Presentation on Placebos in Animals

Here are the notes and slides for a recent presentation on placebo effects in veterinary medicine.

WHAT IS A PLACEBO?
Despite the fact that most people have heard of the placebo effect and feel they have some understanding of what it means, the concept is a complex and contentious one. There is no consensus definition of a placebo or of the placebo effect. However, it is generally accepted that placebos are inert, and they have no direct physiologic effect on a patient’s disease or symptoms. Placebo effects, then, are effects associated with the administration of an inert substance or treatment, and these effects are perceived as beneficial by the patient or observers. Negative effects associated with inert treatments do occur, and these are referred to as nocebo effects.1

There are a number of mechanisms by which an inert treatment can lead to reported or observed responses. Many placebo effects are psychological responses based on belief and expectation, which influence a patient’s perception of his or her symptoms or have physiologic effects through centrally mediated changes in autonomic function.1-2 Placebo effects may also be caused by classical conditioning, in which physiologic responses to active treatments are paired with inert stimuli that are eventually able to elicit the same responses as the active treatment.2

Some effects associated with inert treatments in clinical research studies are actually not placebo effects mediated by conditioning or expectations. Research subjects in a placebo control group may experiences changes in their symptoms or other outcomes for a variety of reasons, and the use of an inert treatment can reveal that these changes are not due to the active treatment. However, not all such changes are true placebo effects.

For example, the Hawthorne Effect is a phenomenon in which subjects improve simply as a consequence of being enrolled in a research study.3 Subjects get more care and attention, they tend to be more compliant with existing treatments because they are being monitored, and their condition may improve due to better overall care regardless of any active test treatment or expectation-based placebo effects.3

Regression to the mean and the natural course of disease are other phenomena that can be seen in subjects receiving placebos in a research study which is not actually a true placebo effect.4 With chronic conditions, symptoms tend to wax and wane spontaneously. And some conditions may resolve spontaneously Patients are more likely to seek care, or enroll in research studies, when their symptoms are waxing, and thus they tend to improve after receiving care or beginning a study due to the natural course of disease. This, again, can be revealed by placebo assignment, but it is not an effect of the administration of the inert treatment.

It is worth noting that all of the factors that cause placebo effects and apparent response to inert treatment can also be seen with active treatments. Pain relievers with direct physiologic activity can elicit a greater reported response than explained by the pharmacological effects of the treatment. Part of the purpose of inert treatments in research trials is not only to assess whether treatments have specific effects but what proportion of the apparent response may be explained by concurrent non-specific effects and placebo responses.

In general use, placebo effects refer to those changes in reported or measured symptoms associated with beliefs or expectations about treatment. However, in the context of medical research, any effect seen in the placebo control group is classified as a placebo effect even if it is due to other factors.1 This complicates the clear use of the term and an understanding of what effects can be attributed to inert treatments and the associated mechanisms. It also impacts the relevance of placebo effects to veterinary patients, in which the relative role of various causes for non-specific treatment effects likely differ from human patients.

PLACEBO EFFECTS IN ANIMALS
It is clear that animal subjects in research studies exhibit changes in symptoms commonly identified as placebo effects when seen in human research subjects. These include subjective symptoms reported by owners or observed by investigators and clinicians as well as objectively measured outcomes.2,5-8 There is no clear research evidence showing such effects in clinical veterinary patients not participating in research. However, the circumstances and variables responsible for placebo effects seen in veterinary research studies are usually also present in the clinical context, so it is likely such effects exist in clinical patients as well as research subjects.

Animals receiving inert treatments often show improvement in subjective outcomes, such as pain, which are assessed by caregivers, clinicians or researchers. While it is generally accepted that most animals are not cognitively capable of having beliefs and expectations about their medical care, and so cannot have the classic direct placebo response, caregivers and other humans involved in these studies are susceptible to such effects. The caregiver placebo effect, in which humans report improvement in subjective  symptoms for animals receiving inert treatment, has been clearly demonstrated.5,7

It is also likely that animals receiving inert treatments may show improvement due to causes other than direct placebo effects. Research has shown human contact has predictable effects on behavioral and physiologic responses in domesticated animals, and these effects can easily be interpreted as improvement in clinical symptoms.2,9 And just as classical condition contributes to placebo effects in humans, such conditioned responses are certainly present in other animals and likely generate changes in the condition of animal patients and research subjects receiving inert treatments.

Even relatively objective outcome measures have been shown to change in response to the administration of inert treatments. Seizure frequency, heart rate, and other objectively measurable outcomes show non-specific treatment effects in animals just as in humans.2,8 Conditioning, the Hawthorne Effect, general response to human contact, and other variables are likely responsible for these apparent placebo effects.

 CLINICAL IMPLICATIONS
The presence of placebo effects and other responses to inert treatments has several important implications for clinical care. One is that apparent responses to treatment, especially in subjectively experienced symptoms such as pain, nausea, and fatigue, may reflect placebo effects rather than true improvement in the underlying condition. Human asthma patients, for example, may report improvements in the symptoms experienced during an asthma attack when given a placebo inhaler.10 However, such responses are not typically seen in objective signs of disease, especially in patients not in clinical trials receiving more intense and comprehensive monitoring and care than clinical patients. For example, the asthma patients who reported feeling better with placebo inhalers had no measurable improvement in lung function, unlike those patients receiving bronchodilator therapy.10

This demonstrates that placebo effects generally improve the perception of symptoms but not the actual physical disease. Such effects can fool patients, caregivers, and clinicians into believing they have provided effective treatment while allowing the disease to remain of progress. Asthma patients consistently treated with an ineffective medication would likely perceive some relief, but they could also be experiencing ongoing lung damage and ultimately have poorer outcomes due to the lack of objectively effective treatment. It is critical, then, that clinical therapies be demonstrated to be truly effective through clinical trial research because uncontrolled clinical observation is an unreliable guide to efficacy.

There are also ethical implications to placebo effects.11-12 In human medicine, there may be some benefit to improving the perception of uncomfortable symptoms, with a placebo or with placebo effects attached to active treatments. However, such effects are typically negligible if patients are informed that they are receiving inert treatments. Obtaining the subjective benefits of placebo effects requires misleading patients into believing they are receiving an active therapy, which is arguably unethical.11

In veterinary patients, placebo effects are largely obtained by proxy through caregivers.5,7 This creates an additional ethical challenge since caregivers and clinicians may perceive benefits the patients are not actually experiencing. This makes the necessity of objective research validation for treatment efficacy even more critical in veterinary medicine.

CONCLUSIONS
Placebo effects, and other related factors that create true or perceived improvement in clinical symptoms, are manifest in veterinary patients and animal research subjects. Controlling for these effects in research studies is crucial to identifying the true benefits of the treatments we employ. The existence of such effects also makes clinical observation of response to therapy highly unreliable as a measure of the true efficacy of our treatments. We, and our clients, often see what we hope or expect to see in response to the therapies we employ, and it is possible to be fooled into believing ineffective treatments are working without appropriate controlled research evidence. This creates an ethical imperative to base our interventions on good-quality research evidence rather than uncontrolled observations. Fortunately, some kinds of non-specific effects seen with inert treatments can also add to the real benefits of active treatments, and we can take advantage of this to maximize the benefits of our therapies once we have established objective efficacy.

REFERENCES

  1. De Crae AJM. Kaptchuk TJ. Tjissen JGP. et al. Placebos and placebo effects in medicine: historical overview. J Royal Soc Med. 1999;92:511-15.
  2. MacMillan FD. The placebo effect in animals. J Amer Vet Med Assoc. 1999;215(7):992-9.
  3. McCarney R. Warner J. Iliffe S. et al. The Hawthorne Effect: a randomised, controlled trial. BMC Med Res Methodol. 2007;7(30).
  4. McDonald CJ. Mazzuca SA. Mcabe PG. How much of the placebo ‘effect’ is really statistical regression? Statistics Med. 1983;2:417-27.
  5. Conzemius MG. Evans RB. Caregiver placebo effect for dogs with lameness from osteoarthritis. J Am Vet Med Assoc. 2012;241(10):1314-9.
  6. 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;4(8):185.
  7. Gruen ME. Dorman DC. Lascelles BDX. Caregiver placebo effect in analgesic clinical trials for cats with naturally occurring degenerative joint disease-associated pain. Vet Rec. 2017;180(19):473.
  8. Muñana KR. Zhang D. Patterson EE. Placebo effect in canine epilepsy trials. J Vet Intern Med. 2010;24(1):166-70.
  9. Zulkifli I. Review of human-animal interactions and their impact on animal productivity and welfare. J Anim Sci Biotech. 2013;4(1):25.
  10. Wechsler ME. Kelley JM. Boyd IOE. Et al. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N Engl J Med 2011;365:119-126.
  11. Asai A. Kadooka Y. Reexamination of the ethics of placebo use in clinical practice. Bioethics.2013;27(4):186-93.
  12. Gold A. Lichtenberg P. The moral case for the clinical placebo. J Med Ethics. 2014;40(4):219-24.

Placebos in Veterinary Medicine Slides

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Presentation on Choosing Diagnostic Tests

Here are the notes and slides for a recent presentation on strategies for effectively choosing diagnostic tests.

GOALS OF DIAGNOSTIC TESTING
Ultimately, the goal of any test we run should be obtaining information that allows us to more effectively treat or prevent health problems in our patients. This seems obvious, but it is all too easy to lose sight of this core purpose. We may feel obligated to run tests to confirm a diagnosis even when the level of confidence is already high and the outcome of the test won’t change what the client chooses to do. We may employ diagnostic tests as a preemptive defense against litigation or because of a perceived pressure from the client to do something even when our action likely won’t change the outcome for the patient. In some situations, we may be completely confused by a case and throw a bunch of tests at it hoping for some insight to emerge.

All of these are understandable, and all too common, reasons for using diagnostic tests, but unfortunately such approaches reduce the reliability and utility of the tests themselves. Effective testing requires not only an understanding of the strengths and weaknesses of the tests we use but also a clear understanding of how to employ them and how to integrate the results into our clinical decision making. We need a rational strategy for when and how to test, how to interpret results, and somewhat counterintuitively, when not to test at all.

BEYOND SENSITIVITY AND SPECIFICITY
The most common measures used to describe diagnostic test are sensitivity and specificity . These are characteristics of the tests themselves, and they indicate how likely, compared with some gold standard, a test is to correctly identify a disease which is present or to correctly identify that a patient does not have the disease. Unfortunately, the meaning of these numbers is often misunderstood. If a test has, for example, a 98% sensitivity, this is the proportion of patients with the disease who will correctly test positive. It is NOT an indication that any patient who tests positive has a 98% chance of having the disease. Under certain conditions, the majority of patients testing positive on such a test may actually not have the disease even with such a high sensitivity.

More clinically useful measures of a test’s reliability are the positive predictive value and the negative predictive value (Fig. 1). These are, respectively, the probability a patient with a positive test actually has the disease and the probability a patient with a negative test result does not have the disease. These numbers depend not only on the test but also how common the disease is in the population being tested.

As an example, if a population of feral cats has an FIV prevalence of 2%, 2/100 cats tested will test positive with a perfectly sensitive test (sensitivity=100%). If the test also has a specificity of 98%, then about 2/100 cats will test positive even though they do not have FIV. The positive predictive value, then, is 50%, meaning half of the cats who test positive do NOT have FIV. Even with a great test, this is a pretty big error rate, especially if we are planning on euthanizing cats diagnosed with FIV!

This example illustrates how important it is we have some idea how likely a disease is to be present before running a test for that disease if we want our test results to be reliable. Which brings us to a new and somewhat fashionable way to look at diagnostic testing….

BAYESIAN ANALYSIS FOR THE MATHEMATICALLY CHALLENGED
The work of 18th-century mathematician Thomas Bayes is enjoying something of a renaissance as an alternative, in some respects, to the frequentist statistical methods most of us were taught in vet school. The details of the math involved are complex, but the logic of the approach is simple and intuitive. Diagnostic tests should not be viewed as determining whether or not a disease is present. They should be viewed, instead, as one piece of evidence shifting the existing probability of a diagnosis higher or lower.

