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In humans, pain due to osteoarthritis has been demonstrated to be associated with insomnia and sleep disturbances that affect perception of pain, productivity, and quality of life. Dogs, which develop spontaneous osteoarthritis and represent an increasingly used model for human osteoarthritis, would be expected to show similar sleep disturbances. Further, these sleep disturbances should be mitigated by analgesic therapy. Previous efforts to quantify sleep in osteoarthritic dogs using accelerometry have not demonstrated a beneficial effect of analgesic therapy; this is despite owner-reported improvements in dogs’ sleep quality. However, analytic techniques for time-series accelerometry data have advanced with the development of functional linear modeling. Our aim was to apply functional linear modeling to accelerometry data from osteoarthritic dogs participating in a cross-over non-steroidal anti-inflammatory (meloxicam) drug trial. Significant differences in activity patterns were seen dogs receiving drug (meloxicam) vs. placebo, suggestive of improved nighttime resting (sleep) and increased daytime activity. These results align with owner-reported outcome assessments of sleep quality and further support dogs as an important translational model with benefits for both veterinary and human health.

Mobility is considered a vital component of health and quality of life in humans and companion animals. Wearable devices for pets that can monitor activity and other aspects of health are increasingly being marketed to veterinarians and owners, with claims around their ability to monitor aspects of health. However, there is little scientific evidence to support the validity of these claims. To address this, the objective of this study was to assess the correlation of the activity measurement from the PetPace device compared to activity output from Actigraph and the validated Actical device. Ten client-owned, healthy dogs were used for the study. The three devices were mounted simultaneously on a dedicated collar and activity was recorded during a period of 7 days. There were moderate correlations between the Actical and the PetPace (r2=0.59, P=

Summary Objective To outline the role that spontaneous osteoarthritis (OA) in companion animals can play in translational research and therapeutic pharmacological development. Outline Narrative review summarizing the opportunities and limitations of naturally occurring, spontaneous OA as models of human OA pain, with a focus on companion animal pets. The background leading to considering inserting spontaneous disease models in the translational paradigm is provided. The utility of this model is discussed in terms of outcome measures that have been validated as being related to pain, and in terms of the potential for target discovery is outlined. The limitations to using companion animal pets as models of human disease are discussed. Conclusions Although many steps along the translational drug development pathway have been identified as needing improvement, spontaneous painful OA in companion animals offers translational potential. Such ‘models' may better reflect the complex genetic, environmental, temporal and physiological influences present in humans and current data suggests the predictive validity of the models are good. The opportunity for target discovery exists but is, as yet, unproven.

Objective To compare quality of life (QOL) and activity measures between healthy control cats and cats with subclinical hypertrophic cardiomyopathy (HCM), and to evaluate the effect of oral atenolol therapy on QOL, activity, and circulating biomarkers in cats with subclinical HCM. Animals Thirty-two client-owned cats with subclinical HCM and 27 healthy control cats. Methods Owner responses to a QOL questionnaire, circulating cardiac biomarker concentrations, and accelerometer-based activity measures were compared prospectively in cats with and without HCM, and in cats with HCM before and after treatment with oral atenolol (6.25 mg/cat q 12 h) for 6 months. Results Owner-assessed activity of daily living score was lower in cats with HCM than in cats in controls (p=0.0420). No differences were identified between control cats and cats with HCM for any activity variable. Compared with placebo, treatment with atenolol was associated with a lower baseline-adjusted mean ± SD heart rate (157 ± 30 vs. 195 ± 20 bpm; p=0.0001) and rate-pressure product (22,446 ± 6,237 vs. 26,615 ± 4,623 mmHg/min; p=0.0146). A treatment effect of atenolol on QOL or activity was not demonstrated. Conclusions This study failed to identify an effect of subclinical HCM on owner-assessed QOL or activity or a treatment effect of atenolol on these variables at the dosage evaluated. These findings do not support a treatment benefit of atenolol for the goal of symptom reduction in cats with subclinical HCM.

Background Effective treatments are needed for idiopathic chronic rhinitis in dogs, but assessment of efficacy requires a practical, quantifiable method for assessing severity of disease. Objectives To develop and perform initial validity and reliability testing of an owner-completed questionnaire for assessing clinical signs and dog and owner quality of life (QOL) in canine chronic rhinitis. Animals Twenty-two dogs with histopathologically confirmed chronic rhinitis and 72 healthy dogs. Methods In this prospective study, an online questionnaire was created based on literature review and feedback from veterinarians, veterinary internists with respiratory expertise, and owners of dogs with rhinitis. Owners of affected dogs completed the questionnaire twice, 1 week apart, to test reliability. Healthy dogs were assessed once. Data were analyzed using the Rasch Rating Scale Model, and results were interpreted using Messick's framework for evaluating construct validity evidence. Results Initial item generation resulted in 5 domains: nasal signs, paranasal signs, global rhinitis severity, and dog's and owner's QOL. A 25-item questionnaire was developed using 5-point Likert-type scales. No respondent found the questionnaire difficult to complete. Strong psychometric evidence was available to support the substantive, generalizability, content, and structural aspects of construct validity. Statistical differences were found between responses for affected and control dogs for all but 2 items. These items were eliminated, resulting in the 23-item Severity of Nasal Inflammatory Disease (SNIFLD) questionnaire. Conclusions and Clinical Importance The SNIFLD questionnaire provides a mechanism for repeated assessments of disease severity in dogs with chronic rhinitis.

