Features June 2003 Issue

Administer Anti-Inflammatory Drugs to Your Dog With Care

Anti-inflammatory drugs are life-savers for many arthritic dogs, but used improperly, they can cause injury or even death.

By Lexiann Grant

When the Norwegian Elkhound rescue came to me and my husband, she couldn’t climb stairs. Attempts to lift the old dog resulted in snaps at our hands. Radiographs revealed that she had severe hip dysplasia and an unrepaired pelvis, broken when she was hit by a car sometime in her past. As a result, Shadow had crippling arthritis. On good days, she would lie in the sun without panting from pain; on bad days, her stiffness rendered her incontinent. We observed her misery and wondered what could be done.

These powerful non-steroidal anti-inflammatory drugs can completely restore a high-quality, comfortable life to an arthritic dog. However, in order to so safely, without also causing serious harm, they must be used strictly according to label instructions.

Our veterinarian prescribed Rimadyl®. Within a few days, Shadow was running in the yard, playing with the other dogs. She bounded up the steps on her own and we no longer had to clean up urine puddles where she napped. The improvement was amazing, so for months, we kept Shadow on a twice-daily dose of the popular canine drug.

One morning we found vomit around her bed. She refused to eat or drink and had to be carried outside, where she laid down instead of emptying her bladder. A rushed visit to the veterinarian and blood tests indicated that Shadow’s liver enzymes where elevated “off the charts.”

Shadow’s liver failure was so extreme, her condition was hopeless. In complete shock, we gave our permission for Shadow to be euthanized.

Because stories about Rimadyl-related deaths were making pet news, we asked if the arthritis drug could be responsible. Our veterinarian was uncertain.

What is certain is that between 20 to 50 percent of older dogs develop osteoarthritis. And, as with human arthritis sufferers, non-steroidal anti-inflammatory drugs (NSAIDs) can help dogs by reducing the inflammation caused by arthritis, thereby relieving stiffness and discomfort. In many veterinary clinics the recommended therapy may be Rimadyl®, EtoGesic®, or Deramaxx™. But, like all medications, these drugs can cause serious side effects, and should not be used without a thorough understanding of their risks.

Powerful new help
In January 1997, when carprofen was first introduced by Pfizer to the veterinary market as Rimadyl, it appeared to be nothing less than a wonder drug. Initial trial results indicated that dogs who were given the drug had increased mobility and decreased pain, and indeed, many dog owners who sought prescriptions for their arthritic dogs were thrilled to see their beloved pets running, jumping, and playing again as they had in pre-arthritic days. Rimadyl became one of the most widely prescribed veterinary drugs of all times.

But with increased usage came an increasing number of reports of dogs who became ill after taking Rimadyl. The Food and Drug Administration’s Center for Veterinary Medicine (FDA CVM) tallied hundreds of “adverse drug experience” (ADE) reports noting side effects including vomiting, altered kidney or liver enzymes, loss of appetite, lethargy, increased urination, diarrhea (often bloody), weakness, confusion, and convulsions.

At first there seemed to be no cause for alarm because the side effects were common to NSAID usage and were similar to those observed during pre-approval testing. Then dogs started dying.

One of the earliest casualties was George, an arthritic Labrador Retriever rescued by Jean Townsend of South Carolina. “I’d read the brochures in my vet’s office about Rimadyl. It sounded like a miracle drug,” says Townsend, “I decided this drug would help George.”

At the end of a 10-day trial period in September of 1997, Townsend returned to her veterinarian to have the dog’s twice daily, 75 milligram (mg) prescription refilled. “George was better,” she says.

One night about 20 days later, Townsend was wakened by a “horrible scratching sound.” She found George crawling in the hall, unable to walk. The next morning, because she thought he had pulled a muscle, she gave him his usual dose of Rimadyl. That night he didn’t eat, and the following day began vomiting. Townsend took him to her veterinarian, who hospitalized the dog.

Despite aggressive treatment, George progressively disintegrated over six days at the vet clinic. Townsend visited her dog daily, but couldn’t stand to see him suffer any longer. “He couldn’t hold his head up. He’d had a blood-filled bowel movement and the whites of his eyes were yellow, his gums were yellow, his skin was yellow. I will never forget the look in his eyes – such hurt and despair,” describes Townsend. “I told them, ‘No more. I have to let him go.’ ”

Townsend’s dog and others like him seemed rare exceptions. Over the next few years, thanks in part to an aggressive marketing campaign by Pfizer, Rimadyl became the drug of choice for 1 million, then 2.5 million arthritic dogs.

