p.1

NSAIDs: What We Do Know
Matt Brunke, DVM, CCRP, CVPP, CVA
Diplomate, American College of Veterinary Sports Medicine and Rehabilitation

p.2

A little about me..... I like to keep busy

p.3

Who
-Use NSAIDs in their practice?
-Dogs?
-Cats?
-Other?
-Themselves?

p.4

NSAID
-Non Steroidal Anti Inflammatory Drug
-Historically for mild, chronic pain
-Humans – classically associated with GI side fx
-Hippocrates showed medical benefits of willow bark
-1971 – Aspirin proposed mechanism of action realized

p.5

What's special about them?
-Potent anti-inflammatory
-End result similar to steroids
-Prostaglandin production decreased
-Central and peripheral effects
-Analgesic
-Antipyretic
-Non-dependence
-Devoid of opioid side fx

p.6

Generalizations of NSAIDs
-Rapidly absorbed by the GI
-Highly protein bound
-Weak acids – accumulate in inflamed tissue
-Metabolized in the liver +/- enterohepatic cycling
-Half lives vary from 2-72 hours
-Effects differ in half life and route of admin

p.7

Where’s the action?
ARACHIDONIC ACID
Lipooxygenase
Leukotrienes
Bronchospasm Inflammation
COX-1
Prostaglandin
Gastric Protection uterine contraction,renal function
Throbocanes
Platelet Aggregation
Tissue damage
COX-2
prostaglandins
Pain inflam mation,renal function

p.8

Mechanisms of Action
-Decreasing production of prostaglandin
-Cyclooxygenase (COX) inhibition
-Neutrophil inhibition
-Glycosaminoglycan synthesis exacerbation
-Metalloproteinase inhibition
-CNS/spinal modulation
-Excitable membranes
-Cell metabolism
-Messenger systems

p.9

Pain Pathway

p.10

Who benefits?
-Orthopedic procedures
-Soft tissue biopsy
-Bone marrow aspirate
-Joint taps
-OVH
-Dental
-Otic/Ophthalmalogic procedures
-OA/DJD
-Polyarthritis
-Cystitis
-Otitis/Uveitis
-Dermatologic disease
-Meningitis
-Bite Wounds
-HOD/panosteitis

p.11

COX
-Cyclooxygenase – prostaglandin synthase
-Its job is to place oxygen into arachidonic acid
-Metabolizes AA
-It produces mediators of function AND pathology
-Thromboxanes, prostacyclin, prostaglandins E2, F2, D2

p.12

COX has (at least) 2 isoforms
COX-1 (good?)
-Constitutive
-Platelets
-Kidneys
-Stomach
-Repro tract
-Maintains homeostasis
-Renal blood flow
-Gastric secretion
mucus COX-2 (bad?)
-Inducible
-Fibroblasts
-Endothelial cells
-Chondrocytes
-Macrophages
-Constitutive
-CNS
-Kidneys
-Main inflammation mediator and of pain

p.13

COX-3???
-Simmons D, et. Al. Proc Nat Acad Sci 2002
-“COX-1 variant or isoform expressed in high amounts in brain and heart”
-Acetaminophen
-Poorly inhibits COX-1 and COX-2
-Greatly inhibits COX-3
-Partial COX-1 or PCOX-1 proteins abundant in canine brain

p.14

How did isoforms influence the industry
-If COX-2 is the enzyme that mediates bad things.........
-Suppressing it alone and sparing COX-1 would limit side effects of
-GI ulcers
-Platelet inhibition
-Renal perfusion

p.15

Classes of NSAID
-Nonselective
-Inhibit both COX-1 and COX-2
-Aspirin, flunixin
-Preferential
-Inhibit COX-1 and COX-2, but less COX-1
-Carprofen, meloxicam
-Selective
-Inhibit COX-2 only
-Deracoxib, firocoxib

p.16

Because enzymes don't read books
-COX-2 can be good in some tissues
-Damaged gastric epithelium
-Hypovolemic and developing renal tissues
-Brain
-Endometrium
-Although COX-2 is mainly “bad” it may also modulate (help decrease) inflammation long term

p.17

Ratio problems; COX-2: COX-1
-Selectivity of a particular NSAID for one isoform or the other is expressed as a ratio.
-The higher the ratio, the less SPARING to COX- 1.