Background Degenerative joint disease (DJD) is highly prevalent in cats, and pain contributes to morbidity. In humans, alterations of cytokine concentrations have been associated with joint deterioration and pain. Similar changes have not been investigated in cats. Cytokine concentrations can be measured using multiplex technology with small samples of serum or plasma, however, serum and plasma are not interchangeable for most bioassays. Correlations for cytokine concentrations between serum and plasma have not been evaluated in cats. Objective To evaluate the levels of detection and agreement between serum and plasma samples in cats. Animals Paired serum and plasma samples obtained from 38 cats. Methods Blood was collected into anti-coagulant free and EDTA Vacutainer® tubes, serum or plasma extracted, and samples frozen at −80 °C until testing. Duplicate samples were tested using a 19-plex feline cytokine/chemokine magnetic bead panel. Results Agreement between serum and plasma for many analytes was high, however correlation coefficients ranged from −0.01 to 0.97. Results from >50% of samples were below the lower limit of quantification for both serum and plasma for nine analytes, and for an additional three analytes for plasma only. Conclusions and clinical importance While serum and plasma agreement was generally good, detection was improved using serum samples.

Background Monocytes/macrophages are likely key cells in immune modulation in dogs with osteosarcoma (OSA). Increased peripheral monocyte counts are negatively correlated with shorter disease-free intervals in dogs with OSA. Understanding the monocyte/macrophage's modulatory role in dogs with OSA can direct further studies in immunotherapy development for OSA. Hypothesis/Objectives That OSA evades the immune response by down-regulating monocyte chemokine receptor expression and migratory function, and suppresses host immune responses. Animals Eighteen dogs with OSA that have not received definitive treatment and 14 healthy age-matched controls Methods Clinical study—expression of peripheral blood monocyte cell surface receptors, monocyte mRNA expression and cytokine secretion, monocyte chemotaxis, and survival were compared between clinical dogs with OSA and healthy control dogs. Results Cell surface expression of multiple chemokine receptors is significantly down-regulated in peripheral blood monocytes of dogs with OSA. The percentage expression of CCR2 (median 58%, range 2–94%) and CXCR2 expression (median 54%, range 2–92%) was higher in control dogs compared to dogs with OSA (CCR2 median 29%, range 3–45%, P = 0.0006; CXCR2 median 23%, range 0.2–52%, P = 0.0007). Prostaglandin E2 (PGE2) (OSA, median 347.36 pg/mL, range 103.4–1268.5; control, 136.23 pg/mL, range 69.93–542.6, P = .04) and tumor necrosis factor-alpha (TNF-α) (P = .02) levels are increased in OSA monocyte culture supernatants compared to controls. Peripheral blood monocytes of dogs with OSA exhibit decreased chemotactic function when compared to control dogs (OSA, median 1.2 directed to random migration, range 0.8–1.25; control, 1.6, range of 0.9–1.8, P = .018). Conclusions and Clinical Importance Dogs with OSA have decreased monocyte chemokine receptor expression and monocyte chemotaxis, potential mechanisms by which OSA might evade the immune response. Reversal of monocyte dysfunction using immunotherapy could improve survival in dogs with OSA.

Background Neutralizing antibodies against nerve growth factor (NGF) are analgesic in rodent models, naturally occurring degenerative joint disease (DJD) pain in dogs, and chronic pain in humans. Objectives To evaluate the efficacy of a fully felinized anti-NGF antibody (NV-02) for the treatment of DJD pain and mobility impairment in cats. Animals Thirty-four client-owned cats with DJD-associated pain and mobility impairment. Methods In a placebo-controlled, pilot, masked clinical study, cats were randomized to a single treatment with NV-02 (0.4 mg/kg SC [n = 11] or 0.8 mg/kg SC [n = 12]) or placebo (saline, SC [n = 11]). Activity was measured objectively. Additionally, owners completed clinical metrology instruments (client-specific outcome measures [CSOM] and feline musculoskeletal pain index [FMPI]) on days 0 (screening), 14 (baseline), 35, 56, and 77. A repeated-measures model was used to evaluate the objective activity data. Results NV-02 significantly increased objectively measured activity overall (P = .017) and at 2 (P = .035), 3 (P = .007), 4 (P = .006), 5 (P = .007), and 6 (P = .017) weeks after treatment. CSOM scores (P = .035) and pain (P = .024) showed a significant effect of treatment 3 weeks after administration. In the treatment group, 83% of the owners correctly identified the treatment administered compared with 45% of owners in the placebo group (P = .013). No treatment-related adverse effects were identified. Conclusions These pilot data demonstrate a 6-week duration positive analgesic effect of this fully felinized anti-NGF antibody in cats suffering from DJD-associated pain.