If, as in the example above, I know that the prevalence of FIV is 2% in this population of cats, I can say the probability of any given cat having FIV is very low. A positive test does not mean a cat has FIV, only that the probability it might have the disease has increased a bit. The test doesn’t make or break the diagnosis, it simply shifts out understanding of the likelihood of the diagnosis.

In a practical sense, then, a Bayesian approach means estimating the probability of a diagnosis based on all of the usual factors we consider (signalment, personal history, prevalence rates, physical exam findings, other test results, etc.). If this probability is high enough or low enough to make or rule out a diagnosis, no additional test is needed. If, however, the probability leaves significant uncertainty, then we should select a test that will meaningfully raise or lower that probability to help us make the diagnosis.

SCREENING
Screening is a special case in which we are testing asymptomatic individuals with the idea of detecting preclinical disease so we can more effectively intervene to reduce symptoms and mortality. Because the prior probability of disease is usually very low by definition in screening, since patients have no symptoms, the positive predictive value of even very good tests is low. It has been recognized in human medicine that screening can often lead to overdiagnosis and overtreatment, which can waste medical resources and ultimately do more harm than good for patients.1There are, therefore, requirements for screening programs, and these include not only accurate tests but proven interventions that actually improve outcomes for patients diagnosed with the disease and rational plans for confirming and following up both positive and negative test results.

In veterinary medicine, we often employ diagnostic tests in asymptomatic patients “just in case” we might find subclinical disease. Whether or not such testing improves outcomes for patients or leads to significant overdiagnosis is almost never evaluated, so the benefits and risks of screening are often assumed but not truly known. This means that significant caution is warranted in conducting screening and interpreting the results of diagnostic tests in clinically well individuals.

 

CARDINAL RULES OF DIAGNOSTIC TESTING

Based on this understanding of the limitations of diagnostic testing, there are a few cardinal rules we can apply to reduce the potential mistakes and harms resulting from our tests:

Cardinal Rule #1

If the results of the test isn’t going to change what you do, don’t run the test.

Cardinal Rule #2

If the prior probability of a diagnosis is very high or very low, don’t run the test.

Cardinal Rule #3

Don’t screen (test asymptomatic individuals) without a plan of action based on solid evidence that the benefits of testing and diagnosis outweigh the risks.

REFERENCES

  1. McKenzie, BA. Overdiagnosis. J Amer Vet Med Assoc. 2016;249(8):884-889.

 

Choosing and Using Diagnostic Tests Slides

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Presentation on Surgical Neutering Techniques

Here are the notes and slides for a presentation I recently gave comparing various surgical sterilization and neutering techniques.

INTRODUCTION
Among the most common surgical procedures in small animal practice are those for sterilization (preventing reproduction) and neutering (removing the gonads). The goal of these procedures is both to prevent reproduction and to provide a net health benefit for the patient. This benefit may include avoiding the risks of reproduction, reducing the incidence of those disease that are more common in intact animals, and reducing behaviors associated with intact status that can lead to relinquishment.1-2

There are many variations on these procedures, and the specific techniques used by individual veterinarians seem to depend more on tradition, personal habit, and cultural preference than on explicit evaluation of the pros and cons from a scientific perspective.3 There is, however, research evidence concerning some of these procedures which we can use to make rational decisions about our choice of technique. We can also use this research to inform the recommendations we make to clients. Pet owners are increasingly aware that there are multiple alternatives to choose from, and they may come to us with strong opinions or misconceptions about the most appropriate procedure to their pets.

Most procedures are intended to prevent reproduction. Some also involve gonadectomy, which has a complex array of both beneficial and harmful effects that depend on breed, sex, age, timing of surgery, and many other factors. The long-term pros and cons of gonadectomy are controversial, and I have reviewed them in detail elsewhere.2 In brief, there appears to be a net health benefit for most female dogs and cats from neutering, though the details of the risks and benefits and the effect of the timing of neutering are quite variable. There is much less evidence for a net health benefit in neutering males, though there are other justifications for doing so. Today I will consider the relative advantages and disadvantages of different surgical sterilization methods for males and females.

STERILIZING FEMALES
The most common spay procedure in the United States is ventral midline ovariohysterectomy (OVH). This is an effective technique for sterilization and neutering of both dogs and cats with very low complications rates when performed by experienced surgeons.4-6 There are many minor variations with no research evidence comparing the relative merits of most.

One exception is the flank approach to ovariohysterectomy, preferred in some countries for cats and small dogs. There are theoretical advantages and disadvantages to this approach, and research evidence comparing flank and midline approaches is mixed. Some comparisons suggest the flank approach is faster with fewer complications,7 but other studies find no difference8, and some indicate more discomfort associated with the flank approach.9-10 Access to both ovaries is more difficult with the flank approach unless bilateral flank incisions are made, which significantly complicates the procedure, and hysterectomy can be difficult by this method.11 The flank and midline methods both achieve the goal of gonadectomy and sterilization.

Traditionally, ovariohysterectomy has been preferred in the United States while ovariectomy (OVE) is the more common choice in some other countries.12 Both techniques are equally effective at achieving gonadectomy and preventing mammary carcinoma and pyometra.12-14 Some studies have suggested that OVE is less painful than OVH15, however other studies have not identified any difference in post-operative pain or other complications.10,16

A relatively recent option is the laparoscopic spay. Both laparoscopic ovariectomy and ovariohysterectomy have been reported, using a variety of equipment and techniques. Comparisons are difficult given the many different approaches, equipment, and assessments used in published studies. In general, the disadvantages of laparoscopic OVE and OVH include the cost of equipment, the need for extensive training and practice to achieve proficiency, and the longer surgical time.17-20 Laparoscopic spay may have the advantage of decreasing post-operative pain, complications, and recovery time, though the literature is not consistent and there is a lack of high-quality studies.21

With a growing awareness of the potential negative effects of neutering, there has been some increased interest among breeders and pet owners in sterilization procedures that do not involve gonadectomy. For females, two such procedures are hysterectomy (sometimes called an “ovary-sparing spay”) and ligation of the fallopian tubes or uterine horns. Both procedures have been described in the literature,22-23 but neither have been widely adopted.

There are no controlled research studies comparing tubal ligation or hysterectomy to OVE or OVH. While ligation of the fallopian tubes or uterine horns can prevent reproduction, it is highly likely that any risks and benefits associated with the presence of ovaries2 are the same for females having a tubal ligation as for those not spayed at all. A complete hysterectomy, including removal of the cervix, likely eliminates the concern for pyometra while the other risks and benefits of intact status remain unchanged.

STERILIZING MALES
Despite the uncertainties, surgical neutering is the most common approach to sterilization of male cats and dogs. For dogs, frequently used techniques include closed castration (removal of the testes without opening the vaginal tunic) and open castration (which involves opening the vaginal tunic prior to ligating the vessels and ductus deferens). Both procedures can be performed through a scrotal or pre-scrotal incision, and there are a number of variations of each.

There is much debate about the relative merits of open and closed castration in dogs, but it is based mostly on theoretical reasoning and anecdotal evidence. Some argue that closed castrations are safer because there is no direct communication with the abdomen, reducing the risk of ascending infections or herniation of abdominal contents. Others claim that open castrations are less likely to lead to hemorrhage or scrotal hematomas. Typically, closed castration is recommended for small dogs and cats and open castration for larger dogs.

There is little research evidence to inform these debates. One prospective randomized trial did find more overall complications in dogs undergoing open castration.24 However, problems with recruitment of subjects for this study significantly limit the strength of this evidence. Overall, serious complications are few in dogs undergoing castration, and it is unclear if there is a consistent advantage to either technique.

The research evidence comparing scrotal and pre-scrotal approaches in dogs is also quite sparse. A randomized, prospective study comparing the two approaches found similar complication rates.25 The scrotal approach had the advantage of inducing less self-trauma and of being about 30% quicker to perform (though the absolute difference, from about 5 minutes to 3 minutes, is of doubtful clinical significance). Once again, both techniques are effective, and it is not clear that one is superior to the other.

Several techniques have been described for neutering male cats,26 but there is virtually no formal research comparing complication rates. A scrotal approach appears to be the most common, and methods for securing the ductus and vessels include suture ligation and various methods of tying the tissues on themselves. One comparative study of these ligation methods found no significant complications and no difference between methods.27

An uncommon surgical technique used for male dogs in some resource-poor countries is pinhole castration. The spermatic cord is ligated with suture percutaneously to induce necrosis of the testes.28 While this technique is less expensive than standard surgical castration and it does reduce functional testicular tissue volume, it is unclear how effective it is as a means of sterilization, and some reports suggest a higher rate of infection, pain, and other complications compared with standard techniques.29-30

Finally, surgical or laparoscopic vasectomy is sometimes recommended as a means of sterilizing male dogs and cats without neutering.26 Both approaches are effective at achieving this outcome. There have been no direct published comparisons between surgical and laparoscopic vasectomy. One small study comparing laparoscopic vasectomy with surgical castration in dogs found few differences except for a subjectively greater level of post-operative discomfort in the surgical patients.31