p.18

COX-2 to COX-1

p.19

Great! That solved it.

p.20

Nope! There is a problem with COX ratios
-Assays were done in vitro, not in vivo
-Recombinant enzymes or whole cell cultures?
-Selectivity for isoform may be lost at greater concentrations (clinical concentration) of drug
-Individual isoform variability
-Length of study
-Species differences

p.21

So things are not as simple as we would like them. Why?
-Genetic expression of isoform differs from individual to individual
-Enzymes which metabolize NSAIDs differ from one individual to another
-At clinically effective doses, some NSAIDs lose their preference for one COX isoform

p.22

NSAIDs Inhibit Both Inflammation and Pain

p.23

Do the Risks Outweigh the Benefits?
- Benefits and risk of any medication is assessed on a case by case basis
- Understanding the different types of adverse events:
- Allows veterinarians to minimize the risk
- Better communicate the actual risks to pet owner
- Appropriate patient selection is key to maximize the benefits of NSAID use
Benefit
Risk
For the Vast Majority of Canine Patients, the Benefits Outweigh the Risks

p.24

Adverse Reactions for All Drugs Fall into Two Major Categories
Inducible Idiosyncratic
Reactions Are Dose-related
Reactions Are Attributable to the Mechanism of Action of the Drug
Predictable
Examples: Antineoplastic Drugs - Neutropenia NSAIDs - GI Signs
Not Dose-related
Not Attributable to the Mechanism of Action of the Drug
Unpredictable and Rare; Maybe Serious
Examples: Penicillins - Anaphylaxis NSAIDs - Hepatic Toxicity

p.25

The Risk of an Adverse Reaction is Greatest Early in Treatment
- The most common seen with NSAIDs are inducible, and include GI irritation
- Typically occur early in treatment
- Idiosyncratic reactions occur infrequently (<1 in 10,000)
- Idiosyncratic reactions are most likely to occur in the first 90 days of treatment
- Although individual response may vary, benefits of NSAID use outweigh the risks or the majority of dogs
Appropriate Patient Selection and Monitoring During Treatment Can Minimize the Potential for Adverse Events
1.Wolf MM et al. NEJM, 340:1888-1899; 1999. 2.Autefage et al. Revue Méd. Vét, 158:119-127; 2007. 3.Innes J et al. Vet Rec 166:226-230; 2010. 4.Lee WM. NEJM, 349:474-448; 2003.

p.26

FDA NSAID Class Language on “Lowest Effective Dose”
- The Label Language: Lowest effective dose for the shortest duration consistent with individual response
- Duration of treatment should be determined by the patient’s response
- Start at lowest FDA Label Dose; some NSAIDs have dose range
- If considering a reduction in dose monitor to ensure that the lower dose is effective
- For idiosyncratic reactions, reducing the dose does not decrease the risk
- Addressing other issues? – Obesity, chondroprotection?
- Decision for dose and duration of treatment is based on patient and Benefit/Risk analysis

p.27

Treating with NSAID on a Patient by Patient Basis
Benefits Risks
Pain Relief GI Signs
Relief of Inflammation Renal Disease
Return to Function Hepatic Disease
Re-establish Human-Animal Bond Other Less Commonly Reported Signs
- Frequency is low for most adverse events and resolve with discontinuation and/or supportive treatment
- With appropriate patient selection and monitoring can maximize the benefits and minimize the risks

p.28

Adverse Effects of NSAIDs
- Gastrointestinal
- Renal
- Platelet function
- Respiratory
- Miscellaneous
- Repro
- CNS
- Cardiac