Background Limited options are available for the treatment of pain in cats. Monoclonal antibodies (mAbs) that neutralize nerve growth factor (NGF) have demonstrated analgesic capacity in rodent models, people with osteoarthritis, and dogs with degenerative joint disease. Hypothesis/Objectives This study describes the design and characterization of a fully felinized anti-NGF monoclonal antibody. In vitro potency, pharmacokinetics, and the ability of the antibody to treat pain in a self-resolving, acute inflammation model were investigated in cats. Animals Thirty-eight cats at a research colony at Charles River Laboratories, Ireland. Methods Felinized anti-NGF mAb, NV-02, was produced using a complementary DNA (cDNA)-based method (PETization). Purified NV-02 was tested for affinity, potency, and immunoreactivity in vitro, then for safety and plasma pharmacokinetic distribution in vivo, and analgesic efficacy in a model of kaolin-induced inflammatory pain. Results Anti-NGF mAb, NV-02 neutralized NGF with high affinity and potency and did not bind complement. NV-02-administered SC had a plasma half-life of 7–15 days and was well tolerated at dosages up to 28 mg/kg. A dosage of 2 mg/kg NV-02 SC significantly decreased signs of lameness on day 2 (P = .0027), day 3 (P = .016), day 4, (P = .0063), day 5 (P = .0085), day 6 (P = .0014), and day 7 (P = .0034) after induction of inflammation. Conclusions and Clinical Importance The high affinity, long plasma half-life, safety, and analgesic efficacy of felinized anti-NGF mAb (NV-02) support further investigation of the analgesic potential of this antibody in the cat.

Background Intervertebral disc herniation is a common cause of spinal cord injury (SCI) causing paralysis and sensory loss. Little quantitative information is available on the loss and recovery of sensation in dogs with SCI. Objectives To determine whether quantitative sensory testing (QST) can be used to establish thermal and mechanical sensory thresholds in chrondrodystrophoid dogs and compare thresholds among normal dogs and dogs with different grades of SCI. Animals Thirty-three client-owned chondrodystrophoid dogs: 15 normal and 18 SCI dogs. Methods Thermal testing was performed by placing a hot (49°C) and cold (5°C) probe on the dorsal metatarsus and mechanical thresholds were tested using calibrated forceps to apply force to the lateral digit. Stimuli were applied until acknowledged, and response rate, latency, and force applied to response were recorded. Test-retest repeatability was determined by calculating intraclass correlation coefficients. Response rates were compared using logistic regression and thresholds were compared using Kaplan–Meier Survival curves. Results Testing was feasible with moderate repeatability. Thresholds and response rates were significantly different between normal and SCI dogs for all modalities (P < .001). When dogs were grouped by their clinical grade, each grade was significantly different from normal dogs, and cold stimuli differentiated among all grades. Conclusion and clinical importance Sensory thresholds can be measured reliably in chondrodystrophoid dogs and are altered by SCI. The differences in sensation among neurologic grades indicate that these techniques can be used to further characterize recovery of SCI dogs.

In the face of increasing recognition and interest in treating chronic pain in companion animals, we struggle with a lack of therapeutic options. A significant barrier to the development of new therapeutics, or the critical evaluation of current therapies, is our inability to accurately measure chronic pain and its impact on companion animals. Over the last 20 years, much progress has been made in developing methods to measure chronic pain via subjective and objective methods - particularly in owner assessment tools and measurements of limb use and activity. Most work has been focused on chronic joint pain conditions, but there has been relatively little work in other areas of chronic pain, such as neuropathic and cancer pain. Although progress has been made, there is a considerable interest in improving our assessment of chronic pain, as evidenced by the multiple disciplines across industry, academia, and clinical practice from the veterinary and human medical fields that participated in the Pain in Animals Workshop held at the National Institutes of Health in 2017. This review is one product of that meeting and summarizes the current state of knowledge surrounding the measurement of chronic pain (musculoskeletal, cancer, neuropathic), and its impact, in cats and dogs.

Most models of acute post-operative orthopedic pain involve the injection of a clinically irrelevant pro-inflammatory agent. The ideal model should, however, be clinically relevant and allow full functional recovery of enrolled animals after research is completed. This study explored the validity of a model employing arthrotomy and objectively measured limb use. Six purpose-bred Beagles underwent arthrotomies on each stifle with a washout period in between. Using a randomized crossover design, each dog received placebo and an extended-release buprenorphine (ER-Bup) preparation. Static and dynamic ground reaction forces (GRFs) were measured prior to and for 72 h following surgery using a pressure sensitive walkway (PSW). GRFs for each hind limb were compared using difference (delta), and symmetry indices (SI). The effects of surgery and of treatment were analyzed using repeated measures ANCOVA. The results indicated significantly decreased limb use compared to baseline for placebo, and significantly increased limb use in the ER-Bup group over placebo at all times for % bodyweight distribution (%BW distrib ), peak vertical force (PVF) and vertical impulse (VI). There was a significant treatment by time interaction for velocity ( P = 0.03) and %BW distrib ( P = 0.01, 0.003). Overall, the data show that reduced limb use was present for at least 72 h following arthrotomy. In addition, the use of the ER-Bup analgesic decreased lameness, confirming the validity of this approach as a model of post-operative pain. Subjective assessments did not detect the pain-inducing effects of arthrotomy or pain-alleviating effects of treatment, and subjective measures of procedural pain in research dogs need to be developed.

