Evidence Update: Associations between Environmental Chemical Exposure and Hyperthyroidism in Cats

One of the great mysteries of veterinary medicine if hyperthyroidism in cats. Benign tumors of the thyroid glad in older cats can produce excessive amount of thyroid hormone, and this can lead to a host of clinical symptoms. Fortunately, the disease is relatively easily treated by various methods. However, the condition seems to be more common than it used to be a few decades ago (though there are no reliable statistics, and it could just as easily be that vets were less likely to diagnose this problem in the past), so this begs the question of what might be the cause of the apparent increase in cases.

There are many theories, and environmental toxins of one kind of another are a popular focus of blame for this disease. In 2015 I wrote about the claim that certain flame retardant chemicals, known as PBDEs, might be associated with thyroid disease in cats, and I provided an update on the literature about this in 2017. At this point, the best we can say is that there has been some association between PBDE levels and thyroid disease in cats, but it is based on very weak data involving few animals, and no strong evidence yet exists to label this as a causal factor.

I recently ran across a new article by the same research group who looked at PBDEs and thyroid disease in 2016, this time suggesting there might be a connection with a different class of environmental chemicals, known as per- and polyfluoroalkyl substances (PFASs for short).

Miaomiao Wang, Weihong Guo, Steve Gardner, Myrto Petreas, June-Soo Park. Per- and polyfluoroalkyl substances in Northern California cats: Temporal comparison and a possible link to cat hyperthyroidism. Environmental Toxicology and Chemistry, 2018; DOI:

This paper appears to be using blood samples from the same groups of cats discussed in the previous paper, 26 sampled between 2008 and 2010, and 22 sampled between 2012 and 2013. The conclusions are similar but even more tentative than those regarding PBDEs. Levels of the chemicals declined between the earlier sampling period and the later (in humans as well as cats), likely due to the phasing out of these chemicals in industrial use.

There was a statistical associated between PFAS levels and thyroid disease in the latter period, but not in the earlier period. However, there was tremendous individual variation and very few cats in the two groups (those with thyroid disease and those without), so it is impossible to identify a clearly meaningful difference. Whether these chemicals even could be a potential cause for hyperthyroidism is unclear. While some lab animal studies have shown that PFASs can affect thyroid hormone levels, the direction of this effect (towards higher or lower levels) and the real-world significance are not at all clear in ab animals or humans.

Interestingly, there was no apparent association between levels of PFASs and PBDEs in these cats. That means that while PBDEs may have been associated with hyperthyroidism, and PFASs may have been associated with hyperthyroidism, there was no association between PBDEs and PFASs. That doesn’t make a lot of statistical sense, and it is likely an example of the limitations of such a small sample of cats.

While papers like these are interesting, they don’t yet add up to any clear or compelling evidence for a causal role of either of these classes of chemicals in feline hyperthyroidism. If anything, they may suggest such a role is unlikely since the levels of both PFASs and PBDEs seem to be going down over the last 10 years, yet there is no sign that thyroid disease is becoming any less common.

Posted in General | 3 Comments

Evidence Update: Still no Convincing Scientific Evidence for any Benefits from Veterinary Hyperbaric Oxygen Therapy

It’s been a few years since I covered the subject of hyperbaric oxygen therapy (HBOT), a treatment that involves placing patients in a sealed chamber and raising the air pressure and oxygen levels above those in the normal atmosphere at sea level. Back in 2013, I summarized the available evidence and reached this conclusion:

HBOT is a biologically plausible therapy with substantial in vitro and animal model research to support possible benefits in a variety of conditions. There is, however, almost no clinical trial evidence to support its use in companion animal species. Justification of veterinary use of HBOT comes only from extrapolation from basic principles, pre-clinical research, anecdote, and extrapolation from research in humans, so this should be viewed as an unproven, experimental veterinary therapy.

There are a few indications for which the human clinical trial research provides at least a moderate degree of confidence that HBOT is effective. There are many others for which there is only limited and low-quality evidence and no clear conclusion can be drawn. Not all uses validated in humans are relevant to veterinary use, and most veterinary applications have not been directly studied in people. Overall, the evidence is strongest for adjunctive use of HBOT to facilitate healing of chronic wounds not resolving with standard therapies.

HBOT is generally quite safe, but there are both minor and serious potential adverse effects, and there is some risk associated with the use of the equipment.

I followed this article with a brief report of warnings from the FDA about unsupported and exaggerated claims for HBOT in humans and a report on a human study showing no benefits for treatment of concussion. Given that I last looked at the literature 5 years ago, I thought it worthwhile to check for any new evidence on this treatment in veterinary patients. Unfortunately, there hasn’t been very much research published since 2013.

A 2017 review by two authors supportive of HBOT concluded:

There is a paucity of data about use of HBOT in veterinary medicine, and no randomized, controlled clinical trials for any condition have been published… HBOT holds therapeutic promise in animals and deserves clinical and research attention. However, the therapy is not benign, and understanding the basics of HBOT and possible complications is critical. Because the clinical information, apart from expert opinion and research experiments with small numbers, remains minimal, research is essential to expand information about the physiology behind the modality, condition-specific treatment parameters, and appropriate and efficacious indications for use in veterinary patients.

Since then, there have been two published veterinary reports. One study evaluated the safety of HBOT by recording any adverse effects noticed during 230 treatments in 12 cats and 78 dogs. Though this was only an observational study of short-term treatment, and there were a few other limitations, no serious adverse effects were seen. Minor effects, suggesting some discomfort and possible inner ear problems, were seen in some patients at a modest rate. This certainly doesn’t rule out the possibility of any more serious harm, and cases of significant injury have been reported in humans. However, this study supports the general findings in the limited veterinary literature that adverse effects of HBOT seem uncommon and typically minor. The only known fatality reported in veterinary HBOT involved an explosion which killed both the patient and the operator at an equine therapy facility in 2012.

There has been one study of HBOT in dogs published since my last review:

Latimer CR, Lux CN, Roberts S. Effects of hyperbaric oxygen therapy on uncomplicated incisional and open wound healing in dogs. Vet Surg. 2018 Aug;47(6):827-836.

This was an experimental study, not a clinical study. Ten lab beagles were given surgical wounds, and then given the same wound care (suturing, bandaging, pain control, etc.) except that 5 were given a series of HBOT treatments as well. Blinded observers evaluated wound healing scores, and biopsies of the wounds were examined. No effect of HBOT was seen, and the wounds healed the same regardless of whether the dogs got HBOT or not.

There are a number of limitations to this study, including the small number of dogs and the use of lab dogs with artificial wounds rather than a real-world population of dogs with the kinds of wounds that would typically be treated with HBOT. Nevertheless, the study certainly suggests there is no dramatic benefit to HBOT in the healing of routine, uncomplicated wounds.

Bottom Line
The literature since 2013 has not provided any reason to alter my original conclusions. While HBOT appears to have promise based on theoretical reasoning, lab animal studies, and some validated uses in humans, there is still no convincing evidence to support any claims of benefits to veterinary patients. While the risks appear to be minimal, there is only weak and unreliable evidence of any benefits. The use of a complex, expensive, and potentially harmful treatment in the absence of any strong evidence for benefits is not the best way to use limited resources in veterinary medicine or to provide the best care to patients. Advocates for HBOT, especially those selling it as part of their practice, ought to focus on supporting rigorous and objective clinical studies to identify what real benefits, if any, there are from this therapy.

