Chronic Feline Pain Management

Chronic Feline Pain Management Classification of Pain Acute < 3 months B Duncan X Lascelles BSc BVSc CertVA PhD MRCVS DSAS(ST) DECVS DACVS Professor of Surgery and Pain Management Chronic > 3 months Classification of Pain Adaptive: pain coupled to noxious stimulus (nociceptive; inflammatory; cancer?) Maladaptive: pain that is uncoupled from a noxious stimulus Neuropathic pain Functional pain Disease-Based Causes of Chronic Pain OA/DJD Cancer Neuropathic/Neurogenic Gingivitis; Stomatitis Cystitis IBD & IBS Otitis Dermatitis Chronic Post-Surgery Evaluation of the prevalence of radiographic signs of degenerative joint disease in a randomly selected population of domestic cats aged from 6 months to 20 years old Cross-sectional observational clinical study Randomized 1

Methods Number of cats in each age range with radiographic DJD in at least one joint or axial segment respectively General physical examination 25 Conscious orthopedic examinations by single ECVS/ ACVS Surgeon Pain score every joint Orthogonal radiographs of every joint and every section of the axial skeleton Pain scale based on palpation 0 No resentment; amount of movement or wriggling 1 Mild withdrawal; mildly resists 2 Moderate withdrawal; body tenses; may orient to site or vocalize 3 Orients to site; forcible withdrawal; may vocalize,hiss or bite 4 Tries to escape/prevent manipulation; bite/hiss Number of cats with DJD 20 15 10 5 0 0 to 5 to 10 10 to 15 15 to 20 0.5 to 5 appendicular axial The most frequently affected joints and spinal areas Relationship between age and total DJD score JOINT Num joints affected HIP 131 (65%) STIFLE 102 (50%) TARSUS 85 (40%) ELBOW 69 (35%) CARPUS 32 (15%) SHOULDER 28 (14%) For each joint N= 200 Spinal segment Num cats affected THORACIC 43 L-S 29 LUMBAR 26 CERVICAL 20 Total DJD Score 0 10 20 30 40 observed predicted 5 10 15 20 Age (years) Jumping Ability Aginst Age 100 90 80 70 R² = 0.28286 25.00 20.00 Total pain score against Age R² = 0.32657 Jumping Score 60 50 40 30 Total Pain Score 15.00 10.00 20 5.00 10 0 0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 Age 0.00 0 5 10 15 20 25 Age in Years 2

! Please mark the circle that best describes your cat over the past week: 1. How is your cat s mobility in general? Very good Good Fair Poor Very poor 2. How does your cat move? No stiffness or limping Mild stiffness or limping 3. What is your cat s ability to run? Moderate stiffness or limping Severe stiffness or limping Extreme stiffness or limping 4. How easily does your cat jump UP? Moderately Barely, or with great effort Easily and with no With mild With moderate 5. How easily does your cat jump DOWN? With severe With extreme Easily and with no With mild 6. How well does your cat go UP stairs? With moderate With severe With extreme Easily and with no With mild difficulty and/or With moderate difficulty and/or With severe difficulty and/or With extreme difficulty and/or! 2015 North Carolina State University Version 11 Not In clinic evaluation of feline DJDassociated pain Gather history and owner evaluation Gait evaluation Observation Performance tests in clinic Orthopaedic examination What should we ask owners about? Activities Jumping up and down; height of jump; walking; moving about in its environment Ability to perform activities Ease of movement Movement Fluidity and ease of movement Enjoyment Happiness Level of engagement Owner Questionnaires (Clinical Metrology Instruments) Item Generation Validation Discrimination Responsiveness Comparison to Gold Standard (Criterion) FELINE MUSCULOSKELETAL PAIN INDEX Feline Musculoskeletal Pain Index go.ncsu.edu/cprl (go to Clinical Metrology Instruments page) Gait Evaluation 1. Walk and/or move easily?!!!!!! Somewhat Barely, or with great effort Don t know or not 2. Run?!!!!!! Somewhat Barely, or with great effort Don t know or not 3. Jump up (how well and how easily)?!!!!!! Somewhat Barely, or with great effort Don t know or not 3

