Nerve growth factor (NGF) is essential for the survival of sensory and sympathetic neurons during development. However, in the adult, NGF and its interaction with tropomyosin receptor kinase A receptor (TrkA) has been found to play a critical role in nociception and nervous system plasticity in pain conditions. Thus, various monoclonal antibody (mAb) therapies targeting this pathway have been investigated in the development of new pharmacotherapies for chronic pain. Although none of the mAbs against NGF are yet approved for use in humans, they look very promising for the effective control of pain. Recently, species‐specific anti‐NGF mAbs for the management of osteoarthritis (OA)‐associated pain in dogs and cats has been developed, and early clinical trials have been conducted. Anti‐NGF therapy looks to be both very effective and very promising as a novel therapy against chronic pain in dogs and cats. This review outlines the mechanism of action of NGF, the role of NGF in osteoarthritis, research in rodent OA models and the current status of the development of anti‐NGF mAbs in humans. Furthermore, we describe and discuss the recent development of species‐specific anti‐NGF mAbs for the treatment of OA‐associated pain in veterinary medicine.

Objectives: The aim of this study was to develop an evidence-based, clinically expedient checklist to identify cats likely to have degenerative joint disease (DJD)-associated pain. Methods: Data were compiled from previously conducted studies that employed a standardized subjective outcome measure consisting of a series of questions. These studies included a prevalence study (with DJD non-informed owners) and therapeutic trials (with DJD-informed owners). For each cat, and each question, response scores were converted to ‘impaired’ and ‘unimpaired’. Cats were categorized as ‘DJD pain’ and ‘non-DJD’ based on orthopedic pain and radiographic DJD scores. These binary data were compared between cat phenotypes (non-DJD and DJD pain) for each question. Sensitivity and specificity of each question were calculated using the binary data; based on this, potential questions for the checklist were selected. Sensitivity and specificity across this group of questions were calculated, and questions sequentially removed to optimize length, sensitivity and specificity. Finally, the proposed checklist was applied to a novel data set to evaluate its ability to identify cats with DJD pain. Results: In total, 249 DJD pain cats and 53 non-DJD cats from five studies were included. Nine questions with adequate sensitivity and specificity were initially identified. Following sequential removal of questions, a checklist with six binary questions was proposed. Based on the data from the cohorts of DJD-informed and DJD non-informed owners, the sensitivity and specificity of the proposed checklist were approximately 99% and 100%, and 55% and 97%, respectively. Conclusions and relevance: The proposed checklist represents a data-driven approach to construct a screening checklist for DJD pain in cats. This checklist provides a clinically expedient tool likely to increase veterinarians’ ability to screen for DJD pain in cats. The identified behaviors comprising the checklist may further provide a foundation for increasing awareness of DJD pain among cat owners.

Objectives: The aim of this study was to investigate the reliability and responsiveness of the Feline Musculoskeletal Pain Index (FMPI) using the collective results of multiple clinical studies and iteratively refine the FMPI for future use. Methods: Data were compiled from previously conducted studies involving client-owned cats with degenerative joint disease (DJD) and which used the FMPI. The reliability of the FMPI was assessed using the data from the initial visits of those studies. For the assessment of responsiveness of the FMPI, only placebo-controlled studies that used analgesic treatments were included. Treatment groups from each study were combined and categorized as ‘placebo’ group and ‘analgesic’ group. Then, the mean change from baseline in score of each FMPI item and across all items within and between these groups were assessed. Based on the results of the reliability and responsiveness of the FMPI, stepwise elimination was used to remove the items that were least able to distinguish between the placebo and analgesic groups. Finally, after the stepwise elimination, a proposed new FMPI-short form (FMPI-sf) was constructed and its reliability was reassessed using the data sets described above. Individual and combined data sets of the studies were also used to compare the responsiveness of the original FMPI and the FMPI-sf. Results: The data from 180 cats from four studies were included. The original FMPI had a reasonable reliability, but low/no responsiveness. The elimination process of FMPI items refined the responsiveness of the instrument while maintaining its reliability. When the responsiveness was compared between the original FMPI (17 items) and the FMPI-sf (nine items), the treatment effect between groups was always greater when the FMPI-sf was used. Conclusions and relevance: The proposed FMPI-sf may be able to better distinguish between placebo and analgesic effects in cats with DJD.

In man, central sensitisation (CS) contributes to the pain of osteoarthritis (OA). Dogs with spontaneous OA may also exhibit CS. Electrophysiological reflex measurements are more objective than behavioural assessments and can be used to evaluate CS in preclinical and clinical studies. It was hypothesised that dogs suffering from OA would exhibit electrophysiological characteristics indicative of CS, associated with reduced diffuse noxious inhibitory controls (DNICs). One hundred and seventeen client-owned dogs were recruited to the study. Hind limb nociceptive withdrawal reflex thresholds, stimulus response, and temporal summation characteristics were recorded, during alfaxalone anaesthesia, from 46 OA dogs, 29 OA dogs receiving nonsteroidal anti-inflammatory drugs (OANSAIDs), and 27 breed- and weight-matched control dogs. Efficacy of DNIC was evaluated in 12 control and 11 of the OA dogs, by application of a mechanical conditioning stimulus to the contralateral forelimb. Nociceptive withdrawal reflex thresholds were higher in OA compared with control dogs (P = 0.02). Stimulus response characteristics demonstrated an augmented response in OANSAID dogs compared with OA (P < 0.001) and control (P < 0.001) dogs. Temporal summation demonstrated exaggerated C-fibre-mediated responses in both OA (P < 0.001) and OANSAID (P = 0.005) groups, compared with control animals. Conditioning stimulus application resulted in inhibition of test reflex responses in both OA and control animals (P < 0.001); control animals demonstrated greater inhibition compared with OA (P = 0.0499). These data provide evidence of neurophysiological changes consistent with CS in dogs with spontaneous OA and demonstrate that canine OA is associated with reduced DNIC.

Arthritis, including osteoarthritis (OA) and other musculoskeletal-associated pain, is a worldwide problem; however, effective drug options are limited. Several receptors, neurotransmitters, and endogenous mediators have been identified in rodent models, but the relevance of these molecules in disease-associated pain is not always clear. Artemin, a neurotrophic factor, and its receptor, glial-derived neurotrophic factor (GDNF) family receptor alpha-3 (GFRα3), have been identified to involved in pain in rodents. Their role in OA-associated pain is unknown. To explore a possible association, we analyzed tissue from naturally occurring OA in dogs to characterize the correlation to chronic pain. We used behavioral assessment, objective measures of limb use, and cellular and molecular tools to identify whether artemin and GFRα3 might be associated with OA pain. Our results using banked tissue from well-phenotyped dogs indicates that artemin/GFRα3 may play an important, and hitherto unrecognized, role in chronic OA-associated pain. Elevated serum levels of artemin from osteoarthritic humans compared to healthy individuals suggest translational relevance. Our data provide compelling evidence that the artemin/GFRα3 signaling pathway may be important in OA pain in both non-humans and humans and may ultimately lead to novel therapeutics.