Leg problems have become more frequent in fast-growing turkeys. The objective of this study was to evaluate the effects of common leg defects on kinetic parameters of gait and biomechanical properties of bone. Nine hundred, day-old, male, Large White turkeys were raised in 48 floor pens. At 42 d of age, turkeys were divided into four categories of leg condition as determined by visual evaluation: Normal, Crooked toes, Shaky legs, and Valgus. Fifteen toms were selected from each group and trained to walk on a pressure sensitive walkway. Gait kinetic data were collected at 92, 115 and 144 d of age. At 145 d of age, turkeys were sacrificed and bones were collected and frozen until analysis. Morphological measurements of femur, tibia and tarsus-metatarsus were recorded. Bone mineral density (BMD) and content (BMC) were obtained using DEXA. Bone strength of tibias was evaluated using a four-point bending test and femurs with a torsion test. ANOVA was used to detect differences among groups, and Tukey's test used for mean separation. There were no differences in BW among different leg conditions. Gait parameters changed as turkeys aged, and age-group interactions were observed on peak vertical force (PVF), contact time, step length (SL) and bipedal cycle. No differences (P0.05) were detected in morphological measurements of femur or tibia. Relative asymmetry of femur length was lower (P0.05) in Normal and Valgus turkeys than in toms with Crooked toes. There were no differences (P0.05) among groups for femur BMD, BMC or strength. Tibia BMD and the area moment of inertia of turkeys with Crooked toes were lower (P0.05) than in toms with Valgus. With all four leg conditions, femur strength was positively correlated with PVF and negatively correlated with SL; BMD and BMC were correlated with tibia strength and gait kinetic parameters. In conclusion, only crooked toes caused consistent differences in gait patterns, bone properties and bone strength, but in general, gait kinetics was correlated with bone biomechanics in turkeys.

Highlights • Nervous system tissue from cats with painful degenerative joint disease (DJD) was analyzed. • Gene expression was determined to investigate the neurobiological signature of DJD pain. • There was decreased NGF and increased CX3CL1 expression in the spinal cord in DJD-affected cats compared to healthy controls. • There was increased expression of ATF3 and CX3CL1 in dorsal root ganglia, in DJD-affected cats compared to healthy controls. • Such studies have the potential to inform about relevant targets for the control of chronic feline pain., Degenerative joint disease (DJD) associated-pain is a clinically relevant and common condition affecting domesticated cats and other species including humans. Identification of the neurobiological signature of pain is well developed in rodent pain models, however such information is lacking from animals or humans with naturally occurring painful conditions. In this study, identification of housekeeping genes (HKG) for neuronal tissue and expression levels of genes considered associated with chronic pain in rodent models were explored in cats with naturally occurring osteoarthritic pain. Fourteen adult cats were evaluated — seven without clinical signs of osteoarthritic pain, and seven with hind limb radiographic DJD and pain. Expression of an investigator-selected set of pain signaling genes (including ASIC3, ATF3, COX2, CX3CL1, NAV1.7, NAV1.8, NAV1.9, NGF, NK1R, TNFα, TRKA) in lumbar spinal cord dorsal horn and lumbar dorsal root ganglia tissues from clinically healthy cats and cats with DJD were studied using quantitative RT-PCR (qPCR). HKG identified as the most stable across all tissue samples were many of the ribosomal protein genes, such as RPL30 and RPS19. qPCR results showed ATF3 and CX3CL1 up-regulated in DJD-affected dorsal root ganglia compared to clinically healthy controls. In spinal cord, CX3CL1 was up-regulated and NGF was down-regulated when DJD-affected samples were compared to healthy samples. Further work is needed to understand the neurobiology of pain in naturally occurring disease and what rodent models are predictive of these changes in more heterogeneous populations such as domestic cats.

Background Chiari-like malformation (CM) and syringomyelia (SM) cause a pain syndrome in Cavalier King Charles spaniels (CKCS). Clinical signs are not consistently apparent on neurologic examination, and owner reporting of signs provides vital clinical history. However, owner questionnaires for this disease are not well developed. Objectives To develop a tool to capture owner-reported clinical signs for use in clinical trials and to compare owner-reported signs with the presence of pain on neurologic examination and SM on magnetic resonance imaging (MRI). Animals Fifty client-owned CKCS. Methods Owners completed a questionnaire and pain/scratch map. Each dog underwent a neurologic examination and craniocervical magnetic resonance imaging (MRI). Questionnaire responses were developed into scores, area of shading for pain/scratch maps was measured, and consistency of responses between these tools was assessed. Owner-reported findings were compared with neurologic examination findings and presence and severity of SM on MRI. Results Thirty-three dogs were symptomatic and 17 asymptomatic; 30 had SM. The most common sign of pain was crying out when lifted (n = 11). Extent of shaded areas on maps positively correlated with questionnaire scores for pain (r2 = 0.213, P = 0.006) and scratch (r2 = 0.104, P = 0.089). Owner-reported findings were not significantly associated with presence or severity of SM or neurologic examination findings. Owner-reported lateralization of signs was significantly associated with SM lateralization (P

Background Recently, a potential association was identified between Bartonella exposure and arthritides in mammalian species other than cats. Hypothesis/Objectives We hypothesized that Bartonella exposure is associated with more severe degenerative joint disease (DJD) and a greater burden of DJD-associated pain in client-owned cats. Animals Ninety-four client-owned cats (6 months to 20 years old), ranging from clinically unaffected to severely lame because of DJD. Methods Using physical examination and radiography, pain and radiographic scores were assigned to each part of the bony skeleton. Sera were tested for Bartonella henselae, B. koehlerae, and B. vinsonii subsp. berkhoffii (genotypes I, II, and III) antibodies using immunofluorescence antibody assays. Variables were categorized and logistic regression used to explore associations. Results Seropositivity to Bartonella was identified in 33 (35.1%) cats. After multivariate analysis controlling for age, total DJD score (OR, 0.51; 95% CI, 0.26–0.97; P = .042), appendicular pain score (OR, 0.33; 95% CI, 0.17–0.65; P = .0011), and total pain score (OR, 0.35; 95% CI, 0.17–0.72; P = .0045) were significantly inversely associated with Bartonella seroreactivity status, indicating that cats with higher DJD and pain scores were less likely to be Bartonella seropositive. Conclusions and Clinical Importance Based upon this preliminary study, Bartonella spp. seropositivity was associated with decreased severity of DJD and decreased DJD-associated pain in cats. Additional studies are needed to verify these findings, and if verified, to explore potential mechanisms.

