Toxicology Brief: Managing acute carprofen toxicosis in dogs and cats


Carprofen, a nonsteroidal anti-inflammatory drug (NSAID) of the propionic acid class, is commonly used in small-animal practice for its analgesic, anti-inflammatory, and antipyretic properties. Its main uses in dogs are to treat pain and inflammation associated with osteoarthritis and control postoperative pain associated with soft tissue and orthopedic surgeries. More than 10 million dogs have been treated to date.1

Available as an injectable solution (50 mg/ml) and 25-, 75-, and 100-mg caplets and chewable tablets, Rimadyl (Pfizer Animal Health) is labeled in the United States for dogs only. The manufacturer's recommended dosage is 2 mg/lb (4.4 mg/kg) orally or subcutaneously daily (alternatively, 1 mg/lb [2.2 mg/kg] b.i.d.), and the injectable product is recommended to be given two hours before surgery to manage postoperative pain. Intramuscular and intravenous routes are extralabel and have also been reported.2 Generic formulations of carprofen—Vetprofen (Vétoquinol), Novox (Vedco), and Carprofen Caplets (Putney)—are also available as 25-, 75-, and 100-mg caplets for dogs only.3

The ASPCA Animal Poison Control Center (APCC) has received many calls regarding carprofen exposures in dogs and cats over the years (ASPCA APCC Database: Unpublished data, 2001-2009). This report details public cases in the computerized database (November 1, 2001 through April 27, 2009) that fulfill the following criteria in dogs and cats:
1. Single agent exposures
2. Observed exposures or those documented by evidence such as a chewed bottle
3. Clinical cases assessed by ASPCA APCC veterinarians as likely related to the agent
4. Acute overdoses only in dogs (to exclude idiosyncratic hepatic reactions)
5. Oral products only

THERAPEUTIC MECHANISM OF ACTION

Like most NSAIDs, carprofen is thought to mediate its beneficial therapeutic effects by inhibiting the enzyme cyclooxygenase (COX), which catalyzes the cyclization and oxygenation of arachidonic acid to prostaglandins. Discovered in 1991, COX-2 is the isoform of the enzyme induced by proinflammatory cytokines and mitogens,4 and COX-2 inhibition is the main intended target for the therapeutic effects of NSAIDs, particularly the more recently approved drugs. A higher ratio of COX-2 to COX-1 inhibition is associated with greater therapeutic efficacy and fewer adverse effects. However, in animals with underlying gastrointestinal disease or in those receiving concurrent NSAID or glucocorticoid therapy, any amount of COX-1 inhibition could be detrimental. Preexisting gastrointestinal inflammation, overdosage, and close temporal use of other NSAIDs or glucocorticoids in dogs receiving a selective COX-2 inhibitor (deracoxib) have resulted in gut perforation and death.5 The literature reports variable selectivity of COX-2 vs. COX-1 inhibition by carprofen.4,6-12

TOXIC MECHANISM OF ACTION

COX-1, the constitutive and cytoprotective isozyme, has many beneficial roles in the body. In the stomach, COX-1 reduces gastric acid secretion by parietal cells, maintains gastric mucosal blood flow mediated by vasodilation, and stimulates mucus and bicarbonate production by epithelial cells.13 Inhibiting this isozyme with NSAID therapy can result in gastrointestinal ulceration, hemorrhage, and gut perforation with septic peritonitis as a sequela. Direct damage to the gastric mucosal microcirculation and the formation of capillary microthrombi can also occur with NSAID use.13

In the kidneys, COX-1 activation results in prostaglandin I, E, and D production,14 which dilates renal vascular beds and diminishes vascular resistance, resulting in enhanced organ perfusion. Inhibition of these beneficial prostaglandins results in decreased renal blood flow, ischemia of the medullary papillae, and papillary necrosis.14

In platelets, COX-1 converts arachidonic acid to thromboxane A2, which is proaggregatory and vasoconstrictive. Its inhibition can be beneficial in preventing myocardial infarction in people3 and has been associated with subclinical increased bleeding times, decreased platelet aggregation, and decreased clot strength in dogs treated with a variety of NSAIDs.15,16

At therapeutic dosages, carprofen has greater selectivity for COX-2 vs. COX-1. Overdoses have been shown to increase COX-1 inhibition4 and the likelihood of adverse effects.

A subset of dogs treated with therapeutic doses of carprofen has exhibited an idiosyncratic hepatocellular toxicosis. A mean onset of clinical signs in dogs about 20 days after the start of therapy has been reported.17 Discontinuing the drug and administering supportive care resulted in complete recovery in most of the dogs in that report. This syndrome has not been reported in cats.

Because of the distinct pathologic mechanisms of idiosyncratic hepatocellular toxicosis vs. those of acute carprofen toxicosis, we will not discuss idiosyncratic hepatocellular toxicosis further. However, we will address hepatocellular injury due to intrinsic, dose-related effects associated with acute carprofen overdoses. The manufacturer reports about a 20-IU increase in alanine aminotransferase activity at doses 5.7 times the therapeutic dose in separate safety studies in dogs given carprofen orally for 13 weeks and one year12 and hypoalbuminemia in two of eight dogs treated at 10 times the therapeutic dose for 14 days.12