CVM asks for changes
By December 1999, a CVM update noted that the CVM had received “a substantial number” of ADE reports for carprofen. In fact, a full 39 percent of the ADE reports in 1998 involved Rimadyl – some 3,626 cases – “considerably more than that received for other animal drugs.” Of these, 13 percent (about 471 cases) resulted in the death or euthanasia of the dogs.

Based on the early ADE reports for Rimadyl, CVM veterinarians met with Pfizer representatives and made several suggestions for changes to the product’s labeling and package inserts. Accordingly, Pfizer issued “Dear Doctor” letters to veterinarians, Animal Health Technical Bulletins detailing “Clinical Experience with Rimadyl,” and patient handouts. New information was inserted into the “Adverse Reaction” sections of the product label.

Because of the possibility for adverse reactions, Pfizer began to (and continues to) recommend that, prior to treatment, dogs be given a complete physical examination, including baseline blood tests. Owners are also advised that periodic monitoring should be done while their pet takes the drug.

One CVM veterinarian went so far, in a January 2000 article in DVM Magazine, to suggest that (in his own opinion) a complete blood profile be taken monthly as long as a dog is given Rimadyl. This is not the CVM’s present recommendation, however. “The labeling has recommendations for baseline testing for preexisting disease and periodic monitoring, which should be determined on a case-by-case basis,” says Dr. John D. Baker, Acting Team Leader in the CVM’s Division of Surveillance.

The use of Rimadyl continues to increase. Today, an estimated 4 million dogs in the United States are given the drug.

Next up at bat
Rimadyl wasn’t the only canine NSAID on the market for long. EtoGesic® is the NSAID entry of Fort Dodge Animal Health, a division of pharmaceutical giant Wyeth. The drug, etodolac, known as Lodine in its human application, was tested and approved for veterinary use in 1998. Fort Dodge claims the drug causes fewer adverse reactions than other NSAID drugs, and notes as a benefit that the drug is given only once a day. Today, according to Fort Dodge, about 1 million dogs take EtoGesic.

The events in the first years following the drug’s approval resembled Rimadyl’s. As the number of dogs who were given EtoGesic increased, so did ADE reports. As with other NSAIDs, its most frequently reported side effects are vomiting, loss of appetite, bloody diarrhea, lethargy, altered liver and kidney enzymes or function, dry eyes, convulsions, and death.

Within two years of the drug’s approval, Fort Dodge was advised to distribute “Dear Doctor” letters and revise the product’s labeling to strengthen the cautions and warnings to veterinarians and dog owners. The “Dear Doctor” letters asked veterinarians to consider baseline lab tests before prescribing EtoGesic and to recommend periodic monitoring tests. A Client Information Sheet was also provided for client handouts.

Despite its smaller market penetration (compared to Rimadyl), in 1999 the CVM listed EtoGesic as the third most commonly reported drug for adverse experiences, detailing 492 ADE reports.

Like Pfizer, Fort Dodge Animal Health continues its veterinarian and dog owner education efforts. Responding to our questions, the company released the following statement:

“The comments you listed including veterinary examinations for proper diagnosis and appropriate prescribing, blood tests for patients, and client education on the importance of early detection of side effects and ongoing veterinary monitoring, are all important issues to assure a beneficial experience with any nonsteroidal anti-inflammatory drug (NSAID).

“Another consideration is to give the NSAID with food. Studies show EtoGesic is readily absorbed with or without food. Owners have found that providing it during feeding is convenient and may help reduce short-term GI upset post-administration. In a study evaluating the development of GI lesions by endoscopy, no significant difference between EtoGesic and the placebo was found over a 28-day dosing period.

“We also stress the importance of regular patient monitoring by a veterinarian and client education. Fort Dodge Animal Health provides education materials to both veterinary clinics and dog owners to provide them with the most current information on the safety, efficacy, and benefits of EtoGesic for the management of pain and inflammation associated with osteoarthritis in dogs.”

New hope or new problems?
Now there is an even newer NSAID. In 2002, Novartis introduced Deramaxx™. Although the product’s initial CVM approval was for post-orthopedic-surgical pain, with treatment lasting five to seven days, expectations are that extra-label approval for treatment of chronic osteoarthritis will be complete by this summer. The drug, deracoxib, is nearly identical in chemical structure to Celebrex, a human arthritis drug in the new COX-2 class of NSAIDs.

Most NSAIDs inhibit the production of two forms of an enzyme called cyclooxy-genase (COX-1 and COX-2), which catalyzes the first two steps in the biosynthesis of agents that result in inflammation. According to their manufacturers, COX-2 drugs inhibit only the COX-2 enzyme, which appears to play a larger role in causing inflammation, and interfere less with the COX-1 enzyme, which appears to be more responsible for normal physiological functions such as maintenance of the gut mucosal barrier, blood clotting, and kidney function. Theoretically, by blocking only the COX-2 enzymes, the COX-1 enzymes are free to work as usual, resulting in fewer side effects such as gastric ulcers or renal failure.

