Therapeutic Options and Controversies (AAEP 2004)
Controversies: A Mixed Bag Of Medications
Wayne McIlwraith, BVSc, PhD, DSc, FRCVS, DrMedVet (hc), Dipl. ACVS, director of Colorado State University's Gail Holmes Equine Orthopaedic Research Center, presented "Licensed Medications, 'Generic' Medications, Compounding, and Nutraceuticals--What has Been Scientifically Validated, Where Do We Encounter Scientific Mistruth, and Where are We Legally?"
The long title was needed for the scope of the discussion, and McIlwraith did a thorough job of educating the veterinarians in attendance on the current state of the industry.
He said many of the medications, supplements, and additives available today to horse owners and veterinarians can raise legal and ethical issues in the industry. He said many unethical and/or unlicensed products cause frustrations for manufacturers who spend millions of dollars researching new drugs, just to have illegal products claiming equivalency and taking product sales from licensed products. To add to the problem, many of the illegal products are not efficacious, or might not even contain the active ingredient.
"Evidence-based medicine" is becoming a common term, he said. This is "the conscientious, explicit, and judicious use of the current best evidence in making decisions about the care of individual patients." He noted that the underpinning of evidence-based medicine is "the application of appropriate experimental designs and statistics to medical research and medical literature." He added that observational, descriptive, and anecdotal studies do not provide proof of efficacy.
McIlwraith used his area of specialty to explain: He noted that the literature on treatments of joint disease "has a number of in vitro studies as well as bioavailability and absorption studies as indirect evidence of proof of effectiveness. Although such studies can be useful pilot studies, they do not answer the bottom-line question of efficacy in treating or preventing the disease process in the living animal and, therefore, need to be carefully examined in that light."
One of the big problems, said McIlwraith, is there is little incentive for manufacturers to prove their products.
FDA Licensing and Generics
"First and foremost," said McIlwraith, "an FDA-licensed medication is legal. It has been subjected to an approval process." An example of an FDA-licensed product is intravenous sodium hyaluronic acid (HA), trade name Legend. The initial FDA approval of Legend was based on a positive-controlled study of traumatic arthritis in a group of horses compared with horses given intra-articular HA.
He explained that after the federal patent expires on an FDA-approved medication, any company can undertake the process to get a license for a generic form of that drug. "A true generic drug must have the exact chemical formulation of the previously patented medication (pioneer drug)," said McIlwraith. It is critical to recognize that a true generic drug is a licensed drug and has been through the FDA process. Representing any medication as a generic that does not follow these guidelines is illegal.
"Two common such misrepresentations involved the products MAP-5 and Chondroprotec," noted McIlwraith. "There are numerous instances of MAP-5 being represented by distributors as generic Legend. In addition to it not being a generic drug, it is not licensed as a drug (it is only licensed as a device for extending semen)."
McIlwraith said Chondroprotec is licensed as a topical wound treatment. "It has been commonly represented as generic Adequan, but it is not," he stated. "This is both illegal and unethical. The fact that the company calls the product Chondroprotec (which implies cartilage protection) and packages it in a container-closure system that is identical to that used for an injectable product is an extreme example of misrepresentation."
Nutraceuticals and Animal Supplements
An ingredient (vitamin, mineral, extract, metabolite, etc.) that is legal to sell for human use is not legal to sell for animal use, McIlwraith said. While the widespread use of nutraceuticals is not necessarily illegal, he said, "It does present a major area of advertising misrepresentation and 'smoke and mirrors' science." He added that not all nutraceuticals and animal supplements are bad or illegal.
He said many nutraceuticals or nutritional supplements marketed for horses are illegal because manufacturers haven't complied with the FDA ingredient-recognition processes, completed ingredient-definition applications as described by the Association of American Feed Control Officials (www.aafco.org), followed state licensing requirements, and/or have made false claims on the label. He reminded listeners that such a product (as opposed to a licensed drug) cannot make medical claims, such that it can be used to remedy any illness or problem.
