACVIM Proceedings, 2004.

7. Trepanier L. Drug Interactions and Differential Toxicity of NSAIDs. ACVIM Proceedings, 2002.

8. DeMaria AN, Weir MR. Coxibs - Beyond the GI Tract: Renal and Cardiovascular Issues. Journal of Pain and Symptom Management 25(2S):S41-S49, 2003.

9. http://www.vetmed.wsu.edu/org_cgs/newsletter/spring98.htm.

Acknowledgement

Cat under Flowering Cactus and Banana Leaves November 2, 2004 by Marcio Melo is from the 2004 collection on his website and is used with permission of the artist..

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