Pain management in veterinary medicine: What’s new?

Rethinking arthritis management through a One Health lens

Veterinarians are taught osteoarthritis (OA) is a cartilage disease, but we were also taught that cartilage is aneural, so why does arthritis hurt? It hurts because the synovium contains a concentration of nociceptors, sensory neurons that detect pain. The synovium creates the environment of the joint, pain sensation, proprioception, producing joint fluid, and other vital functions, so that OA must be considered a synovial disease, not a cartilage disease.^1,2

As a recent review proposed, OA management should be multimodal, with a focus on managing synovial inflammation (synovitis).³ Understanding the pathophysiology of OA has led to targeted, disease-modifying approaches.⁴ A translational approach for musculoskeletal care from humans to companion animals to zoological species has since taken place, benefitting numerous animals and their caregivers.

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While managing musculoskeletal pain in equines is probably the most recognized, canines, felines, and exotics, including wildlife, have also benefitted from recent advancements in the use of targeted, injectable therapy.^5-6 Recently, a monoclonal antibody targeting nerve growth factor has been introduced for dogs and cats, but there are significant concerns about musculoskeletal adverse events, and the authors recommend very careful use of this therapy.^6-9

Perhaps a less-considered component of OA is the environmental impact of chronically used medicines such as non-steroidal anti-inflammatories (NSAIDs) or steroids. One study reported that accumulation of NSAIDs from wastewater to aquatic ecosystems poses serious threats to aquatic species.¹⁰ Another looked at glucocorticoids entering the environment from wastewater and the significant effects they may cause on fish.¹¹

The purpose of this article is to review some of the intraarticular therapies for the management of OA. These therapies can be considered for many species due to a shared pathophysiology of OA. These studies and the common knowledge of adverse systemic effects of traditional pain management for OA symptoms have driven research in pursuit of novel techniques and treatments for the disease.

OA as a synovial disease across species

OA was often thought of as a normal process for the body as joints “wear and tear” over time or due to trauma or congenital abnormalities. Now, its recognized as a pathologic disease process caused by synovitis and the resulting cartilage degradation, osteophyte formation, and subchondral bone remodeling. Whether repetition, acute trauma, congenital deformities, or obesity initiates the process, once the extracellular matrix is damaged in a joint, structural integrity is lost and damage-associated molecular patterns (DAMPs) initiate the inflammation resulting in OA progression and its self-sustaining cycle.⁴ This pathophysiology, and the associated pain, is similar across species—fromhumans, equines, canines, felines, leopards, sea lions, elephants, and avian species. While domestic canines often have secondary OA due to a developmental orthopedic disorder (elbow dysplasia, hip dysplasia, cranial cruciate ligament tear, etc.), domestic cat OA is often primary, and in humans and exotic species, OA can be either.^3,5,12,13 Due to this shared pathophysiology, small mammals are often used as animal models in studying spontaneous, naturally developing, genetic, or induced OA.

With improved understanding of OA pathophysiology, disease-modifying strategies have emerged to address the underlying mechanisms and modify associated structural damage to prevent long-term joint disability.

What’s new in targeted, intraarticular OA therapies?

Sn-117m microparticles have been investigated as a safe and effective therapeutic for treating OA by reducing synovial inflammation by halting the cycle of OA.^4,14 When introduced into the joint, Sn-117m provides low-level irradiation that suppresses synovial inflammation and thus provides pain relief for up to a year, as found in several studies evaluating canine elbow OA.^14-17 Sn-117m only penetrates <0.3 mm, sparing articular cartilage, subchondral bone, and other deeper tissues. This also means Sn-117m does not leak into systemic circulation, preventing radioactive bodily fluids and requiring minimal restrictions for interaction post injection. As a result, Sn-117m has been approved for use in canine patients. One author (MWB) has successfully used Sn-117m in over 150 canines (predominately elbows), 3 domestic cats, and a Komodo dragon with elbow and stifle OA at a major United States zoo.¹⁸ Additionally, Sn-117m has been used in 2 other Komodo dragons for OA and a tiger at other facilities with other clinicians.^19-21

Two and a half percent synthetic cross-linked injectable polyacrylamide hydrogel (2.5 iPAAG) is a nonabsorbable and nondegradable material that has been used to treat OA in humans and horses.^22,23 When injected intraarticularly, 2.5 iPAAG localizes to the subintima of the synovial lining, acts as a bioscaffold, and induces a low-level phagocytic response.²⁴ When studied in goats, 2.5 iPAAG was found to thicken the synovial membrane by allowing angiogenesis and increasing collagen and synovial cells, which lead to increased joint elasticity and lasting viscosupplementation.²³ One author, Brunke, has successfully used 2.5 iPAAG in domestic canine and felines, and non-domestic species such as an amur leopard and fennec foxes.

Platelet-rich plasma (PRP) is a blood-derived product that consists of plasma with a platelet concentration higher than that of peripheral blood. Aside from their role in blood clotting, platelets release growth factors that stimulate angiogenesis, chondrocyte proliferation, and reduce chondrocyte apoptosis.²⁵ PRP therapy for OA involves obtaining a blood sample from the affected patient, which is then processed to produce platelet-rich plasma, and injecting it intraarticularly with effects lasting 3-9 months. Use of PRP in equine OA management is well documented and has also been utilized in domestic species for intraarticular OA therapy. ^25,26 In many zoo and wildlife species, such as South American sea lions (Otaria flavescens), bottlenose dolphins (Tursiops truncatus), and some species of marine turtles, PRP has been utilized more often for wound management.^27-29

Mesenchymal stem cells (MSCs) are progenitor cells with the ability to differentiate into numerous cell types, such as bone, cartilage, and connective tissue cells. The mechanism of action is still not understood. MSCs can be autologous, allogenic, or xenogeneic. Cells are collected from subcutaneous tissue or bone marrow, cultured and expanded in vitro, and then administered via an intra-articular injection. Effects can last up to 6 months. This is a more costly procedure, as cell culture requires 7-10 days and 2 anesthetic events are required. Potential for donor-site morbidity and adverse immune reactions with allogenic preparations must be considered. Other disease-modifying strategies in OA management include autologous conditioned plasma (ACP), bone marrow aspirate concentrate (BMAC), stromal vascular fraction (SVF), autologous conditioned serum (ACS), and autologous protein solution (APS). Each offering different mechanisms to address joint inflammation and tissue repair.³⁰

Risks associated with therapeutic joint injections (TJIs) in small animals include transient soreness, GI side effects, and one reported case of possible sepsis.³¹ For equine orthobiologics, joint flare can be seen, but no other adverse events were reported in a recent systematic review and meta-analysis.³² For the 2.5% iPAAG treatment, transient joint soreness was reported in a small number of equine and human cases, and in the authors’ experience this is similar in dogs and cats.^23,33 

Future research and conclusion

While these advancements pose novel techniques for a multitude of species, there remains a need for continued collaborative research and species-specific dosing, delivery, and outcome tracking. Physical activity monitors (PAMs) have been a significant tool in companion animal osteoarthritic research and present an opportunity for translational studies across species. Case reporting is a crucial aspect of spreading knowledge within the veterinary community, especially for zoo and wildlife medicine.³⁴

Utilizing a One Health approach can advance pain management across species. Intraarticular therapies like Sn-117m, 2.5% iPAAG, PRP, and MSCs are improving outcomes in a wide range of species and can continue to be researched in medicine. Ongoing innovation, clinical curiosity, and cross-species learning are key to treating OA and chronic pain in all animals under our care.

References

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