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THE PET PHARMACY
By Wendy C. Brooks, DVM, DipABVP
Educational Director, VeterinaryPartner.com

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Etodolac (EtoGesic, Lodine)

Brand Name: Lodine

Available in 200 mg, 300 mg, 400 mg, 500 mg, and 600 mg tablets

Background

Etodolac is a member of the class of drugs known as NSAIDs (non-steroidal anti-inflammatory drugs), the same class as such common over-the-counter remedies as Advil (ibuprofen), Aleve (naproxen), and aspirin.  This class of drug is used for pain relief successfully in humans, but safe NSAIDs for pets has only been achieved relatively recently.

The problem with the pet use of NSAIDs made for humans has been unacceptable, even life-threatening, side effects:

  • Stomach ulceration - even perforation and rupture of the stomach can occur. This is not only painful but life-threatening.
  • Platelet deactivation - platelets are the cells controlling the ability to clot blood and, as a general rule, it is preferable not to promote bleeding. We would prefer platelets to remain active and able to function should we need them.
  • Decreased blood supply to the kidney - this could tip a borderline patient in to kidney failure.

The veterinary profession had been in need of an NSAID that could effectively relieve pain without the above risks. Etodolac is a human NSAID that turns out to offer important safety aspects to both dogs and cats.

This new plane of safety is made possible by new scientific knowledge. Many of the biochemicals responsible for the pain and inflammation we want to allieviate are produced by an enzyme called cyclo-oxygenase 2. The goal is to inhibit this enzyme without inhibiting its counterpart cyclo-oxygenase 1. Both enzymes produce prostaglandins but we want to keep our constitutive prostaglandins that help maintain our bodies (these come from COX-1) but not make the inflammatory prostaglandins that come from COX-2. NSAIDs like aspirin inhibit all COX enzymes, good and bad alike. Most human bodies are okay with this but most dogs and cats are not.

Etodolac is what is called a COX-preferential NSAID, which means that it inhibits COX-2 much more strongly than COX-1 and this new plane of safety has enabled dogs to have long-term orally administered pain relief with minimal side effects potential. Many canine lives have been extended with good quality because of the advent of this class of pain relief.

How this Medication is Used

Etodolac is used to treat pain either for short-term or long-term use. Because of the tablet strengths available, smaller dogs cannot be dosed accurately. Etodolac's veterinary formula with more appropriate canine sizes is no longer being marketed. The human formulation can be used but only in dogs for whom the tablet size is workable.

A dog that is potentially a candidate for long-term use of any NSAID should have a complete examination by the veterinarian, a screening blood panel to establish baseline biochemical values, and ideally some kind of recheck testing two weeks after starting the NSAID. This work is because most adverse reactions, unusual as they may be, occur within this initial time frame, and it is important that they be recognized before they get out of hand. After this initial period, complete blood panels should be given every six months, which is an important step with any medication for long-term use, not just the NSAIDs.

Etodolac can be used in dogs but should not be used in cats.

Side Effects

The side effects of concern are the same with all NSAIDs: stomach ulceration, loss of kidney function, and inappropriate bleeding, though etodolac has a special side effect of concern: “Dry Eye” (keratoconjunctivitis sicca). Development of these side effects are dependent both on the dose of medication used and on risk factors of the host (for example: an aged pet may not efficiently clear a dose of medication from its body leading to stronger and longer activity of the drug). There is also a particular idiosyncratic reaction for NSAIDs which has received a great deal of press. An idiosyncratic reaction is one that is not dose-dependent nor predictable by any apparent host factor; it simply happens out of the blue. This particular idiosyncratic reaction is a liver toxicity which is so rare that it did not show up in any of the initial 400 test subjects, nor in the U.K. use of the carprofen and was not recognized until carprofen was used in over a million dogs in the U.S. after its release as the first NSAID. While it was carprofen use which allowed this reaction to be discovered, it is now generally agreed that any veterinary NSAID could yield this reaction (simply using an NAID other than carprofen will not prevent this potential reaction). We will review this reaction as well as the other side effects below.

  • Dry eye (Keratoconjunctivitis Sicca) is a lack of tear production. This side effect seems to be unique to etodolac and not a problem with other veterinary NSAIDs. The exact mechanism by which etodolac may cause this side effect is still unclear; in fact, studies cannot establish true causality between dry eyes and etodolac use (we only know there is correlation). In some dogs, discontinuing the etodolac leads to recovery but in some dogs tear production never recovers. Dogs who took etodolac less than 6 months seem to be four times more likely to recover from this side effect. If there are specific risk factors that make a dog on etodolac more likely to develop dry eye, we do not know what those risk factors are at this time.

