1. Companion Animal Pain Management – Cats and Dogs
Cory Theberge, PhD UNE College of Pharmacy
MPA Spring Conference CE 2015

2. Learning Objectives
Identify the physiological characteristics of cats and dogs that affect pain medication absorption, metabolism, and excretion
Recognize the indications, side effects, and counseling points of pain management treatment options in cats and dogs
Recall veterinary-label medications used for cat and dog pain management

3. Outline Background Feline Glucoronidation/APAP OTC Pain Medications
Prescribing for Cats and Dogs
Dietary Preferences
Cat Pain Posture
Feline Glucoronidation/APAP
OTC Pain Medications
NSAIDs
Opiods (Brief Section)
Gabapentin
Glucosamine and Chondroitin

4. Veterinary Prescribing Refresher
All of these drug categories require a prescription from a veterinarian:
Veterinary prescription drugs used in any way not on the FDA-approved label
Veterinary OTC products used in any way not on the FDA- approved label
All human prescription and OTC drugs
All compounded drugs
When human-approved OTC drugs are used in animals, pharmacists must dispense these drugs with a prescription label, just like any other prescription drug.

5. Cat and Dog Dietary Preferences
Humans and dogs are omnivorous
Urinary pH varies, depends on the amount of protein consumed
Cats are obligate carnivores
Cats eat meat as their main source of protein.
Grain-free diet
A cat’s urinary pH is relatively acidic.
Differences in urinary pH can impact the way a drug is eliminated.
ASA and APAP are sensitive to this difference.

6. Head held down or hidden
Cat Pain Posture
“Marjaryasana”
Majari = cat
Head held down or hidden
Eyes squinted
Hunched back

7. Cats – Glucoronidation/APAP

8. Cats Are Glucuronyl Transferase-Deficient
Cats are deficient in the liver enzyme glucuronyl transferase
Many medications undergo glucuronidation metabolism
Glucuronidation is a major route of elimination of acetaminophen

9. Acetaminophen (APAP) Doses:
Dogs: mg/kg PO q12h
Beneficial for dogs with renal dysfunction
Contraindicated in cats
Dogs: may be combined with codeine, hydrocodone, or tramadol for moderate pain
Plumb DC Veterinary Drug Handbook. Seventh Edition. Pages 6-7.

10. Cats and Acetaminophen (APAP)
Cats can’t breakdown APAP by glucuronidation
APAP undergoes transformation in the cytochrome P-450 system to a reactive intermediate, NAPQI.
NAPQI is the toxic metabolite of APAP that causes hepatocyte death.
Normally, glutathione binds to NAPQI and forms a non- toxic metabolite.
In cats, most of the drug is transformed into NAPQI,
The glutathione stores are not capable of binding all of the NAPQI, so NAPQI is left unbound.
This causes liver damage and death in cats.

11. APAP Toxicity NOT TOXIC TOXIC
Cat have limited ability for glucuronidation, glutathione conjugation takes over
Once the glutathione stores have been depleted, NAPIQ accumulates, producing adverse effects
TOXIC

12. What happens if a cat takes APAP?
Methemoglobinemia
Elevated methemoglobin
The hemoglobin has a decreased ability to bind free oxygen
The hemoglobin has an increased affinity for bound oxygen.
This leads to an overall reduced ability of the red blood cell to release oxygen to tissues
Results in tissue hypoxia
Hemolytic anemia
Hepatic necrosis
Facial and paw swelling
Hematuria
Jaundice
Methemoglobinemia
metHb = ferric [Fe3+] rather than ferrous [Fe2+] hemoglobin in the blood.
The hemoglobin has a decreased ability to bind free oxygen
But…the ferric iron has an increased affinity for bound oxygen.
The binding of oxygen to methemoglobin results in an increased affinity of oxygen to the three other heme sites (that are still ferrous) within the same tetrameric hemoglobin unit.
This leads to an overall reduced ability of the red blood cell to release oxygen to tissues.
When methemoglobin concentration is elevated in red blood cells, tissue hypoxia can occur.
Plumb DC Veterinary Drug Handbook. Seventh Edition. Pages 6-7.

13. APAP Toxicity Treatment
Emesis (if ingested within <2 hours)
Activated charcoal
Acetylcysteine
Precursor to glutathione
Oxygen therapy
Ascorbic acid for methemoglobinemia
Acetylcysteine:
Replenish hepatic stores of glutathione
Oxygen:
Counteract methemoglobinemia and anemia
Ahrens F. Pharmacology: The National Veterinary Medical Series. Blackwell Publishing: Ames, Iowa; Page 175.

