Top 5 Situations for Judicious NSAID Use

NSAIDs are commonly used in veterinary medicine to control pain and inflammation and include COX inhibitors (eg, carprofen, deracoxib) and grapiprant, a newer prostaglandin-receptor antagonist. NSAIDs act by reducing the production or action of proinflammatory prostaglandins and are generally well-tolerated, although potential adverse effects may include GI upset, nephrotoxicity, and hepatotoxicity.

Following are the authors’ 5 most common uses of NSAIDs, along with important considerations for patient safety.

1. Osteoarthritis

A common application of NSAIDs is the management of osteoarthritis (OA). Because OA is characterized by both chronic and acute flare-ups of pain and inflammation secondary to joint pathology, the analgesic and anti-inflammatory properties of NSAIDs can be helpful with intermittent or continuous therapy.^1,2 Numerous NSAIDs (eg, carprofen, meloxicam, firocoxib, deracoxib, grapiprant) are labeled for management of OA in dogs; however, no NSAIDs are currently FDA-approved for long-term use in cats.

Although NSAIDs are typically well-tolerated in veterinary patients, sustained use to treat OA in older patients warrants close monitoring for potential adverse effects in the GI tract, kidneys, and liver. GI adverse effects have been linked to a variety of mechanisms (eg, direct irritation of the GI mucosa, inhibition of prostaglandin E₂) and potentially include ulceration, gastritis, enteritis, and perforation.³ COX expression in the kidneys can lead to production of prostaglandins, which help maintain renal homeostasis by affecting renal blood flow and glomerular filtration rate, among other functions.⁴ Thus, use of NSAIDs in dogs may exacerbate underlying chronic kidney disease or lead to acute kidney injury, reversible renal insufficiency, or papillary necrosis.^5-8

Adverse effects in the liver are uncommon and can be attributed to idiosyncratic reactions.⁹ Hepatopathy has been suggested or documented with NSAID use.^10-15 Idiosyncratic hepatotoxicity that occurs with carprofen administration typically involves acute hepatic necrosis, and signs of toxicosis (eg, marked increase in serum ALT) usually occur ≈2 to 4 weeks after initiation of carprofen.¹¹

In patients receiving long-term NSAID therapy, baseline laboratory work, (ie, patient hematocrit, liver enzymes, kidney values, and urinalysis) should be performed to help determine whether the patient has underlying renal or hepatic dysfunction. In addition, ongoing clinical monitoring of renal and hepatic parameters is recommended, and the pet owner should monitor for evidence of GI intolerance (eg, inappetence, vomiting, diarrhea, melena) at home. The authors recommend blood work be rechecked ≈2 to 4 weeks after initiation of NSAID treatment, then every 3 to 6 months. In patients that develop adverse effects while receiving an NSAID, the drug should be stopped and laboratory work (minimum CBC and serum chemistry profile) repeated to assess for possible drug toxicity.

2. Management of Postoperative Pain

NSAIDs are frequently used to provide analgesia during surgical procedures (eg, ovariohysterectomy, fracture repair, mass removal) but are generally contraindicated in patients undergoing GI surgery, as there are risks for ulceration and delayed healing.^16-21 COX-1 and COX-2 expression is increased in inflammatory conditions (eg, those induced during surgery). NSAIDs inhibit COX-1 and COX-2 expression, thus decreasing the production of inflammatory mediators (eg, prostaglandins, thromboxanes) responsible for peripheral and central sensitization to pain stimuli.^3,22

A primary consideration in patients with postsurgical pain is the timing of NSAID administration in the perioperative period. NSAIDs have been shown to provide better postsurgical analgesia when administered prior to surgery rather than immediately following surgery.^23-30 However, human and veterinary patients have frequently experienced hypotension while under anesthesia, and the kidneys are highly vulnerable to hypotensive insult.³¹ COX-1 and COX-2 expression play a major role in maintaining renal blood flow, particularly during hypotension, and preoperative inhibition of COX expression by NSAIDs may contribute to postoperative renal dysfunction.³² Several studies evaluating renal function after NSAID administration and anesthesia have not found evidence of significant dysfunction; however, these studies primarily included young, healthy dogs, with the oldest being 89 months of age.^24-26,33,34 Accordingly, preoperative use of NSAIDs may be reasonable in healthy patients that do not have underlying renal disease or increased risk for hypotensive events; blood pressure monitoring is recommended in patients under anesthesia. Because patients with existing renal disease may be at increased risk for AKI, NSAIDs should not be used during anesthesia for these patients.

