Editor’s note: Eric Troncy, DV, MSc, PhD, DUn is a professor at the University of Montreal in Quebec City, Canada, and a member of the Quebec Pain Research Network (http://qprn.ca/en). Troncy studies the assessment of pain in companion animals. He recently co-authored a review article in PAIN that discusses how natural animal models of pain could be used by the pain field to better understand pain and enhance translation. Troncy spoke by phone recently with Dara Bree, a postdoctoral fellow at Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, US, to discuss his review article and his research. Below is an edited transcript of their conversation.
What was your path to pain research?
I am a veterinarian by training and always had an interest in pain assessment in animals. I came to the University of Montreal after completing my veterinary degree in France to work on epidural anesthesia in dogs, which is a major interest of mine. I was also investigating critical care and cardiovascular function in pigs and dogs at the time, but decided in the end to concentrate solely on pain.
What is the focus of your research?
My lab focuses on the assessment of pain in companion animals—pets—such as cats and dogs, and subsequently validating these assessments. This also includes work on rodent pain models, as well as with dairy cattle and horses.
We were not satisfied with the common veterinarian and owner subjective assessment of pain using the original pain rating scales in these animals. To combat this, we started to introduce and validate objective pain measurements in pets using, for example, kinetic gait analysis, electrodermal activity, and quantitative sensory testing (QST), which worked really well for osteoarthritis in cats and dogs.
Using these techniques in dogs, we were able to validate four compounds that were originally investigated in rodent experimental models and subsequently went on to be validated in human clinical trials. It was really exciting for us to see this and led us to believe that both basic pain neurobiology as well as drug testing in companion animals such as dogs or cats could be a valuable intermediary step between lab and human studies.
You recently co-authored a review article for PAIN, titled “Translational pain assessment: could natural animal models be the missing link?” What do you mean by a natural animal model?
Natural animal models refer primarily to naturally occurring diseases in companion animals. My interest is in painful diseases affecting veterinary patients. These diseases are almost always naturally occurring and can closely resemble painful conditions observed in humans such as osteoarthritis, cancer pain, interstitial cystitis, or diabetic neuropathy, and thus can be termed natural animal models of pain as opposed to experimentally induced ones commonly used in laboratories. The most accessible veterinary patients for study are commonly kept species like domesticated animals—pet dogs and cats—but also livestock such as horses, swine, sheep, and cattle.
In regard to pain models in animals, whether experimentally induced or naturally occurring, what are the key components for a model to be considered valid?
The challenge with any pain model is to recreate the disease conditions and also to define clinically relevant and translatable outcome measures. In order for a model to be considered valid, it should encompass the key elements of the human pain experience as faithfully as possible and try to measure aspects relevant to the pain experience.
It is important to understand the current limitations of experimental models of pain. These models, mostly in rodents, have allowed us to generate incredible knowledge with respect to the molecular and cellular aspects of pain, though this typically involves invasive assessment. However, there are numerous aspects of these experimental models that are not ideal, including the fact that they primarily involve young male subjects, are generally restricted to confining and unvarying environments, and often can have poor reproducibility among different laboratories. Natural models of pain in companion animals offer distinct advantages over laboratory-based ones, which make them a valuable tool for pain researchers.
What are some of those advantages?
Natural animal models better reflect the complex genetic, environmental, and physiological variations present in human patients. Companion animals, specifically, often share the same environment as humans, and are exposed to similar epigenetic and disease-modulating factors, which is obviously not the case with laboratory models. Also, companion animals often live to old age, allowing long-term study of painful disease. Pet dogs and cats receive high-quality health care, particularly in later life, and owners are motivated to seek out improved treatment options, which helps in the recruitment of veterinary patients for clinical trials.
Of course, the causes of spontaneous painful disease in veterinary patients are variable, and the pathophysiology may differ in these animals compared to humans, even for apparently similar diseases such as osteoarthritis. However, the proximity of physiological factors, such as nociceptive transduction, transmission, and modulation as well as biochemistry or nutritional processes, to those of humans for large animals such as dogs and cats over rodents is well established.
How do you envision the role of natural animal models in pain research?
The use of these models could come after preclinical laboratory research and before human clinical trials, and act to complement laboratory studies and potentially reduce failure rates in clinical trials. As we already know, many analgesics that make it to clinical trials are declared negative, cost millions of dollars to develop, and in the end it’s 10 years of work with nothing really to show for it. Often this failure is due to poor assessment of efficacy and pharmacokinetics. These parameters could be determined sooner and perhaps with greater relevance with the use of natural animal models of pain.