Posted in General | 9 Comments

FDA Webinar Discussing Dietary Risk Factors for Dilated Cardiomyopathy

The FDA has recently held a webinar with a representative of the agency, a nutritionist, and a representative of the pet food industry to provide an update on the state of the ongoing investigation of certain diets and possible heart disease risk. Here is the link to the recording along with my summary notes.

Martine Hartogensis– FDA
Cardiologists reported ~ 150 cases dilated cardiomyopathy (DCM) in atypical breeds to FDA

FDA noted ~ 30 case reports had been filed with them with dogs on grain-free and legume/tubers containing diets.

FDA followed up on 30 cases and did not see low taurine in the foods but did find low taurine in some of patients

Now total of 160 dogs reported with DCM (149 case reports), 39 deaths, mostly from 2017-2018

8 cats reported (in 4 cases) with 1 death, these are from 2015-16

90% of dog cases had grain-free/legume/tuber-containing diet history

Prospective study ongoing checking foods and dogs for cysteine/methionine/taurine

Lisa Freeman– Tufts
DCM 2nd most common canine heart disease after valvular disease

A variety of different diets and breeds linked to taurine deficiency/DCM over the years

Dr. Sterns at UC Davis has been looking at taurine-deficient DCM in Golden Retrievers for about 3 years

Some dogs with DCM on grain-free or legume-containing diets are taurine deficient but even those that aren’t sometimes improve on taurine supplementation

Roughly 3 groups of dogs-

  1. Typical breed primary DCM cases (Boxers, Dobermans, etc.)
  2. Taurine-deficiency DCM in both typical and atypical breeds
  3. Diet-associated DCM with normal taurine levels in either typical or atypical breeds. These are not just grain-free but also “boutique” and exotic protein diets (“BEG” diets). The majority of DCM cases on these BEG diets have NOT been taurine deficient.

May be deficient in taurine or precursors, decreased absorption, increased elimination, other variables

Recommendations-
All DCM cases should have full diet history, screen for taurine, supplement taurine whether low levels or not, change to more typical diet

Greg Aldrich– KSU/Industry
Lots of manufacturers are now adding taurine to diets even though it is not clear this is the answer

Grain-free diets are ~ 25% of the dog food market, so not going away
Even with a large supply of relevant amino acids in meat meal, if the bioavailability is not high enough there may not be enough on an as-fed basis

Legume seeds/pulses lower in methionine than traditional cereals and lower bioavailability. They also have some soluble fibers in them which can influence bacterial fermentation in the colon which can deplete taurine.

Potatoes don’t really contribute to the protein in a diet, so unclear how any association with taurine levels might work

Q&A
Hartogensis-
FDA uses cat taurine levels as guideline since likely to be higher than dogs need, so in foods identified as not deficient this means they meet the cat requirement

Number of reports has, of course, increased since FDA announced it is investigating this, and many do not appear to be genuinely related to this issue; The 160 dogs mentioned are confirmed DCM diagnoses by echocardiogram.

Even though most notable association has been legumes/tubers/boutique diets the FDA is looking at other possible causal factors but so far no other clear signals. No clear pattern related to particular protein source in diets.

Freeman-
BEG Diets= boutique (small manufacturers but not willing to define specifically), exotic ingredient, grain-free diets. Reiterated majority of DCM cases on these diets have not been taurine deficient.

Aldrich-
Worth bearing in mind that < 200 animals known to be affected out of ~100 million pet dogs, so scale of the problem does not yet appear very large

Aldrich/Freeman-
Bear in mind taurine may not be the whole story so adding taurine to foods or supplementing individual dogs may not be appropriate if it turns out some of these cases are associated with other risk factors

Hartogensis/Freeman-
Recommendation to pet owners is to speak with veterinarian about nutrition since a lot of the information and advice people seek and use to guide feeding comes from marketing, pet food stores, and other sources without necessarily a sound, science-based approach.

Freeman-
Very few reports from countries outside the U.S. at this point.

Resources-
Petfoodology

The Science Dog

 

Posted in Nutrition | 21 Comments

Herbal Medicine Will not be a Recognized Medical Specialty

For over a year now, I have been covering the petition from the American College of Veterinary Botanical Medicine (ACVBM) seeking recognition as a medical specialty from the American Board of Veterinary Specialties (ABVS). I have argued that the discipline does not yet have adequate scientific evidence to support this status and that the ACVBM is dominated by proponents of Traditional Chinese Medicine and other pseudoscientific folk practices and cannot be trusted to take a truly scientific approach to herbal medicine when the leadership ignores or rejects scientific methods and relies primarily on tradition and personal belief in their own herbal prescribing.

The ABVS has apparently rejected the ACVBM petition, though the only indication of this comes from a brief statement on the ACVBM website:

Unfortunately [the ABVS] rejected our petition to be a stand alone college as we are a relatively new entity to them, but did open the door for us to apply under a currently existing college, specifically the College of Clinical Pharmacology.  At the ACVIM in June, representatives of the ACVBM will be meeting with representatives of the College of Clinical Pharmacology to discuss what being under their ‘wing’ will entail.

I have asked the ABVS if they intend to make their decision or the outcome of their review of the ACVBM petition public in any form, but they have not yet responded.

A subspecialty status under the American College of Veterinary Clinical Pharmacology (ACVCP) has some advantages over an independent specialty status in that the ACVCP is a soundly scientific organization and would, hopefully, hold herbalists to a higher, more scientific standard of evidence than they would require of themselves. It is still problematic, however, in that it creates the impression of scientific legitimacy for herbal prescribing practices before they have done the work of validating specific treatments for specific conditions or even demonstrated the validity of most basic theoretical principles underlying the discipline.

The inclusion of unproven or clearly ineffective methods under the auspices of otherwise legitimate specialty areas is not unusual. The American College of Veterinary Sports Medicine and Rehabilitation (ACVSMR), for example, includes chiropractic, acupuncture, herbal medicine and even the quintessential quackery of homeopathy as 3-6% of the content of the examination for board-certification under the Trojan Horse label of “Integrative Medicine.” I’ve discussed many times before how such a concept is a dangerous opening for unproven and useless therapies to weasel their way into mainstream medicine without going through the process of demonstrating true safety and efficacy via legitimate scientific methods. It would not surprise me if subspecialty status for herbal medicine under the ACVCP exacerbated this problem. I will have to see, of course, the details of any such application before I can draw any conclusions about whether it might serve to make herbal medicine a truly scientific discipline or give a patina of legitimacy to mystical folk medicine practices.

For now, I will wait with interest to see if the ABVS makes any additional information available and how the potential integration of herbalism into the ACVCP proceeds.

Addendum 8/21/2018- The ABVS has responded to my inquiry and will only indicate that they recommended the ACVBM seek recognition as a subspecialty under an existing specialty college. Apparently, no additional information about the process or the decision will be made public.