3. Fever

NSAIDs are also used to provide clinical relief from fever, as their antipyretic effects are mediated by central and peripheral thermoregulatory mechanisms. The primary antipyretic action decreases prostaglandin E₂ levels in the hypothalamus by inhibiting COX.³⁵ Fever at sites of tissue inflammation is reduced via suppression of pyrogenic cytokines, increased release of endogenous antipyretics and anti-inflammatory molecules, and decreased adhesion molecule expression to reduce endothelial cell interactions with leukocytes.³⁵ This can allow NSAIDs to rapidly reduce fever, potentially controlling life-threatening febrile reactions and significantly improving patient comfort.

Although NSAIDs are effective at reducing fever, they usually do not treat the underlying cause. Resolution of a low- to moderate-grade fever can indicate the appropriate treatment is being used (eg, antimicrobials for system infection, glucocorticoids for immune-mediated polyarthritis). Patients with fever of unknown origin that were referred for further diagnostics and given NSAIDs, glucocorticoids, or antibiotics within 24 hours of presentation had significantly prolonged time to diagnosis as compared with patients not treated within this period.³⁶ In addition, pyrogenic fever is a protective mechanism in patients with sepsis or fungal infections. A mild febrile response in humans with pyrogenic fever secondary to infection has been shown to improve clinical outcomes.³⁷ Thus, NSAIDs should be used with caution in patients with fever of unknown origin, especially in cases in which infectious disease has not been ruled out or immune-mediated disease is likely and treatment with glucocorticoids may be indicated.

4. Antineoplastic Therapy

NSAIDs used in conjunction with metronomic chemotherapy are important in the management of cancer patients and can be used as a single-agent treatment for some tumors.^38-40 For metronomic chemotherapy, conventional oral cytotoxic chemotherapy agents can be given at relatively low doses and regular intervals (eg, every 24-48 hours) over a sustained period. Metronomic chemotherapy agents are often delivered with other agents (eg, NSAIDs, small-molecule inhibitors).³⁸ Therapy is aimed at altering tumor microenvironment, primarily via antiangiogenic mechanisms, rather than directly targeting the tumor cells. COX-2 inhibition via NSAIDs can decrease cell proliferation, reduce production of proangiogenic factors (eg, vascular endothelial growth factor), and increase the rate of apoptosis.⁴¹ Adjuvant metronomic chemotherapy has been explored in a variety of tumor types (eg, hemangiosarcoma, soft tissue sarcoma) and can safely be incorporated in treatment regimens for cancer patients.³⁸

Carcinomas (eg, urothelial carcinoma, mammary carcinoma, nasal adenocarcinoma, anal sac adenocarcinoma) express COX-2.^42-45 NSAIDs have activity against canine urothelial carcinoma, with several different COX inhibitors (eg, piroxicam, deracoxib, firocoxib) reported.^39-40,46 NSAIDs may be recommended as part of standard therapy for carcinomas because of their potential antitumor activity and ability to provide analgesia. One study reported a median survival time of 181 days in dogs with urothelial carcinoma treated with piroxicam alone as compared with 291 days in dogs treated with piroxicam in combination with mitoxantrone.⁴⁶ NSAIDs are more effective when combined with conventional chemotherapy agents for treatment of urothelial carcinoma but can be used alone when conventional chemotherapy is not possible.

The effectiveness of NSAIDs for antineoplastic therapy should be balanced against possible adverse effects. GI adverse effects may limit the use of NSAIDs, especially in patients also being treated with conventional chemotherapy agents or small-molecule inhibitors that may independently cause GI adverse effects. NSAIDs should not be used concurrently with glucocorticoids, which are often used in the treatment of round cell neoplasias (eg, lymphoma, mast cell tumors). Owners of patients treated with NSAIDs as part of antineoplastic therapy should be advised to monitor for signs of GI adverse effects. Baseline and follow-up laboratory work is also recommended (as described for OA; see Osteoarthritis).

5. Musculoskeletal Injury

NSAIDs are also frequently used in patients with acute musculoskeletal injuries. Pain associated with acute injuries persists during both the inflammatory and healing phases and may last up to 3 months before being considered chronic.¹⁷ During the inflammatory phase, prostaglandin expression may increase up to 80-fold, making COX inhibition a valuable target for therapeutic intervention.⁴⁷

Patients with acute musculoskeletal injuries are typically given shorter courses of NSAID therapy, reducing the risk for potential adverse effects in the kidneys, GI tract, and liver, as compared with patients given sustained NSAID therapy. However, caution is recommended in patients with pre-existing GI disease, and screening for renal or hepatic dysfunction should be done prior to NSAID administration, especially in older patients.

Conclusion

NSAIDs are important therapeutics because of their ability to reduce inflammation and provide effective analgesia. With appropriate monitoring for GI, renal, and hepatic adverse effects, NSAIDs can be used safely to treat a variety of conditions in small animal patients.