Background Tramadol is a centrally acting analgesic that is often used in conjunction with nonsteroidal anti-inflammatory drugs (NSAIDs). The effect of coadministration of tramadol and indomethacin on gastric barrier function in dogs is unknown. Hypothesis/Objectives That coadministration of a nonselective NSAID (indomethacin) and tramadol would decrease recovery of barrier function as compared with acid-injured, indomethacin-treated, and tramadol-treated mucosa. Animals Gastric mucosa of 10 humanely euthanized shelter dogs. Methods Ex vivo study. Mounted gastric mucosa was treated with indomethacin, tramadol, or both. Gastric barrier function, prostanoid production, and cyclooxygenase expression were quantified. Results Indomethacin decreased recovery of transepithelial electrical resistance after injury, although neither tramadol nor the coadministration of the two had an additional effect. Indomethacin inhibited production of gastroprotective prostanoids prostaglandin E2 (acid-injured PGE2: 509.3 ± 158.3 pg/mL, indomethacin + acid injury PGE2: 182.9 ± 93.8 pg/mL, P

Osteoarthritis (OA) is a debilitating disease in dogs. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat OA; however, many dogs do not obtain adequate pain relief with an NSAID alone. This pilot study evaluated the systemic anti-inflammatory and mobility enhancing effects of an eggshell membrane-based nutritional supplement in dogs with OA-associated pain and mobility impairment. Twenty-seven dogs with OA-associated pain were enrolled into a randomized, double-masked, placebo-controlled, proof of principle pilot study and received either placebo or an eggshell membrane-based nutritional supplement over a 12-week period. Inflammatory biomarkers (IL-2, IL-6, IL-8, tumor necrosis factor-α, C-reactive protein, S100A12, and N-methylhistamine) were measured at Day 0 and Day 84. Owner questionnaires (CBPI and LOAD) were completed at Day 0, Day 42, and Day 84. Differences between groups over time were calculated. Twenty-two dogs completed the pilot study. Inflammatory biomarker IL-2 decreased in the supplement group, compared to the placebo group. Although small, the difference was statistically significant at an alpha of 0.1 (P=0.069). LOAD scores were numerically lower in the supplement group, but not significantly different from the placebo group at Day 0. Day 84 LOAD scores were significantly lower in the supplement group compared to the placebo group (P=0.034). CBPI results did not show the same pattern. The changes in biomarkers and LOAD scores were small, and do not provide definitive evidence of positive effects. However, these pilot results provide a rationale for performing a larger placebo-controlled study of the potential effects of the eggshell membrane-based nutritional supplement.

The estimation of long-standing pain in companion animals through the measurement of different dimensions impacted by pain is a fundamental requirement if pain management, and pain therapeutic development, are to advance. Although pain management in veterinary medicine has advanced considerably in the last 20 years, there is much critical work to do in the area of measurement of chronic pain. To date, most work has centered on musculoskeletal pain, and has been focused around the measurement of limb use and the development of owner-completed questionnaires, or clinical metrology instruments (CMI). Recent areas of research have extended to developing measures of activity, sensory function (quantitative sensory testing; nociceptive withdrawal reflexes), and quality of life (QoL). Across all these areas, more data on validity are needed, and studies should be extended to other painful disease states. By necessity, assessing measurement tools requires testing in field studies, which incur considerable time and expense. Facilitating these studies could be optimized with a collaborative (industry, academia and private practice) approach, and the utility of the information produced from all field studies would be enhanced by full and transparent reporting and data sharing, including data already generated by industry in the form of studies submitted to the regulatory authorities.

Background: Detection of clinically relevant pain relief in cats with degenerative joint disease (DJD) is complicated bya lack of validated outcome measures and a placebo effect.Hypothesis/Objectives: To evaluate a novel approach for detection of pain relief in cats with DJD.Animals: Fifty-eight client-owned cats.Methods: Prospective, double-masked, placebo-controlled, stratified, randomized, clinical study. Enrolled cats were6–21 years of age, with owner-observed mobility impairment, evidence of pain in at least 2 joints during orthopedic exami-nation, and overlapping radiographic evidence of DJD, and underwent a 2-week baseline period, 3-week treatment periodwith placebo or meloxicam, and 3-week masked washout period. Outcome measures were evaluated at days 0, 15, 36, and57.Results: Both groups significantly improved after the treatment period (day 36) on client-specific outcome measures(CSOM) and feline musculoskeletal pain index (FMPI) (P

The objectives of this study were to determine whether thermal quantitative sensory testing (QST) can be performed in client-owned dogs, is repeatable and whether QST differs between normal dogs and dogs with hind limb osteoarthritis (OA). This clinical, prospective, observational study used clinically normal dogs (n=23) and dogs with OA-associated hind limb pain (n=9). Thermal QST was performed in standing dogs using a high-powered light source delivered by a previously validated system. Dogs were tested on two occasions, 2 weeks apart. Five tests were performed on each hind limb at each time point. Repeated measures analysis of variance was used to evaluate the effects of leg, time point and OA/normal status on thermal threshold latencies (TTL). Additionally, paired t tests were used to compare the TTL of left and right limbs within groups and between time points. Thermal thresholds were successfully measured in 32 client-owned dogs without prior training. TTL were significantly different between normal and OA dogs (P=0.012). There was no difference between limbs (P=0.744) or time periods (P=0.572), when analyzed by repeated measures analysis of variance, and no interactions between group and limb, visit and limb, or visit and group. In conclusion, thermal thresholds can be measured in client owned dogs with no prior training and are repeatable from week to week. Further data are required to determine if OA results in thermal hypoalgesia as measured at the distal hind limb and whether this is an indication of central sensitization.