Addendum 9/2/2018-
One of the members of the ACVBM petition organizing committee directed me to a recent newsletter from the World Association of Traditional Chinese Veterinary Medicine (WATCVM) for more information about the ABVS response to the petition:

Additional tentative ‘Big News’, Herbal medicine including TCVM, has a potential ‘door opened’ as The American College of Veterinary Botanical Medicine’s petition to be recognized as a boarded veterinary specialty was not rejected, but not accepted. The ACVBM was told that although the petition was impressive and complete, the ABVS feels unwilling to have the ACVBM as a stand-alone college. So the petition to be a stand-alone college was not accepted. But, the ABVS instructed the ACVBM to resubmit the petition under the ‘wings’ of a pre-existing college, specifically the College of Clinical Pharmacology. I am sure all are aware of the irony of this, as drug therapy is a molecular perversion of herbal medicine.

The ACVBM will start exploring this route being clear that the ACVBM must retain its autonomy and ability to hold true to the herbal traditions that are the foundation of herbal medicine. The ACVBM will need to re-submit its petition by November of 2018.

I have to wonder how eager the College of Clinical Pharmacology will be to accept as a subsidiary specialty a group whose leadership views their discipline as “a molecular perversion of herbal medicine?”

Posted in Herbs and Supplements | 6 Comments

Grain-free Diets and Heart Disease in Dogs

For some years now, grains such as wheat and corn in dog and cat foods have been demonized by many in the alternative medicine world. There has never been any real scientific evidence to support all the hysterical claims about grains as a risk factor for disease, and there is no reason to believe so-called “grain-free” diets have any health benefits at all. Sadly, many pet food companies have chosen to play into this fad by offering such diets and marketing them in ways that suggest they are better for our pets than diets which contain such ingredients. This has led to an increase in potato and taro root and other alternative carbohydrate sources in dog and coat food with no evidence that these are in any way safer or healthier than the much-despised wheat and corn.

I’ve been fairly neutral towards this diet fad. While I have always maintained that the claims about grains are implausible and unsubstantiated, I assumed that as long as the alternative diets met the established nutritional standards for pet foods generally, they were probably no worse than existing diets even if there was no reason to think they were better. I have a natural dislike for pseudoscientific fads, but I still believe in judging claims on the evidence, and without any evidence I refrained from any judgement against such diets.

Earlier this year, however, I saw a couple of golden retrievers with an unusual heart condition, known as Dilated Cardiomyopathy (DCM). This can be caused by a variety of genetic and environmental factors, but these cases were a bit atypical, and after some testing we discovered that these dogs had a deficiency in an amino acid called taurine, which has been associated with DCM. This deficiency is unusual in dogs fed balanced and complete commercial diets, and these dogs were on commercial grain-free diets that supposedly included all necessary nutrients.

Further investigation turned up low taurine levels in some additional dogs of the same breed and on similar diets. Since then, the cardiology and nutrition services at the UC Davis School of Veterinary Medicine have begun investigating the potential link between grain-free diets and DCM in golden retrievers, and potential other breeds. The Food and Drug Administration (FDA) has issued a notice warning pet owners about the potential that diet, including grain-free diets and those with unusual primary protein sources or other uncommon ingredients, may be a risk factor for this disease, and the national media has begun to raise alarms about this issue.

Dr. Jennifer Larsen, a nutritionist at UC Davis, has written an excellent summary of the nuances of this issue, and she has agreed to let me share some of it here:

Taurine is not required to be present in dog foods. Taurine is an amino acid that is not nutritionally essential for dogs; however, there are dietary factors (such as protein source, fiber type and concentration, and cooking or processing methods) and individual dog characteristics (such as breed and calorie needs) that impact how efficiently taurine may be made and used by the body. The sulfur amino acid content and bioavailability in food is important though. The problem with dietary deficiency-related cardiac disease is multifactorial and is not just seen in goldens.

1- in many grain free diets, legumes are used to provide the carb (starch) but also protein and fiber – you cannot tell which ingredients are providing various proportions of nutrients from an ingredient list

2- legume protein is low in sulfur amino acids (methionine and cystine- the precursors for taurine synthesis)

3- some fiber types/concentrations increase fecal taurine content and promotes bacterial degradation of taurine (dogs and cats must use taurine to conjugate bile acids) so taurine recycling is not as efficient and more is lost

4- dogs need an adequate supply of precursors and to be able to make taurine fast enough to replace obligatory as well as excessive losses. When Newfoundlands and beagles were compared (during the Investigation into the lamb and rice issue with DCM in the 90s), it was found that Newfoundlands made taurine more slowly, so there are differences among breeds and probably individuals

5- dogs with lower than predicted calorie needs (“easy keepers”) also might not eat enough food and therefore enough protein to supply adequate precursors

6- some grain free diets (and other types of diets), are not high in protein (and therefore sulfur amino acids) since they use more expensive exotic or uncommon sources.

Any of these or a combination may impact taurine status in the dog.

There have been recent cases seen in our hospital and elsewhere of dilated cardiomyopathy secondary to taurine deficiency in dogs that have been associated with commercial diets containing certain ingredients (such as legumes – beans, lentils, and peas – and root vegetables – white and sweet potatoes). Data collection and interpretation is ongoing for these recent cases.

In the past we have also seen cases of dilated cardiomyopathy and taurine deficiency in dogs eating home-prepared diets (with either cooked and raw ingredients and those with and without meat), and other commercial diets with various ingredients and nutritional profiles. Some of those cases and investigations have been published (others can be found on PubMed):

Backus RC, Cohen G, Pion PD, Good KL, Rogers QR, Fascetti AJ. Taurine deficiency in Newfoundlands fed commercially available complete and balanced diets. J Am Vet Med Assoc. 2003 Oct 15;223(8):1130-6.

Fascetti AJ, Reed JR, Rogers QR, Backus RC. Taurine deficiency in dogs with dilated cardiomyopathy: 12 cases (1997-2001). J Am Vet Med Assoc. 2003 Oct 15;223(8):1137-41.

Tôrres CL, Backus RC, Fascetti AJ, Rogers QR. Taurine status in normal dogs fed a commercial diet associated with taurine deficiency and dilated cardiomyopathy. J Anim Physiol Anim Nutr (Berl). 2003 Oct;87(9-10):359-72.

Bélanger MC, Ouellet M, Queney G, Moreau M. Taurine-deficient dilated cardiomyopathy in a family of golden retrievers. J Am Anim Hosp Assoc. 2005 Sep-Oct;41(5):284-91.

Freeman LM, Michel KE, Brown DJ, Kaplan PM, Stamoulis ME, Rosenthal SL, Keene BW, Rush JE. Idiopathic dilated cardiomyopathy in Dalmatians: nine cases (1990-1995). J Am Vet Med Assoc. 1996 Nov 1;209(9):1592-6.

Due to the variable and sometimes incomplete reported diet history information for recently affected dogs, the inability to predict diet performance in any individual from nutritional profile/ingredient information, and lack of proof of causation, it is not possible to identify specific dietary characteristics nor specific products that are or are not recommended at this point.