Promising as this sounds, considering its short career, there have been a surprising number of ADE reports filed on Deramaxx. From its introduction (including approved and extra-label use) in August 2002 through mid-February 2003, the CVM received more than 100 ADE reports involving Deramaxx.

The adverse experiences are typical for NSAIDs: vomiting, inappetence, lethargy, and altered kidney and liver enzymes. According to a CVM coordinator, death is eighth on the list of side effects reported in the ADEs. If dogs who were euthanized are added to the total of dogs who died, it jumps to third on the list.

However, until estimates of the number of dogs who have taken the drug are tallied, it can’t be known what percentage of dogs have experienced side effects. Until then, Novartis can only observe the trends provided by the ADE reports.

According to Dr. Guy Tebbit, Vice President of Research and Development at Novartis Animal Health, the trends that its “pharmaco-vigilance” team has witnessed so far indicate that the drug is performing in line with its makers’ expectations. “What we have seen thus far has been very normal,” says Dr. Tebbit. “It’s tracking right along the lines for the information on the label that accompanies the drug.”

According to Dr. Tebbit, Novartis has no current plans for altering the label warnings or information sheets that accompany the drug, since, thus far, Deramaxx is behaving as expected and as already described on the current labels. “If we saw a trend in the ADEs that was different from what we expect, then we would have to sit down with the FDA and agree to new label language. But, so far, the trends we are seeing are very consistent with the existing labeling,” he says.

Dr. Tebbit adds, “We’re delighted with the drug and its performance. We have a lot of confidence in Deramaxx – confidence derived from our experience with it in our pre-market testing. We are very happy with the results.”

Number crunching
The moral of the story is to make certain you – your dog’s guardian – completely understand the potential for benefits and risks of the medication prescribed by your veterinarian. In order to do this effectively, you need to read and understand the product label, or be thoroughly briefed by your veterinarian (who should read and understand the material).

Unfortunately, busy veterinarians may fail to give a new product more than a cursory look at its insert information. Most vets are happy to be able to offer effective products for keeping their patients comfortable. And unless one of their own patients suffers a drug-related complication, some veterinarians may not closely review the information listed for the products’ contraindications, precautions, and adverse reactions.

Even a curious, committed veterinarian or dog owner who reads all the manufacturers’ literature describing the veterinary drugs may be unable to successfully interpret the statistics regarding the drug’s premarket studies. Most of the pharmaceutical companies do not publish actual numbers of ADE reports, but express the cases in ratios – a practice (intentional or not) that minimizes the impact of the actual number of problems.

For example, Pfizer’s reporting (in its August 1999 Technical Bulletin on Rimadyl) that death was reported in 1.8 cases per 10,000 dogs treated with Rimadyl in 1997. In the same report, the company claimed Rimadyl had been (at that time) prescribed for more than 2.5 million canine patients. If the 1997 ratio held, one could extrapolate that as many as 450 of those 2.5 million dogs could have been expected to die as a result of being given Rimadyl.

The CVM, at least, uses actual numbers, not ratios, when expressing the ADEs for veterinary drugs. The CVM ADE reports on carprofen (Rimadyl) break out 371 canine deaths in 1999, 470 in 2000, and 537 in 2001. Its ADE reports on etodolac (EtoGesic) for 1998 through 2001 indicate that 1,224 cases were reviewed and 135 dogs died.

Who is responsible?
Given that death is a potential result of NSAID use, dog owners and veterinarians alike should pay close attention to the warnings and suggestions for these and any other drug products. However, for a number of reasons, many dog owners fail to hear this information.

Veterinarians must accept some of the blame. With millions of dogs experiencing relief from the drugs, and with side effects occurring in only a small percentage of these patients, some veterinarians fail to heed the warnings or take them seriously enough to discuss them at length with their clients. Some are lax about insisting on periodic lab tests that can indicate whether problems are beginning to develop.

“Most owners are not told what the side effects are and their pets are not monitored with blood and urine tests,” alleges Shawn Messonier, DVM, owner of the Paws and Claws Animal Hospital in Plano, Texas, and author of The Arthritis Solution for Dogs.

But owners should also be held responsible for failing to practice due diligence before medicating their pets. Every drug – and every herb, homeopathic remedy, nutraceutical supplement, etc. – can cause unwanted or unexpected side effects, and owners need to educate themselves about the potential for harm before blindly accepting any treatment for their dogs.

