Toxicology Brief: Naproxen toxicosis in dogs

Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) used in people as an analgesic and antipyretic to treat multiple diseases including cancer, gout, arthritis, lupus, and musculoskeletal injuries. It is sold by prescription for human use as an oral suspension (25 mg/ml); 250-, 375-, and 500-mg tablets; and 750-mg extended-relief tablets, and is also sold over-the-counter as naproxen sodium in 220-mg tablets.1 In the past, naproxen was used as an extralabel drug in dogs, but most veterinarians currently prescribe NSAIDs labeled for use in dogs.2

PHARMACOKINETICS AND MECHANISM OF ACTION

Oral naproxen is absorbed rapidly and has an oral bioavailability ranging from 68% to 100% in dogs. It is highly protein-bound, resulting in a low volume of distribution (0.13 L/kg in dogs). In most species, including people and horses, naproxen is eliminated in urine. However, in dogs, naproxen is eliminated in the feces and undergoes extensive enterohepatic recirculation. This accounts for the long half-life of 74 hours in dogs.3

GETTY IMAGES/HANS LAUBEL

Naproxen has been used therapeutically in dogs at an oral dosage of 2 mg/kg every other day to treat osteoarthritis and other musculoskeletal inflammatory diseases. However, because of potential adverse effects, it is now recommended that veterinarians only consider prescribing naproxen when FDA-approved NSAIDs have been ineffective.2

Like other NSAIDs, naproxen blocks the enzyme cyclooxygenase to prevent the synthesis of prostaglandins. There are two commonly known forms of cyclooxygenase: COX-1 and COX-2. COX-1 is considered a constitutive enzyme, meaning it is always present. Prostaglandins formed by COX-1 are important for normal physiologic function. They protect both the gastrointestinal (GI) tract and the kidneys. COX-2 is an inducible enzyme. It plays a role in the formation of prostaglandins that mediate inflammation. Naproxen is a nonselective inhibitor of cyclooxygenases; therefore, it inhibits both COX-1 and COX-2.1

Prostaglandins formed by COX-1 protect the GI tract by inhibiting gastric acid secretions, increasing the production of bicarbonate by epithelial cells, increasing mucosal blood flow, and promoting epithelial cell repair and turnover. Loss of these protective prostaglandins can lead to GI tract irritation and ulceration.

In the kidney, protective prostaglandins act as vasodilators. They maintain adequate renal blood flow and glomerular filtration rate, mediate renin release, and are involved in electrolyte transfer. Therefore, a decrease in these prostaglandins can lead to adverse renal effects, including vasoconstrictive acute renal failure, acute interstitial nephritis, fluid and electrolyte abnormalities, and renal papillary necrosis.4

TOXICITY

Most cases surveyed in the literature on naproxen toxicosis in dogs report repeated exposure over multiple days. In one of these case reports, a 13-year-old male basenji was treated with 125 mg of naproxen orally twice a day for seven days for joint stiffness, arthritis, and mandibular swelling.5 The patient's weight was not included in the report; however, assuming a weight of 20 to 25 lb (9.07 to 11.34 kg), the daily dosage would have been about 22 to 28 mg/kg.

This patient developed anorexia, weight loss, abdominal pain, melena, and anemia (most likely related to GI hemorrhage since no other sources of blood loss or destruction were identified). Urinalysis showed numerous granular and hyaline casts indicating renal tubular damage. Results of a serum chemistry profile showed a normal blood urea nitrogen (BUN) concentration of 22 mg/dl (reference range2 = 7 to 26 mg/dl). The serum creatinine concentration was not reported. Naproxen was discontinued.

At the three-week recheck, the dog had improved and gained weight. The melena resolved. No other treatment was documented in the case report.5

A second case report describes a 9-year-old male Samoyed that received 5.6 mg/kg naproxen once daily for seven days for periodic shoulder stiffness.6 The patient developed vomiting and melena. Clinical pathology changes included anemia, increases in BUN and serum creatinine concentrations, increases in alkaline phosphatase (ALP) and alanine transaminase (ALT) activities, and a urine specific gravity of 1.019. The patient was treated with intravenous fluids for four days, a blood transfusion, antacid therapy (dimethicone, calcium carbonate and magnesium hydroxide combination), and cimetidine. The dog subsequently recovered.6