If you have concerns specific to your own pet, we encourage you to reach out to your primary care veterinarian for guidance, possible testing (which may include a physical exam, blood tests, radiographs and/or an echocardiogram), and dietary recommendations. Taurine status can be assessed by measuring it in blood. Ideally two blood samples are assessed at the same time, and collected *prior to changing the diet or adding supplements*: 1) heparinized whole blood and 2) plasma that has been centrifuged and separated from blood cells immediately after collection.

Bottom Line
Nutrition and metabolism are complicated, and the exact relationship between dietary composition, breed genetics, and other factors leading to DCM is not yet clear. It is too early to say with certainty whether the diets are the primary cause of DCM in these dogs or whether other breeds may also be at risk. However, it is clear that the idea behind the health claims for grain-free diets is speculative at best and very likely untrue. Extreme diet fads hardly ever turn out to be a good idea in people, and the same is probably true for pets.

If you are feeding a grain-free diet, there is no need to panic. If you own a golden retriever or other breed that has been shown to be develop DCM in the past, it makes sense to talk to your vet and potentially have taurine levels tested or other diagnostics done depending on the circumstances. The diet you are feeding may be perfectly fine, but it is also probable not any better than any other diet with more conventional ingredients, and there is now some small indication that it may place some dogs at greater risk for this preventable disease.

The links above to the FDA and UC Davis Vet School will provide more information.

Posted in Nutrition | 63 Comments

Evidence Update: Promising Clinical Trial of CBD for Arthritis Treatment in Dogs

Introduction
At long last, there is a published veterinary clinical trial of a cannabis-based treatment! As I say in nearly every article I write, a single study neither definitively proves nor disproves even the specific hypothesis being studied, much less all of the other claims that might be made about the treatment being studied. Nevertheless, this is an important and welcome beginning to the process of a science-based evaluation of cannabis as a potential therapy for veterinary patients.


The Study
Gamble L-J, Boesch JM, Frye CW, Schwark WS, Mann S, Wolfe L, Brown H, Berthelsen ES and Wakshlag JJ (2018) Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs. Front. Vet. Sci. 5:165. doi: 10.3389/fvets.2018.00165


This study was conducted at the Cornell University College of Veterinary Medicine. It had two components. First, 4 beagles were given a commercial cannabis-based product containing predominantly cannabidiol (CBD), with low levels of THC and other compounds, in an olive oil base. Previous research has suggested that an oil-based formula is much more readily absorbed than other oral forms of CBD. The investigators measured the blood levels of CBD obtained at two doses (2mg/kg and 8mg/kg), and calculated the half-life of elimination, which provides an estimate of how long these blood levels may be maintained and, thus, how often it might be necessary to give a drug to achieve effective levels. These beagles were also observed for any obvious adverse effects.

The second component of the study was a randomized, double-blinded, placebo-controlled crossover clinical trial looking at the potential effects of the product on measures of pain and function in dogs with arthritis. 22 dogs were enrolled in the study, and 16 completed the trial and were included in the data analysis. Two validated owner-employed scales of pain and function were used, the Canine Brief Pain Inventory (CBPI) and the Hudson Visual Analogue Scale (Hudson). The dogs were also evaluated for pain, lameness, and weight-bearing by veterinarians. Some objective measures were used as well (force-plate measurements), but due to the fact that most dogs were lame in multiple legs, these data were unreliable and so not included in the analysis.

The design involved randomly assigning dogs to receive 4 weeks of either CBD or placebo treatment and evaluation at 2 and 4 weeks, then a washout period followed by a switch to the other treatment. Bloodwork was also done at the start of each treatment and at 2 and 4 weeks into the treatment for both placebo and CBD periods. An olive oil placebo with anise and peppermint oil was used as a placebo to mimic the appearance and odor of the CBD product (no measures were used, however, to determine if the owners and vets were effectively fooled by this technique). The subjects received the CBD, at the 2mg/kg dose, or the placebo every 12 hours.

The patients were mostly medium to large dogs (18-50kg), and about 2/3 were females. The subjects had arthritis in a variety of joints, and 9/16 were taking either carprofen or meloxicam during the study. The authors indicated that fish oil and glucosamine/chondroitin were also permitted but didn’t report whether any of the subjects were taking these agents.


Results
Pharmacokinetic Study
This component of the study showed significant absorption of CBD. The higher dose, not surprisingly, resulted in blood levels more than 4 times those achieved with the lower dose. There is no reliable data, in dogs or any other species, for how much CBD one has to get into the blood to achieve a desirable effect or how much might cause harm, so this preliminary data is useful. It isn’t yet clear, however, what concentration should be seen as a therapeutic target or as an upper limit.

The elimination half-life was about 4 hours. This suggests that to maintain consistent blood levels, it might be necessary to dose this product 3-4 times per day. As the authors indicate, longer-term pharmacokinetic studies with a variety of dose and administration intervals are needed before the optimal amount and frequency can be known.

Clinical Trial
There were statistically significant and clinically meaningful decreases from baseline in CBPI and Hudson indices at 2 and 4 weeks during the CBD dosing, and there were no changes in these levels during the placebo period. Veterinary assessments more mixed, with decreases in pain measures during CBD administration but no apparent effect on lameness or weight-bearing (as opposed to NSAID use, which did reduce lameness score as well as pain)

Bloodwork showed few changes during the treatment and placebo periods. Creatinine and BUN increased during both periods, and this was associated with NSAID use, however the numbers always stayed within the normal range. The only clinical laboratory change that appeared meaningful was an increased in the liver enzyme alkaline phosphatase (ALK) in dogs receiving CBD. Previous research has shown that CBD affects the cytochrome enzyme system in the liver, and this kind of change in lab value is likely a reflection of this. The ALK elevation by itself does not suggest any harm to the liver, but the effects of CBD on the cytochrome system could lead to interactions with other drugs, which could present safety or efficacy concerns for these drugs.

The authors did not report any adverse effects in the study subjects, but they also did not report any mechanism for monitoring or evaluating undesirable effects, so it’s unclear whether any formal monitoring of adverse effects was done as part of the study.


Strengths
All research studies have strengths and limitations which must be taken into account in order to determine how much confidence to place in the results and the extent to which the results can be applied to real-world patients, who may differ from the research subjects in various ways. The major strength of this study was a solid design incorporating most of the major tools for minimizing bias and other errors.

The subjects were randomly assigned to treatment order, and the crossover design further reduces potential differences between treatment and placebo groups that can confuse the results. Both owners and veterinarians were blinded to the treatment, though there was no specific measurement of whether the method used for blinding was successful. About half of the owners were “intimately involved in veterinary medical care,” presumably being vets or veterinary technicians/nurses. It is unclear how many of the owners had previous experience with medical or recreational cannabis and might have been able to distinguish the treatment product from the placebo.

Appropriate statistical methods were employed, and the outcome measurement tools (the CBPI and Hudson index) were established and validated measures of clinically relevant signs.

Limitations
The authors themselves acknowledge that the sample size of 16 dogs is a limitation of this study. Extensive evidence shows that smaller studies are more likely to generate unreliable results which don’t accurately predict the effects of treatments in larger populations.