The aim of this systematic review was to identify, assess, and critically evaluate the quality of evidence of nonsteroidal anti-inflammatory drug (NSAID)-induced adverse effects in dogs. Original prospective studies published in peer-reviewed journals in English (1990-2012) that reported data on the safety of NSAIDs administration in dogs were searched. For each study, design type (I, II, III, or IV) and assessment of quality (+, O, -) were rated. For each drug, quantity and consistency rating (***, **, *) and strength of evidence (high, moderate, low, or extremely low) were identified and evaluated. The strength of evidence was defined in terms of how applicable and relevant the conclusions were to the target population. Sixty-four studies met the inclusion criteria. Thirty-five (55%) research studies and 29 (45%) clinical trials were identified. A high strength of evidence existed for carprofen, firocoxib, and meloxicam; moderate for deracoxib, ketoprofen, and robenacoxib; and low for etodolac. Quality and consistency rating were as follows: carprofen (***/***), deracoxib (**/***), etodolac (*/unable to rate), firocoxib (***/**), ketoprofen (**/***), meloxicam (***/***), and robenacoxib (**/**), respectively. Adverse effects were detected in 35 studies (55%) and commonly included vomiting, diarrhea, and anorexia. Three studies (5%) reported a power analysis related to adverse effects of ≥80%. In randomized, placebo-controlled, blinded studies (n = 25, 39%), the incidence of adverse effects was not statistically different between treated and control dogs. Finally, most studies were not appropriately designed to determine the safety of NSAIDs, and involved a healthy nongeriatric population of research dogs.

Background Progressive nonsteroidal anti-inflammatory drug (NSAID) dose reduction appears logical; however, there is no evidence-based medicine indicating that efficacy is maintained as dose is reduced. Objective To determine if NSAID dose can be reduced and pain relief and mobility can be maintained in dogs with osteoarthritis (OA). Animals Client-owned dogs (n = 59) with OA-associated impaired mobility and pain. Methods Prospective, randomized, blinded study. After 14 days wash-out, dogs were randomized to reducing dose (RDG) (n = 30) or maintenance dose (MDG) (n = 29). MDG received standard dose meloxicam. RDG received a reducing dose from D28 onward, reducing to 0% of maintenance for the final 2 weeks. Assessments were at D14, 28, 42, 56, 70, 84, 98 and 112 using subjective owner assessments, accelerometry (AM), and standing percent body weight distribution (%BW). A Kaplan–Meier survival curve described how dogs dropped out because of insufficient pain control. A Log-rank test compared the groups. Results More dogs in RDG (13) dropped out because of owner-evaluated insufficient pain control compared with MDG (5) (P = .029; odds ratio: 3.67; median dropout time: 84 days in each group). For the dogs that did not drop out (n = 41), there were no significant differences between groups in owner assessments (P > .2 for each), %BW placed on the index limb (P = .750), or accelerometer-measured activity (P = .14). Conclusion and Clinical Relevance Dose reduction is a less effective means of pain control compared with maintained dosing. However, NSAID dose reduction with maintained efficacy is possible, but success appears to be individual dog dependent.

Background: Feline degenerative joint disease (DJD) is common and there are no approved therapies for the alleviation of the associated pain. Objective: To test a diet high in eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) content and supplemented with green-lipped mussel extract and glucosamine/chondroitin sulfate (test-diet) for its pain-relieving and activity-enhancing effects in cats with painful, mobility-impairing DJD over a 9-week period. Animals: Forty client-owned cats. Methods: Randomized, controlled, blinded, parallel group, prospective clinical study. Cats with no detectable systemic disease, and with at least 1 appendicular joint with radiographic evidence of DJD where manipulation elicited an aversive response were included. Cats were randomly allocated to the test-diet or control diet (C-diet). Outcome measures were subjective owner and veterinarian assessments, and objective activity monitoring (accelerometry). Nonparametric statistics were used to evaluate changes within and between groups for both subjective and objective data, and locally weighted scatterplot smoothing regression analysis was used to predict activity changes. Results: The primary objective outcome measures indicated that activity declined significantly (P < .001) in the C-diet group, significantly increased (P < .001) in the test-diet group and there was a significant difference between the groups (P < .001). Conclusion and Clinical Importance: A diet high in EPA and DHA and supplemented with green-lipped mussel extract and glucosamine/chondroitin sulfate improved objective measures of mobility. Dietary modulation might be 1 method to use to improve mobility in cats with DJD-associated pain.

