By Brennen McKenzie, MA, MSc, VMD, cVMA

One major challenge for primary care veterinarians trying to practice evidence-based medicine is the lack of high-quality evidence. Though there are thousands of veterinary research articles published every year, many of them relate to topics of little relevance to general practice. Research on the cutting edge of medicine, which is of interest to academics or suited to advancing academic careers, is often not the most useful for informing primary care.

Due to the paucity of high-quality research evidence, veterinarians are accustomed to using therapies without the support of such data. Therapies suspected to be useful based on pathophysiologic reasoning or clinical experience are often widely used for long periods of time before they are properly tested in controlled research studies, if they ever are. While this is a necessary evil (and we would have few therapies to offer our patients if we were limited only to those for which there was robust research evidence), there are some unfortunate consequences to the situation.

One is that many therapies used extensively for years eventually prove ineffective, or even unsafe, when formally tested. I have written about several examples of such therapies. Tramadol is still widely used as an oral analgesic for dogs despite research evidence showing it to be ineffective.¹ There also is serious doubt about the efficacy of glucosamine for osteoarthritis, lysine for viral upper respiratory infections in cats, cranberry extract for urinary tract infections, and many other therapies that have been routinely employed on the basis of low-quality evidence.^2–5

Another problem with the routine use of therapies that have not been validated through rigorous scientific testing is veterinarians become accustomed to relying on low-quality evidence, and they may be resistant to abandoning common therapies when higher-quality evidence becomes available showing they are not as effective as believed. The natural difficulty of changing one's belief about a familiar practice in the face of new evidence means ineffective therapies often persist well past the point at which they have been demonstrated to be ineffective.^6–8

The many examples of once widely trusted medical treatments that turned out to be useless or dangerous when properly studied should encourage all of us to limit our confidence in treatments we use that do not have strong supporting scientific evidence, even if they "seem to work" based on personal experience. It also should encourage us to be open-minded about new evidence showing our clinical experiences with specific treatments may not be reliable, and we should be willing to adapt to such evidence and abandon these treatments when the balance of evidence is against them.

Common problem, little research

The latest example of a ubiquitous therapy that has never been properly tested scientifically involves one of the most common clinical problems primary care veterinarians are faced with— diarrhea.^9,10 Though the average primary care veterinarian rarely goes a day without seeing a case of acute idiopathic diarrhea, academics and research institutions have not rushed to provide abundant, high-quality research evidence evaluating common treatments for this condition. It is self-limiting, rarely serious, and not the sort of problem one can build an academic career trying to solve. Nevertheless, this condition meaningfully impacts quality of life for many dogs, and their owners, and general practitioners are expected by clients to offer some help. Good evidence showing the effects of common treatments for this condition is needed to support appropriate clinical management of diarrhea.

One recent study has shed some light on one of the oldest and most widely used treatments for acute diarrhea: the antibiotic metronidazole.^11,12 This drug has some efficacy against the protozoal parasite Giardia, a common cause of diarrhea, as well as some immunomodulatory activity and effects on the bacterial flora of the gastrointestinal tract.^13–21 These properties, along with abundant clinical experience, have long been cited to support the use of metronidazole as a treatment for acute diarrhea. However, there has been little clinical trial research investigating this practice.

Studies show metronidazole is useful in the treatment of canine giardiasis, though estimates of efficacy vary widely.^14–19 It has been shown not to add any benefit when combined with prednisone for treatment of inflammatory bowel disease or with amoxicillin-clavulanate for acute hemorrhagic diarrhea.^22,23 Until now, however, there have been no placebo-controlled studies specifically testing empirical use of metronidazole for acute idiopathic diarrhea.

In a recent clinical trial, dogs with acute diarrhea and no evidence of a specific underlying cause (e.g. parasitosis, endocrinopathy, organ dysfunction, etc.) were randomized to treatment with metronidazole, a commercial probiotic, or a placebo. Based on owner-reported fecal scores, diarrhea resolved in 4.8 +/- 2.9 days in dogs given the placebo, 4.6 +/- 2.4 days in dogs taking metronidazole, and 3.5 +/- 2.2 days in dogs on the probiotic. The differences between groups were not statistically significant.¹²

Reasonable doubt

While one study is rarely perfect or definitive evidence for any complex clinical question, this trial does provide strong reason to doubt the value of metronidazole in acute idiopathic diarrhea in dogs. Given the absence of previous controlled research evidence supporting the use of this drug for this problem, it is appropriate to conclude metronidazole is likely ineffective for acute diarrhea and should not be prescribed unless new supporting evidence appears. The temptation to cite clinical experience to justify continued use of metronidazole for this problem should be resisted, as anecdotal evidence is unreliable and inferior to such clinical trial findings.

It is interesting the apparently shorter duration of diarrhea in those dogs given the probiotic was not statistically different from the outcome in the other groups. The authors did report the probiotic deteriorated over time, though there was no apparent difference between subgroups of dogs given the probiotic in the first and second halves of the trial. The study also did not enroll enough dogs for a difference of one day in the duration of diarrhea to reach statistical significance. It is possible the difference of one day, which is large enough to have some clinical impact, might be real and might be statistically significant in a larger study. However, it also is possible the probiotic used in this study simply did not meaningfully affect the clinical course of the subjects and the difference seen was only due to chance.

Previous research evidence evaluating the use of probiotics for diarrhea is mixed.^24-32 Some studies show clinically and statistically significant differences in the time to resolution of diarrhea between dogs taking probiotics and placebos, and others do not. The cause of the diarrhea, the probiotic organism used, the dose and form, the viability of specific products, and many other factors likely influence the results of such studies, so while probiotics may have meaningful benefits for acute diarrhea in some cases, the value of particular products in specific patients can be difficult to predict. It is important to remember, as well, that most cases of acute idiopathic diarrhea eventually resolve spontaneously, even in the absence of any treatment.

Conclusion

There has never been strong evidence to support the use of metronidazole to treat acute idiopathic diarrhea for dogs, and the results of the first clinical trial evaluating this practice indicate it is probably not effective. This information should discourage the use of metronidazole as a treatment for acute diarrhea.

In addition, the study found no statistically significant effect of a commercial probiotic on the duration of diarrhea. However,
the existing mixed evidence concerning probiotics and acute diarrhea in dogs does offer some support for the use of these products, though the impact of particular products on individual patients is not reliably predictable. l

Brennen McKenzie, MA, MSc, VMD, cVMA, discovered evidence-based veterinary medicine after attending the University of Pennsylvania School of Veterinary Medicine and working as a small animal general practice veterinarian. He has served as president of the Evidence-Based Veterinary Medicine Association and reaches out to the public through his SkeptVet blog, the Science-Based Medicine blog, and more. He is certified in medical acupuncture for veterinarians. Columnists' opinions do not necessarily reflect those of Veterinary Practice News.

References

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² McKenzie BA. Is cranberry effective for treating UTIs? Vet Pract News. April 2019:38.

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⁴ McKenzie B. Lysine: A therapeutic zombie? Vet Pract News. May 2018:26-28.

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³²McKenzie BA. Probiotics and today's pets. Vet Pract News. January 2018:30-31.