REFERENCES

  1. New JC. Characteristics of shelter-relinquished animals and their owners compared with animals and their owners in U.S. pet-owning households. Journal of Applied Animal Welfare Science 2000;3(3):179–201.
  2. McKenzie B. Evaluating the benefits and risks of neutering dogs and cats. CAB Reviews: Perspectives in Agriculture, Veterinary Science, Nutrition and Natural Resources. 2010;5(45):1-18. Updated version available at: https://goo.gl/pWCKYl
  3. May S. The flank cat spay: eminence-driven fashions in veterinary surgery. Veterinary Record. 2012;170:460-461.
  4. Howe LM. Surgical methods of contraception and sterilization. Theriogenology. 2006 Aug;66(3):500-9.
  5. Berzon JL. Complications of elective ovariohysterectomies in the dog and the cat at a teaching institution: clinical review of 853 cases. Veterinary Surgery. 1967;8:89–91.
  6. Burrow R. Batchelor D. Cripps P. Complications observed during and after ovariohysterectomy of 142 bitches at a veterinary teaching hospital. Veterinary Record 2005;157:829–833
  7. Kiani FA. Kachiwal AB. Shah MG. et al. Comparative Study on Midline and Flank Approaches for Ovariohystrectomy in Cats. Journal of Agriculture and Food Technology. 2014;4(2):21-31
  8. Coe RJ. Grint NJ. Tivers MS. et al. Comparison of flank and midline approaches to the ovariohysterectomy of cats. Veterinary Record. 2006;159(10):309-313
  9. Oliveira JP. Mencalha R. dos Santos Sousa CA. et al. Pain assessment in cats undergoing ovariohysterectomy by midline or lateral celiotomy through use of a previously validated multidimensional composite pain scale. Acta Cirúrgica Brasileira. 2014;29(10):633-38.
  10. Burrow R. Wawra E. Pinchbeck G. et al. Prospective evaluation of postoperative pain in cats undergoing ovariohysterectomy by a midline or flank approach. Veterinary Record. 2006;158(19):657-60.
  11. Janssens LA. Janssens GH. 1991. Bilateral flank ovariectomy in the dog—surgical technique and sequelae in 72 animals. Journal of Small Animal Practice. 32: 249– 252.
  12. Van Goethem B. Schaefers-Okkens A. Kirpensteijn J. Making a rational choice between ovariectomy and ovariohysterectomy in the dog: a discussion of the benefits of either technique. Veterinary Surgery. 2006;35(2) 136-143.
  13. DeTora M. McCarthy R. J. 2011. Ovariohysterectomy versus ovariectomy for elective sterilization of female dogs and cats: is removal of the uterus necessary? Journal of the American Veterinary Medical Association. 239: 110
  14. Okkens AC. Kooistra HS. Nickel RF. Comparison of long-term effects of ovariectomy versus ovariohysterectomy in bitches. Journla of Reproduction and Fertility Suppl 1997;51:227–31.
  15. Lee SS. Lee SY. Park S. et al. Comparison of ovariectomy and ovariohysterectomy in terms of postoperative pain behavior and surgical stress in dogs. Journal of Veterinary Clinics. 2013 30 3 166-171
  16. Peeters ME. Kirpensteijn J. Comparison of surgical variables and  short-term postoperative complications in healthy dogs undergoing ovariohysterectomy or ovariectomy. Journal of the American Veterinary Medical Association. 2011:238;189-194.
  1. Davidson EB. Moll HD. Payton ME. Comparison of laparoscopic ovariohysterectomy and ovariohysterectomy in dogs. Veterinary Surgery. 2004;33:62–69.
  2. Ataide MW. de Brun MV. Barcellos LJ. et al. Laparoscopic-assisted or open ovariohysterectomy using Ligasure AtlasTMin dogs. Ciência Rural. 2010;40(9):1974-1979.
  3. Gower S. Mayhew P. Canine laparoscopic and laparoscopic assisted ovariohysterectomy and ovariectomy. Compendium of Continuing Education for the Practicing Veterinarian. 2008;30:430–440.
  4. Case JB. Boscan PL. Monnet EL. et al Comparison of surgical variables and pain in cats undergoing ovariohysterectomy, laparoscopic-assisted ovariohysterectomy, and laparoscopic ovariectomy. Journal of the American Animal Hospital Association. 2015;51(1):1-7.
  5. Phypers C. In Cats and Dogs Does Laparoscopic Ovariectomy Offer Advantages Over Open Ovariectomy for Postoperative Recovery?. Veterinary Evidence. 2017; 2(2). doi:http://dx.doi.org/10.18849/ve.v2i2.59
  6. Grier RL. Tubal ligation-alternative sterilization operation. Iowa State University Veterinarian. 1973;35(2):49-50
  7. Belfield WO. Partial spay (hysterectomy). Veterinary Medicine. 1972;1223-1224.
  8. Hamilton KH. Henderson ER. Toscano M. et al. Comparison of postoperative complications in healthy dogs undergoing open and closed orchidectomy. J Small Anim Pract. 2014 Oct;55(10):521-6.
  9. Woodruff K. Rigdon-Brestle K. Bushby, PA. et al. Scrotal castration versus prescrotal castration in dogs. Vet Med. 2015;110(5):131-135.
  10. Howe LM. Surgical methods of contraception and sterilization. Theriogenology. 2006 Aug;66(3):500-9. Epub 2006 May 23.
  11. Karen Maciel de Oliveira, Leonardo Augusto Lopes Muzzi, Bruno Benetti Junta Torres, et al. A comparative study among three open orchiectomy techniques in cats. Acta Scientiae Veterinariae. 2010;38(2):177-183.
  12. Okwee-Acai J. Omara R. Onyait JS. et al. evaluation of pinhole castration as an alternative technique for dog population control in resource-poor communities. Bulletin of Animal Health and Production in Africa An. 2013;61(3):337-345.
  13. Baba MA, Fazili MR, Athar H, et al. Pinhole castration technique: an alternative to orchiectomy in stray dogs. Anim Reprod Sci. 2013;137(1-2):113-8.
  14. Abd-el-Wahed RE. Korritum AS. Abu-Ahmed HM.et al. Evaluation of pinhole castration technique compared with traditional method for castration in dogs. Alexandria Journal of Veterinary Sciences. 2014;42:90-98.
  15. Anburaja Mahalingam; Naveen Kumar; Maiti S.K. et al. Laparoscopic sterilization vs. open method sterilization in dogs: a comparison of two techniques. Turkish Journal of Veterinary & Animal Sciences. 2009;33(5):427-436.

 

OVE, OVH, OMG: Pragmatic Review of Surgical Neutering Techniques Slides

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Presentation on Cannabis for Pets

I recently gave a presentation for veterinarians on Cannabis as a potential source of medical therapies for veterinary patients.  There haven’t been many new studies in veterinary species since my last post on the subject in 2016, but that is about to change. A number of veterinary schools have studies in progress, one pharmacokinetic study has already been reported, and a study of CBD for arthritis in dogs has reportedly been completed but not yet published. There has also been a recent article on CBD for refractory epilepsy in children, and this product looks likely to be approved by the FDA very soon.

Hopefully, this wave of evidence will come soon, and we will start to better understand the potential in Cannabis-based treatments.  In the meantime, here is the summary and the slides from my recent presentation on the subject.

INTRODUCTION
Medical marijuana for humans has been a hot topic for many years. Much of the debate about it has focused on ethical and legal issues that aren’t directly answerable through scientific research. Participants in these debates often gravitate towards ideological extremes. For some, any use of marijuana, medical or recreational, is immoral and dangerous. For those at the other extreme, marijuana is a perfect, risk-free cure for anything from depression to cancer.

In the last several years, these debates have migrated to veterinary medicine, with both extremes well represented. It has grown easier and more common for animal owners to provide their pets with cannabis-based remedies, both marijuana itself and products specifically produced for companion animals.

Insufficient attention, however, is generally given to the critical scientific question, “What are the risks and benefits of medicinal use of cannabis-based products?” Any consideration of the medical use of cannabis should be based on rational, objective evaluation of the scientific evidence concerning risks and benefits, uninfluenced by the surrounding ethical and legal debates.

RISKS AND BENEFITS: WHAT’S THE EVIDENCE?
Cannabis sativa contains a bewildering variety of chemical compounds. Some have been shown to have significant effects on many different body systems, from the CNS to the GI tract to the immune system. Different varieties of Cannabis have different concentrations of various cannabinoids as well THC, the compound responsible for the psychotropic effects of marijuana and humans and the toxic effects in some animal species. This variation makes it likely that medical and recreational products will differ significantly in their constituency and effects.

In vitro and lab animal research shows a variety of promising effects for some of the many compounds in Cannabis as well as multifaceted and complex potential physiologic effects. There is, therefore, good reason to believe cannabis-derived medicine could have real benefits, as well as real risks, in veterinary patients. However, the vast majority of compounds which appear promising in pre-clinical studies never prove safe or effective in actual clinical patients, so such evidence only provides potential avenues for clinical research, not a validation of claims for real-world effects.

Unfortunately, so far there is no reliable clinical research evidence for the use of cannabis-based remedies in small animal patients. That means we cannot say with confidence what the benefits or risks of any such remedy might be. We can hypothesize, based on the pharmacology of cannabis compounds or on anecdotal evidence. We can also extrapolate from studies in lab animals or humans. However, we have no direct, reliable evidence to support any claim about any veterinary medical marijuana treatment.

This lack of research is primarily due to strict laws regulating the availability of marijuana, for research purposes as well as medical or recreational use. Hopefully, as these laws change, more data will be produced. For now, the best we can do is look at what we know about the risks of marijuana in veterinary species, as well as the risks and benefits identified in humans.

A recent comprehensive literature review has been produced by the National Academies of Science, Engineering, and Medicine.7 This review evaluates those risks and benefits of cannabis-based therapies that have been studied in humans, and classifies them using a straightforward system. The strength of evidence is rated as insufficient to draw a conclusion, limited, moderate, substantial, or conclusive.

Here are the conditions for which moderate or better evidence exists in humans for a beneficial effect and which might be relevant to veterinary patients:

  • In adults with chemotherapy-induced nausea and vomiting, oral cannabinoids are effective anti-emetics.
  • In adults with chronic pain, patients who were treated with cannabis or cannabinoids are more likely to experience a clinically significant reduction in pain symptoms.

For these conditions the effects of cannabinoids are modest; for all other conditions evaluated there is inadequate information to assess their effects.

While it is encouraging that some Cannabis-derived products have validated clinical benefits for these indications in humans, this still leaves us far from having reasonable evidence to support veterinary use. Our patients often respond quite differently to medicinal compounds than humans, and extrapolation across species is a risky proposition.

With any medical intervention that has benefits, there are certainly going to be risks, and these must be identified and understood in order to balance risks and benefits in the context of specific patients. Many of the risks identified for humans may not be relevant to veterinary patients (such as the risk of impaired driving). However, cannabis use has been associated with increased risk of schizophrenia and other psychoses and with some anxiety disorders in a dose-dependent relationship in people, and this raises the possibility of adverse behavioral effects in veterinary patients.

It is clear that marijuana exposure can have toxic effects on dogs and cats.1-2 These range from mild to severe, though exposure is rarely fatal. There is also evidence that the greater availability of marijuana associated with legalization for human medical or recreational use can increase the incidence of marijuana toxicosis in pets in some areas.3 These effects are likely due to products which contain relatively high levels of THC, and it is likely, though unproven, that products with little THC and higher levels of other cannabinoids might be safer for veterinary patients.

There are many cannabis-based products on the market specifically for use in animals. Unfortunately, there is virtually no information on the safety of any of these products. Assessment of both benefits and risks is entirely based on anecdote, which is a very unreliable form of evidence. One survey of owners using such products, for example, did report low rates of undesirable effects, as well as some perceived benefits.4 However, history is full of medical products for which anecdotal evidence has proven a poor guide to the true risks and benefits.

There is also concern about the consistency and labeling accuracy of medical cannabis products. Some states that allow medical marijuana use in humans have standards for labeling and quality control testing. However, there is evidence cannabis products are frequently inconsistent in composition and labeling despite these regulations.5-6 Given the complete absence of regulation or testing for veterinary cannabis-derived remedies, it is impossible to evaluate the consistency or labeling of these products, but they are likely to be at least as unreliable as products intended for human use. Even if the safety and clinical benefits for some Cannabis compounds is validated in veterinary patients, veterinarians and animal owners cannot rely on specific products having the appropriate type and amount of these compounds with no regulatory oversite or objective quality assurance mechanisms in place.

THE FUTURE
Ideally, changing attitudes towards cannabis will allow more clinical research to be done and the true risks and benefits for veterinary patients will be determined. Cannabis have many active chemical compounds., and it is likely some will turn out to have beneficial therapeutic effects. There is substantial evidence for only a couple of uses in humans, including pain and chemotherapy-induced nausea. There is no direct evidence for any use of cannabis in dogs and cats, though there is clear evidence for the toxicity of marijuana. All veterinary cannabis products are unregulated, and most have not been tested for safety or quality control, much less clinical benefits. Until further research is available, use of cannabis in dogs and cats is entirely experimental and based only on anecdote, and it is most likely illegal for veterinarians to provide or recommend any of these products.

REFERENCES

  1. Janczyk, P. Donaldson, C. W. Gwaltney, S. Two hundred and thirteen cases of marijuana toxicosis in dogs. Vet and Human Toxicol 2004 46 1 19-21
  2. Donaldson, C. Marijuana exposure in animals.Vet Med. 2002;97(6):437-439.
  3. Meola SD, Tearney CC, Haas SA, et al. Evaluation of trends in marijuana toxicosis in dogs living in a state with legalized medical marijuana: 125 dogs (2005-2010). J Vet Emerg Crit Care (San Antonio). 2012 Dec;22(6):690-6.
  4. Kogan, LR. Hellyer, PW. Robinson, NG. et al. Consumer perceptions of hemp products for animals. J Amer Holistic Vet Med Assoc. 2016;42:40-48.
  5. Vandrey, R. Raber, J. C., Raber, ME. Et al. Cannabinoid dose and label accuracy in edible medical cannabis products. 2015;313:2491–2493.
  6. Thomas, BF. Pollard, GT. Preparation and Distribution of Cannabis and Cannabis-Derived Dosage Formulations for Investigational and Therapeutic Use in the United States. Frontiers in Pharmacol. 2016;7:285.
  7. National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press. Accessed on April 30, 2017 at https://www.nap.edu/read/24625/chapter/1

Confused About Cannabis Presentation Slides

Posted in Herbs and Supplements, Presentations, Lectures, Publications & Interviews | 6 Comments

Actually, Raw Chicken Likely Can Lead to Paralysis in Dogs.

I recently reported on a study out of Australia that found an association between feeding raw chicken, infection with the bacterium Campylobacter, and a serious neurologic disease call Acute Polyradiculoneuritis (APN). Not surprisingly, advocates of raw diets are desperate to find ways to dismiss this study so they can continue to claim raw diets are as safe, or safer than commercial cooked pet foods. Cognitive dissonance, the discomfort that one feels when confronted with evidence that one’s beliefs about something may be wrong, is a powerful force, and it can lead even smart, educated people to engage in extreme mental gymnastics to dismiss such evidence and preserve cherished beliefs.