McIlwraith said there seem to be two principal issues with the lack of regulation of nutraceuticals and supplements. The first is that this group of products is relatively low on the FDA radar because the ingredients are not being given to food animals. Second is that there is no incentive for a manufacturer of, say, a glucosamine-chondroitin sulfate product, to get licensed. "Such products are not proprietary, and other companies can simply grab on to the coattails of the company that has gone to the trouble of getting approval," he said.
"Compounding has always been a part of veterinary medicine and remains of value," stated McIlwraith. "However, there has been a proliferation of compounding pharmacies and instances of unethical and possibly illegal practices, including use of licensed drugs' trade names."
He also mentioned the requirement of FDA-licensed drug manufacturers to report all adverse reactions. Compounders don't have that requirement.
Licensed Medications vs. The Pretenders
McIlwraith then discussed several commonly used medications and their levels of scientific proof.
HA is purported to improve lubrication of the joints. He discussed several studies done since 1970, and noted that in his clinical experience, HA is useful for mild synovitis, but any condition beyond mild synovitis would need adjunctive corticosteroid therapy.
He said when intravenous HA (Legend) was introduced, he was skeptical, but a controlled study in an equine model showed it to be quite effective. The value of intravenous HA for prophylactic use (to prevent joint problems) is a little harder to prove, said McIlwraith. He said in two studies positive trends were noted, but that wasn't positive proof of effectiveness.
An oral HA has been introduced into the market (Conquer), and McIlwraith said that just showing increased blood levels of HA after oral administration is not evidence for efficacy of the product in joints or for treating osteoarthritis.
McIlwraith also discussed non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and the compounding of corticosteroids. One study done at Colorado State confirmed that injecting the cortico-steroid methylprednisolone acetate (Depo-Medrol) into normal joints damaged
cartilage. He said the most commonly used intra-articular steroids in horses have been carefully evaluated, and reports of untoward effects are generally fictitious.
He said a new topical NSAID called Surpass has been scientifically validated.
While McIlwraith again noted that none of the oral supplements or oral nutraceuticals are licensed, there has been research done. "There have been a number of scientific studies done with Cosequin," said McIlwraith. "Most other products have simulated Cosequin and attempted to compete on the basis of decreased cost (with no proof of comparable efficacy) or other added ingredients."
He said evidence of the oral absorption of chondroitin sulfate has been shown in the horse. Studies also have shown that a product with lower molecular weight is better. He said glucosamine is absorbed by the horse, but at a low rate. It is unknown if these rates of absorption mean the ingredients are at a high enough level to have pharmacologic action in the horse.
He said there are problems with "truth in advertising" with some nutraceuticals.
McIlwraith's take-home message after this long and complicated discussion was simple: When equine veterinarians are involved initially in the diagnosis of a problem, the horse gets better care.
More information: www.TheHorse.com/ViewArticle.aspx?id=5423.
Co-moderators Kevin May, DVM, CVA, of the El Cajon Valley Veterinary Hospital in El Cajon, Calif., and James Kenney, DVM, of Kenney & Ketner in Colt's Neck, N.J., discussed how to incorporate acupuncture and chiropractic in to a Western medicine practice during a Sunrise Session. Out of the 10-15 veterinarians in the session, four or five were already using acupuncture and chiropractic in their practices and imparted what they had learned to the other veterinarians who were just checking these modalities out for the first time, or who were just learning to apply them after becoming certified.
Some veterinarians in the room have exclusively become referral veterinarians in these areas, and others have added one or both as adjuncts to their practices.
Discussion in the session primarily revolved around personal experiences with courses in acupuncture and chiropractic, incorporation of what they've learned, and the reminder that Western medicine should never be forgotten when treating patients.
"When that person comes to you with a horse for your evaluation and suggestion for treatment, you're offering them another bottle on the shelf," said May. "These modalities are nothing more than that."