A great example is the canine Comparative Oncology Trials Consortium, which is part of the US National Cancer Institute, where they have established a network of 20 academic comparative centers across 22 sites to study cancer in dogs. The consortium is able to test innovative therapeutics in dogs and to get fast-track validation or confirmation for human trials. It proves that this approach is both possible and feasible, and it’s very exciting to think what the possibilities could be for the pain field using a similar approach involving veterinary science and human medicine.
There is also the option to partner with commercial veterinary clinics, of which there are thousands across North America. Many of these have been developed with standardization in mind, as they are owned by the same consortium and are all working off similar protocols, enabling and facilitating multicenter trials with enormous recruitment potential.
What are some of the disadvantages or limitations associated with the use of natural animal models to study pain?
Although there are large networks of academic veterinary centers and commercial veterinary clinics, a large proportion of initial presentations of animal patients occur in private veterinary practices with relatively small caseloads. These private practices may be unaware of open veterinary clinical trials. Fortunately, the American Veterinary Medical Association recently launched an online Animal Health Studies Database with the aim of connecting researchers with primary care veterinarians.
Another limitation is that invasive procedures or tissue harvesting may not be possible in these models unless they are a benefit to the animal, such as in the case of medically indicated surgery or a diagnostic biopsy. Tissue collection may also be performed at necropsy, and as euthanasia of pets is commonly performed, these pets could be phenotyped before euthanasia, based on medical records, for example, to aim for and ensure proper and adequate specimen collection.
The variability in environment, nutrition, and exercise among pets would likely contribute to difficulties in assessment, for example in proof-of-concept therapeutic studies. We know that the gut microbiome has an influence on pain sensation, which is very dependent on an organism’s diet and environment. The result of this would be larger sample sizes for more robust analysis, which again requires more recruitment and increased complexity in design and interpretation of studies. Having said that, I still think that the information gained from a study with natural animal models with spontaneous diseases is more translationally relevant than, say, a study with lots of mice.
In the review article, you cite osteoarthritis as a good example of a natural animal pain model with translational relevance for both veterinary patients and people. Are there any other disease models that might be as relevant?
Cancer pain in animals offers another major area of interest for its translational value, particularly with the canine Comparative Oncology Trials Consortium I mentioned, which the pain field could take advantage of. There is concordance between human and canine oncology with respect to cellular and molecular aspects of bone cancer, lymphoma, and bladder cancer. Some tumors such as osteosarcoma are associated with severe pain, but no study has yet to comprehensively evaluate the pain characteristics associated with cancer in cats or dogs. We have started to address this with a trial in cancer veterinary patients where we are trying to validate cancer pain outcomes we developed in our laboratory conditions.
Other natural models with high translational potential are those of neuropathic pain. They can be congenital such as syringomyelia (a cyst within the spinal cord) in Cavalier King Charles Spaniels or acquired such as intervertebral disc disease-associated radiculopathy. The actual prevalence of neuropathic conditions in companion animals is unclear due to difficulties in assessment and diagnosis, and although the translational potential is high, we need better outcome measures that are more valid and reliable.
Inflammatory bowel disease is commonly encountered in dogs and cats whose pathophysiology involves neurogenic inflammation. The same goes for dermatological irritating conditions. In companion animals, the prevalence of chronic postoperative pain is probably underappreciated, especially in procedures that involve transection of nerve terminal branches, like declawing in cats, and there are increasing calls to abolish this procedure based on reports of neuropathic pain.
In the future, do you see the incorporation of natural animal pain models as a necessary or even required step in the translational development of pain therapeutics?
That would be wonderful! Actually, in Canada, government directorates such as the Therapeutic Products Directorate and Veterinary Drugs Directorate, similar to other international and regional authorities, require safety testing in at least two mammalian species, including one non-rodent species, prior to trials in humans for most toxicology studies. Usually this is confined to laboratory conditions, but we know that this is not ideal, so why not use natural models in dogs and cats? These models are present, accessible, and offer the opportunity to make the translational process for pain therapeutics more beneficial. Adding in natural models of pain could also offer valuable information about efficacy and dosing regimens, because when you consider the deficiencies we see in human clinical trials with novel pain therapies, often this comes down to poor initial assessment of pharmacokinetics and pharmacodynamics in preclinical testing.
The potential is there for veterinarians, physicians, and scientists to come together to develop a system that would be applicable to everyone involved in pain research and care. This will optimize the development of compounds to better serve all areas of translational pain research.
The review by Troncy et al. discussed in this interview is a PAIN Editor’s Choice article that is freely available here. An accompanying video is available here.