Many of the criticisms of the Australian study are simplistic and obviously wrong or irrelevant. It is sometimes dismissed as ”just one study.” This would be a fair criticism if it were true and if there were substantial evidence of benefits to feeding raw that balanced the potential risks, but unfortunately neither of these is the case. There is abundant and robust evidence that raw meat poses a greater risk for infectious disease and parasites than cooked meat, both in terms of studies of contamination of raw pet foods (1,2,3,4,5,6) and the overwhelming evidence in humans that handling and eating raw meat increases these risks and cooking reduces them. It is simply a fact that raw meat is more dangerous than cooked meat, and there is no good argument or evidence that this is not true for pets as it is for people.

A more complex attempt to dismiss the APN findings, and one which is getting some attention online, comes from a raw feeding advocate (and perhaps not surprisingly a marketer of raw foods and other alternative health products), Dr. Conor Brady.

Dr. Brady has a PhD in animal behavior and states that is research focus involved nutrition, so one would expect him to at least present a scientifically reasonable argument. Any study has limitations, and the Australian APN study is no exception, so a science-based critique would be a normal and welcome part of the scientific process.

Sadly, this is not what Dr. Brady offers. Instead, he lurches from scientifically sloppy arguments to cherry-picking of evidence to empty ad hominem attacks on the pet food industry. What he fails to do is provide any real reason to doubt the findings of the APN study.

What Does the Australian Study Actually Say?

Let’s start by looking at what the APN study actually says. The core of the argument made in the study is this:

  1. Up to 40% of Guillain-Barre Syndrome (GBS) cases in humans may be triggered by the bacterium Campylobacter.
  2. Most Campylobacter infections in humans come from eating or handling raw poultry.
  3. APN is believed to be a canine version of GBS, so the study sought to see whether there was an association between APN, Campylobacter, and eating raw chicken.
  4. APN did turn out to be associated with Campylobacter. 48% of dogs with APN had this bacterium while only 23% of healthy digs did. When looking at recent Campylobacter infections, which would be the most likely to serve as a trigger for autoimmune diseases like APN, three times as many APN dogs had it compared with control dogs.
  5. APN was also associated with feeding raw chicken. 96% of APN dogs were fed raw chicken while only 26% of control dogs were. Only 1 APN case was not fed raw chicken, and this dog had daily contact with live poultry.

Give these clear associations, it is likely that Campylobacter acquired from raw chicken is a trigger for some APN cases, as it is a trigger for GBS in humans. There are likely other triggers as well, but in this population of dogs feeding raw chicken seems a clear risk factor which would be easily eliminated. If there were clear and proven benefits to feeding raw chicken that outweighed this risk, it might still make sense to do so, but no such benefits have ever been demonstrated.

Dr. Brady’s Attempted Rebuttal

So now let’s turn to Dr. Brady’s comments on this study. He begins reasonably enough by acknowledging that Campylobacter is a serious infectious organism and that raw chicken is a common source for it:

Raw chicken is certainly a source of Campylobacter and a lot of raw dog foods are based on raw chicken. What’s more, Campylobacter is well known to put you on your ass, or at least pooing a lot out of it. It is the most common bacterial cause of enteric disease worldwide, with two million American cases reported annually.

From there, though, he goes through a series of objections which range from reasonable but misleading to completely ridiculous. Let’s take each in turn.

  1. Do most dogs have Campylobacter in their intestines regardless of what they are fed?

The prevalence of Campylobcater in healthy dogs varies. Some studies show rates from 25-58%, as Dr. Brady claims, but others show much lower rates (such as this study in Poland with infection rates < 5%). Dr. Brady is being misleading, however, in suggesting that the rate in the Australian APN study was irrelevant because it was “normal” or the same as in normal dogs in Australia. The only other study looking and Campy in Australian used mostly stray dogs, which obviously have different diets and health status from owned pet dogs.

Certainly, not all dogs with Campylobacter will get sick, and not all varieties of Campylobacter are pathogenic. However, that has little to do with the results of the APN study. The dogs with APN still had Campy at a much higher rate than the dogs without APN, and this difference doesn’t magically go away just because other dogs in other places have had Campylobaxcter without having APN. As Dr. Brady acknowledges, Campylobacter is a potentially serious infection often acquired by exposure to raw chicken, and this remains true even if some strains are worse than others and not all dogs exposed to it get sick.

  1. There are many potential triggers for GBS and APN.

So what? If Campy from eating raw chicken is a risk factor (potentially causing 40% of human GBS cases), shouldn’t we do what we can to eliminate this and reduce the risk? Dr. Brady’s argument is like saying that because some people die in car crashes from reasons other than not wearing a seatbelt, we can ignore the fact that not wearing a seat belt is a major reason people do die in car wrecks. Medicine and public health are about reducing risk where we can, not creating a risk-free world. Until there is evidence of benefit from feeding raw meat (and right now there isn’t!), doing so despite the risk of diseases like Campy and APN makes no sense.

Dr. Brady makes a number of misleading or false statements in this section of his post. For one, he cites a paper that found no association between APN and Campylobacter to suggest this contradicts the Australian study. What he ignores is the fact that the paper he cites studied an entirely different population of dogs in another part of the world, it used less reliable measures of Campylobacter infection (serology rather than culture and PCR), and none of the dogs in that study were fed raw meat. In implying that this paper undermines the conclusion of the Australian study, Dr. Brady is either being disingenuous or showing a lack of understanding of basic principles in science and epidemiology.

Interestingly, the study he cites here implicated a different pathogen, Toxoplasma, as a potential trigger for APN. Since this parasite is also mostly acquired in humans from eating undercooked meat, this would actually provide another reason to avoid feeding raw meat to dogs. Dr. Brady cherry picks not only the studies he cites but the parts of them he refers to.

Brady also mentions vaccinations as a potential trigger for APN. In doing so, he cites a case report, which is a much lower level of evidence than the Australian case-control study he is dismissing here. He chooses which evidence to accept and which to reject based primarily on what agrees with his beliefs, not objective scientific criteria for the strength of the evidence.

Even more ridiculous is Dr. Brady’s reference to a study he suggest shows that APN can occur in dogs not even being fed “real food” but still nursing (how mother’s milk is not “real food” isn’t made clear). The study he cites, however, is actually a case report of dogs with a protozoal parasite invading their brains and causing neurologic symptoms, which is not even the same disease as the immune-mediated APN in the Australian study. This fast-and-loose approach to scientific evidence is another example of how Brady seeks only to legitimize his existing beliefs with reference to cherry-picked or misconstrued research, not to really listen to the evidence.

  1. Was the study too small or poorly done?

The short answer is, “No.” Sample size is always an issue in veterinary research, especially when studying uncommon diseases like APN. Most of the time, too small a sample either leads to false negative results due to low statistical power (that is, not finding something that is actually true because you didn’t have enough examples to get a statistically significant result). The other problem with small samples is that random variation between individuals can more easily lead to the appearance of differences between groups that don’t really exist. If you measure the height of five people to determine the average height in the entire country, a sample that includes only men or only NBA basketball players is likely to give you a result that doesn’t accurately reflect the whole population.

A larger sample would certainly strengthen the results of the APN study, but the results were quite consistent and distinctive even with the numbers used. The results were also consistent with the existing evidence regarding the link between Campy and eating raw chicken as well as the link between Campy and GBS in humans. To borrow a phrase from Dr. Brady, it is “extremely unlikely” that the results of this study are due to chance effects from a small sample population.

His second criticism is less reasonable and betrays a surprising lack of understanding of research methods for someone with a PhD. He complains that the control group was not selected “randomly.” He is correct that it was not, but he is confusing this study, which was a case-control study, with a randomized clinical trial, which is a very different design with different methods.

In a case control study, you start by collecting patients with the disease you are interested in. This is commonly done for rare diseases because simply studying a bunch of patients at random would likely never give you enough cases to learn anything from. Once you have your cases, you select controls that are matched to your cases so that they are likely to be representative of the same group that the cases came from. That means deliberately looking for patients with similarities to the patients with the disease such as age, sex, race, etc. This is not a mistake, it is a core feature of the type of study being done.

Dr. Brady then makes a bunch of comments about how the case selection method invalidates the results which illustrate that he doesn’t understand very well the research methods he is critiquing. He complains that selecting staff pets means they aren’t comparable to the APN dogs because they were less likely to be fed raw chicken. However, the fact that dogs without APN are less likely to be fed raw than dogs who are eating raw meat is exactly the thing being studied. If the control dogs and the APN dogs were all eating raw, there would be no way to tell if this was a risk factor or not!

Similarly, Brady complains that the dogs were not matched on weight, implying again this invalidates the results. But once again, this was a deliberate part of the design to allow the investigation of weight as a potential risk factor, as is actually explained in the published study report: “Very coarse frequency matching by dog size (so that this variable could still later be analyzed for associations with case-control status).” It turned out that weight wasn’t a risk factor associated with APN anyway, but breed size category was. Small breeds were more likely to be APN cases that larger breeds.

Now, the authors hypothesized this might be because small breeds were more likely to be fed raw chicken and get Campylobacter, which are the main risk factors associated with APN in this study. Dr. Brady seems to agree that small breeds are more likely to be fed raw chicken, but he makes the odd conclusion that instead of this leading to Campy infection which triggers APN, small dogs are more likely to get APN for some other reason and the fact they eat raw chicken more often is unrelated.

If this is true, then of course we have to ignore all the evidence of association between Campy and GBS and between raw chicken and Campy and just assume there is some other reason small breed dogs get more APN. This is not supported by any reasoning or evidence. It is ultimately just a guess intended to deflect any potential acknowledgement of the risks of raw feeding.

4. Couldn’t Campy in APN dogs be due to something else? Anything else?! ANYTHING BUT RAW!!

At this point, Dr. Brady loses even basic coherence in his argument. He asks the rhetorical question “Might there be another reason dogs with APN shed Campylobacter” and proceeds to admit he doesn’t know, but he is willing to speculate wildly so long as the reason is anything but feeding raw meat. All the evidence that eating raw meat is associated with Campy in humans and other animals is ignored as he grasps at straws to find another answer more compatible with his faith in raw feeding.

He meanders into unsubstantiated musings about reverse causality, suggesting APN weakens the immune system which leads to Campy infection. This is clearly nonsense since APN is an inappropriate immune system reaction, not a weakened immune system, and the overwhelming majority of Campy is associated with eating raw meat in people and dogs without APN.

Brady then launches into a tirade about the evil of feeding dogs carbohydrates that has absolutely nothing to due with Campy, APN, and the Australian study. This is simply hand-waving to distract from the lack of a coherent explanation for the study findings. He also turns the lack of evidence for raw feeding on its head, suggesting that the lack of any research evidence showing health benefits to feeding raw rather than conventional diets is actually a reason to choose raw diets. Talk about smoke and mirrors! The decades of research on conventional diets is casually dismissed by reference to “industry,” which is not only silly but hypocritical for someone who makes his living selling unproven supplements, diets, and dietary advice.

Finally, he launches into a lofty rhetorical assault on the pet food industry, full of sound and fury but also full of bullshit and woefully lacking in facts. Here is a brief sample:

Lacking any evidence to support the use of their junk food products over fresh ingredients, all they have left to convince you to hand over €5 per kilo for what is Weetabix with cows toenail and crushed centrum tablet in it, is smoke and mirrors. And the best smoke is fear. Fear you will do it wrong. Fear they will get sick. Fear you will get sick. Fear your kids will get sick.

…as cereal-based dry food sales stutter and fall worldwide, to be replaced by more natural, raw dog food products not yet owned by them, the multi-billion industry is not going to go down without a fight. The notion of fear and danger will keep coming up, more and more in the future. ..while raw dog food is yet to kill a dog or harm a single human, dry food cannot say the same in either instance. Injury aside, dry foods’ body count from chemical and microbiological contamination is absolutely shocking.

There isn’t a dry-versus-raw debate guys, any more than there is a global warming debate. There is only skewed, industry nonsense and everyone else. Fear is their weapon. Truth is their enemy. The really scary bit is that what is true and what is industry-nonsense will become harder and harder to detect.