It is also concerning that 27% of the subjects initially enrolled dropped out of the study, since loss to followup greater that 20% is often considered a risk for bias in such studies. The authors report the reasons for dropout of 5 of the 6 patients not included, and there is no obvious pattern of differences in withdrawal between the study and control periods to suggest these cases would affect the final results.

The subjects were predominantly large breed and about 2/3 were female. This is reasonably representative of the population of dogs seen for treatment of arthritis in general practice, but it does limit the generalizability of the study results to small-breed dogs.

Both the pharmacokinetic and clinical trial components of the study were short (24 hours after single dose, and 4 weeks respectively). These are reasonable and practical starting points for clinical research, but longer-term studies are needed to better evaluate optimal dosing and the effects of CBD over the long term.

The outcome measurements used were subjective instruments, but they were both commonly used and formally validated tools, and the assessors were blinded, so this likely had little impact on the results. Meaningful improvement on objective measures would certainly be a desirable indication of the true impact of CBD on arthritis symptoms.

The fact that many of the owners were apparently veterinary professionals is also an interesting wrinkle to this study. Certainly, this is not representative of the general pet-owning population, and both the use and evaluation of CBD products might very well be different in the hands of owners without medical training. However, the blinding of the owners (if it was effective) should at least diminish any impact of this on the results.

There was no apparent placebo effect in this study, which is highly unusual for an arthritis study, especially one using subjective measurement instruments. The authors suggest one explanation for this may be that so many owners were veterinary professionals and might be less susceptible to placebo effects. This is a common but inaccurate notion, and studies of other arthritis treatments have shown that caregiver placebo effects impact veterinarians to nearly the same extent as pet owners. It’s not clear what, if any implication this lack of a placebo effect might have for the results of the study in general, but it is a little odd.

Also concerning is the lack of any reported adverse effects of the CBD. Human trials showing benefits from CBD and other cannabis-based treatments have consistently showed relatively high rates of minor side effects, as well as some that limit the tolerability of the treatment. This is actually a good sign since any real, truly effective medicine is going to have some risks and undesirable effects that have to be balanced against its benefits. Any study showing no adverse effects at all is a bit worrisome since it could be a sign the treatment is not truly active or that the study did not properly detect side effects that may emerge once the treatment is more widely used in the real world.


Other Issues
There are a couple of other interesting issues that arise in this study which are not, strictly speaking, limitations of the study itself but which might influence the application of the results to clinical practice.

The only treatments reported for study subjects other than the CBD and placebo were NSAIDs, either meloxicam or carprofen. The authors indicated that fish oil and glucosamine/chrondroitin were allowed, but they didn’t report whether or not any subjects were taking these. Glucosamine and chondroitin very likely have no meaningful clinical effects, so this would probably not have affected the results. There is some weak evidence that fish oil, however, might improve arthritis symptoms, so hopefully this was not an overlooked variable in this study.

NSAID use was associated with improvement in pain and in function, as expected. Whether or not the CBD had more or less impact given with or without concurrent NSAID use could not be determined from this small study. This is an important open question given that it seems many owners are choosing CBD as a first-line therapy prior to using NSAIDs due to beliefs about the safety and efficacy of the two treatments that are not always evidence based. One of the most common problems in human medicine is the unanticipated interactions between new drugs and other treatments that emerge when drugs go from carefully controlled studies to widespread use, and this will have to be kept in mind going forward with cannabis in veterinary patients.

The authors also mentioned that a significant reason for choosing the 2mg/kg dose was that the the cost of the product was prohibitive for larger dogs at higher doses. Cost is always a consideration in the use of veterinary treatments, since many owners are limited in what they are able and willing to spend on veterinary care. Unfortunately, the more work a company puts into developing and testing a product and ensuring good quality control, the more expensive that product is likely to be.

Given the abundance of untested and unregulated cannabis products on the market, several of which have already proven unreliable in quality, it is possible that owners may use the data for this product as justification for using CBD and then choose another, cheaper product that hasn’t undergone the same clinical testing or quality control. I have seen this happen in the past, when a probiotic product with better supporting research evidence than others on the market was often refused by clients, and ultimately withdrawn from the market, partly due to its higher cost.

Quality control has been a particular problem for cannabis-based remedies, with many failing government or independent testing of their contents and label claims. It is important for pet owners to realize that research evidence is often specific to the treatment tested, and it can’t always be generalized to other products that claim to be similar. While I don’t endorse any particular product over others in the absence of head-to-head comparison studies, which are almost never done, I would caution veterinarians and owners not to make the assumption that one encouraging arthritis study for one product validates the use of all the other products out there.

In the same vein, this study is very specific to arthritis in dogs. It says nothing whatsoever about the use of CBD for other conditions, including epilepsy, pain associated with other diseases, nausea, etc. These uses for CBD have to be validated in their own right. And other cannabis-based compounds also cannot be assumed to be safe and effective, for arthritis or anything else, based on this study of CBD. In medicine, the details matter a lot, and generalizing from even good studies such as this is a dangerous practice.


Bottom Line
One small study of CBD for arthritis is not one giant leap for cannabis-based medicines in pets. Additional studies on the pharmacology and clinical effects, both positive and negative, need to be conducted, and rash generalizations from this study to other compounds, other conditions, other species, and other products is not justified.

That said, this is a good-quality study with limitations that are important but certainly not fatal. It is an excellent beginning to the science-based use of cannabis in dogs. Based on the existing evidence, including this study, I believe it is reasonable to consider oral CBD as a treatment for dogs with arthritis with the following caveats:

  • Other treatments with better supporting evidence, such as calorie restriction for weight loss and NSAIDs, should be attempted first
  • This product or others with verifiably similar formulation and quality control should be used
  • Patients must be closely monitored for adverse effects and potential drug interactions which are almost certain to appear in larger, more diverse populations of patients than used in this study

As I have said before, the evidence for cannabis as a medical therapy is limited but encouraging and growing rapidly. The political and legal climate appears to be changing in ways that will hopefully make it easier to conduct the needed research and make use of cannabis products that can demonstrate safety and efficacy for veterinary patients. This study is unquestionably an important milestone, and I look forward to more and better evidence and ultimately the integration of cannabis, where justified, as yet another tool in the toolbox of science-based veterinary medicine.

 

Posted in Herbs and Supplements | 27 Comments

Misleading Caregiver Placebo Effects Occur with Cats as well as Dogs

I’ve written about placebo effects in animals several times. These appear in both clinical research studies and in real-world medical practice in many different ways. However, one of the most significant phenomena that fools us into thinking useless therapies are working in our pets is the caregiver placebo effect. This is when people, including owners, vets, and researchers, see what they hope and expect to see rather than what is really happening to the animals in their care. Since our pets can’t speak for themselves, we interpret their actions in deciding whether they feel better or worse, and we fool ourselves easily and often.

The classic illustration of the caregiver placebo effect in dogs comes for a study of arthritis medication. When given a placebo, a fake treatment that does nothing at all, about half of owners, and nearly as many vets, saw significant improvement in subjective measures of pain and function. Objective measures, such as the amount of weight a dog puts on an arthritic leg, did not show improvement with placebo because such measures are harder to fool than our unaided observations.

