One Pain: how pets can contribute to translational research

Dr Duncan Lascelles BVSc BSc CertVA PhD DipECVS DSAS(Soft Tissue) DipACVS FRCVS

Fellowship Day 2019

Report of presentation

The veterinary profession has “come a long way” in its ability to measure pain in animals, said Dr Duncan Lascelles, professor in small animal surgery and pain management at North Carolina State University, who had been welcomed into the RCVS Fellowship earlier in the day.

While he had spent his career thus far figuring out ways to measure pain, what he really wanted to do was to move new therapies into clinical practice, particularly therapies and drugs for chronic pain control.

“And that’s not happening,” he said. “We’re not getting those new therapies; there have been no novel analgesics for chronic pain in veterinary medicine in 25 years.” There had been various different presentations and combinations of analgesics, but no new drugs with different modes of action.

Why was this? One reason was a lack of candidate analgesics to test. Such candidate drugs came from human translational pain research into new analgesics for human medicine. To understand why no candidate drugs were emerging, it was important to understand a little about translational pain research.

Translational research began an animal model to assess what parameters were altered by a pain condition. “That leads you to a pathway, or a receptor – some sort of target – and you then develop a therapeutic to hit that target,” Dr Lascelles explained.

Once the putative analgesic had been developed, it was then tested in the same types of rodent model that had been used for finding the target. Various steps followed, including testing of efficacy in rodents, before the drug entered human clinical trials

While, in some respects, translational pain research was a stepwise, logical process, Dr Lascelles commented that, at the point where it moved from rodents into human clinical trials, there was “not a step, but a huge leap”.

Pets could play a valuable role in overcoming some of the problems associated with the current translational research mechanism, Dr Lascelles suggested. They suffered chronic conditions that were associated with pain and, in many respects, those conditions reflected the genetic, environmental and temporal characteristics present in human pain conditions. “In many respects, I think they [pets] are better models of the human pain conditions,” he said.

Because it was possible to measure pain in animals, pets with naturally occurring painful conditions could be used to test putative analgesics and to optimise the translational process.

“Not only can we measure, but we can measure pain in a way that is meaningful to humans. We can measure the dimensions that are impacted by pain in people – cognitive function, anxiety, fear, the ability to perform the activities of daily living.”

These types of measurement would be more relevant to humans than the reflexive measurements made in rodent models. He also noted that a number of potential analgesics that had worked in rodents had failed in both dogs and humans. Dogs and cats, therefore, could be predictive models for the efficacy of potential analgesics in humans.

Returning to the earliest stage of translational research – that of selecting a target for an analgesic – Dr Lascelles said that, unless the biological rationale for selecting that target was sound, any drug development programme would fail.

“Remember how those targets are selected,” he said. “You induce a model, see what’s altered, and then you create a drug against what’s altered.”

However, in these rodent models, the pain was created artificially, which led to questions about the relevance of the models and the targets derived from them for naturally occurring painful conditions in humans.

“I think we’re in a very fortunate position in veterinary medicine,” he said. “We can measure pain, which means we can phenotype animals. We have access to tissues, we can then take those tissues and perform discovery. We can answer the question ‘What is actually altered? What is actually driving that pain state?’ Then we can take that target back into a rodent model to figure out the mechanisms.”

Pets, he said, could act as a verification bridge interposed between rodent work and human clinical trials, allowing the process to be optimised and saving on costly, failed clinical trials.

Concluding, Dr Lascelles said that if one believed in the concept of ‘one pain’ – that the drivers and experiences of pain were similar across species – there had to be some way of using the information available in veterinary medicine to inform human translational pain research.

“Why would we do that?” he asked. “We do it because we will benefit – humans will benefit, veterinary medicine will benefit from the extra information that we will learn and also from resources being directed at veterinary species, the species that we are interested in.”

A number of questions following Dr Lascelles’ presentation concerned the use of pet animals in translational research. The point was made that, while vets saw pet animals that could be naturally occurring models of human disease in their practices every day, there was currently no ethical framework available to guide how the concept of translational research might be introduced into clinical practice. Dr Lascelles was asked how this ethical barrier might be overcome, and how regulation might have to evolve to allow the use of pet animals in such studies.

Any steps in this area had to be done ethically, sensitively and with full owner consent, and always with the appropriately trained veterinarian oversight, he replied. “This is not something which should be ever run by, for example, a pharmaceutical company without veterinary oversight. Owners should be fully informed of the potential benefits and risks.”

The profession should “figure out how to do this”, he said, adding that an ethically responsible mechanism that was “completely defendable to the general public” was needed.

As far as regulation went, he believed it was important to find a way to allow such studies to be performed, with appropriate oversight and appropriate owner consent. “We are losing such great opportunities to benefit veterinary medicine and human medicine,” he warned.

Dr Lascelles was also asked whether cannabinoids were “the new frontier in pain management”. In response, he said that this was very exciting area, but the endocannabinoid system was very complex, which made it difficult to understand how to interact with it. Cannabinoid products were also complex. High-quality research in the field was hampered by government regulations and, while he was optimistic about the future, he was pessimistic about the present.