Actually, I find the really scary bit to be the ability of a smart, scientifically educated person like Dr. Brady to ignore and distort evidence to preserve his beliefs at any cost. One can speculate on the financial motives that might influence his thinking, as he clearly believes it influences the thinking of anyone who dares to disagree with him, but I actually doubt that’s a major factor. I think he is simply a true believer who fancies himself a brave warrior against the Evil Empire and is unable to accept any facts that might undermine that belief. The real scary bit is that people might belief the rhetoric and the distortions and suffer for it. Despite his bold claim to the contrary, raw food can harm your pets and you and, yes, your children. Here is just one recent example:

The Minnesota Department of Health reports that two children in a single household were exposed to contaminated Raws for Paws product, which was used to feed the family dog. One child’s illness resulted in septicemia (blood infection) and osteomyelitis, a painful and serious bone infection.

Testing performed by the Minnesota Department of Health and the Minnesota Department of Agriculture demonstrated that the same strain of S. Reading found in the ill children was also found in four samples of Raws for Paws Ground Turkey Food for Pets that was used to feed the family pet.

Dr. Brady can call me a dupe or lackey of Big Pet Food if he wants (and I suspect he will). The truth is, I am open to the idea that fresh food, even raw food, might have health benefits. However, the evidence is clear that raw has risks, and it is up to the proponents of raw diets to prove there are benefits that make these risks worth taking. Not with anecdotes, faulty logic about what is “natural,” rhetorical assaults on the pet food industry, or mere passion. They should prove it with data, with reliable evidence derived from appropriate scientific research. Until they do so, there is no reason for pet owners to take the risks they deny exist for ourselves, our pets, or our families.

Posted in Nutrition | 33 Comments

Yet Another Study Shows the Real Dangers of Raw Diets for Dogs

I have covered the raw diet issues since the very start of this blog, which is about nine years now. My articles on the subject are collected here. Very little has changed in my assessment of the evidence over this time. The bottom line is clear:

There is evidence of risk in feeding raw, including infectious disease, parasites, and injury from raw bones. There is no scientific evidence, only anecdote and dubious theories, to demonstrate any benefits from feeding raw.

A new study has recently been published which adds to the already considerable evidence of risk from infectious disease.

Martinez-Anton, L., Marenda, M., Firestone, S.M., Bushell, R.N., Child, G., Hamilton, A.I., Long, S.N. and Le Chevoir, M.A.R. (2018), Investigation of the Role of Campylobacter Infection in Suspected Acute Polyradiculoneuritis in Dogs. J Vet Intern Med, 32: 352–360.

This was a case control study conducted in Australia and designed to look for associations between the occurrence of a serious neurologic disease, Acute Polyradiculoneuritis (APN) and infection with the bacterium Campylobacter sp. This bacterium has been identified as a common trigger for the analogous disease in humans, Guillain-Barré Syndrome. Because exposure to raw chicken is a common source of Campylobacter infection in humans, the feeding of raw chicken, and other raw meats, was one of the variables evaluated in this study.

The results were quite clear. Dogs with APN were far more likely to be have Campylobacter than healthy dogs, and dogs with APN were also much more likely to have been fed raw chicken and other raw foods.

This type of study only shows an association, not a definitive cause-effect relationship. A prospective randomized controlled trial would be needed to prove feeding raw chicken can cause Campylobacter infection which can then cause APN. However, such studies are not always necessary or appropriate to guide us in reducing our risk of disease. Case-control studies are the main source of evidence showing smoking increases the risk of lung cancer, and certainly a randomized trial in which some people are made to smoke for years and others are not to definitively prove this relationship would be unnecessary and unethical.

We are more often willing to inflict harm on animals in order to investigate the causes of disease, so it is possible someone will do such a study in dogs even though we would not do it in humans. However, it is clear that this study, in the context of the existing evidence in veterinary and human medicine, supports the clear health risks eating raw meat.

Proponents of raw diets will certainly argue that the risk is small compared to the benefits. Unfortunately, no scientific evidence yet exists to show any benefits, and personal anecdotes or theories about the natural history of dogs are not sufficient reason to ignore the robust scientific evidence of the harm that raw diets can cause. Unless some reliable research evidence emerges to show meaningful health benefits from raw feeding, there is no good reason for pet owners to participate in this dangerous fad.

 

Posted in Nutrition | 75 Comments

FDA Proposed Updated Regulation of Homeopathy- Time to Comment Again!

The wheels of government turn slowly, but they turn. Over the last several years, we’ve seen a number of governments around the world catch up to the science that shows homeopathy is worthless quackery. In Europe, the UK, and Australia, both human and veterinary medical organizations have been acknowledging this simple fact and taken steps to discourage people from being fooled into using this pointless treatment. Even here in the US, where regulation in general is widely resisted and there is robust anti-science sentiment in many quarters, the Federal Trade Commission (FTC) has acknowledge that homeopathy is nothing more than a placebo and should not be marketed as effective medicine. Such consistent, broad-based progress gives me reason for hope that science and reason can still have a positive impact on people’s beliefs and actions.

One critical agency that has chosen to re-examine how it regulates homeopathy is the Food and Drug Administration (FDA). Under the standards the FDA uses to determine whether medicines can be sold as safe and effective, homeopathy could never be allowed. Unfortunately, a politician who was a homeopath snuck the practice into the original law establishing the FDA in 1938. The last time the FDA reviewed its non-regulation of homeopathy, in 1988, it chose to continue the practice to be used regardless of the evidence it is ineffective.

In March, 2015, I wrote about a public comment process the FDA had initiated in order to review its regulation of homeopathy. More than two years later, the FDA has issued a draft guidance updating that issued in 1988. This document does not establish legal mandates regarding homeopathy, but indicates the general posture of the agency towards the subject and hints at what kinds of actions the FDA might be willing to take in the future.

What I recommended in my comments to the agency in 2015 was the following:

  1. Draft and submit to Congress a report identifying homeopathy as ineffective and recommending changes in the agency’s authorizing legislation to prohibit the marketing and use of homeopathy without fulfillment of the same new drug licensing requirements applied conventional drugs.
  2. Produce educational materials for healthcare providers and patients in both human and animal health fields identifying the ineffective nature of homeopathy for the treatment or prevention of human and animal disease.
  3. Require all OTC homeopathic products to carry a label similar to that required for dietary supplements under DSHEA, “This/these statement(s) have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.”
  4. Vigorously enforce regulations in both human and animal health fields prohibiting treatment and prevention claims for homeopathic remedies without fulfillment of the requirements of a NDA.

 

Not surprisingly, the draft guidance doesn’t go nearly as far as I would have liked. Still, it is an improvement on the existing policy, and it might help reduce the harm done by homeopathy if it is actually carried out.

The agency begins by asserting that it has authority to regulate homeopathic products and that it could, if it chose, prohibit the marketing of any without completion of a new drug application requiring the same standards of proof for safety and efficacy as required for real medicine:

…all drug products labeled as homeopathic are subject to the premarket approval requirements in section 505 of the FD&C Act or section 351 of the PHS Act. There are no drug products labeled as homeopathic that are approved by FDA.

The FDA further acknowledges that the failure of homeopathic remedies to be held to this standard means they cannot be considered safe and effective and that this presents a potential hazard to public health:

Drugs marketed without required FDA approval may not meet modern standards for safety, effectiveness, quality, and labeling. The continued marketing of products that have neither been approved by FDA nor found to be 82 GRAS/E is a public health concern.

While the FDA does not yet intend to require this standard of evidence, this guidance makes it clear that it could and that no homeopathic remedy has ever met this standard. Instead, the FDA indicates that it considers some homeopathic practices more dangerous than others and intends to focus on discouraging those most likely to cause harm:

The Agency generally intends to apply a risk-based enforcement approach to the manufacturing, distribution, and marketing of drug products labeled as homeopathic…FDA intends to prioritize enforcement and regulatory actions involving drug products labeled as homeopathic and marketed without the required FDA approval in the following categories:

  • Products with reported safety concerns. For example, MedWatch reports or other information submitted to the Agency can indicate or signal a potential association between the product and an adverse event, medication errors, or other safety issues.
  • Products that contain or purport to contain ingredients associated with potentially significant safety concerns. For example, potentially significant safety concerns are raised by products that contain or purport to contain:
  • An infectious agent with the potential to be pathogenic
  • A controlled substance, as defined in the Controlled Substances Act, 21 U.S.C. 147 812; 148
  • Multiple ingredients that, when used in combination, raise safety concerns due to possible interactions, synergistic effects, or additive effects of the various ingredients
  • Ingredients that pose potential toxic effects, particularly when those ingredients are concentrated or in low dilution presentations (e.g., 1X, 2X, or 1C), or are not adequately controlled in the manufacturing process.
  • Products for routes of administration other than oral and topical. For example, unapproved injectable drug products and unapproved ophthalmic drug products pose a greater risk of harm to users due to their routes of administration (e.g., bypassing some of the body’s natural defenses, differences in absorption) and the potential risk of harm from contamination.
  • Products intended to be used for the prevention or treatment of serious and/or life-threatening diseases and conditions. Unapproved products for serious and/or life-threatening diseases and conditions raise public health concerns, in part, because they may cause users to delay or discontinue medical treatments that have been found safe and effective through the NDA or BLA approval processes.
  • Products for vulnerable populations. For example, patient populations such as immunocompromised individuals, infants and children, the elderly, and pregnant women may be at greater risk for adverse reactions associated with a drug product, even if it contains only small amounts of an ingredient, due to their varying ability to absorb, metabolize, distribute, or excrete the product or its metabolites. These populations may also be at greater risk of harm as a result of foregoing the use of medical treatments that have been found safe and effective through the NDA or BLA approval processes or under the OTC Drug Review.

 

What all this means is that the FDA recognizes the main causes of harm from homeopathy: direct harm from remedies made improperly or containing dangerous ingredients and indirect harm from delayed diagnosis and effective treatment. The agency is not interested in banning over-the-counter sugar pills used to treat mild, self-limiting problems, but it is willing to intervene when homeopaths make remedies that are actively harmful or when they try to sell them to people who are really sick and need real medical care. It remains to be seen how willing the agency is to enforce such standards if they are adopted.

The next step is for the public to weigh in on this guidance. As usual, the highly motivated proponents of homeopathy are likely to be dis-proportionally represented in such public input. However, the very existence of this draft guidelines suggests that substantive, evidence-based input did have an influence on the FDA during the previous comment period, so we should all continue to participate in this process.

Eventually, comments will be accepted online at https://www.regulations.gov/. I will update this post when the comment page is available.

 

 

 

Posted in Homeopathy, Law, Regulation, and Politics | 3 Comments

Trump Leading the Charge Against Science and Reality

The focus of this blog is science, and the role of science in medicine, especially veterinary medicine. However, politics, law, and other non-scientific fields are covered from time to time when they impact the core subjects of science and medicine.  I have covered more politics than usual in the last year primarily because of the unprecedented attacks against science, and the entire edifice of Enlightenment thinking, that have made modern medicine, and the civilization as we know it, possible. This is a unique and dangerous time here in the United States, and the predominant threat to science and medicine now comes not from post-modernist ideology or the infiltration of faith-based visions of so-called alternative medicine into mainstream medical science, but from the open hostility towards science and the very concepts of facts and truth exhibited by the individuals running much of our national government.

I first  wrote about Donald Trump’s anti-science views a little over a year ago, before he was elected president. While all the candidates had some questionable views on at least one scientific topic, Trump set himself apart with his climate change denialism and his embracing of anti-vaccine activists. Andrew Wakefield and several of the most extreme quacks I’ve written about here proudly endorsed him for this.

