B.D.X. Lascelles

Amantadine in a Multimodal Analgesic Regimen for Alleviation of Refractory Osteoarthritis Pain in Dogs

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.

Evaluation of a Therapeutic Diet for Feline Degenerative Joint Disease

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.

Systematic Review of Nonsteroidal Anti-Inflammatory Drug-Induced Adverse Effects in Dogs

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 (+, Ø, -) 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.

Kinetic evaluation of normal walking and jumping in cats, using a pressure-sensitive walkway

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 owners presence and a purpose-built tunnel) at a target speed of 0·6 m/s (and an acceleration of less than ± 0·1 m/s2). 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 (P<0·001) 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 (P<0·01) 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).

Reliability and discriminatory testing of a client-based metrology instrument, feline musculoskeletal pain index (FMPI) for the evaluation of degenerative joint disease-associated pain in cats

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 Cronbachs 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 (Cronbachs 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<0.001 for all components). This initial evaluation of the FMPI suggests that this instrument is worthy of continued investigation.

Dose reduction of meloxicam in dogs with osteoarthritis-associated pain and impaired mobility.

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.

Feline Musculoskeletal Pain Index: Responsiveness and Testing of Criterion Validity

BACKGROUND 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. HYPOTHESIS That an appropriately developed subjective owner-completed instrument (Feline Musculoskeletal Pain Index-FMPI) to assess DJD-associated impairment would have responsiveness and criterion validity. ANIMALS Twenty-five client-owned cats with DJD-associated pain. METHODS 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. RESULTS 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. CONCLUSIONS AND CLINICAL IMPORTANCE 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.

Detection of Clinically Relevant Pain Relief in Cats with Degenerative Joint Disease Associated Pain

Background Detection of clinically relevant pain relief in cats with degenerative joint disease (DJD) is complicated by a 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 were 6–21 years of age, with owner‐observed mobility impairment, evidence of pain in at least 2 joints during orthopedic examination, and overlapping radiographic evidence of DJD, and underwent a 2‐week baseline period, 3‐week treatment period with placebo or meloxicam, and 3‐week masked washout period. Outcome measures were evaluated at days 0, 15, 36, and 57. Results Both groups significantly improved after the treatment period (day 36) on client‐specific outcome measures (CSOM) and feline musculoskeletal pain index (FMPI) (P < .0001 for both); there was no difference between the groups on CSOM or FMPI score improvement. After the masked washout period, more cats that received meloxicam during the treatment period had a clinically relevant decrease in CSOM score (P = .048) and FMPI score (P = .021) than cats that received placebo. Conclusions and Clinical Importance Using both a client‐specific and a general clinical metrology instrument, owners of cats with DJD were able to detect evident recurrence of clinical signs after withdrawal of active medication than after withdrawal of placebo, and that this study design might be a novel and useful way to circumvent the placebo effect and detect the efficacy of pain‐relieving medications.

Feasibility and repeatability of thermal quantitative sensory testing in normal dogs and dogs with hind limb osteoarthritis-associated pain.

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.

A Feline-Specific Anti-Nerve Growth Factor Antibody Improves Mobility in Cats with Degenerative Joint Disease-Associated Pain: A Pilot Proof of Concept Study.

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.