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Pharmacologic studies help DVMs dispel commonly held myths


Is tramadol a new miracle treatment for pain?

There are no efficacy studies yet available to indicate the value of tramadol for treating pain in animals. Tramadol has gained recent popularity because the generic formulations are very inexpensive, and safety problems have apparently not been an issue. It is premature to consider tramadol as a safe and effective treatment for pain in small animals. However, the pharmacokinetic data available from animals and experience in people suggest that its use may be promising. Tramadol is a unique oral analgesic drug that currently is not registered as a controlled substance. The exact mechanism of action for tramadol is uncertain, but there is probably more than one mechanism that contributes to its clinical effects. Tramadol has some mu-opioid receptor action, and it also inhibits the reuptake of norepinephrine (NE) and serotonin (5-HT). One of the isomers has greater effect on serotonin reuptake and greater affinity for mu-opiate receptors.

The other isomer is more potent for norepinephrine reuptake and less active for inhibiting serotonin reuptake. Taken together, the effects of tramadol may be explained through inhibition of serotonin reuptake (similar to fluoxetine and other antidepressant drugs), action on alpha-2 receptors (similar to medetomidine and xylazine), and activity for opiate mu-receptors (similar to morphine).

Although tramadol is a weak opioid compared with morphine, the metabolite (desmethyltramadol, also called M1) may have greater opiate effects than the parent drug (for example, 200 times in opiate receptor binding). Studies have shown that tramadol is absorbed orally in dogs and was well-tolerated. Dogs produce sufficient metabolite (M1) that may contribute to the analgesic effects. Clearance is higher than in people, which will necessitate a higher dose for dogs. Although safety and efficacy studies are not available, based on pharmacokinetic studies the recommended doses is 5 mg/kg every six to eight hours orally in dogs.

Are COX-2 drugs really safer or more dangerous than other NSAIDs?

The nonsteroidal anti-inflammatory drugs (NSAIDs) have as their most-common adverse effect, gastrointestinal (GI) toxicity. Common reactions are vomiting, diarrhea and nausea. GI ulcers are more rare. In the late 1990s, we became convinced through developments of new drugs for people, called the COX-2 inhibitors (coxibs), that drugs specific for the COX-2 isoenzyme may be safer than traditional therapies. In late 2004 studies revealed (from human medicine) that these drugs may safety problems. Two of them (rofecoxib and valdecoxib) later were withdrawn from the market because of concerns for adverse cardiovascular events.

Drugs for humans were developed that are highly COX-2 specific, celecoxib (Celebrex), valdecoxib (Bextra) and rofecoxib (Vioxx). These are often referred to as the coxibs because they share some similar chemical properties. Other drugs can be somewhat selective for COX-2 and belong to other drug classes (e.g., meloxicam). In human medicine, the coxibs became among the top-selling prescription drugs of any category in human medicine. Deracoxib was the first veterinary drug in this group. The newest in this class is firocoxib (Previcox), which is more specific for COX-2.

There is no evidence that the problems in humans that caused the withdrawal of two of the coxibs exist in animals. Incidence of adverse cardiovascular events is much rarer in animals, and safety data in animals does not reveal increased risk of cardiovascular events.

In people, the studies indicating that the coxib were safer for the gastrointestinal tract were later criticized. Some skeptics have proposed that selective COX-2 inhibitors may not be appropriate for all patients because COX-2 enzyme products may be involved in actions other than inflammation. For example, COX-2 products may be biologically important for angiogenesis, renal function, regulation of bone resorption, reproductive function and healing of gastroduodenal ulcers.

In veterinary medicine, it has not been possible to compare gastrointestinal safety among drugs from large controlled, prospective trials. The only comparisons have come from some evaluations from limited clinical trials used for drug registration. These trials are available from the drug sponsor and, in general, have shown that the incidence of common GI signs are not much different among the NSAIDs. In the limited clinical trials conducted for the product's registration in dogs, the rate of gastrointestinal ulcers when the drugs were used at approved doses was so small that comparisons among drugs are not possible. However, despite high COX-2 specificity, as measured from in vitro COX-1-to-COX-2 inhibitory ratios, a selective COX-2 inhibitor has been associated with gastroduodenal ulcers in some dogs.

Dr. Hoskins is owner of DocuTech Services. He is a diplomate of the American College of Veterinary Internal Medicine with specialities in small animal pediatrics. He can be reached at (225) 955-3252, fax: (214) 242-2200 or e-mail:


Source: DVM360 MAGAZINE,
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