Background In veterinary clinical pain studies, there is a paucity of data on test-retest variability in Clinical Metrology Instruments (CMIs), and it is unknown whether CMIs should be administered using independent (respondents not permitted to see previous answers) or dependent (respondents shown previous answers) interviewing. Objectives To compare baseline variability in CMIs designed to assess pain in dogs with osteoarthritis, and compare CMI scores using independent (InD) and dependent interviewing (DI) for the Canine Brief Pain Inventory (CBPI) and the Client-Specific Outcome Measures (CSOM). Animals Fifty-one client-owned dogs with radiographic evidence of osteoarthritis and associated pain. Methods Clinical Metrology Instruments data were collected during 2 randomized, double-masked, placebo-controlled, proof of principle pilot studies with parallel treatment groups. Enrolled dogs received either placebo or antinerve growth factor antibody (NV-01). Results Agreement between baseline CMI scores was good (CBPI Pain P = .29, CBPI Interference P = .32, CSOM P = .036, LOAD P = .67, HCPI P = .27), being best for the LOAD (ICC = 0.89). CMI responses collected during independent and dependent interviewing were not statistically different (CBPI Pain P = .33, CBPI Interference P = .28, CSOM P = .42) and showed good agreement. Additionally, dependent interviewing resulted in increased treatment effect sizes. Conclusions and Clinical Importance There is little difference between independent and dependent interviewing, however, dependent interviewing resulted in increased treatment effect sizes. By using dependent interviewing, investigators could increase clinical trial power through minimal change to study design. Further research is warranted to investigate the use of dependent interviewing.

Data from a survey conducted in 1996–1997 suggested a low level of perioperative analgesic administration to cats and dogs in the UK. In order to evaluate current practice and attitudes with regards to perioperative analgesic prescription, a cross-sectional survey of UK practising small animal veterinary surgeons was undertaken in spring 2013. Four thousand one hundred paper questionnaires were distributed and the survey was made available online. Seven hundred and twenty valid responses were received and analysed. All respondents had access to at least one non-steroidal anti-inflammatory drug (NSAID) and one opioid within their practice. Respondents considered analgesic efficacy, and degree of intraoperative pain, the most important factors governing their selection of NSAID and opioid analgesics. Perioperative NSAIDs were administered by approximately 98 per cent of respondents to dogs and cats undergoing neutering. Multimodal (opioid+NSAID) analgesia was prescribed by the majority of respondents. Neutering was considered more painful in dogs than in cats, and lower rates of opioid and postdischarge NSAID prescription were reported for cats. Orthopaedic, abdominal and dental surgeries were considered equally painful in dogs and cats. Local analgesic techniques were not commonly used. Analgesic prescription has increased since previous surveys, which should translate to improved animal welfare.

A literature review identified six placebo-controlled studies of analgesics in client-owned cats with degenerative joint disease-associated pain. Five studies with 96 cats had available data. Caregiver responses on a clinical metrology instrument, Client-Specific Outcome Measure (CSOM), were compared to measured activity. Cats were categorised as 'successes' or 'failures' based on change in CSOM score and activity counts from baseline. Effect sizes based on CSOM score were calculated; factors that were associated with success/failure were analysed using logistic regression. Effect sizes ranged from 0.97 to 1.93. The caregiver placebo effect was high, with 54-74 per cent of placebo-treated cats classified as CSOM successes compared with 10-63 per cent of cats classified as successes based on objectively measured activity. 36 per cent of CSOM successes were also activity successes, while 19 per cent of CSOM failures were activity successes. No significant effects of cat age, weight, baseline activity, radiographic score, orthopaedic pain score or study type on CSOM success in the placebo groups were found. The caregiver placebo effect across these clinical trials was remarkably high, making demonstration of efficacy for an analgesic above a placebo difficult. Further work is needed to determine whether a potential placebo-by-proxy effect could benefit cats in clinical settings.

SummaryA Helica short-stemmed femoral prosthesis that was identified as being loose one year after implantation was revised with a standard long stem cementless BFX femoral pros-thesis. A double pelvic osteotomy was also performed to improve the orientation of the stable acetabular cup. Despite complete resorption of the femoral neck, and a large perforation of the lateral femoral cortex, the revision stem did not subside or rotate. The prosthetic joint did not dislocate. At re-evaluation two years after revision surgery, the prosthetic components were stable. Signs of bone ingrowth into the stem and cup were evident on radiographs. The dog had a seven percent greater thigh muscle girth in the limb implanted with the hip prosthesis compared to the contralateral limb, and was very active with no lameness.

Four immature dogs were presented with ectrodactyly. Two dogs were initially treated with distraction osteogenesis of a hypoplastic ulna and all had surgical correction of the cleft deformity. In each case proximal metacarpal apposition with or without carpal arthrodesis formed the basis of surgical treatment. Follow-up information was available for three cases and all showed improved limb function. Corrective surgery appears to be a viable alternative to amputation for treatment of ectrodacty1y.

Progress in establishing if therapies provide relief to cats with degenerative joint disease (DJD)-associated pain is hampered by a lack of validated owner-administered assessment methods.That an appropriately developed subjective owner-completed instrument (Feline Musculoskeletal Pain Index-FMPI) to assess DJD-associated impairment would have responsiveness and criterion validity.Twenty-five client-owned cats with DJD-associated pain.FMPI responsiveness (ability to detect the effect of an analgesic treatment) and validity (correlation with an objective measure) were explored through a stratified, randomized, double blinded, placebo-controlled, crossover 10-week clinical study. Meloxicam was administered to effect pain relief. A linear mixed model, backward stepwise regression, and Pearson correlations were used to assess responsiveness and criterion validity with the assumption that the NSAID would increase activity.Positive responses of cats to placebo (P = .0001) and meloxicam treatment (P = .0004) were detected; however, the instrument did not detect any difference between placebo and meloxicam (linear mixed model), even for the high impairment cases. Percent meloxicam target dose administered, temperament, and total baseline FMPI score were covariates that most affected FMPI scores. Controlling for significant covariates, most positive effects were seen for placebo treatment. Positive treatment effects on activity were detected, but only for the cases designated as most highly impaired.Neither responsiveness nor criterion validity were detected by the inclusion criteria for cases in this study. The data suggest that further work is indicated to understand factors affecting activity in cats to optimize inclusion criteria.

