Defining a pain phenotype that is predictive of altered central pain processing in dogs with spontaneous osteoarthritis

Until very recently, pain in people was considered to be a single uniform entity; the nature of the pain experienced by an individual was considered to be similar regardless of the underlying cause. However this concept has now been challenged, which of course fits with everyone's own unique experience of pain resulting from tissue injury, trauma or surgery. The nature and quality of pain caused by each disease condition is different and reflects the underlying changes in the sensory system responsible for causing pain. For example, people may show differing changes in sensitivity to warm or cold stimuli, reflecting different underlying aetiologies or mechanisms of pain. In man this has led to personalized therapy for pain. It is now possible, in people, to identify distinct pain patterns (termed pain phenotype) that relate to distinct changes in sensory processing and target these underling changes in sensory processing with specific drugs. This has resulted in improved pain management in people in chronic pain. The aim of this current proposal is to translate the concept of personalized pain therapy from people to dogs and subsequently increase our capability to provide adequate pain relief to dogs suffering from chronic pain.

A very common cause of chronic pain in dogs is osteoarthritis. We currently assume that all dogs with osteoarthritis suffer similarly from pain and show similar altered sensitivity to sensory stimuli such as heat and pressure. However, in people suffering from osteoarthritis, different types of pain associated with different sensory sensitivities are recognized, and these distinct pain patterns are likely associated with different underlying changes in the sensory nervous system. We predict, given the similarity between the disease of osteoarthritis in dogs and man, we will be able to identify similar distinct pain patterns in dogs suffering from osteoarthritis. We will study pet dogs with osteoarthritis, recruited through liaison with veterinary surgeons. The dogs will benefit from a detailed clinical assessment of their osteoarthritis with follow up advice about optimising their pain management, provided by European Specialists in canine osteoarthritis and animal pain management.

A major discriminator in the underlying pain mechanisms is whether the pain results primarily from changes in sensory processing in the peripheral nervous system (i.e. in the processing of sensory stimuli localised to the site of the disease process, in the case of osteoarthritis this would be the affected joint) or whether pain is caused by changes in the periphery (the joint) and in the central nervous system (i.e. the spinal cord and brain). Once pain is associated with peripheral AND central nervous system changes it becomes much more difficult to manage effectively and also requires different pain management strategies, for example different types of pain killing drugs are necessary. We will use a simple, validated experimental paradigm to distinguish whether both peripheral OR peripheral AND central changes in sensory processing are present in individual dogs with osteoarthritis. This test will be carried in dogs that are anaesthetised and therefore unaware. Subsequently, in awake animals, we will map the individual pain pattern or pain phenotype to allow us to link pain mechanism with clinical pain expression. This will be achieved by testing sensitivities to warmth, heat, cold and pressure stimuli. Ultimately, we hope that a veterinary surgeon will be able to examine a dog with osteoarthritis in their clinic, and determine using simple and non-invasive tests, their pain phenotype, and use this information to derive knowledge of the underlying pain mechanisms. This will allow the veterinary surgeon to target or personalize pain medication to the patient, with the goal of improved pain management and the lifelong welfare of the individual animal.

In man it is recognised that distinct types of pain, with different underlying causes, exist. However, clinical pain in animals is still considered to be a single entity, regardless of the cause. Knowledge of different patterns of clinical pain (i.e. pain phenotypes) in animals and subsequently the relationship between pain phenotype and underlying aetiopathogenesis of pain is required to advance our understanding of pain mechanisms in animals with spontaneous disease, and to allow a mechanism-based approach to analgesic treatment. The aim of the current proposal is to investigate the relationship between pain phenotype and pain mechanisms using hip and stifle osteoarthritis (OA) in dogs as a spontaneous pain model.