p.29

GI
- Related to inhibition of COX-1
- COX-1 regulates numerous functions
- Motility
- Mucosal blood blow
- Prostaglandin cytoprotection
- When a GI ulcer forms
- COX-2 needed for repair
- Even COX-2 inhibitors will delay healing

p.30

GI Side Effects – Clinical Importance
- Patients with overt GI upset should not be given NSAIDs
- Stressed?
- Cushing’s?
- In patients with pre-existing GI ulcers, NSAIDs, (especially COX-2 selective) should not be used
- Perfusion and oxygen tension should be considered

p.31

What about NSAIDs in pancreatitis?
- Bang UC, et al. World J Gastroenterolo. 2008 May 21;14(19):2968-76. Pharmacological approach to acute pancreatitis
- “The NSAID indomethacin and diclofenac have in randomized studies showed potential as prophylaxis again pancreatitis”
- Otsuka, T. et al. J Gastroenterol. 2012 Aug;47(8):912-7. Low dose rectal diclofenac for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a randomized controlled trial.
- “Pain was significantly more frequent in the control group than in the diclofenac group (37.7 vs. 7.8%). There was no adverse effects related to diclofenac. Low dose rectal diclofenac can prevent PEP”

p.32

But if we need to use NSAID, what protects the GI best?
- Tolbert K, Bissett S, King A, et al. Efficacy of oral famotidine and 2 omeprazole formulations for the control of intragastric pH in DOGS. J Vet Intern Med 2011;25;47-54.
- “Co administration of misoprostol 3mcg/kg PO q8-12h or based on a combination of canine antacid efficacy and human recommendation data – omeprazole approximately 2mg/kg PO daily, q24h or divided.

p.33

And even more info
- Bersenas AME, Mathew KA, Allen DG, et al. Effects of ranitidine, famotidine, pantoprazole, and omeprazole on intragastric pH in dogs. Am J Vet Res, 2005, 66:425-31.
- “Compared to standard or high dose H2RAs, PPIs (proton pump inhibitors) appear superior at acid reduction in dogs."

p.34

Great, until we add tramadol?
- Hill T, Blikslager A. Co-Administration of NSAIDs and Tramadol Decreases Gastric Mucosal Barrier Function. ACVIM 2011
- Recovery of gastric barrier function after acid injury was inhibited by co-administration of tramadol and indomethacin but not by tramadol or indomethacin alone.
- Torring ML, et al. Perforated peptic ulcer and short-term mortality among tramadol users. Br J Clin Pharmcol. 2008 Apr;65(4):565-72
- “Among patients hospitalized for perforated peptic ulcer, tramadol appears to increase mortality at a level comparable to NSAIDs.”

p.35

Some of that info gave me an ulcer...

p.36

So let’s move on to renal adverse effects
- Related to inhibition of COX-1 and COX-2
- COX-2 necessary for renal development
- Basal kidney function doesn’t depend on COX or its prostaglandin production
- But....during hypovolemia or hypotension
- COX-1 maintains blood flow
- COX-2 mediates renin release and tubular function

p.37

Perioperative NSAID use
- Crandell DE et al. Effect of meloxicam and carprofen on renal function when administered to healthy dogs prior to anesthesia and painful stimulation. Am J Vet Res. October 2004;65(10):1384-90.
- “When administered 1 hour before onset of anesthesia and painful electrical stimulation, meloxicam or carprofen did not cause clinically important alteration of renal function in young healthy dogs.

p.38

More evidence for perioperative NSAID
- Goodman LA, et al. Effects of meloxicam on plasma iohexol clearance as a marker of glomerular filtration rate in conscious healthy cats. Am J Vet Res. July 2009;70(7):826-30.
- “Short term meloxicam administration did not measurable alter the glomerular filtration rate as assessed via plasma clearance of iohexol.”