The only case report in a dog after a single dose of naproxen involved an elderly dachshund that received 35.7 mg/kg of the drug.7 The next day the dog became lethargic and developed abdominal discomfort, vomiting, diarrhea, and profuse hematemesis and melena. The dog recovered after receiving supportive treatment. Detailed treatment information was not included in the report.7

ASPCA Animal Poison Control Center data

The ASPCA Animal Poison Control Center (APCC) database contains 4,404 cases of naproxen exposures in dogs dating from 2001 to 2011.8 Only the single-exposure cases that the APCC staff determined had a high or medium likelihood of causing the patient's clinical findings are included here. The most commonly reported signs after ingestion of naproxen in dogs were vomiting, lethargy, diarrhea, and anorexia.8

In dogs, single doses ranging from 1 to 7 mg/kg resulted in vomiting and lethargy. In a 1-year-old dog, 7.7 mg/kg of naproxen resulted in multiple episodes of vomiting that eventually became bloody. In two elderly dogs, 7.4 mg/kg of naproxen resulted in diarrhea, inappetence, and melena in one dog, and melena and a mildly increased BUN concentration (likely due to GI bleeding) in the other dog.8 Hemorrhage into the GI tract is catabolized by the body similar to any other dietary protein source, leading to increased urea.9

In a 2-year-old dog, ingestion of 13.4 mg/kg of naproxen resulted in mild increases in BUN (38 mg/dl; reference range = 7 to 26 mg/dl) and serum creatinine (2 mg/dl; reference range = 0.6 to 1.4 mg/dl) concentrations. Whether these increases in BUN and serum creatinine concentrations were prerenal or renal in origin was not determined; however, no GI effects, such as vomiting and diarrhea, associated with increased risk for dehydration were reported in this patient.

In two 5-year-old dogs, doses of about 14 mg/kg of naproxen resulted in azotemia. In the first dog, 13.9 mg/kg of naproxen resulted in melena, inappetence, and a mild increase in serum creatinine concentration (2 mg/dl; reference range = 0.6 to 1.4 mg/dl). Because of the presence of GI signs in this dog, it is possible that the azotemia was prerenal in origin. In the second dog, 14.2 mg/kg of naproxen resulted in vomiting and azotemia. Urine specific gravity was 1.008, the BUN concentration was 64 mg/dl (reference range = 7 to 26 mg/dl), and the serum creatinine concentration was 5.8 mg/dl (reference range = 0.6 to 1.4 mg/dl), which can be interpreted as renal in origin based on the isosthenuria.

In both cases, APCC treatment recommendations included GI-protectant medications (sucralfate, H2 blockers, and misoprostol) and fluid diuresis. The actual treatments and outcomes subsequent to consultation were not reported for these patients.8

The APCC data suggest that a one-time dose of 7 mg/kg or greater can cause clinical signs of GI irritation and ulceration (vomiting, diarrhea, melena, anorexia), whereas azotemia is possible at doses ranging from 13 to 15 mg/kg. GI effects most frequently develop within two to 24 hours, and renal effects develop within 24 to 48 hours.8 The risk of adverse GI or renal effects increases with concurrent use of other NSAIDs or corticosteroids.4 Elderly patients also may be at increased risk for adverse renal effects if renal insufficiency is already present.4

DECONTAMINATION

Decontamination may not be required for a dose less than 7 mg/kg in a dog but may decrease the risk of GI irritation. If ingestion of naproxen was recent (less than two hours) and the patient shows no clinical signs, emesis can be induced by using apomorphine (0.03 mg/kg intravenously; or, in the conjunctival sac, 0.25 mg/kg after dissolving the tablet in saline solution) or 3% hydrogen peroxide (2 ml/kg orally with a maximum of 50 ml). If emesis is unproductive, consider using activated charcoal (1 to 3 g/kg orally).2

If the patient exhibits no clinical signs and the ingestion occurred more than two hours before evaluation, consider administering activated charcoal (1 to 3 g/kg orally). The first dose of activated charcoal should be administered with a cathartic. However, with repeat doses of activated charcoal, a cathartic should not be used, particularly if the patient is dehydrated or has diarrhea.10

In dogs with ingestions of naproxen greater than 13 mg/kg, an initial dosage of activated charcoal (1 to 3 g/kg orally) may be followed with half the original amount every six to eight hours for 24 to 48 hours after ingestion to interrupt any enterohepatic recirculation.