The underlying aetiopathogenesis of pain in individual dogs suffering from OA will be established by determining whether there is only altered peripheral (i.e. joint) processing of pain or whether there is altered peripheral AND central (brain and spinal cord) pain processing, by measuring hindlimb nociceptive withdrawal reflexes, temporal summation and assessment of diffuse noxious inhibitory control in dogs with OA and a cohort of healthy CONTROL animals. Subsequently we will define pain phenotypes in our study population by assessing sensitivity to multiple sensory modalities to characterise altered pain sensitivity in dogs with OA relative to CONTROL animals. We will then explore and categorise pain phenotypes that are associated with altered central and/or peripheral pain processing. This proposal represents the first step in understanding the relationship between neurobiological mechanisms and pain phenotype in non-human species and will significantly improve the lifelong welfare of many dogs by: 1) Allowing rational selection of analgesic drugs that target the underlying aetiopathogenesis of the pain; and 2) Identifying clinically relevant and translational QST biomarkers that can be used to provide goal directed analgesic therapy.

The key beneficiaries will be 1) other academics working in chronic pain research; 2) veterinary surgeons in clinical practice; 3) owners of dogs with osteoarthritis or dogs with other chronically painful conditions 4) Pharma; both in terms of veterinary and human analgesic drug development; 5) dogs suffering from chronic pain.

1) Academics will benefit from knowledge linking pain phenotype with the underlying aetiopathogenesis of the pain in dogs. This knowledge will a) further validate the use of canine osteoarthritis as a translational pain model for osteoarthritis research; bringing the benefits associated with the study of a clinical disease model compared with the well recognized limitations of laboratory animal models of osteoarthritis; b) facilitate detection of other conditions causing chronic pain that are associated with central dysregulation of sensory processing in dogs and therefore identify other spontaneous clinical disease models for translational pain research; c) in canine research it will allow much tighter recruitment criteria to be set for studies investigating the efficacy of analgesics in dogs with chronically painful conditions, for example only cohorts of dogs with central dysregulation of sensory processing might be included in a study, thereby reducing the natural variability in the study population. This would increase the statistical power of many clinical studies and increase the robustness of the generated data in terms of its clinical applicability to dogs in pain; d) the development of novel validated quantitative sensory testing methods that can predict central dysregulation of sensory processing in dogs can also be applied to other pain studies assessing the efficacy of analgesics in chronic pain models.
2) Transfer of knowledge to veterinary surgeons about tests that are predictive of central dysregulation of sensory processing that can be applied in day to day clinical practice will allow veterinary surgeons to implement a mechanism based approach to analgesic therapy. This will improve their capability to manage pain effectively in their patients and also provide a means to monitor response to drug therapy or change in analgesic requirement / pain level over time.
3) Owners are very keen to be educated about diseases in their pet, particularly with respect to knowledge that might facilitate improved treatment. Therefore the dog owning community can also benefit from knowledge transfer about the complexity of chronically painful conditions in dogs and be trained to recognize indicators of altered pain states in their pet. Owners also benefit from improved therapeutic management on chronic pain in their own dog. Successful pain management and the resulting increased quality of life helps to maintain or restores the relationship between the owner and their pet that can deteriorate when the dog is unwell and unable to enjoy life or exercise normally.
4) The project is not expected to generate any new IP, however the support of the project by Pfizer Animal Health is an indication of the potential importance of data generated by the project to Pharma. Knowledge of the relationship between pain phenotype and pain mechanisms in dogs will be advantageous in R&D studies of analgesic drug development and drug efficacy, both in terms of development of new analgesic molecules for dogs, but also in the use of canine osteoarthritis as a spontaneous disease model. Commercially, increased knowledge about the importance of central mechanisms in chronic pain states will likely be used to guide Pharma recommendations to veterinary surgeons about analgesic drug selection and duration of therapy.
5) Dogs suffering from chronically painful conditions will benefit from implementation of analgesic strategies that result in improved pain management. This could significantly improve the lifelong welfare of dogs suffering from chronic pain and reduce early euthanasia due to inadequate pain management.