14. APAP Counseling Points
Contraindicated in cats at any dosage.
Not overly toxic to dogs at recommended dosages.
Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

15. Notable for Cats: Drugs That Undergo Glucuronidation
Morphine
Testosterone
Oxazepam
Zidovudine
Bilirubin
Many NSAIDs
Acetaminophen
Not meloxicam
Carbamazepine
Valproic Acid
Codeine
Lamotrigine
Lorazepam
Temazepam
King C, Rios G, Green M, Tephly T (2000). "UDP-glucuronosyltransferases". Curr. Drug Metab. 1 (2): 143–61. doi: / PMID

16. Human OTC Options for Pain

17. Cats and Aspirin Aspirin elimination:
Some glucuronidation
Some eliminated unchanged in the urine
Since cats are deficient in glucuronyl transferase, they can only eliminate the aspirin renally
Cats have relatively acidic urine
Aspirin (a weak acid) is more readily reabsorbed in cats. (Like dissolves like)
Unlike APAP, ASA does not form toxic metabolites, so it is not contraindicated in cats.
Primarily relief of minor musculoskeletal pain (arthritis)

18. Cats and Aspirin Aspirin has a significantly longer half-life in cats
Half-life lengths
Cat: 25 – 45 hours
Dog: 8 – 9 hours
Human: 3 hours
If aspirin is prescribed, the dosing interval is extended to hours to avoid accumulation.
Doses:
Dog: 10 mg/kg PO q12h
Cat: 10 mg/kg PO q48-72h
Fink-Gremmels J. (2008) Implications of hepatic cytochrome P450-related biotransformation processes in veterinary sciences. Eur J Pharmacol 585:
Plumb DC Veterinary Drug Handbook. Seventh Edition. Pages 83-6.

19. Aspirin Toxicity
Symptoms: Depression, vomiting, anorexia, hyperthermia, increased respiratory rate
Effects
Hyperpyrexia
Acid-base disturbances
Dehydration (from vomiting and sweating)
Treatment
Gastric lavage, activated charcoal, or dialysis
Sodium bicarbonate
Raises the urinary pH and therefore increases aspirin excretion
IV fluids
Respiratory alkalosis (due to hyperventilation)
Then respiratory acidosis (due to CNS depression)
The metabolic acidosis
-release of H+ from salicylic acid
-uncoupling of oxidative phosphorylation
-increased fat metabolism ketoacidosis
-depression of renal function
IV fluids—corrects metabolic acidosis and dehydration
Ahrens F. Pharmacology: The National Veterinary Medical Series. Blackwell Publishing: Ames, Iowa; Pages
Plumb DC Veterinary Drug Handbook. Seventh Edition. Pages 83-6.

20. Aspirin Counseling Points
Buffered or enteric-coated is aspirin is recommended to reduce GI side effects.
Cats are relatively sensitive to salicylates (dose carefully).
Dogs are relatively sensitive to GI effects (bleeding).
Always give with food, due to stomach irritation.
Watch for signs of bleeding
Dark, tarry stool
Hematemesis
Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

21. Naproxen Not indicated for cats Use in dogs is discouraged
Reports of GI ulcers and perforation
May be overly sensitive to the adverse effects
Nephritis
Nephrotic syndrome
Increased liver enzymes
Only give one NSAID at a time
Never give with corticosteroids
Watch for signs of bleeding
Use has declined due to the development of newer, less GI- toxic NSAIDs
Approved for use in horses only
Nephrotic syndrome: protein in the urine, low blood protein levels, high cholesterol levels, high triglyceride levels, and swelling.
No corticosteriods- increased risk of GI ulceration and bleeding
Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

22. OTC Cat and Dog Summary Drug Dog Cat Aspirin (only buffered or EC) Yes
With food
Short-term use only No
Only by vet. One 325mg tab is 8x the recommended dose for an 8-lb cat.
Acetaminophen
Up to 15mg/kg PO TID
One 500mg tab is lethal to a 10-lb cat.
Ibuprofen
Naproxen Sodium
Only by vet
APAP lethal dose in cat = 50 – 100mg/kg