This phenomenon is known from studies of caregivers for human patients as well as for dogs, and last year another paper appeared showing us that the exact same phenomenon affects owners and vets when evaluating pain in cats.

Gruen, M. E., Dorman, D. C., & Lascelles, B. D. X. (2017). Caregiver Placebo Effect in Analgesic Clinical Trials for Painful Cats with Naturally-Occurring Degenerative Joint Disease. The Veterinary Record, 180(19), 473. http://doi.org/10.1136/vr.104168

This review looked at six published clinical trials of treatments for arthritis in cats. They assessed the apparent improvement reported in cats getting a placebo on both subjective and objective measures. What they found was that 50-70% of cats getting placebo (meaning fake, useless treatment) were classified as treatment successes on subjective client measures. This means that a majority of clients truly felt their cats were better just because they mistakenly believed they were given an effective treatment. However, only 10-50% of objective measures showed an improvement with placebo. (the reasons cats may have improved even while getting no treatment at all are other aspects of placebo effects, which I have discussed elsewhere.)

This finding reinforces, yet again, that we cannot trust anecdotes or our own observations to determine if treatments work or not. We need placebo controlled, blinded studies with real, objective measures of effect or we risk making ourselves feel better without actually helping our patients and pets.

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What’s the Truth behind “The Truth About Pet Cancer” Videos?

The Truth About Pet Cancer (TAPC) is a slick bit of propaganda. Although it contains some interesting, even promising ideas, these are unfortunately served with a heavy seasoning of misinformation and fear-mongering. Hypotheses and opinions are presented as established facts, and anyone who disagrees is suggested to be ignorant at best, venal and corrupt at worst.

You can read my full article on the Science-based Medicine Blog-

What’s the Truth behind The Truth About Pet Cancer?

 

 

Posted in General | 3 Comments

Dietary Carbohydrates are NOT “Toxic” to Cats

Folks who are critical of commercial pet foods or advocates for raw diets and other alternatives often rail against the evils of carbohydrates. The idea that dietary carbs cause disease is a central thesis of the recent “Truth About Pet Cancer” video series (my response to which is coming soon!). With cats in particular, the claim is made that since they are obligate carnivores, carbohydrates are effectively poison for this species, causing diabetes, cancer and all sorts of other diseases. There’s only one small problem with this claim: it isn’t true!

What is true is that cats are obligate carnivores, meaning that they only eat animal prey in the wild. However, the idea that this means animal prey is all they can eat is a fallacy. Cats do have biological adaptations to eating prey, which means they have no requirement for carbohydrates in the diet, and they require more protein, and somewhat different amino acids in the diet than dogs and humans. However, this is a far cry from the wild claims made about carbohydrates causing disease.

At the recent American College of Veterinary Internal Medicine (ACVIM) forum, there was a great evidence-based presentation reviewing this subject:

Laflamme D. Cats and Carbohydrates: Why is this Still Controversial. ACVIM Forum, Seattle, WA. June, 2018.

Dr. Laflamme begins by referring to a 2010 ACVIM consensus statement which I reported on many years ago. Though no complete consensus was reached, the bottom line was that the most important dietary risk factor for cats, and the most common nutrition-related disorders (diabetes and obesity) are due primarily to excessive calorie intake, NOT dietary carbohydrate content.

Research has shown that cats can digest and utilize carbohydrates nearly as well as dogs, so they are an appropriate source of calories.1-4 Carbophobes often behave as if all carbohydrates are the same, and that any carbohydrate is equivalent to eating pure sugar. That is, of course, nonsense. While too much refined simple sugar in the diet can have negative effects on both humans and cats, complex carbohydrates and fiber do not, and can actually have positive effects. Dr. Laflamme points out that while it is possible to raise blood sugar in cats with extreme dietary manipulations (fasting them then feeding a single meal very high in carbs and low in protein), the normal type of carbohydrates used in cat foods fed in a normal manner has no apparent effect on glucose or insulin levels, so there is no reason to believe these diets would increase the risk of diabetes.

In a more real-world type of study, there have been three reports looking at what actual pet cats are fed and whether this influences the risk of diabetes. One of these found a greater chance of diabetes in cats fed only dry or only canned compared with a combination of the two.5 This makes little sense physiologically, and the study did not consider changes in diet that often go along with the diagnosis and treatment of diabetes, so this result is questionable. Two other similar studies which did look specifically at the diet fed before the onset of diabetes found no association between dry diets and diabetes.6-7  It is also worth noting that the vast majority of cats in the U.S. and Australia eat at least half dry food, and almost half of cats eat only dry. If dry food causes diabetes, a lot of cats should have this disease, yet this disease only occurs in between 0.2% and 0.75% of cats.

Another important health concern often blamed on carbs is obesity. Contrary to the claim that dietary carbohydrates cause obesity in cats, there is evidence that diets relatively higher in carbs than in fat actually reduce the risk of this problem. Cats naturally limit their own carbohydrate intake, and carbs are less caloric than fat, so cats on higher carb diets tend to eat fewer calories and so are less likely to be obese. Some of the low-carb dets marketed to reduce obesity and diabetes risk based on the idea that carbs are “bad” for cats actually raise the risk of obesity because they are high-fat and very caloric!8

Of course, anything can be harmful in excess, even water and oxygen. Extremely high carbohydrate diets, above about 50% of calories, can cause diarrhea and potentially raise blood sugar levels in cats. Such diets also make it difficult to ensure adequate protein intake. However, the existing evidence suggests that in appropriate forms and amounts, there is no reason to believe dietary carbohydrates are harmful to cats, and they even have some potential benefits.  The fear-mongering about carbs and commercial diets promoted by advocates of raw food and alternative medicine simply isn’t consistent with the facts.

 

Refernces

  1. Carciofi AC, et al. J Anim Physiol Anim Nutr. 2008;92:326–336.
  2. De-Oliveira LD, et al. J Anim Sci. 2008;86:2237–2246.
  3. Fekete SG, et al. J Anim Physiol Anim Nutr. 2005;89:199–202.
  4. Morris JG, et al. Brit J Nutr. 1977;37:365–373.
  5. McCann TM, et al. J Feline Med Surg. 2007;9:289–299.
  6. Sallander M, et al. Acta Vet Scand. 2012;54:61
  7. Slingerland LI, et al. Vet J. 2009;179:247–253
  8. Verburgghe A., et al. Vet Sci. 2017;4(4):55.

 

Posted in Nutrition | 15 Comments

Tramadol for Pain in Dogs and Cats

Introduction
Awareness of the importance of analgesia for veterinary patients has increased significantly over the last couple of decades. It is widely considered important, for medical and ethical reasons, to provide effective pain relief for dogs and cats, whether their pain is due to surgical procedures, acute injury, or chronic medical conditions.1 This growing awareness has been accompanied by a proliferation of pain control options, including new drugs labeled for veterinary use and many more compounds routinely used off label.