MONITORING AND TREATMENT

Monitor the serum sodium concentration regularly if activated charcoal is given because administration of activated charcoal may be associated with hypernatremia.10 Hypernatremia may manifest clinically as muscle fasiculations, tremors, and seizures. If the patient is not vomiting, allow access to water.11 If hypernatremia develops, the APCC recommends warm-water enemas in addition to administration of appropriate intravenous fluids to lower the serum sodium concentration and decrease resultant adverse effects to the central nervous system.12

Monitor for signs of GI irritation and ulceration, and initiate GI protection by using a combination of sucralfate (0.5 to 1 g orally t.i.d.), misoprostol (2 to 5 μg/kg orally every 8 to 12 hours), and famotidine (0.1 to 0.2 mg/kg orally, subcutaneously, intramuscularly, or intravenously b.i.d.) or omeprazole (0.5 to 1 mg/kg orally once a day).2 Continue administering GI-protective medications for at least seven to 14 days because of the long half-life of naproxen in dogs. Control vomiting with antiemetics as needed.12 If severe gastric ulceration develops, colloid therapy or blood transfusions may be needed.4

For dosages at which adverse renal effects are possible, obtain a baseline serum chemistry profile, a complete blood count, and a urinalysis including a urine specific gravity before initiating fluid diuresis. Repeat a renal panel (BUN and serum creatinine and electrolyte concentrations) at 24, 48, and 72 hours. Repeat the complete blood count and urinalysis if indicated. Initiate intravenous fluid diuresis. Because of the long half-life of naproxen in dogs, the APCC recommends twice maintenance fluids for at least 72 hours. If results of the renal panel are within the reference range 72 hours later, gradually decrease the rate of fluid administration over the next 24 hours.

Increased liver enzyme activity has been reported subsequent to NSAID exposure in people4 and after naproxen intoxication in dogs.6 Monitor liver enzyme function and initiate liver-protective medications if marked elevations in liver enzyme activity develop. S-adenosyl-methionine (SAMe) (20 mg/kg orally once daily2) may be administered.

PROGNOSIS

Gastrointestinal irritation or ulceration typically resolves with appropriate treatment. Patients that develop GI ulceration are at risk for GI perforation and death from GI bleeding or sepsis. Renal effects of NSAIDs generally are considered reversible if they are discovered early and treated aggressively.12 Patients with underlying GI or renal disease are more at risk, as are patients that receive medications that interact with NSAIDs.

Camille DeClementi, VMD, DABT, DABVT, ASPCA Animal Poison Control Center, 1717 S. Philo Road, Suite 36, Urbana, IL 61802

REFERENCES

1. Naproxen. In: POISINDEX System [intranet database]. Version 5.1. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc.

2. Plumb DC. Veterinary drug handbook. 7th ed. Ames, Iowa: Blackwell Publishing, 2011. Online edition.

3. Frey HH, Rieh B. Pharmacokinetics of naproxen in the dog. Am J Vet Res 1981;42:1615-1617.

4. Talcott PA. Nonsteroidal antiinflammatories. In: Peterson ME, Talcott PA eds. Small animal toxicology. 2nd ed. St. Louis, Mo: Elsevier Saunders, 2006;902-933.

5. Roudebush P, Morse GE. Naproxen toxicosis in a dog. J Am Vet Med Assoc 1981;179:805-806.

6. Gilmour MA, Walshaw R. Naproxen-induced toxicosis in a dog. J Am Vet Med Assoc 1987;191:1432-1432.

7. Steele RJ. Suspected naproxen toxicity in dogs. Aust Vet J 1981;57:100-101.

8. AnTox Database. Urbana, Ill: ASPCA Animal Poison Control Center, 2001-2011.

9. Meyer DJ, Coles EH, Rich LJ. Veterinary laboratory medicine: interpretation and diagnosis. Philadelphia, Pa: WB Saunders Company, 1992:79.

10. DeClementi C. Prevention and treatment of poisoning. In: Gupta RC, ed. Veterinary toxicology basic and clinical principles. New York: Academic Press Elsevier, 2007;1145-1146.

11. Mathews KA. Veterinary emergency and critical care manual. Guelph: Lifelearn Inc., 2006;382-385.

12. DeClementi C. Naproxen toxicosis in an elderly greyhound. NAVC Clinician's Brief 2012;10:29-31.