Pharmacologic studies help DVMs dispel commonly held myths
There are no efficacy studies yet available to indicate the value of tramadol for treating pain in animals.
Q: Could you address some of the common misconceptions in the market?
A: Dr. Mark G. Papich at the 2006 American College of Veterinary Internal Medicine Forum in Louisville, Ky., gave a lecture on myths and misconceptions in small animal therapeutics. Some relevant points in this lecture are provided here.
In small animal therapeutics there are many legends, outdated treatments, misconceptions and myths that persist. Data is now available through pharmacologic studies to dispel many of these old thoughts and concepts.
Are generic drugs as effective as proprietary drugs?
It is a common misconception that generic drugs are inferior or less effective than proprietary drugs. For a generic drug to be registered by the Food and Drug Administration (FDA), it must meet criteria for bio-equivalence. Drugs are considered therapeutic equivalents if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling. This does not necessarily mean that the generic formulation of a drug has been tested in therapeutic trials. It simply means that when equivalent doses are administered as the proprietary drug formulation (also known as the pioneer drug or innovator drug), the blood concentrations are equivalent based on the shape and profile of a concentration versus time curve. If a generic drug meets these criteria, one assumes that if plasma concentrations of a drug are equivalent, the therapeutic response also must be equivalent. There are no instances documented in veterinary medicine in which an FDA-approved drug has not been equivalent to the proprietary drug. Therefore, a claim that generic drugs are not effective is unproven. However, veterinarians recognize that among generic drug formulations, excipients, vehicles, colors, packing, tablet shape and release characteristics can vary. It is theoretically possible that differences in these additional ingredients could change the therapeutic response. Because there are few generic drugs registered for veterinary medicine, most generic drugs used in animals are human drugs. Even though bioequivalence may have been demonstrated in people, there is no assurance that the pattern of absorption, metabolism and excretion would be similar in animals.
Are compounded drugs equivalent to brand-name drugs?
Compounding is the practice of modifying a dose form in order to facilitate administration to a patient. Compounding can be a therapeutic necessity because veterinarians lack the availability of medications to treat the variety of diseases in animals. For example, human dose formulations must be modified to administer to a dog, cat or exotic animal. Sometimes compounding is performed to ease administration, mask a bitter taste or accommodate an animal's small size. Compounding is allowed by federal law, provided that it is performed on a patient-by-patient basis and other restrictions are met. The FDA Center for Veterinary Medicine restricts compounding from bulk chemicals containing the active pharmaceutical ingredient, especially if it is performed on a large scale.
Compounded formulations may provide an equivalent therapeutic response to a proprietary formulation in many instances. However, there may be problems with solubility, stability and potency for some drugs. The inactive ingredients and excipients added to drug formulations are done to ensure the stability of the drug, provide an optimum chemical environment, pH, or increase the ease of packaging or handling. Adding other chemicals, flavorings, vehicles or interfering with protective coatings of tablets in the course of compounding may interfere with the stability of the drug, decreasing its potency, oral absorption and efficacy. The most-common interaction is that from a change in pH. Drugs known to be compromised when compounded for animals include omeprazole, fluoroquinolone antimicrobials, diazepam, antifungal drugs (e.g., itraconazole) and poorly soluble basic drugs.
There may be clues that compounding has affected drug quality, purity or potency. Oxidation is often visible through a color change (color change to pink or amber for example). Loss of solubility may be observed through precipitation. Some drugs are prone to hydrolysis from moisture. A rule of thumb for veterinarians is that if a drug is packaged in blister packs or moisture-proof barrier, it is probably subject to loss of stability and potency if mixed with aqueous vehicles. If compounded formulations of solid dose forms show cracking, caking or swelling, the formulation has probably accumulated moisture and may have lost potency.
Do transdermal gels really work?
To meet the growing demands for more transdermal medications for animals, compounding pharmacies have prepared existing drugs (both human and veterinary drugs) into transdermal formulations. Most drugs cannot be absorbed across the skin without some enhancement. Their lipophilicity or solubility characteristics otherwise prevent the drug from penetrating the skin. Therefore, veterinary compounding pharmacies have mixed drugs with penetration enhancers (PE) to facilitate transdermal absorption. The most popular PE used by veterinary pharmacists is pleuronic lecithin organogel (PLO), which is lecithin (derived from eggs or soybeans) mixed with isopropyl palmitate and a poloxamer (pluronic). The ingredients in PLO act as surfactants, emulsifiers and solubilizing agents. There is little data available to suggest that drugs applied in a PLO vehicle are actually absorbed systemically in animals. Most published reports of transdermal application of drugs to cats showed that absorption was incomplete, nonexistent or highly inconsistent. Drugs examined so far have included glipizide, dexamethasone, buspirone, amitriptyline, fentanyl, morphine, fluoxetine, buspirone, morphine, fentanyl, enrofloxacin, diltiazem and methimazole. Drug absorption through the skin is actually more challenging than expected. The barriers of stratum corneum, hair and first-pass metabolism limit this route. In addition, some drugs may not be soluble or compatible in a transdermal vehicle. Many drugs are not potent enough to be delivered in the small volume (often 0.1 ml) required for practical transdermal therapy.
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: firstname.lastname@example.org.