Multimodal analgesia has also become common, with the concurrent use of multiple local and systemic analgesics considered an optimal pain control practice.1 The inevitable limitations and adverse effect profiles of all analgesic drugs require a variety of options to allow effective pain control tailored for each individual patient. Some of the most widely used analgesic drugs, such as the non-steroidal anti-inflammatories, have side-effects which can be potentially serious, though in general they are a very safe and effective class of compounds for both dogs and cats.2-3 The current concern about opioid abuse in humans and shortages in the supply of these drugs has encouraged veterinarians to consider alternatives to traditional narcotic analgesics in our patients.

Tramadol is an opioid and serotonergic agonist analgesic drug used in humans, and it has become very popular in veterinary medicine due to the perception of a wide therapeutic index and low potential for abuse. There has been significant and ongoing debate, however, about both the abuse potential in humans and the clinical efficacy of tramadol in dogs. Tramadol is now a Schedule IV drug due to the conclusion of the Drug Enforcement Administration that it does have significant potential for dependence and abuse.4 A large amount of indirect evidence, and a few direct clinical studies, are also available to assess the question of whether tramadol is an effective analgesic in dogs and cats.

Cats
In cats, the pre-clinical evidence is relatively encouraging. Pharmacologic studies suggest adequate bioavailability, and plasma levels of the active metabolite appear to be high enough to potentially achieve analgesic effects.5-6 Laboratory studies looking at the effects of tramadol on response to nociceptive stimuli (pressure and heat) also generally support the potential analgesic effects of this drug in cats. Studies of oral6 and intramuscular7 administration have reported reductions in the thermal nociceptive threshold. One study of low-dose subcutaneous administration,8 however, found only “limited” effects on thermal and pressure stimuli.

Clinical studies in cats also appear to show some real-world analgesic efficacy, though there are typical limitations to these studies. Studies of surgical pain have found analgesic effects after ovariohysterectomy5,10-11, castration5, and dental procedures.9 However, these studies have used parenteral administration and different doses and pain measurement tools, so it is difficult to compare them or extrapolate their findings to feline patients given oral tramadol for these or other conditions. Some also compared tramadol to no analgesia at all, which is not an appropriate or useful measure of its value in a more appropriate, comprehensive analgesic plan.11 In terms of comparison to other analgesics, one study reported meloxicam to be superior to tramadol9 while another found tramadol to be superior to the NSAID vedaprofen.11

The only study evaluating oral tramadol for chronic pain in cats reported more activity and subjective benefits assessed by owners for treatment of arthritis.12 However, this study had a high dropout rate, used a placebo rather than a positive control, and did report a meaningful number of adverse effects.

Overall, it appears that tramadol likely does have some analgesic effect in cats given parenterally for acute pain, and it may have benefits given orally for chronic pain. The literature has significant limitations, however, so we can only have a low level of confidence in these conclusions at this point.

Dogs
There is considerably more research evidence investigating tramadol for dogs. As always, the published data are not perfectly consistent, but a clear trend against efficacy is apparent.

In preclinical studies, it has been difficult to convincingly show that oral tramadol is absorbed and metabolized to the active metabolites to a degree that would be expected to produce meaningful analgesic effects. While some studies do suggest adequate absorption and metabolism,12 most indicate that dogs generally appear to produce very little of the active metabolite of tramadol, and this seems to persist for too short a time to provide reasonable analgesia.13-19 While these studies vary in rout, dosage, and formulation, the trend is clear that the absorption and metabolism of tramadol in dogs is unlikely to support effective clinical use as an analgesic, especially with oral administration. Studies evaluating intravenous tramadol and thermal nociception in dogs have also failed to find a clear effect.20

The clinical research results for parenteral tramadol are less clear, with most but not all studies suggesting limited efficacy.  Most of these studies compare tramadol with another analgesic. It has been reported to be inferior to buprenorphine,21-22 methadone,23-24 morphine,25 tapentadol,25 and nefepam.26 It has also been reported to be equivalent to morphine27-29 and superior to buprenorphine,30-31 banamine,32 meloxicam,33 and ketoprofen.33 These studies all differ significantly in tramadol dose and route of administration, clinical indication, method of measuring pain, and use of concurrent analgesics, so it is challenging to sift through the details and identify the underlying direction of effect, if any.

Clinical studies of oral tramadol are also mixed but with a trend against any meaningful analgesic effects. One study reported that tramadol and dipyrone combined provided analgesia in dogs with chronic cancer pain and that addition of an NSAID did not improve the quality of pain control.34  On its own, however, tramadol has been reported to be inferior to carprofen for dogs undergoing enucleation,35 equivalent to hydrocodone/acetaminophen with both being inadequate for dogs undergoing TPLO surgery,36 inadequate for dogs undergoing ovariohysterectomy,37 and both inferior to carprofen and equivalent to placebo for dogs with osteoarthritis.38  Despite differences in indication, pain assessment, and other important variables, these studies suggest oral tramadol is not likely to be useful as an analgesic for dogs for acute or chronic pain.

Bottom Line
Tramadol has become a commonly used oral analgesic in small animal medicine, especially in dogs. While it appears to have a wide margin of safety and minimal adverse effects, both pre-clinical and clinical research evidence suggest it is unlikely to have meaningful benefits in dogs.  Even parenterally, it is unclear how useful tramadol is for pain in this species. The evidence is strong enough that tramadol should not be relied on as a sole or first-line analgesic.

For cats, it seems more likely that tramadol may be useful. The pre-clinical literature demonstrates that it is at least possible tramadol may suitable as an analgesic in this species. Clinical studies are mixed but somewhat encouraging for parenteral tramadol. Unfortunately, the only study of oral tramadol for chronic pain in cats has significant methodological limitations and does not provide strong evidence for this use of the compound.

More research in both species may help to clarify the potential effects of tramadol, but at this point the widespread use of oral tramadol is not justified by reliable scientific evidence.