p.39

Yet more evidence
- Hellyer P et al. AAHA/AAFP pain management guidelines for dogs and cats. JAAHA 2007;43:235-48.
- “Before an elective surgery, use an opioid that also reduces the anesthetic requirement. Before or during surgery, use a local anesthetic at the incision to block the transmission of noxious stimuli. During anesthetic recovery, use an NSAID to decrease the inflammation from the surgical trauma."

p.40

My own rules for perioperative NSAIDs
- Avoid NSAIDs in patients with
- Clinical ARF
- Failure vs. chronic disease
- Severe dehydration
- Hypovolemia
- Hypotension
- Hemorrhage
- Cats
- Intraop
- Postop if not ASA I

p.41

More of my own rules
- ASA I and II patients: NSAID likely fine without fluids or support in elective short procedures; administer pre or intra
- ASA III: Provide fluid support and BP monitoring to patients, admin post-op
- ASA IV: Weigh pros/cons
- ASA V: I don’t use them in the immediate perioperative period

p.42

Platelet function and NSAIDs
- Aggregation of platelets is dependent on thromboxane A2
- Which is produced by COX-1
- Problems related to NSAIDs inhibiting COX-1 - no platelet aggregation
- Aspirin irreversibly inhibits COX-1
- COX-2 inhibitors (selective and preferential) preserve platelet function

p.43

Better safe than sorry
- Mullins KB et al. Effects of carprofen, meloxicam, and deracoxib on platelet function in dogs. Vet Anes/Anal 2012 39(2) 206-17.
- “Individual assessment of platelet FUNCTION is advised when administering these drugs prior to surgery, particularly in the presence of other risk factors for bleeding.”
- Pt/Ptt, BMBT

p.44

Other NSAID side effects
- COX inhibition can cause bronchospasm
- COX-2 inhibition can result in increase neuron activity in seizure patients
- Human studies: risk of thrombosis in patients with pre-existing disease increases with COX-2 inhibition
- Chronic blockade of COX-1 and COX-2 may aggravate hypertension in humans
- COX-2 in repro
- Prolonged labor
- Decrease myometrial contraction
- Decreased embryo implantation

p.45

NSAIDs as chemotherapeutics
- Bommer NX, et al. Clinical features, survival times and COX-2 expression in cats with transitional cell carcinoma of the urinary bladder treated with meloxicam. J Feline Med Surg August 2012;14(8):527-33.
- “Ten of the cats showed clinical improvement (reduction of hematuria and or dysuria) with a mean survival time of 311 days (range 10-1064)."

p.46

Chemo
- Bulman-Fleming JC et al. Evaluation of adverse events in cats receiving long-term piroxicam therapy for various neoplasms. J Feline Med Surg April 2010;12(4):262-8.
- “Piroxicam administration was not significantly associated with hematologic, renal or hepatic toxicities. Adverse effects were not correlated with dosage. Adverse events were reported in 29% of cats, and were greatly mild or transient.”

p.47

Chemo
- McMillian SK, et al. Antitumor effects of deracoxib treatment in 26 dogs with transitional cell carcinoma of the urinary bladder. JAVMA October 2011;239(8):1084-9.
- “Of 24 dogs for which tumor response was assessed, 4 had partial remission, 17 had stable disease, 3 had progressive disease. (17/71/13%)”

p.48

NSAID long term safety - canine
- Innes JF, et al. Review of the safety and efficacy of long-term NSAID use in the treatment of canine osteoarthritis. Vet Rec Feb 2010;166(8):226-30.
- “The balance of evidence for the efficacy of NSAIDs supports longer-term use of these agents for increased clinical effect. There is no indication in the literature that such an approach is associated with a reduction in safety, although robust data on the safety of long-term NSAID use is lacking in large numbers in dogs.”