23. Topical OTC Pain Products
Local anesthetics like lidocaine, tetracaine, benzocaine or pramoxine are found in many human topical ointments and suppositories.
Cats can absorb these local anesthetics through their skin or ingest them during grooming.
Cats have a unique hemoglobin structure, which is easily damaged by these anesthetics and are at an increased risk for toxicity.
In large amounts, seizures, tremors and cardiac arrhythmias can occur.
Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

24. Never recommend OTC NSAIDs
NSAIDs can cause kidney and liver toxicity
NSAID therapy and organ toxicity must be monitored by veterinarians.
NSAIDs are poorly tolerated by cats
If an NSAID is approved for a cat, a black box warning usually accompanies that drug.
Meloxicam (Metacam) black box warning: repeated doses cannot be given because of risk of renal failure and death in cats.

25. Animal Label Non-steroidal anti-inflammatory drugs (NSAIDs)

26. Background Used for analgesic and anti-inflammatory properties MOA
Inhibit COX enzymes
Variable effects on:
Gastric mucosal lining
Platelet function
Renal function and regulation
Many NSAIDs are metabolized in the liver by glucuronidation (Not for cats!)
Meloxicam undergoes oxidation

27. Butazolidin, Butatron, Equipalazone
Generic
Vet-Labeled
Human-Labeled
Dog
Cat
Carprofen
Rimadyl, Vetprofen -
Yes
Only for post-op pain
Etodolac
Etogesic
Lodine No
Phenylbutazone
Butazolidin, Butatron, Equipalazone
Ketoprofen
Ketofen
Orudis KT, Oruvail
Meloxicam
Metacam
Mobic
Only labeled for a one-time dose. Others uses are off-label.
Deracoxib
Deramaxx
Firocoxib
Previcox
Flunixin
Banamine, and many others
Only for horses and cattle. (Remember EPM?)
This table does not include NSAID ophthalmic preparations, such as bromfenac and flurbiprofen.
Plumb DC. Plumb’s Veterinary Drug Handbook. Seventh Edition.

28. Side effects usually surface 48-72 hours after starting NSAIDs.
Decrease or increase in appetite or drinking habits
Jaundice
Vomiting
Yellowing of gums
Change in bowel movements
Yellowing of skin
Diarrhea
Yellowing of whites of the eyes
Black, tarry, or bloody stools
Change in urination habits
Change in behavior
Frequency
Decreased or increased activity level
Color
Smell
Aggression
Skin changes
Redness
Scabs
Itching
Side effects usually surface hours after starting NSAIDs.
Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

29. Counseling Points Decreases T4 in some dogs
Always give with food to minimize GI side effects.
Dogs are particularly susceptible to bleeding and hepatotoxicity.
Cats are particularly susceptible to kidney failure, especially if dehydrated or not eating.
Etodolac
Decreases T4 in some dogs
Less impact on bleeding times than other NSAIDs
A one-day wash-out period is recommended when discontinuing carprofen and switching to another NSAID.

30. Opioids (Briefly) – Cats and Dogs

31. Mechanism Of Action Three opioid receptors: μ, δ, κ
Raise the pain threshold
Decrease the perception of pain
Act at the dorsal horn of the spinal cord and several other brain areas
Opioids inhibit postsynaptic nociceptive projection neurons
May inhibit release of substance P presynaptically
Opioids generally have less bioavailability in dogs than in humans
Nociceptive = of, relating to, or denoting pain arising from the stimulation of nerve cells
Substance P
Neuropeptide
The sensory function of substance P is thought to be related to the transmission of pain information into the central nervous system.
Substance P coexists with the excitatory neurotransmitter glutamate in primary afferents that respond to painful stimulation.
Keates HL, Cramond T, Smith MT. Intra-articular and periarticular opioid binding in inflamed tissue in experimental canine arthritis. Anesth Analg 89: , 1999.