Reducing the risks
My husband and I had heard stories about NSAID-related deaths and health complications when we administered Rimadyl to our rescued Elkhound, Shadow, and knew there was a possibility that she could suffer side effects if she stayed on the drug. Yet, without Rimadyl, the quality of her life was poor. We thought we made the right decision. In retrospect, had we been armed with more information, we could have made different choices about her treatment plan.

If, like Shadow, your dog could benefit from treatment with one of these drugs, take the following steps to reduce their risk:

• Get a proper diagnosis. Not all lameness is caused by arthritis. Have your dog evaluated, with x-rays, to rule out injury, bone cancer, or other causes of joint disease.

• Have laboratory tests done prior to treatment. The labels of all canine NSAIDs indicate that blood tests are required for safe prescribing. A blood and urine profile is needed to check your dog’s hepatic, renal, gastrointestinal, cardiovascular, and pancreatic function. That’s because you must . . .

• Give NSAIDs only to healthy dogs. Dogs with bleeding disorders, or kidney, liver, and/or cardiac disease are not good candidates for NSAID therapy. Extreme caution should be taken with dogs who have even borderline high-normal liver enzymes, or chronic disease, such as mild kidney disease – conditions that are common in older dogs, who are more susceptible to problems with these drugs.

• Monitor liver and kidney enzymes during treatment. Your veterinarian should run periodic blood tests to make certain that no problems develop. How often depends on the health of your pet, possibly every three, four, or six months.

• Give NSAIDs with a meal. This can reduce the chance of stomach upset.

• Be cautious with concurrent drug use. Some drugs, like those used to treat epilepsy or certain anesthetics, may not be compatible with NSAIDs. Because of the potential to cause gastrointestinal ulcers, the combined use of aspirin, multiple NSAIDs, or steroids is not advised. Ask your veterinarian to advise you as to which drug combinations are safe and which are not.

• We’ll say it again: Read the drug’s client information sheet. If you are not handed one when you receive your dog’s prescribed drug, ask for it. Some veterinary practices buy the drugs in bulk and repackage them when dispensing. That’s okay, but they should also make a copy of the original product package insert for you.

• Familiarize yourself with signs of all the possible adverse reactions to NSAIDs. If your dog exhibits any one of these signs, discontinue the drug’s use and seek veterinary care immediately.

• Discuss the risks, benefits, and alternatives to NSAID use with your veterinarian. If your vet doesn’t take time to discuss your concerns, or brushes them off without answering, find another vet.

A viable choice?
Veterinarians at the CVM regard canine NSAIDs to be safe and effective as long as consumers take precautions and pay attention to the labels and insert warnings. The CVM’s 1999 “Update on Rimadyl” goes so far as to say that NSAID therapy should not be considered as an elective therapeutic choice, but rather the “primary therapy available for maintaining an acceptable standard of life due to the long-term debilitating effects of osteoarthritis.”

Most veterinarians interviewed about NSAIDs report seeing improvement in their patients. Many state that they have not seen cases of adverse reactions to the drugs in their clinics, and believe that the risks are worth taking for many dogs.

“I have seen hundreds of dogs who would have been euthanized without these drugs,” says Tammy Smith, DVM, of the Colonial Animal Hospital in Belpre, Ohio.

Even one owner whose dog died after being given NSAID therapy recognizes the drugs can be helpful. Elsa Norton, of Saugerties, New York, said her veterinarian thought that her geriatric dog’s health problems leading up to his death “possibly” may have been triggered by NSAID use.

Norton says she wishes she made a different choice regarding her dog’s treatment, but adds, “Rimadyl has been a miracle drug for some dogs and I’m grateful that those animals have been helped. If I had it to do over, I would have started with alternative treatments. Anyone considering (NSAIDs) should research these alternatives first. But, if your animal is in such pain that the other option is euthanasia, then by all means try the medication.”

NSAIDs can be effective tools in relieving the pain and stiffness of arthritis when used properly and measures are taken to prevent problems. Weigh the benefits against the risks – and don’t forget there are effective alternatives available.


Also With This Article
Click here to view "What You Can Do."
Click here to view "Adverse Drug Experience (ADE) Reports."
Click here to view "Possible Side Effects of NSAIDs."
Click here to view "Stop Use Immediately If Side Effects Occur."
Click here to view "Do NOT Switch NSAIDs Quickly."
Click here to view "Alternatives to NSAID Therapy."

Lexiann Grant is a member of the Dog Writers Association of America and an eight-time recipient of the Maxwell Medallion for excellence in dog writing. She and her husband live in southeastern Ohio with their four dogs and two cats.

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