Veterinarians discussed their successes in treating difficult cases, which included everything from a stubborn corneal ulcer to helping mares with raging heats. "You will find cases that will benefit from acupuncture/chiropractic," said one vet. "But don't forget your 'bread and butter,' " better known as your Western medicine workup.
Acupuncture vs. Chiropractic
When you have the choice of both, what do veterinarians use? It was suggested that the veterinarian do a thorough examination first using the acupuncture points, then adjust the horse using chiropractic ("sometimes you find that a lot of those painful points go away," one vet said), then check the acupuncture points again and perform acupuncture.
"It is good to use acupuncture when the horse is too painful for chiropractic," added a vet. Kenney said these modalities are safe when done properly, and May added, "If the horse is so painful that you have anesthetize him to treat him, then you probably don't need to be treating with chiropractic."
More information: www.TheHorse.com/ViewArticle.aspx?id=5410.
Therapeutic Options Forum
The Therapeutic Options Forum focused primarily on acupuncture and chiropractic. Moderators May and Kenney, and about 40 attendees, discussed relevant research presented in the last year, vet schools providing instruction in these modalities, mainstream continuing education events, the issue of non-veterinarians practicing these modalities, and their ethical use.
"Research is very scarce, particularly the gold standard double-blind type," Kenney said. He described two papers on acupuncture published in Equine Reseach--one on recurrent airway obstruction, the other on equine herpesvirus (EHV) testing. The first (which in Kenney's opinion had questionable methods) found that acupuncture during an recurrent airway obstruction (RAO) attack yielded no more improvement than handling (i.e., removing the horse from a dusty environment); the second found that sensitivity at certain acupuncture points in EHV cases seemed to correlate with physical and neurological examination findings, but the association wasn't unequivocal.
"There's not much (alternative therapy research) out there because it hasn't been long since we started using these modalities on animals," said Kenney. "For example, we've only been doing acupuncture on animals for about 20 years. In order to make these modalities part of mainstream veterinary medicine, we have to show that they work. We need to be more educated in the science of doing this.
May made the following comments regarding acupuncture: "We need to know what points are used in research, how they were treated, and if it didn't work, that's just as important for us to know as if it did."
There isn't a lot of research out on chiropractic, they said, while noting that Kevin Haussler, DVM, DC, PhD, of Cornell University's College of Veterinary Medicine, will publish a book on equine chiropractic in 2005. May said Haussler presented a paper at the 2003 convention on finding sensitive points and treating them; he demonstrated a measurable increase in pain-pressure thresholds in 10 out of 10 vertebral locations treated compared to controls. However, only five of 10 had a statistically significant increase in values.
"We need objective measurement of the way horses move--documentation of pre- and post-treatment kinetics, exactly how much joints bend, etc.--to help us be objective in evaluating horse, especially those with sacroiliac back pain where the horse doesn't limp," said one attendee. "These problems are very obvious to some vets and riders, but not to others."
Schools offering programs and continuing education events were discussed. One attendee noted that the American Veterinary Medical Association convention each year includes a track on alternative therapies, including all-day wet labs for people with no formal education.
Rick Mitchell, DVM, of Fairfield Equine Associates in Newtown, Conn., made these comments: "I think a wet lab is the way to go, to teach people some cookbook acupuncture to help some specific problems; teach some specific techniques and diagnostic points that go with specific conditions. We can't teach acupuncture or even all of the theory in a day, but if they can walk out there and do something, those are the ones that will go out and get IVAS (International Veterinary Acupuncture Society) training."
One attendee agreed that motion palpation would be a benefit to many veterinarians (in motion palpation, the chiropractor examines each complex spinal joint to analyze the degree to which it might lack proper motion). Advanced courses were suggested, but someone else said people often aren't even at beginner level, and that any chiropractic wet lab needs to be at the beginner level.
Another attendee said, "We need to have horses with known, specific joint lamenesses for people to palpate, block him sound, then re-palpate those points and see the difference to convince people there is diagnostic value to chiropractic evaluation."