The objective of this study was to test the readability, reliability, repeatability and discriminatory ability of an owner-completed instrument to assess feline degenerative joint disease (DJD)-associated pain (feline musculoskeletal pain index, FMPI). Readability was explored using four different formulas (Flesch, Fry, SMOG and FOG) and the final FMPI instrument was produced. To assess the instrument, client-owned cats that were defined as normal (normal group) or as having DJD-associated pain and mobility impairment (pain-DJD group) were recruited. A total of 32 client-owned cats were enrolled in the study (normal, n=13; pain-DJD, n=19). Owners completed the FMPI on two occasions, 14days apart. Internal consistency (reliability) and repeatability (test-retest) were explored using Cronbach's α and weighted κ statistic, respectively. Data from the two groups were compared using analysis of covariance (controlling for age) to evaluate discriminatory ability. The FMPI was constructed with 21 questions covering activity, pain intensity and overall quality of life. It had a 6th grade readability score. Reliability of the FMPI was excellent (Cronbach's α>0.8 for all groupings of questions in normal and pain-DJD cats) and repeatability was good (weighted κ statistic >0.74) for normal and pain-DJD cats. All components of the FMPI were able to distinguish between normal cats and cats with DJD (P

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) do not always provide sufficient pain relief in dogs with osteoarthritis (OA). Hypothesis: The use of amantadine in addition to NSAID therapy will provide improved pain relief when compared with the use of nonsteroidal analgesics alone in naturally occurring OA in dogs. Animals: Thirty-one client-owned dogs with pelvic limb lameness despite the administration of an NSAID. Methods: The study was randomized, blinded, and placebo controlled with parallel groups (days 21–42). On day 0, analgesic medications were discontinued. On day 7, all dogs received meloxicam for 5 weeks. On day 21, all dogs received amantadine (3–5 mg/kg once daily per os) or placebo for 21 days, in addition to receiving meloxicam. Assessments were performed before the study and on days 7, 21, and 42. Primary outcome measures were blinded owner assessments of activity using client-specific outcome measures (CSOM) on days 0, 7, 21, and 42. Data were analyzed by a mixed model approach. Results: For CSOM activity, there was a significant time by treatment effect (P=.009). On the basis of the planned post hoc t-tests of postrandomization means, there was a significant difference between treatment groups on day 42 (P=.030), with the amantadine group being more active. Conclusions and Clinical Importance: In dogs with osteoarthritic pain refractory to an NSAID, physical activity is improved by the addition of amantadine. Amantadine might be a useful adjunct therapy for the clinical management of canine osteoarthritic pain.

NSAIDs are the cornerstone of medical management of canine osteoarthritis (OA). Meloxicam is a daily-administered NSAID widely available in a liquid formulation and manufacturer's summary of product characteristics (SPC) advise that it is given at the lowest effective dose. Mavacoxib is a long-acting NSAID given as a monthly tablet. This study compares these drugs in the management of canine OA. In all, 111 dogs with OA of the elbow, hip or stifle were randomly assigned to receive one of these NSAIDs for a 12-week period, and to administer them as per the manufacturer's SPC. Outcomes, including ground reaction forces and three validated clinical metrology instruments, were measured at baseline, 6 and 12 weeks. Improvements were seen in all outcome measures for both groups to a similar degree, and adverse events occurred at a similar rate. There were significant improvements in outcome measures from week 6 to week 12, as well as from baseline. Long-term meloxicam dose was more important than recent dose. Clinical efficacy and adverse event rates are similar for meloxicam and mavacoxib when administered as per their UK SPC. This is relevant information for veterinary surgeons when prescribing NSAID treatment for canine OA.

The kinetic parameters of the limbs of 23 normal, client-owned cats were evaluated by encouraging them to walk and jump normally on a pressure-sensitive walkway. Each cat was encouraged to walk across the walkway five times over a period of 30 to 45 minutes (by using food, toys, the owner's presence and a purpose-built tunnel) at a target speed of 0.6 m/s (and an acceleration of less than +/- 0.1 m/s(2)). They were then encouraged to jump on to the walkway from a height of 1 m five times at five-minute intervals. The kinetic parameters of peak vertical force (PVF) and vertical impulse (VI) were measured for each limb (the forelimbs only for the jumps), and expressed as a percentage of bodyweight (PVF(%BW) and VI(%BW/S)). Fifteen of the 23 cats satisfactorily completed three to five walks and two to five jumps that could be analysed. There were no significant differences between the PVF or VI of the left and right limbs, but both parameters were significantly greater for the forelimbs than the hindlimbs (P0.001) for the walking data. The mean (sd) PVF(%BW) for the forelimbs and hindlimbs were 48.2 (6.0) and 38.3 (4.0), respectively, and the mean VI(%BW/s) were 16.9 (3.2) and 13.3 (2.8). Jumping down generated significantly greater PVF (P0.01) and slightly greater VI than during walking; there were no significant differences between the left and right forelimbs. The mean PVF(%BW) was 148.9 (16.4) and the mean VI(%BW/s) was 18.1 (4.3).