  • Approximately 5% of dogs on etodolac develop nausea, appetite loss, vomiting or diarrhea. If any of the above are noted, etodolac should be discontinued and the dog brought in for a liver enzyme blood test. In most cases, the reaction is minor and resolves with symptomatic relief, but it is important to rule out whether or not the patient has more than just a routine upset stomach.

  • If a patient has borderline kidney function, NSAIDs should not be used as they reduce blood flow through the kidneys. It is also important that NSAIDS not be given to dehydrated patients because of this potential side effect.

  • The Hepatopathy Side Effect (usually occurs within the first 3 weeks of use)? An NSAID reaction that has received special attention is hepatopathy, a type of liver disease. Symptoms include nausea, appetite loss, and/or diarrhea as well as marked elevations (3-4 times higher than the normal range) in liver enzymes measured in the blood. ??Dogs with this syndrome show improvement with support 5 - 10 days after discontinuing the NSAID. It is important that the NSAID be discontinued and the patient evaluated in the event of upset stomach signs in case of this syndrome. Even though this is a rare syndrome (one in 5000), it can become life-threatening if ignored.  Appetite loss or other intestinal signs do not necessarily indicate a hepatopathy but since they might, it is important not to ignore these signs should they occur. There is no way to predict which dogs will experience this side effect.

  • All NSAIDs are removed from the body by the liver. If the patient’s liver is not working normally due to another disease or if the patient is taking other drugs that are also removed by the liver, it is possible to over work the liver and exacerbate pre-existing liver disease. If there is any question about a patient’s liver function, another class of pain reliever should be selected.

The hepatopathy reaction usually occurs in the first 3 weeks after starting the NSAID but could theoretically occur later.

It is important to realize that COX-selectivity is not the sole factor in safety. In humans, the incidence of kidney function-related side effects was unchanged by the development of COX-2 preferential NSAIDs and we expect the same is true with dogs. Still, these drugs have an excellent track record for safety. The important issue is to recognize risk factors for adverse reactions and take preventive steps (see the Concerns and Cautions section below). Many exaggerated reports and rumors have surfaced on the internet and it is important to consider only confirmed and properly investigated information.

Interactions with Other Drugs

Multiple drugs of the NSAID class should not be used concurrently as the potential for NSAID side effects increases. This means a greater chance of exactly what we had hoped to avoid by using a COX-preferential NSAID instead of a non-preferential NSAID: stomach irritation/ulceration, altered kidney function, inappropriate bleeding. For similar reasons, NSAIDS should not be used in conjunction with corticosteroid hormones such as prednisone, dexamethasone etc. A 5 to 7 day rest period is recommended when changing from one NSAID to another. Aspirin poses an exception due to its strong abilities to inactivate platelets so 10-14 days is recommended when switching to a veterinary NSAID from aspirin. Allow at least one week between prednisone and a veterinary NSAID.

If etodolac is used concurrently with phenobarbital, it is especially important that appropriate liver monitoring be performed. (My hospital recommends bile acids testing every 6 months for dogs on phenobarbital.) These two drugs interact such that neither may work well if they are used together.

ACE inhibitors such as enalapril or benazepril may not be as effective with etodolac. (ACE inhibitors are used in the treatment of hypertension or heart failure.) This is because ACE inhibitors depend on the dilation of blood vessels in the kidneys and such dilation can be interfered with by NSAIDs. The diuretic effect of furosemide may be reduced with concurrent etodolac and the heart medication digoxin may achieve higher than normal blood levels. All of these side effects are particularly relevant to heart failure patients.

When combined with cyclosporine, an immunomodulator, etodolac may increase blood levels of cyclosporine and thus increase the potential for cyclosporine side effects.

Concerns and Cautions

Etodolac has not been tested in pregnant or nursing females and thus is not recommended for use in such individuals, particularly since COX-2 is important in reproductive function. 

Etodolac should not be used in dogs with pre-existing liver or kidney disease. In order to screen for those, it is a run a blood chemistry panel prior to starting long term etodolac.

It is probably prudent to periodically monitor tear function in patients on etodolac.

Any dog on long-term medication of any kind should probably have blood chemistry rechecks every 6 months.

The blood pressure-related side effects that have made COX-2 selective NSAIDs controversial in humans are not significant factors in canine use.

Etodolac should not be used in patients with pre-existing GI ulcerations.

Safety has not been established for etodolac in patients under 12 months of age.

Etodolac, like the other veterinary NSAIDs, may alter thyroid test results.

Read the product insert for Etogesic.

 

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