Since the election, science advocacy groups have highlighted the many ways in which Trump and his administration have led a full assault on science. Six months into his term, the Union of Concerned Scientists reported on the anti-science activities of the administration:

  • Sidelining independent science advice. The Trump administration has weakened federal advisory committees that provide scientific advice to the government.
  • Appointing conflicted individuals to scientific leadership positions. President Trump has appointed to the highest positions in government individuals with little science background and with strong ties to the industries they are charged with regulating.
  • Leaving key science positions vacant. President Trump has taken an unusually long time to fill many high-level science positions, signaling the low priority his administration places on science.
  • Revoking science-based safeguards. Aided and abetted by Congress, President Trump has allowed politics to supersede science by signing an unprecedented 13 congressional resolutions rolling back science-based protections, including safe drinking water standards and safeguards to prevent worker exposure to harmful chemicals.
  • Misrepresenting climate science and rolling back climate change safeguards. Attacking science-based policies and communications on preparing for and mitigating climate change is a clear focus for the Trump administration. Officials have misrepresented climate science, removed climate-related content from several government communications, and proposed sharp reductions in climate research.
  • Weakening science-based pollution standards without scientific justification. The administration has delayed or repealed several science-based pollution standards designed to protect public health, including protections against mercury, air toxics, and coal wastewater, without replacing them with new, scientifically defensible standards.
  • Undermining protections from hazards at work and home. The Trump administration has delayed many science-based rules intended to keep communities safe from dangerous chemical spills and to safeguard workers from harmful toxins, with little to support halts except for letters and petitions from companies or industry trade associations.
  • Altering scientific content on federal websites. The scientific content of federal agency webpages, including those of the Environmental Protection Agency, the State Department, and the Department of Energy, has been altered or deleted since January, particularly in regard to climate change science.
  • Reducing public access to data. The Trump administration has reduced public access to scientific data and information. The administration also has stopped collecting certain data for programs that benefit disadvantaged groups. And it has withdrawn requests to industry to supply data that would help inform public health and environmental protections.
  • Restricting communication of scientists. The Trump administration is making it more difficult for government scientists to speak publicly about their work, as well as about misconduct within an agency. It has restricted communication with Congress, placed vague gag orders on agency staff, and failed to affirm the ability of scientists to share their expertise publicly.
  • Creating a hostile environment for scientific staff. Evidence is growing that a culture of fear is increasing at government agencies, undermining scientific research and communication. Scientists are speaking to the media anonymously out of fear of retaliation; some are afraid to utter the words “climate change.”

Many news organizations have reported on how Trump and his appointees are ignoring and attacking science, including:

The New York Times

The LA Times

The Guardian

Time

The latest article, from the Washington Post, illustrates the administration’s open and clear desire to suppress any scientific research or thought that might conflict with the ideology and agenda of the Trump White House. It also illustrates an Orwellian approach of demeaning the very concept of truth and trying to control language so as to control thought. The following headline should have been from a satirical news source like The Onion, but it is, in fact, a direct report of an actual Trump administration policy:

Trump administration gives CDC a list of forbidden words, including “fetus,” “transgender,” and “evidence-based.”

The full list of words the Centers for Disease Control (CDC) are forbidden from using in official documents being prepared for next year’s budget is as follows:

vulnerable
entitlement
diversity
transgender
fetus
evidence-based
science-based

You might have noticed a couple of my favorites on that list. Fortunately, I don’t work for the CDC, so I will continue to talk about “evidence-based” and “science-based” medicine. The fact that anyone could believe it is in the best interests of the public to prevent public health scientists from talking about these subjects, however, is bizarre and terrifying.

All politicians, and really all human beings, will sometimes dismiss or ignore science when it conflicts with their beliefs or ideology. But Donald Trump goes well beyond such normal human failings. He appears to truly believe that suppressing science and destroying confidence in the concepts of objective truth and simple facts is the right thing to do if it gets him what he wants.

What it will really get us, if successful, is a return to the pre-Enlightenment darkness of superstition and faith without reason or true understanding. I have talked about the Age of Endarkenment before, when I was disappointed by the triumph of politics and belief over reason and science. In the past, it was merely a poetic turn of phrase to describe my sense that progress towards ever more accurate and effective science-based understanding of nature, and the application of this understanding in medicine, was less steady than I would like. Now, I have to honestly wonder if it might be a more accurate description of the future of my country than I ever dreamed, even at my most cynical. Certainly, it is a vision some in the government appear to desire rather than fear.

The great science advocate Bill Nye has referred to Trump and his administration as “the last gasp of the anti-science movement.” He seems confident that we are, as a people, not stupid enough to buy the toxic bullshit trump is selling. I can’t say as I share that confidence, but I will try to have hope. I will certainly try to defend science against the latest assault, as I have against less potent ones before, because I believe it is our best bet for understanding the universe and for improving our lot in it.

Posted in Law, Regulation, and Politics | 6 Comments

Colloidal Silver- Colorful Snake Oil but not Medicine

Introduction
Colloidal silver illustrates many of the classic characteristics of quack alternative medicines. It has a history of mainstream use based on tradition and theory, but it was abandoned by science-based medicine in favor of safer and more effective treatments. There are a few legitimate uses of silver-containing compounds, and these are misrepresented as supporting inappropriate uses of these and other silver-containing substances. There is some laboratory research that shows biologic effects of silver in test tubes, and this too is misused to justify giving silver products to sick patients. There is virtually no research on colloidal silver in actual patient, and what there is fails to meet basic standards of quality. There are, however, lots of anecdotes which people wrongly believe can be used to support treatment with this snake oil.

Colloidal silver is a liquid, usually water, with microscopic particles of silver suspended in it. While some medical uses of silver are legitimate, none involve oral colloidal silver. Topical use of ointments for burns and to prevent eye infections in newborns, and impregnation of catheters and other medical equipment with silver, do have some benefits. However, taking colloidal silver orally is an entirely different thing, and there are no proven benefits from this practice. There are, however, significant risks.

I haven’t previously covered this topic because the risks and lack of benefits from colloidal silver have been thoroughly covered elsewhere, and fortunately it is not at the top of the list for alternative treatments of pets. However, a reader recently drew my attention to a “study” of colloidal silver in dogs. As poorly conducted and unreliable as this paper is, undoubtedly some will claim it as evidence supporting the use of colloidal silver in dogs, so I felt it was worth discussing why it is not.

First, though, here are a few sources discussing the lack of benefits and the real risks of colloidal silver in humans:

Benefits?

There are no high quality studies on the health effects of taking colloidal silver, but we do have good evidence of its dangers.

Silver has no known function or benefits in the body when taken by mouth.

Silver is not a nutritionally essential mineral or a useful dietary supplement.

There are no legally marketed prescription or over-the-counter drugs containing colloidal silver that are taken by mouth.
National Center for Complementary and Integrative Health

All over-the-counter (OTC) drug products containing colloidal silver ingredients or silver for internal or external use are not generally recognized as safe and effective and are misbranded. FDA is issuing this final rule because many OTC drug products containing colloidal silver ingredients or silver salts are being marketed for numerous serious disease conditions and FDA is not aware of any substantial scientific evidence that supports the use of OTC colloidal silver ingredients or silver salts for these disease conditions.
Food and Drug Administration

Colloidal silver isn’t considered safe or effective for any of the health claims manufacturers make. Silver has no known purpose in the body. Nor is it an essential mineral, as some sellers of silver products claim.
Mayo Clinic

There is no data to support silver to treat infections.

So for what diseases is there evidence for which colloidal silver is efficacious? Well, nothing.  Pubmed is silent on taking colloidal silver to benefit any disease, infection or otherwise. There are no clinical trials to show efficacy. Nothing.
Science-based Medicine 

Risks

When taken orally, silver can interact with and reduce the effectiveness of tetracycline, quinolone, and penicillamine. Long term use can cause silver deposition in the skin and mucous membranes leading to an irreversible condition called argyria, characterized by bluish-gray to gray-black pigmentation. Other adverse effects include seizures (6) and kidney damage. Pregnant women should not consume colloidal silver as it can cause developmental abnormalities in the fetus.
Memorial Sloan-Kettering Cancer Center

Colloidal silver can cause serious side effects. The most common is argyria, a bluish-gray discoloration of the skin, which is usually permanent.

Colloidal silver can also cause poor absorption of some drugs, such as certain antibiotics and thyroxine (used to treat thyroid deficiency).
National Center for Complementary and Integrative Health

Brain and nerve damage from silver exposure is rare, but colloidal silver can cause kidney damage, stomach distress, and headaches.

The most common problem associated with silver exposure is argyria: The skin turns a bluish gray as granules of silver accumulate in the body.
Harvard Medical School

So we have a product with no proven benefits, only anecdotal claims and inappropriate extrapolation from lab studies. We also have proven significant risks. Seems like a pretty clear case for abandoning the treatment, as science-based medicine has done. Unfortunately. It is still easy to find alternative practitioners recommending colloidal silver, for veterinary patients as well as for people.

A Veterinary “Study” of Colloidal Silver
These practitioners may be tempted to claim validation from a paper published last year. This “study” failed to meet even the most basic standards of clinical research, which is probably why it was published in a nanotechnology journal rather than a medical journal. It is effectively a collection of anecdotes dressed in the trappings of scientific research, and it does not justify using colloidal silver in dogs.

Bogdanchikova N. Vázquez-Muñoz R. Huerta-Saquero A. et al. Silver nanoparticles composition for treatment of distemper in dogs. International Journal of Nanotechnology. 2016;13(1-3):227-237.

The paper reports a comparison of dogs with canine distemper, a viral infection, treated with colloidal silver or with standard medical treatment for this disease. It purports to show that silver improved the survival of dogs with distemper as long as they did not have neurologic symptoms. Dogs without such symptoms who were treated with silver appeared to be more likely to survive the disease than dogs without neurologic signs who received standard care. The authors then confidently claim silver was effective in treating dogs with distemper as long as they did not have the neurologic form of the disease.

It would be fantastic if this were true since standard care is not very effective for many dogs with canine distemper. Unfortunately, there are very many reasons why this study cannot, in fact, support the claims the authors have made for colloidal silver. To explain this, I will briefly review how scientific research is supposed to be different from mere anecdote, and why this paper doesn’t meet the basic criteria for reliable research.

I’ve discussed at length previously why stories, sometimes called anecdotal evidence, are not reliable for judging the safety of effectiveness of medical treatments or the causes of disease. Scientific research, while still imperfect, does a better job because it has methods built into it which compensate for common flaws and limitations in human observation and judgment. In clinical trials designed to test medical treatments, these methods include:

Randomization of patients– When comparing two groups, one of which gets a treatment and one which does not, the patients in the groups must be as similar as possible in every way except for the treatment, Otherwise, differences between them might be due to something other than the treatment being tested. Assigning patients to groups randomly, that is by chance, helps ensure the groups are comparable. Any way of assigning patients that is not completely left to chance introduces bias into the study.

Blinding to randomization– Since all our choices and decisions are unconsciously, if not consciously, biased by our existing beliefs, if we are aware of who gets assigned to the test treatment or the comparison group, we can influence this in a way that defeats the purpose of randomization. For this reason, clinical trials require that people involved in the trial don’t know which group any patient is assigned to (they are “blinded” in the language of medical research).

Blinding to treatment– Just as people in the study shouldn’t know which group patients are assigned to, they also shouldn’t know which treatment people are getting. Anyone treating or evaluating patients who knows which group they are in will inevitably unconsciously skew their actions and the results in favor of the outcome they expect or hope for.

Statistical comparisons– Various kinds of mathematical tests are used to compare differences between groups to help identify how likely those differences are to be due to chance rather than the treatment. These methods have many flaws and limitations, but they help make research results more reliable than simple observation.

The paper which claims to report a research study comparing dogs with canine distemper infections treated with colloidal silver and those treated with standard medical care does not meet even these basic criteria for a controlled clinical trial. It looks like a scientific study, but without these controls for bias, it is simply a collection of anecdotes.

To begin with, dogs were assigned to colloidal silver treatment or standard care based on whether or not their owners were offered silver treatment and agreed to allow it. There is nothing random about this. The doctors and the owners simply decided who would get the experimental treatment and who wouldn’t, which guarantees the patients will differ in ways likely to affect the outcome. If, for example, owners of sicker dogs were afraid to try an experimental treatment while owners whose dogs were not as ill were more willing to accept it, then dogs in the control group would automatically be sicker, and have worse outcomes, than dogs in the treatment group. This is just one of many ways in which the lack of randomization or blinding to randomization could influence the results of this study.

There is also no indication that owners, caregivers, or research personnel were blinded to which group patients were part of. If this is true, the lack of this most basic control for bias means the people involved in the study could have intentionally or unconsciously influence the results in many ways.