References

  1. Epstein M. Rodan I. Griffenhagen G. et al. 2015 AAH/AAFP pain management guidelines for dogs and cats. JAAHA. 2015;51(2):67-84.
  2. Monteiro-Steagall BP. Steagall PVM. Lascelles BDX. Systematic review of nonsteroidsl anti-inflammatory drug-induced adverse effects in dogs. JVIM. 2013;27:1011-19.
  3. Sparkers AH. Heine R. Lascelles BDX. Long-term use of NSAIDs in cats. J Fel Med Surg. 2010;12:521-38.
  4. Drug Enforcement Administration. Schedules of controlled substances: Placement of tramadol into Schedule IV. Federal Register. 2014;79(127):37623-30.
  5. Cagnardi P. Villa R. Zonca A.et al. Pharmacokinetics, intraoperative effect and postoperative analgesia of tramadol in cats. Res Vet Sc. 2011;90(3): 503-9.
  6. Pypendop BH. Ilkiw JE. Pharmacokinetics of tramadol, and its metabolite O-desmethyl-tramadol, in cats. J Vet Pharma­col Ther. 2008;31:52–9.
  7. Jiwlawat S. Durongphongtorn S. The antinociceptive effects of tramadol on the thermal threshold response in cats. Thai J Vet Med. 2011;41(2):171-7.
  8. Steagall PVM. Taylor PM. Brondani JT. et al. Antinociceptive effects of tramadol and acepromazine in cats. J Fel Med Surg. 2008;10(1):24-31.
  9. Pahlavan P. Tavakoli A. Tramadol vs. meloxicam in controlling postoperative pain in dental extractions in cats. Iranian J Vet Surg. 2017;12(1):49-54.
  10. Basiri B. ChenHui C. Alimah Rahman N. Analgesic efficacy of pre-operative tramadol in combination with acepromazine in cats undergoing ovariohysterectomy. Pakistan Veterinary Journal, 2014, 34, 3, pp 403-405
  11. Brondani JT. Luna SPL. Beier SL. et al. Analgesic efficacy of perioperative use of vedaprofen, tramadol or their combination in cats undergoing ovariohysterectomy. J Fel Med Surg. 2009;11(6):420-9.
  12. KuKanich B. Papich MG. Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs. J Vet Pharmacol Therapeutics. 2004;27(4):239-46.
  13. Kukanich B, Papich MG. Pharmacokinetics and antinocicep­tive effects of oral tramadol hydrochloride administration in Greyhounds. Am J Vet Res 2011;72:256–262.
  14. Malek S, Sample SJ, Schwartz Z, et al. Effect of analgesic therapy on clinical outcome measures in a randomized con­trolled trial using client-owned dogs with hip osteoarthritis. BMC Vet Res 2012;8:185.
  15. McMillan CJ. Livingston A. Clark CR. et al. Pharmacokinetics of intravenous tramadol in dogs. Canadian J Vet Res. 2008;72(4):325-31.
  16. Saccomanni GM. Lebrowska-Wieruszewska B. Kowalski C. Pharmacokinetic evaluation of tramadol and its major metabolites after single oral sustained tablet administration in the dog: a pilot study. Vet J. 2009;180(2):253-5.
  17. Lebrowska-Wieruszewska B. Kowalski C. Saccomanni GM. et al. Pharmacokinetics of tramadol and its major conjugates after a single per os administration of a sustained tablet and per rectum suppositories formulations in dogs. Medycyna Weterynaryjna. 2009;65(10):687-92.
  18. Benitez ME. Roush JK. KuKanich B. et al. Pharmacokinetics of hydrocodone and tramadol administered for control of postoperative pain in dogs following tibial plateau leveling osteotomy. Amer J Vet Res. 2015.’76(9):763-70.
  19. Giorgi M. Carlo S. del. Saccomanni G. et al. Pharmacokinetic and urine profile of tramadol and its major metabolites following oral immediate release capsules administration in dogs. Vet Res Comm. 2009;33(8):875-85.
  20. Schütter AF. Tünsmeyer J. Kästner SBR. Influence of tramadol on acute thermal and mechanical cutaneous nociception in dogs. Vet Anaesth Analg. 2017;44(2):309-16.
  21. Giudice E. Barillaro G. Crinò C. et al. Postoperative pain in dogs undergoing hemilaminectomy: comparison of the analgesic activity of buprenorphine and tramadol. J Vet Behav Clin Applic Res. 2017;19:45-9.
  22. Gupta AK. Bisla RS. Kuldip Singh. et al. Evaluation of buprenorphine and tramadol as pre-emptive analgesics following ovariohysterectomy in female dogs. Indian J Vet Surg. 2009;30(1):22-6.
  23. Uscategui RAR. Tiosso C. Moro JV. et al Pre-emptive methadone or tramadol analgesia for mastectomy and ovariohysterectomy in bitches. Revista Colombiana de Ciencias Pecuarias. 2017;30(1):39-47.
  24. Cardozo LB. Cotes LC. Kahvegian MAP. et al. Evaluation of the effects of methadone and tramadol on postoperative analgesia and serum interleukin-6 in dogs undergoing orthopaedic surgery. BMC Vet Res. 2014;10(194).
  25. Kögel B. Terlinden R. Schneider J. Characterisation of tramadol, morphine and tapentadol in an acute pain model in Beagle dogs. Vet Anaesth Analg. 2014;41(3):297-304.
  26. Zhang, S.; Li, J. N.; Luan, L.; et al. Comparison of the effects of nefopam and tramadol on postoperative analgesia in dogs undergoing ovariohysterectomy. Veterinární Medicína. 2017;62(3):131-7.
  27. Kongara K. Chambers JP. Johnson CB. Effects of tramadol, morphine or their combination in dogs undergoing ovariohysterectomy on peri-operative electroencephalographic responses and post-operative pain. New Zealand Vet J. 2012;60(2):129-35.
  28. Kongara K. Chambers JP. Johnson CB. et al. Effects of tramadol or morphine in dogs undergoing castration on intra-operative electroencephalogram responses and post-operative pain. New Zealand Vet J. 2013;61(6):349-53.
  29. Mastrocinque S. Fantoni DTA. A comparison of preoperative tramadol and morphine for the control of early postoperative pain in canine ovariohysterectomy. Vet Anaesth Analg. 2003;30(4):220-8.
  30. Capik I. Nagy O. Analgesic effect of tramadol and buprenorphin in continuous propofol anaesthesia. Folia Veterinaria. 2016;60(1):47-52.
  31. Morgaz J. Navarrete R. Muñoz-Rascón P. et al. Postoperative analgesic effects of dexketoprofen, buprenorphine and tramadol in dogs undergoing ovariohysterectomy. Res Vet Sci. 2013;95(1):278-82.
  32. Yazbek KVB. Fantoni DT. Evaluation of tramadol, an “atypical” opioid analgesic in the control of immediate postoperative pain in dogs submitted to orthopedic surgical procedures. Brazilian J Vet Res Anim Sci. 2005;42(4):250-8.
  33. Mondal P. Nandi SK. Ghosh D. Evaluation of post-operative analgesia of ketoprofen, meloxicam and tramadol in bitches undergoing ovariohysterectomy. Indian J Anim Sci. 2005;75(5):513-15.
  34. Flôr PB. Yazbek KVB. Ida KK. et al. Tramadol plus metamizole combined or not with anti-inflammatory drugs is clinically effective for moderate to severe chronic pain treatment in cancer patients. Vet Anaesth Analg. 2013;40(3):316-27.
  35. Delgado C. Bentley E. Hetzel S. et al. Comparison of carprofen and tramadol for postoperative analgesia in dogs undergoing enucleation. JAVMA. 2014;245(12):1375-81.
  36. Benitez ME. Roush JK. McMurphy R. et al. Clinical efficacy of hydrocodone-acetaminophen and tramadol for control of postoperative pain in dogs following tibial plateau leveling osteotomy. AJVR. 2015;76(9):755-62.
  37. Goudie-DeAngelis EM. Woodhouse KJ. Evaluation of analgesic efficacy and associated plasma concentration of tramadol and O-desmethyltramadol following oral administration post ovariohysterectomy. Inter J Appl Res Vet Med. 2016;14(1):105-13.
  38. Budsberg SC. Torres BT. Kleine SA. et al. Lack of effectiveness of tramadol hydrochloride for the treatment of pain and joint dysfunction in dogs with chronic osteoarthritis. JAVMA. 2018;252(4):427-32.

 

Posted in Science-Based Veterinary Medicine | 9 Comments