Observation Tosh: 156990 Feline Orthopedic Evaluation 4

In clinic evaluation of feline DJDassociated pain Gather history and owner evaluation Gait evaluation Observation Performance tests in clinic Orthopaedic examination Mechanisms from animal models Known analgesics in human pain conditions Best guess at therapy for veterinary clinical patients Placebo Effect Double masked; placebo controlled; randomized Deterioration / Return of Clinical Signs Masked wash-out with placebo Pain Relief 66 64 62 60 58 56 54 52 50 48 D0 D21 Max score = 85 () Placebo Treatment Pain Relief 66 64 62 60 58 56 54 52 50 48 D0 D21 D42 Placebo Treatment Gruen et al. A novel approach to the detecdon of clinically relevant pain relief in cats with degeneradve joint disease associated pain. Journal of Veterinary Internal Medicine, 2014 Feb 10. doi: 10.1111/jvim.12312. [Epub ahead of print] Gruen et al. A novel approach to the detecdon of clinically relevant pain relief in cats with degeneradve joint disease associated pain. Journal of Veterinary Internal Medicine, 2014 Feb 10. doi: 10.1111/jvim.12312. [Epub ahead of print] Feline Musculoskeletal Pain Index go.ncsu.edu/cprl (go to Clinical Metrology Instruments page) 1. Walk and/or move easily?!!!!!! 2. Run? Somewhat Barely, or with great effort Don t know or not!!!!!! Somewhat 3. Jump up (how well and how easily)? Barely, or with great effort Don t know or not!!!!!! Somewhat Barely, or with great effort Don t know or not Assessment Tools 3-ways of using these: Detecting compromised patients Discussion with & education of owner Detection of MS pain through instrument score Evaluating efficacy during treatment Return of clinical signs as measure of efficacy Coming Soon: comprehensive guidelines on how to use these in the clinic. CPRL Website 5

Long-term NSAID use approvals in the US (cat) NSAIDs Long-term approvals in the EU Meloxicam (Metacam ) EU approval 0.1 mg/kg PO on day 1, followed by 0.05mg/kg PO daily (unlimited time period) (Chronic musculoskeletal disorders) Detection of Clinically Relevant Pain Relief in Cats with Degenerative Joint Disease Associated Pain M.E. Gruen, E. Griffith, A. Thomson, W. Simpson, and B.D.X. Lascelles JVIM 2014 Meloxicam: 0.035mg/kg daily PO for 3 weeks First clinical evidence of a beneficial effect of lower dose of meloxicam Feline NSAID Post-operative approvals in the U.S. Meloxicam 0.3mg/kg single injection (Metacam and Loxicam ) For control of postoperative pain and inflammation Feline NSAID Post-operative approvals in the U.S. Robenacoxib (Onsior ) Tablets (1 mg/kg target dose) & injection (2mg/kg) once daily for up to 3 days Tablets and injection interchangeable for max of 3 doses Indicated for the control of post-operative pain and inflammation 6

Robenacoxib, peri-operative, cats Switzerland: 11 days EU, Australia: 6 days Date of Approval: March 8, 2011 FREEDOM OF INFORMATION SUMMARY ORIGINAL NEW ANIMAL DRUG APPLICATION NADA 141-320 ONSIOR Robenacoxib tablets Cats ONSIOR tablets are indicated for the control of postoperative pain and inflammation associated with orthopedic surgery, ovariohysterectomy and castration in cats > 5.5 lbs (2.5 kg) and > 6 months of age; for up to a maximum of 3 days. Sponsored by: Novartis Animal Health US, Inc. 6 month safety study for the 3 day perioperative US claim 0, 2.4, 7.2 and 12 mg/kg once daily (up to 5 to 12 times recommended dose) No deaths *** Few adverse effects Adequate safety margin demonstrated Original Article Clinical safety of robenacoxib in feline osteoarthritis: results of a randomized, blinded, placebocontrolled clinical trial Journal of Feline Medicine and Surgery 1 11 ISFM and AAFP 2015 Reprints and permissions: sagepub.co.uk/journalspermissions.nav DOI: 10.1177/1098612X15590870 jfms.com Jonathan N King 1, Stephen King 2, Steven C Budsberg 3, B Duncan X Lascelles 4,5,6, Stephen E Bienhoff 2 *, Linda M Roycroft 2 and Elizabeth S Roberts 2 Robenacoxib 1-2mg/kg daily OR Placebo 28 day administration. Prevalence and classification of chronic kidney disease in cats randomly selected from four age groups and in cats recruited for degenerative joint disease studies Journal of Feline Medicine and Surgery 0(0) 1 8 ISFM and AAFP 2013 Reprints and permissions: sagepub.co.uk/journalspermissions.nav DOI: 10.1177/1098612X13511446 jfms.com Christina L Marino 1, B Duncan X Lascelles 2,3, Shelly L Vaden 1,3, Margaret E Gruen 2,4 and Steven L Marks 1 7