"One reason for advanced seminars is to raise the bar," commented one attendee. "Wet labs will fill up with those who want instant usage, but we need to raise the level of awareness of what the state of the art in these practices is. Wet labs are good idea, but I think an in-depth seminar would help raise awareness."
The discussion then turned to non-veterinary practitioners of these modalities, including licensed human chiropractors who turn to animal work as well as those with no chiropractic certification. Liability, legal, and insurance concerns were voiced, as were issues of non-veterinarians doing work on their own or only after referral from a licensed veterinarian.
One attendee noted that a couple of years ago, some in Pennsylvania tried to restrict equine chiropractic to vets only, but there was such a furor that they dropped it.
"The AAEP needs to address lack of knowledge at state board and attorney general level about people who aren't qualified enough to do this, and prosecute those individuals doing harm," said an attendee.
More information: www.TheHorse.com/ViewArticle.aspx?id=5391.
Controversies: Immunomodulation Indications and Preparations
Horses transported more than 500 miles have a reduction in pulmonary macrophage function (responsible for clearance of small inhaled particles from the lung) for approximately three weeks, said Bonnie Rush, DVM, MS, Dipl. ACVIM, clinical instructor of equine internal medicine at Kansas State University. This is indicative of a reduction in how well the immune system can fight off invaders, and it is a good situation in which to use immunostimulants.
"The indications for immunostimulant therapy in horses are relatively specific, and these compounds are not intended to treat a broad spectrum of conditions," Rush explained. "The mechanism of action of non-specific immunostimulation is induction of macrophages to produce proinflammatory cytokines that drive a T-1-based (helper cells) immune system response. Immunostimulation therapy may not be effective in patients with acute, fulminating (suddenly occurring) infections, because the immune response is (already) maximally stimulated by the pathogen."
One preparation she discussed was non-viable Propionibacterium acnes, the immunostimulant activity of which has been recognized for over 30 years. The first reported use in horses was more than a decade ago. She said that in equine medicine, P. acnes is labeled for treatment of chronic respiratory disease and is recommended for cases that are unresponsive or transiently responsive to conventional antibiotic treatment. "In addition," she said, "it is recommended for prophylactic administration before stressful events that may impair pulmonary defense mechanisms, including weaning and long-distance transport."
She said P. acnes also has been anecdotally recommended for treatment of endometritis, osteomyelitis, papillomatosis (warts), abdominal abscess, fistulous withers, and sarcoid skin tumors. Rush said in her experience, P. acnes was effective for treatment of viral papillomatosis, but its effects against sarcoid skin tumors were less consistent.
There are side effects to the use of P. acnes, especially after the first administration. They include fever, anorexia, and lethargy within 12-24 hours of administration. She noted that subsequent injections usually elicit milder reactions.
Another preparation she discussed was the bacillus Calmette-Guerin (BCG) vaccine, which was developed from an attenuated (less virulent) strain of Mycobacterium bovis. She said that live BCG, whole-inactivated BCG, and mycobacterial cell wall fractions have been used as non-specific immunostimulants and vaccine adjuvants for decades.
Rush noted that mycobacterial cell wall products are used in horses to treat infectious respiratory disease and sarcoid skin tumors. She reported a study where this product was given to horses with respiratory disease resulting from stress, transportation, bacteria, and/or viral infections. The study noted that within seven days after administration of a single dose, 83% of treated horses were clinically normal, but only 36% of untreated horses were free from clinical signs.
Rush noted that a new product was introduced in late 2004 called Settle; it is a mycobacterial cell wall fraction labeled to treat endometritis in mares caused by Streptococcus zooepidemicus. She said the product could be used intrauterine or IV, and that in studies it showed a reduction in bacteria and fluid in seven days (clinical cure of 75% at seven days).
More information: www.TheHorse.com/ViewArticle.aspx?ID=5424.
Therapeutic Options Table Topic, www.TheHorse.com/ViewArticle.aspx?id=5451.
BY KIMBERLY S. HERBERT, STEPHANIE L. CHURCH, AND CHRISTY WEST
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