There were certainly no statistical comparisons made in the paper. It is possible that even the authors recognized that the lack of standard methods for controlling bias and error in the study made any such mathematical comparison inappropriate and meaningless. However, it may also be that they felt the results were so clear and obvious that statistical comparisons were unnecessary. In either case, the lack of these comparisons further reduces the reliability of the results.

There are a number of other serious problems with this paper, some of which have to do with the nature of canine distemper infection and how it is diagnosed and treated. Canine distemper virus (CDV) affects different dogs differently. Many do not develop serious illness at all. Puppies get sicker than older dogs, and dogs with other diseases or poor immune system function are more likely to get seriously ill or die than healthier dogs. Different strains of the virus also produce different degrees of illness. All of these variations mean that the course of illness and chances of survival vary greatly between dogs. This is exactly the kind of variation that requires randomization and blinding to randomization to ensure that study subjects getting different treatments are truly comparable. Without these controls, it is quite likely that dogs getting silver treatment were different in relevant ways from dogs not getting silver, and any differences in survival could easily be due to these other differences.

It is even possible that some of the dogs in this study did not have CDV at all. There are other diseases that can similar to those of CDV, especially when there is no neurologic involvement. symptoms. The more typical symptoms a dog has, and the more consistent their physical exam findings and lab tests are with CDV, the more likely they are to have the disease. Dogs with respiratory and gastrointestinal signs who do not have neurologic disease may actually have other causes of illness, not CDV.

These are precisely the dogs in this study who appeared to recover with silver treatment. While the authors did test for antibodies to CDV, these can also be found in dogs with CDV who are sick for other reasons and in dogs who have been recently vaccinated for CDV. Very few other clinical findings or lab tests were reported to support the diagnosis. The design of this study, therefore, does not allow us to say with any certainty that the dogs who fared better did so because of the treatment. It is also possible they may not have had as severe a form of the disease as the dogs who died, or that they didn’t have CDV at all.

The death rate for CDV is also highly variable. Studies have suggested from 50-80% of dogs with distemper will die. However, most animals with mild symptoms will recover, adults are much less likely to die than puppies, and dogs with neurologic signs have a higher mortality rate than those without. Therefore, comparisons of mortality between groups treated differently must account for these differences, which was not done in this study.

As an example, while dogs without neurologic signs were similar in average age between the two groups (19 months for the silver group and 14 months for standard treatment), the ages of dogs in these groups with neurologic symptoms were very different (14 months on average for the silver group and 40 months for the standard treatment). Age is one factor that influences the likelihood of CDV and the mortality rate, so such differences can influence differences in outcomes regardless of the treatment given.

As mentioned before, dogs were assigned to standard treatment or silver based on the choices of owners and investigators. It is likely the severity of illness would differ between groups when patients are assigned in this way. Also, the type of treatment within the silver group varied, with sicker animals getting treatment more often and during a different period of time. This further complicates any attempt to compare groups.

Mortality rates differed between the treatment groups, which is the main basis for the claim that the colloidal silver had some effect. However, given the failure to ensure the groups were truly comparable, these differences can’t be used to determine if there is any effect from the treatment. All but one of the dogs with neurologic symptoms died regardless of treatment. All of the dogs with other symptoms also died with standard care, while all of the dogs with non-neurologic signs survived in the silver group. This would be a dramatic difference if it were seen in a study with appropriate methods and more than the 9 animals in the treatment group. With these limitations, unfortunately, this apparent difference is meaningless, a mere anecdote rather than a true scientific comparison.

Bottom Line
Colloidal silver has been abandoned as a medical treatment by mainstream medicine because there is no reason to believe it works and it is clear it has significant risks. While silver has some effect on infectious disease organisms in test tube studies, so do bleach and gamma radiation. This doesn’t mean any of them are appropriate as treatments for infection in living patients. There is no good clinical research evidence to justify using colloidal silver in humans or veterinary species. The research that is available, such as the study of colloidal silver in dogs with presumed canine distemper, is inadequate to draw conclusions and amounts to anecdotes made to look like scientific research.

 

Posted in Herbs and Supplements | 11 Comments

Herbalists Apply for Medical Specialty Recognition- An Update

I have been covering the application of the American College of Veterinary Botanical Medicine (ACVBM) for recognition as a specialty in several posts throughout the year (1, 2). My conclusion is that this recognition is not justified for several reasons:

  1. There is very little high-quality or reliable scientific evidence to support the use of herbal products in veterinary patients.
  2. Herbal prescribing is dominated by Chinese Medicine, Ayurveda, and other unscientific folk belief systems, and those proponents who take a more scientific approach are a small minority generally unwilling to reject the claims or methods of alternative herbal medicine.
  3. Herbal products are unregulated, inconsistent and unpredictable in their chemical composition, frequently contaminated with toxins or even undisclosed pharmaceutical drugs, and almost none have been properly tested for safety or efficacy. There is ample evidence of serious harm to human patients from herbal products. The ACVBM supports industry self-regulation rather than the kind of government oversight accepted as necessary for pharmaceutical medicines without any sound reason for doing so.
  4. The majority of the leadership of the ACVBM are dedicated proponents of alternative medicine, not only for herbal products but homeopathy, acupuncture, energy medicine, and many other unproven or pseudoscientific practices. Many have said clear and troubling things that display a contempt for science and science-based medicine and a desire to use the appearance of scientific methods to gain acceptance for alternative practices. This makes it very likely that approval of the ACVBM as a specialty board would serve as a Trojan horse for the legitimization of other alternative therapies.
  5. The potential of herbal medicines would be better explored from a rigorously scientific approach involving specialists in pharmacology, toxicology, nutrition, epidemiology, and other existing medical specialties.

The ACVBM has just released a revised version of their application. While I haven’t exhaustively compared this to previous versions, a couple of sections caught my interest because they directly address some of my concerns and also because they further illustrate the perspective of the group regarding the key issues of science and evidence.

Some material has been added to emphasize why the ACVBM should be a separate specialty college rather than investigating herbal treatments under the auspices of existing specialties.

Veterinary botanical medicine is a distinct discipline that differs in substance, methodology and philosophy from conventional veterinary medicine.

I will briefly comment on some of the specific arguments made to justify this claim.

While many conventional drugs are derived from plants, a veterinarian who prescribes botanical medicine is using whole herbs in preference to isolated active constituents. The whole herb or extracted herb is complex, containing hundreds of constituents that have complex actions…Veterinary herbalists are aware of differences in plant chemistry that may result from the plant’s origins.

The first half of this statement is certainly correct. Whole plants and herbal combinations are chemically very complex. This is usually identified as an advantage (as will be seen below), but it is actually one of the reasons herbal medicine is problematic. The consistency, efficacy, and safety of such complex combinations with variable ratios of different compounds that depend on multiple factors makes it very difficult to accurately predict the effects of such remedies. Herbalists claim to have specialized expertise in doing so, but when investigated these claims amount only to a belief that personal clinical experience or folk medicine traditions are reliable information, which is manifestly untrue more often than not.

That the whole plant is more therapeutic than a constituent is a fundamental principle of botanical medicine supported by research.

Well, the first half of this statement is true as well, but the second half is not. Herbalists believe whole plants to be better than isolated compounds (also known as medicine), but they have in no way proven this through research.  There are studies that show combinations of plant chemicals to be more effective in some uses than each used separately. Most of this is experimental research rather than clinical studies, which is important since the use of such combinations in actual patients is significantly more complex and uncertain.

The idea that combinations of chemicals may have greater effect than the same chemicals used separately is not all that surprising or unique to herbal medicine. Combination regimes of chemotherapy are often more effective than single-drug treatment. And some infections require multiple antibiotics given together to address all the pathogenic organisms involved. However, this does not prove some kind of general principle that combinations are always safer or more effective than single agents. It is equally likely that combinations may have greater toxicity (as if often the case when conventional medicines are used in combination), and sometimes they may interfere with one another. The fact that the compounds occur naturally together in a plant is no reason to imagine we can assume they are better as medicine when given together.

The principle of synergism may turn out to be true in many, some, or only few cases, but these need to be validated through clinical research. The assumption that this is true stems from pre-scientific folk beliefs about “natural” remedies or religious notions that God has provided for the needs of human beings by packaging remedies for our ills in nature. These beliefs have not been validated scientifically despite the claims to the contrary. Many interesting hypotheses are advanced in the application for how herbal combinations could potentially be more effective or safer than isolated compounds, but these are just hypotheses, not the established fact claimed in the document.

The application goes on to respond to concerns about the use of folk myth and pre-scientific tradition rather than science in the use of herbal remedies. The ACVBM is clearly trying to mitigate the impression that herbalists rely primarily on “traditional knowledge” rather than science in their practice.

The ACVBM differentiates themselves by interest in the rich knowledge base of traditional botanical medicine use and ethnobotany combined with modern scientific, chemical, toxicological, pharmacological clinical application and research in a practice that could be appropriately termed rationale phytotherapy to distinguish from colleagues who may only embrace traditional findings or who may eschew scientific findings. This is an evidence-based system that encourages in vitro and in vivo studies to explain mechanisms of action, pathophysiology, pharmacokinetics and bioavailability as well as efficacy of botanical medicines.

This is the application of plant based medicine (supported by science and/or traditional use) to conventional diagnosis, multiple diagnoses and complex cases and to address individual signs and problem lists; or for prevention of disease by protecting organ health and /or optimizing animal health through actions not available with conventional drugs.

I certainly believe that the best hope for making effective use of the potential in plant compounds as medicines is in a strong scientific approach, one that views traditional use only as a weak foundation for hypotheses to test, not as a sufficient basis for clinical practice. I am, however, not convinced that the ACVBM as a whole truly embraces this view. I have investigated the public statements are claims of the members of the Organizing Committee in detail, and I have followed many of them for years. A couple seems genuinely interested in bringing scientific rigor to the field. Most, however, have been quite consistent in expressing the view that science is useful only when is supports their beliefs, derived primarily from personal experience and tradition, and that scientific invalidation of anything they “know” already is nearly impossible. Science is more of a marketing tool, to convince the skeptics, not a path to testing and questioning their own views rigorously and sincerely. There are hints of this even in this document, despite efforts to suggest agreement with the view than science is necessary and tradition merely a jumping-off point.

Veterinarians using botanical medicine have a patient centered approach, whereby the botanical medicines are selected based on the individual signs and pathophysiology as well as the diagnosis. So that two dogs with diabetes for example, may be treated with two different sets of botanical medicines.

What they don’t say here is that this “individualization” is not based on scientifically established knowledge but folk tradition, personal experience, and gut feelings.

The document also discusses various sources of information in detail, with an obvious effort to rationalize the role of tradition and personal experience in the absence of significant reliable scientific evidence. This is not inherently mistaken, since the same sources of information are used in conventional medicine, and we always have to balance the availability of information against its reliability. Personal experience is easy to find but highly unreliable. Consistent, high-quality clinical research is a lot better but a lot harder to come by.

Traditional use-
The bewildering variety of ethnoveterinary practices, ethnobotanical uses and folk practices around the world coupled with confounding aspects of cultural, placebo and other non-specific effects make reliable conclusions from any one tradition difficult. Frequently however, traditional use informs research and pharmacological activity is often found to be closely correlated. There are recurring themes in traditional medicine and persistent therapeutic approaches consistent with the use of “archetypal” chemical groups within plants.

Contrary to the implications here, traditional folk practices do not consistently or accurately predict the pharmacology or clinical effects of plant chemicals. The vast majority of traditional herbal uses have not been tested. Many of these, however, make absolutely no sense and so are unlikely to be a productive foundation for research. The idea of sympathetic magic, that if things which have superficial similarities these can predict deeper connections with therapeutic value, is clearly nonsense. Plants that may resemble a penis in some people’s eyes do not consistently turn out to be aphrodisiacs. Plants that are wrinkled like the brain or lobed like the lungs or that otherwise have some subjective superficial similarity to an organ in the body do not turn out to be plants with medical value for treating diseases of those organs, despite many folk medicine traditions holding this belief.