p.49

Cats and NSAIDs
- Most NSAIDs are metabolized via glucuronidation
- Cats deficient in glucuronyl transferase enzymes
- Toxic metabolites increase rapidly with repeat dosing of certain NSAIDs
- Subclinical renal impairment likely in this species
- Operative monitoring of perfusion is very tough, hence most operative problems common, let alone those with NSAIDs
- Acetaminophen toxicity
- Impaired gluconate conjugation
- Toxic metabolites overwhelm glutathione reductase

p.50

Cats and NSAIDs
- Carprofen - UK
- Ketoprofen – inj only
- Meloxicam – inj yes, BLACK BOX oral
- Piroxicam
- Robenacoxib (Onsior)
- 3 days in USA
- 6 days in Europe

p.51

Long term robenacoxib in cats

p.52

Safety of NSAIDs in cats
- Girauder JM, et al. Evaluation of orally administered robenacoxib versus ketoprofen for treatment of acute pain and inflammation associated with musculoskeletal disorders in cats. Am J Vet Res July 2010;71(7):710-9.
- “Safety was assess by monitoring adverse events, clinical signs, and hematologic and plasma biochemical variables (before and after treatment). Results: no significant differences were detected among the 3 treatment groups for any primary or secondary efficacy endpoints or for tolerability variables.”

p.53

One more
- Gowan RA, et al. 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 October 2011;13(10):752-61.
- “There was no difference in sequential serum creatinine concentration or USG measurements between the non-renal group treated with meloxicam compared to control cats not treated with meloxicam. - There was less progression of renal disease in the renal group treated with meloxicam compared to the age and IRIS matched cats with CKD not given meloxicam. - These results suggest that a long term maintenance dose of 0.02/mg/kg of meloxicam can be safely administered to cats older than 7 years even if they have CKD."

p.54

Contraindications – Cats and Dogs
Avoid in
- ARF
- Dehydration, hypovolemia, hemorrhage
- Liver failure
- Hypoalbuminemia
- Hypocoagulopathy
- Suspected or overt ulcerative GI dz
- Coagulopathy
Decrease interval dose or increase dosing - Impaired liver function
- Clinical renal disease
- Myocarditis patients
- Asthmatic patient

p.55

Minimizing the Risk: Patient Selection
- All dogs should undergo a thorough history and physical examination before initiating NSAID therapy
- Appropriate hematological and serum baseline data is recommended prior to and periodically during administration
- Avoid in dogs with a history of renal disease
- NSAIDs are not recommended for dogs with bleeding disorder
- Dogs that have adverse reactions from other NSAIDs, may have adverse reactions with other NSAIDs
- Dogs at greatest risk
- Dehydrated or on concomitant diuretic therapy
- Dogs with renal failure, cardiovascular and or hepatic dysfunction
1. Deramaxx Package insert, NADA # 141-203, 2008 Novartis Animal Health.
2. Etodolac Package insert, NADA 141-108, 2008 Fort Dodge.
3. Metacam Package Insert, NADA 141- 213, 2010, Boehringer Ingelheim Vetmedica, Inc.
4. Previcox package insert NADA 141-230, 2010,
5. Rimadyl Package insert, NADA 141- 111, 2007 Pfizer Animal Health,
6. http://www.fda.gov/AnimalVeterinary/SafetyHeal th/ ProductSafetyInformation/ucm055434.htm, FDA Website. Merial.

p.56

Minimizing the Risk: Concurrent Medications
- Concomitant use of NSAIDs with other anti-inflammatory drugs such as corticosteroids and other NSAIDs should be avoided
- Pet owners may not disclose that they are treating dogs with aspirin
- 7% veterinarians recommend aspirin to treat canine osteoarthritis7
- 28% of pet owner indicated that they use aspirin to treat their dogs osteoarthritis7
- Studies to determine the activity of NSAIDs when administered concomitantly with other protein-bound or similarly metabolized drugs have not been conducted
- Drug compatibility should be monitored closely in patients requiring cardiac, anticonvulsant and behavioral medications

1. Deramaxx Package insert, NADA # 141-203, 2008 Novartis Animal Health.
2. Etodolac Package insert, NADA 141- 108, 2008 Fort Dodge.
3. Metacam Package Insert, NADA 141- 213, 2010, Boehringer Ingelheim
5. Rimadyl Package insert, NADA 141- 111, 2007 Pfizer Animal Health,
6. http://www.fda.gov/AnimalVeterinary/SafetyHealth/Product SafetyInformation/ucm055434.htm, FDA Website. PAH GMR, Canine OA Compliance Study, April 2011.