The prevalence of CKD pos SK and CKD neg cats in the RS and DJD groups Robenacoxib 1-2mg/kg daily Cats with CKD IRIS Stage 2 or 3, and concurrent DJD (nb: on average, ~6.0kgs) Gowan et al 2011 Retrospective case-control study of the effects of long-term dosing with meloxicam on renal function in aged cats with degenerative joint disease J Feline Med Surg Retrospective; cats >7yo; DJD & mobility impairment 38 cats; median maintenance dose 0.02mg/kg daily 22 with IRIS stage 1-3 (median 467days treatment) 16 non-renal (median 327days treatment) Age and IRIS matched untreated controls Outcome measures: chemistry; UA; bodyweight (No measures of efficacy) NSAIDs and cats Are there any completely safe NSAIDs in cats? NSAIDs and renal disease in cats and dogs Does chronic renal insufficiency get worse when cats are on NSAIDs? Not necessarily Hydration status important No. Are cats more at risk (compared to dogs) of renal impairment when administered NSAIDs? Not known 8

Non-NSAID drugs for chronic pain Drug doses: https://www.researchgate.net Lascelles & Robertson (2010) Management of DJD in cats (Downloadable) Steroids Often particularly effective in cats in the management of DJD pain Why? Doses: 0.5-1.0mg/kg daily OR Depo injections Side effects: gradual muscle mass loss, ligament & tendon weakening; systemic disease Gabapentin No evidence-based medicine for pain relief in cats (or dogs) Cats appear to respond favorably more frequently to gabapentin than dogs Particularly useful when excess sensitivity / hypersensitivity is present Dose: 10mg/kg q12h Reduce dose gradually before stopping? 9

4.5kg DSH FS Lumbosacral degeneration and neuropathic-like pain Some improvement on steroids (1mg/ kg q12h for 3 months) Added in gabapentin (50mg q12h, 4 weeks); improvement in demeanor and decrease in hypersensitivity Added minocycline (50mg q12h); marked improvement after 4 weeks Maintained on 4-6 week pulses of gabapentin and minocycline as needed 191822 Ji et al 2013 Pain 154: S10-S48 Scholz & Woolf 2009. Nature Neuroscience 10: 1361-1368 Environment Modification Allows cats to access the resources they need Gives the owner a sense of control Enrichment may distract from the emotional component of the pain Consider: access to height/hiding, food and water, litter tray. Nutrition Nutrition Nutrition is recognized as playing an important role in disease OA / DJD is the perfect paradigm of a pathology where the treatment of which could be addressed by nutrition Role of obesity in feline DJD? Role of dietary components in feline DJD? Pain relief through diet modulation.. 10

Methods: Diets Improvements in activity and jumping ability in the DJD-diet group, none in control diet group Increased activity in the DJD-diet group, decreased in the control diet group Average change in acbvity counts from start of study to end of study (9 weeks) 6am-12pm Whole day PSGAGs Polysulphated Glycosaminoglycans (PSGAGs) Possible mild pain relief through antiinflammatory actions? (different mechanism to NSAIDs) Beneficial effects in canine HD de Haan JJ et al.. Vet Surg 1994;23:177-181. Lust et al.. Am J Vet Res 1992;53:1836-1843 Dosing in cats: 5mg/kg twice a week for 4 weeks, once a month thereafter (no evidence base) IM or SC NSAID approvals Biologics Nerve Growth Factor Antibody PGE 4 receptor antagonist Allogenic stem cells Pentosan Polysulfate (next generation) Greater understanding of non-drug therapies: Acupuncture Exercise Physical Modalities 11

Nerve Growth Factor Anti-NGF mab Study NV-02 low NV-02 high Placebo Day 0 Screening Day 14 Day 35 Outcome Day 56 Outcome Day 77 End of Treatment assessments assessments study Activity data collected continuously Baseline activity Antibodies to nerve growth factor have potential as a treatment for pain 11weeks = 1848 hours = 110,880 minutes for 1 cat 3,548,160 data points for the study Mean change in activity count per minute for each week compared to baseline Plot of percentage change from baseline (Wk1/2) in mean weekly activity counts by group (treatment/placebo) for each week of study Pain Matters. 15 10 Tx P 5 0-5 -10 Wk1/2 Wk3 Wk4 Wk5 Wk6 Wk7 Wk8 Wk9 Wk10 Wk11 Study Week Felinized Anti-NGF mab Gruen et al. In Press, JVIM Support our work to find pain relief options for cats 12