And systems which are arbitrary and unconnected with scientific reality are not good predictors of the medical value of plants used in those systems. Chinese medicine, for example, emphasizes the balance of imaginary forces, such as Heat, Wind, Damp, etc. Other systems, such as Western Humoral Medicine and the related Indian Ayurvedic approach, also emphasize balancing various forces to achieve or restore health. However, the forces involved are imaginary constructs that don’t correlate to physical reality. Most of the specific practices based on these theories don’t work, which is why thousands of years of using these ideas to guide medicine accomplished almost nothing in terms of improving health or fighting disease. The fact that the systems have similar concepts doesn’t make relying on the concepts, or the interventions derived from them, any more effective.

Collective clinical experience over decades-
There is also the clinical experience of veterinary practitioners to consider- thousands of educated veterinary practitioners worldwide prescribe herbal medicines in their work. This has advantages of being in a modern veterinary context. Veterinary practitioners of botanical medicine have written texts and taught other veterinarians to achieve repeatable results within the botanical framework.

Clinical experience is often the basis for treatment decisions in medicine. It is widely recognized in science-based medicine to be a shaky and unreliable foundation for decision-making compared to controlled scientific research, but often we lack research evidence to fully inform all the care we give. Unfortunately, we all tend to rely too much on experience, and it is common for clinicians to continue employing practices that seem effective to them based on their experience even when better scientific evidence has shown them not to work.

As a community, alternative medicine proponents are even less amenable to abandoning disproven methods than the science-based medicine community. The reverence for tradition and the relatively greater lack of research evidence to support alternative practices leads to a greater trust in experience even than conventional clinicians. Certainly, there are individuals who are committed to a rigorously scientific approach to herbal medicine. However, many of the leaders of the ACVBM have repeated expressed the view that science is predominantly a way of proving to others what they already know to be true from their own experience, rather than honestly testing their beliefs. Science does not yet support the claim here that herbal practitioners can achieve “repeatable results,” and unfortunately it is unlikely that the leaders of this group will change their minds and give up practices they believe to be effective even if good research evidence shows this.

The available published literature on phytochemistry and preclinical pharmacology (that frequently involve animal models exploiting mice, rats, rabbits and less so cats and dogs) of plant extracts is prolific. There are peer-reviewed journals devoted to the subject. Researchers have no doubt that nature is still the preeminent synthetic chemist and that in plants there are infinite reserves of fascinating constituents with actual and potential effects on health and disease. As such information accumulates it is often easier to better understand traditional uses of plants.

They do not however provide confirmation of a clinical effect; experience in practice is that the effect of the whole plant is rarely predicated on the effects of its parts. However such studies help to provide a rationale for the mechanisms of action of a herb.

For once, I agree completely. The bulk of research evidence concerning plant compounds is pre-clinical basic lab research. There is a lot that suggests these compounds may have significant medical value when used in the right way for the right problems. However, this kind of research does not justify the extensive use of herbal remedies in actual patients, which is precisely what the ACVBM is not only recommending but suggesting should be viewed as a legitimate medical specialty.

There are few well conducted placebo controlled double blind clinical trials on the effects of herbs in veterinary medicine. These are expensive to conduct and present methodological and logistical challenges. However, the evidence is accumulating in human medicine and rising in veterinary medicine.

Again, first half true, second half merely opinion. The overwhelming majority of the medical use of herbs in humans has not been proven in clinical trials to be safe or effective. Even some of the most widely used and promising herbal interventions that have been studied for decades, such as St. John’s Wort, have failed to show benefits that outweigh the risks. There is no repeatable, high-quality clinical trial evidence for any herbal prescribing in veterinary species. Such research must be conducted before we can even know if herbal medicine is useful, much less before we can call it a medical specialty.

No single source can absolutely confirm that herbs are a rational treatment strategy.Therefore, it is appreciated that herbs have been dismissed by many in the profession as the refuge of the uncritical. However, when all the sources of information come together and are integrated with pharmacological insights, something important happens; unique treatment strategies for treating notoriously difficult clinical problems become possible and the desire of the ACVBM is for animals to benefit from the efforts of this group to further develop the field.

Pure faith here. All of the evidence sources taken together suggest that some herbal products might be useful for some conditions in some cases, and these are worth testing. Nothing here shows convincingly that any herbal practice is dramatically effective or that herbal medicine has advanced to the point where it should be a medical specialty on a par with oncology, internal medicine, or other specialty areas in which the level of research evidence is dramatically higher.

The section on “philosophy” is especially interesting. A number of elements have been omitted, including the notion of non-physical spiritual or “energetic” forces involved in health and disease, which many of the leaders of the ACVBM have promoted elsewhere as integral to their practice. However, this section still shows some of the beliefs and assumptions behind herbalism which are problematic from the point of view of science.

The universal role of plants in the treatment of disease is exemplified by their use in all the major systems of traditional medicine and ethnomedicine irrespective of their underlying philosophical premise.

This may or may not be true, but it is irrelevant and an example of the appeal to popularity fallacy. Because something is widely practiced or believed has no bearing on whether it is true or should be accepted or adopted. The majority of pre-scientific folk medicine traditions also include specific religious or spiritual beliefs and practices, but that doesn’t mean these should be incorporated into science-based veterinary medicine.

The practitioner of botanical medicine regards the whole formula or whole extract as the “active ”component” in the therapeutic context.

The concept of polyvalent or multifaceted activity of the medicine is central to botanical medicine
-in the context of the advantage of chemical complexity -and even a single herbal extract is a natural multi agent medicine that can simultaneously target a range of desirable pharmacological effects.

The veterinary botanical practitioner prefers not just to prescribe chemically complex herbs, but often administers them in complex formulations, compared to conventional medicine preferring to prescribe a single drug. The practitioner chooses herbs or formulas for a cooperative or facilitating effect between the components to address therapeutic goals

Again, we see the commitment to the idea that plant chemicals are “natural” and that they are safer or more effective the more are mixed together in an herbal treatment, There is no compelling evidence for this belief, and it is contrary to much of the science of pharmacology that has led to so many medicine far more effective than any pre-scientific herbal treatment. There is a reason we take aspirin instead of chewing willow bark- the results is more predictable and effective. While there may be some combinations of herbal ingredients that work better or have fewer side effects when given together, this has to be proven for each by rigorous science, not simply accepted as fact based on traditional beliefs and unscientific theories.

Philosophically the veterinary botanical medicine practitioner practices conventional medicine but overlays that practice with the use of botanical medicines in a framework of botanical principles to expand their options for treatment of disease and optimizing health.

This is the standard claim of integrative medicine. It has a number of problems, which I’ve discussed in detail many times before. Basically, the addition of unproven or ineffective treatments to conventional scientific medicine doesn’t add value for the patient. Adding herbal medicine to conventional treatment will only help patients if those herbal treatments are shown to work. And any particular treatment that works should simply be part of medicine as a whole, not a separate category of “integrative medicine.”

If one is going to use alternative therapies, it is at least better not to use them as replacements for science-based medicine. However, even when practitioners of such therapies say this is what they do, there is reason to be skeptical. The same individuals often promote their treatments as safer and more effective than conventional medicine. If they believe this, wouldn’t they reach for these treatments first? Wouldn’t they likely tell their clients that their herbal treatments are better and safer, which would likely discourage these clients from pursuing conventional care? If they practice Chinese Medicine, as most of the members of the ACVBM leadership do, aren’t they going to evaluate patients and assign treatments based on the principles of this system? Since this is unscientific folk medicine, how is it compatible with a scientific approach to healthcare? The apparently simple claim that herbs aren’t meant to replace conventional treatment raises a lot of questions.

Practitioners appreciate traditional knowledge as just one potential source of information, when coupled with published research and clinical experience, herbs can be prescribed safely and effectively.

Of course, they recognize traditional folk knowledge as a reliable and important source of information, equal if not superior to scientific information about herbal remedies. This is a major danger of validating this approach as a specialty. It treats folk tradition as reliable knowledge, not merely speculations and beliefs that might or might not lead to useful insights and treatments. This attitude erodes the reliance on science that has supported all the tremendous progress in healthcare in the last 150 years and which has made us healthier that all the folk medicine of the preceding millennia.

The ACVBM also makes claims about the scientific basis of herbal medicine. I addressed some of these previously, and the updates to the application don’t add much to the previous discussion.

The ACVBM acknowledges the concerns regarding the scientific basis of veterinary botanical medicine. Where there are published scientific and clinical data supporting the overall safety and benefits of many plant medicines, the research might be dismissed as having methodological bias thus being of inferior quality to trials conducted on conventional drugs.

More accurately, the bulk of research on herbal treatments is pre-clinical, not evaluation of specific treatment approaches in specific groups of patients. The clinical research that does exist is methodologically weak and subject to bias compared with the research literature for conventional medicine. Therefore, very few of the day-to-day practices of herbal veterinarians are based on good science compared to those of conventional practitioners. This needs to be remedied before we can call herbal medicine a specialty.

However to be fair, this is also the case for clinical trials generally. for example in dogs and cats a review of  clinical trials uncovered a need for more high-quality studies. And more recently a cross sectional study of veterinary randomised controlled trials of pharmaceutical interventions funded by different sources was examined and it was found that a failure to report primary outcomes, justify sample sizes and the reporting of multiple outcome measures was a common feature in all of the clinical trials. The authors suggested that findings may be affected by the source of the funding and that some RCT’s provide a weak evidence base and targeted strategies are needed to improve the quality of veterinary RTCs to ensure there is reliable evidence on which to base clinical decisions.

The evidence base for conventional veterinary medicine is far weaker and more limited than it should be. It is also far stronger than the evidence base for veterinary herbalism. And the limitations in the former don’t erase or mitigate the limitations in the latter. The focus should be on building better evidence, not on designating some of the least evidence-based practices as a board-certified specialty.

By increasing awareness, the ACVBM will help the profession as a whole practice botanical EBM. Evidence based medicine however includes not just research, but also incorporates the needs and biases of the client and patient; and the clinical experience of the practitioner; in veterinary botanical medicine this last item has been developed without official support from the veterinary profession and its regulatory bodies, yet is essential to safe and effective practice.

This is a bit of a mischaracterization of evidence-based medicine. It is a system for recognizing the strengths and weaknesses of different kinds of evidence and for making the integration of scientific research evidence into daily practice explicit and formal. Clinical experience is acknowledged as both indispensable and highly unreliable as a guide to the safety and efficacy of treatments.

The ACVBM generally privileges tradition and experience over scientific evidence by claiming that herbal therapies can be broadly described as safe and effective and worthy of specialty status in the absence of any robust body of clinical research literature. The very act of seeking specialty recognition first and then promising to do the research later shows the lack of understanding that such research is not just nice to have but a necessity if we are to have any real confidence in our treatments.

If the ACVBM wishes to advance EBM and make the profession as a whole more evidence based, they would do better to form and fund a vigorous research community doing high-quality research to validate their core beliefs (such as the superiority of whole-plant remedies and mixtures over isolated compounds) and the clinical effectiveness of their treatments. Once a strong body of evidence is available, integration of such methods and recognition as a specialty would make sense.

Bottom Line
There are some positive changes in this updated application. It is clearly an attempt to allay concerns expressed about the lack of evidence for herbal treatments, the reliance on folk wisdom and tradition to guide herbalism, and the lack of a good foundation for treating herbalism as a medical specialty rather than simply evaluating and using herbal remedies scientifically within the existing framework of science-based medicine.

However, the changes to the document do not alter the fundamental objections I raised at the beginning of this post. Ultimately, there is not yet sufficient scientific evidence to validate most of the claims made for herbal remedies. The ACVBM leadership consists predominantly of individuals who espouse unscientific approaches to health and diseases, such as Chinese Medicine, and who have demonstrated the belief that science serves not to test the truth of their beliefs but to aid in marketing them to the rest of the profession.

The best thing this group could do, for herbal medicine and for veterinary medicine as a whole, would be to stop seeking recognition and formal acceptance of their existing practices and beliefs but instead to commit to a rigorous and objective scientific evaluation of those beliefs and practices. The talent and resources spent lobbying and promoting herbalism would be far more valuable if used to test herbal treatments in objective, unbiased scientific studies. If they don’t work, then we’ll know and we can move on. If they do work, then we’ll know and we can make use of them. Either way, veterinary medicine and our patients will benefit. Recognizing unproven folk beliefs and practices as a medical specialty will not advance veterinary medicine or benefit our patients.

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