p.57

Minimizing the Risk: Pet Owner Communication
- Always provide a Client Information Sheet with prescription
- Pet owners should be:
- Informed regarding potential adverse events
- Advised to discontinue NSAID therapy if side effects occur and contact their veterinarian
- Store palatable formulations out of reach of dogs, in a secured location. Severe adverse reactions may occur if large quantities of tablets are ingested
- Made aware of the importance of periodic follow-up for
- Safety, Efficacy, Compliance
- Development of unrelated conditions

p.58

Not recommended when
- Hyperbilirubinemia
- Elevated ALT, AST and GGT
- If any of these are elevated alone or in combination, with or with out signs of hepatic disease
- Albumin decreased – Recommend workup for renal, GI or hepatic dysfunction
- Clotting disorder
- Elevated ALP with clinical signs of liver or Cushing’s disease

p.59

ALP is elevated, but normal dog
- Could be Benign Nodular Hyperplasia
- Is fairly common in older dogs
- ALP can be 2.5x to >10x normal
- Ultrasound and Bile Acids to rule out other disease
- Additional diagnostic as needed
- Consider NSAIDs if no other underlying disease detected
- Monitor to ensure no further elevation or other abnormalities (within 10–30 days, then periodically)
- Any further increases in hepatic enzymes warrants further evaluations

p.60

My NSAID Rules
- Use one or two in your clinic. Be comfortable with them.
- Don’t mix NSAID & NSAID. Don’t mix steroid & NSAID.
- It’s not working. Can it handle it alone? Do we need a helper? (gabapentin, amantadine)
- Client handouts, emails and “if vomiting, diarrhea, dark tarry stools STOP med and CALL OFFICE” on EVERY LABEL.

p.61

More rules
- Use manufacturers dosing. Tapering to “least effective” could bring back windup, and we under diagnose pain already...
- If I have to change NSAID (or to/from pred): washout (5-7 days) bridge (Gabapentin, buprenorphine, Tylenol)
- I stick with brand names. – Product support, reliability.
- Break a tablet in half – is it equally distributed?
- Have a problem? Report it

p.62

What is GALLIPRANT® (grapiprant tablets)?
- Galliprant is a first-in-class non-cyclooxygenase (COX) inhibiting, non-steroidal anti-inflammatory drug (NSAID) in the piprant class.
- Piprants are a newly recognized drug class, established and defined by the World Health Organization in 2013 as prostaglandin receptor antagonists (PRA).
- Unique mechanism of action by antagonizing the prostaglandin E2 (PGE2) EP4 receptor.
- PGE2 its physiologic effects through binding of four different receptors, EP1, EP2, EP3, and EP4.
- EP4 receptor has been identified as the primary receptor responsible for mediating pain and inflammation associated with osteoarthritis. GALLIPRANT selectively blocks the EP4 receptor, thus blocking PGE2 elicited pain.

p.63

Aratana - Galliprant®

p.64

Key Points to Consider When Choosing an NSAID
- NSAIDs in general are safe and efficacious
- Start treatment using preferred NSAID
- Monitor pet owner – efficacy, compliance safety and - With and outweigh monitoring, appropriate the risk benefits patient for most will selection dogs
- Consider consequences of not treating
Benefit
Risk
- Change in NSAID maybe required based on patient’s response
- One drug maybe more effective than another drug
- One drug may be better tolerated
- Pharmacogenetics may play a role in the variability

p.65

Contact info
- VOSM - Veterinary Orthopedic & Sports Medicine Group
- drmattbrunke.com
- 10975 Guilford Rd
- Annapolis Junction, MD 20701
- (240)295-4400 (office)
- www.vosm.com
- drbrunke.wordpress.com