32. Side Effects Dogs Cats CNS stimulation Mydriasis Sweating Tachycardia
CNS depression
Miosis
Hypothermia
Bradycardia
Respiratory depression
Constipation
Commonly vomit (especially with morphine)
CNS stimulation
Mydriasis
Sweating
Tachycardia
Panting
Constipation
May vomit
Miosis = pupil constriction
Mydriasis = pupil dilation
Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: Gilman AG, Goodman LS, Rall TW, eds. The Pharmacologic Basis of Therapeutics, 7th ed. New York: Macmillan, 1985:
Booth NH. Neuroleptanalgesics, narcotic analgesics, and analgesic antagonists. In: Booth NH, McDonald LE, eds. Veterinary Pharmacology and Therapeutics, 5th ed. Ames, IA: Iowa State University Press 1982:

33. Counseling Information
Many opiods utilized in both cats and dogs
Dog dosing is often greater than cat dosing
Morphine
Tramadol
DDI: Meperidine plus MAOIs = Serotonin Syndrome
Tylenol 3 OK for Dogs, NOT for Cats
Pharmacists should be alert to owners seeking opiates for diversion
Lumb and Jones’ Veterinary Anesthesia and Analgesia. 4th ed. Edited by William J. Tranquilli, John C. Thurmon, and Kurt A. Grimm.
Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

34. Gabapentin

35. Mechanism of Action What is gabapentin?
A GABA molecule covalently bound to a lipophilic cyclohexane ring
Designed to be a GABA agonist, but does not bind to GABAA or GABAB receptors
Blocks voltage-dependent calcium channels
Modulates excitatory neurotransmitter release that participates in nociception
Is GABA inhibitory or excitatory? Inhibitory

36. Gabapentin Uses in animals
Incisional pain
Arthritis
Reduces “wind-up” pain
Good for chronic pain management in dogs and cats
Typically not used for adaptive pain
Don’t use the xylitol-containing human-labeled liquid in dogs
Mao J, Chen LL. Gabapentin in pain management. Anesth Analg 2000;91:
Plumb, DC. Plumb’s Veterinary Drug Handbook. 6th edition.
Hellyer, P., Rodan, I., Brunt, J., Downing, R., Hagedorn, J. E., & Robertson, S. A. (2007). AAHA/AAFP pain management guidelines for dogs & cats. J Am Anim Hosp Assoc, 43(5),

37. Side effects Dizziness *Sedation* Peripheral edema
Abrupt discontinuation leads to withdrawal
Titrate dose to minimize these side effects.
Plumb, DC. Plumb’s Veterinary Drug Handbook. 6th edition.

38. Glucosamine & chondroitin

39. Uses Classified as nutraceuticals
*Adjunctive treatment for osteoarthritis in cats, dogs, and horses*
Used for feline lower urinary tract disease (FLUTD)
Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

40. Mechanism of Action Glucosamine Chondroitin Sulfate
Cartilage cells use glucosamine to produce glycosaminoglycans and hyaluronan
Regulates the synthesis of collagen and proteoglycans in cartilage
Mild anti-inflammatory effects due to its ability to scavenge free radicals
Chondrocytes normally make glucosamine from glucose and amino acids, but this ability diminishes with age, disease, or trauma.
FLUTD: Works due to the presence of glycosaminoglycans in the protective layer of the urinary tract
Inhibits destructive enzymes in joint fluid and cartilage
Stimulates the production of glycosaminoglycans and proteoglycans in joint cartilage
Thrombi formation in microvasculature may be reduced
Shellfish derived – may cause allergic reactions in clients/owners.
Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

41. Dosing Dosing is based on chondroitin component
Dogs: mg/kg PO qd or qod
Cats: 15-20mg/kg PO qd or qod
Many veterinary-labeled products – always check dosing!
Bioequivalence between products cannot be assumed. Independent analysis has shown a wide variation in products.
Glucosamine and chondroitin sulfate are considered nutritional supplements by the FDA.
No standards have been accepted for potency, purity, safety or efficacy by regulatory bodies.
Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

42. Counseling Points Overall, well tolerated
Minor GI effects
Flatulence
Stool softening
Clinical improvement may take 2-6 weeks.
Chondroitin sulfate is extremely hygroscopic
Store in tight containers at room temperature
Avoid storing in direct sunlight
Administration
Pets can be pilled
Tablets
Given with a treat
Crumbled and mixed with food
Capsules
Pulled apart and sprinkled over food
Wet or moist food works best
Wrapped in food
Hygroscopic = Tends to absorb moisture from the air
Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

43. Summary
Human-label OTC NSAIDs should not be used without a veterinary Rx
Dosing cats with aspirin or human OTC NSAIDs is not common and not recommended
A variety of animal-label NSAIDs are available
Opiate side effects and dosing are distinctly different between cats and dogs
Nutraceuticals glucosamine and chondroitin are used in cats and dogs as adjunctive pain therapy for OA