COMPANION ANIMALPAIN MANAGEMENT – CATS AND DOGSCory Theberge, PhD UNE College of Pharmacy

MPA Spring Conference CE 2015

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

Outline

Background Prescribing for Cats and Dogs Dietary Preferences Cat Pain Posture

Feline Glucoronidation/APAP OTC Pain Medications NSAIDs Opiods (Brief Section) Gabapentin Glucosamine and Chondroitin

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.

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.http://pharmacistsletter.therapeuticresearch.com/ce/cecourse.aspx?pc=12-221&fromce=021811

Cat Pain Posture

“Marjaryasana”Majari = cat

Head held down or hidden

Eyes squintedHunched back

http://www.yogajournal.com/poses/2468http://www.scoutshouse.com/wp-content/uploads/2009/12/Pain-Management-in-Cats.pdf

Cats – Glucoronidation/APAP

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

http://pharmacistsletter.therapeuticresearch.com/ce/cecourse.aspx?pc=12-221&fromce=021811

Acetaminophen (APAP)

Plumb DC Veterinary Drug Handbook. Seventh Edition. Pages 6-7.

Doses: Dogs: 10-15 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

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.

http://pharmacistsletter.therapeuticresearch.com/ce/cecourse.aspx?pc=12-221&fromce=021811

APAP Toxicity

http://archive.ispub.com/journal/the-internet-journal-of-toxicology/volume-6-number-2/acetaminophen-poisoning-case-report.article-g02.fs.jpg

TOXIC

NOT TOXIC

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

http://emedicine.medscape.com/article/204178-overviewPlumb DC Veterinary Drug Handbook. Seventh Edition. Pages 6-7.

APAP Toxicity Treatment

Emesis (if ingested within <2 hours)

Activated charcoal Acetylcysteine

Precursor to glutathione

Oxygen therapy Ascorbic acid for

methemoglobinemiahttp://www.ansci.cornell.edu/plants/toxcat/toxcat.htmlAhrens F. Pharmacology: The National Veterinary Medical Series. Blackwell Publishing: Ames, Iowa; 2007. Page 175.

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.

Notable for Cats: Drugs That Undergo Glucuronidation

Morphine Oxazepam Bilirubin Acetaminophen Carbamazepine Codeine Lamotrigine

Lorazepam Temazepam Testosterone Zidovudine Many NSAIDs

Not meloxicam Valproic Acid

King C, Rios G, Green M, Tephly T (2000). "UDP-glucuronosyltransferases". Curr. Drug Metab. 1 (2): 143–61. doi:10.2174/1389200003339171. PMID 11465080.

Human OTC Options for Pain

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.

http://pharmacistsletter.therapeuticresearch.com/ce/cecourse.aspx?pc=12-221&fromce=021811

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 48-72 hours to avoid accumulation.

Doses: Dog: 10 mg/kg PO q12h Cat: 10 mg/kg PO q48-72h

http://pharmacistsletter.therapeuticresearch.com/ce/cecourse.aspx?pc=12-221&fromce=021811.Fink-Gremmels J. (2008) Implications of hepatic cytochrome P450-related biotransformation processes in veterinary sciences. Eur J Pharmacol 585:502-509.Plumb DC Veterinary Drug Handbook. Seventh Edition. Pages 83-6.

Aspirin Toxicity

Ahrens F. Pharmacology: The National Veterinary Medical Series. Blackwell Publishing: Ames, Iowa; 2007. Pages 173-4.Plumb DC Veterinary Drug Handbook. Seventh Edition. Pages 83-6.

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

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.

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

Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

OTC Cat and Dog Summary

Drug Dog Cat

Aspirin(only

buffered or EC)

YesWith food

Short-term use only

NoOnly by vet. One 325mg

tab is 8x the recommended dose for

an 8-lb cat.

Acetaminophen

YesUp to 15mg/kg PO

TID

NoOne 500mg tab is lethal

to a 10-lb cat.

Ibuprofen No No

Naproxen Sodium

NoOnly by vet No

http://pets.webmd.com/cats/guide/safe-cat-pain-medicationshttp://pets.webmd.com/dogs/guide/dog-pain-medications

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.

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.

http://www.scoutshouse.com/wp-content/uploads/2009/12/Pain-Management-in-Cats.pdf

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

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

http://www.scoutshouse.com/wp-content/uploads/2009/12/Pain-Management-in-Cats.pdf

Generic Vet-Labeled

Human-Labeled Dog Cat

Carprofen Rimadyl, Vetprofen - Yes Only for post-

op pain

Etodolac Etogesic Lodine Yes No

Phenylbutazone

Butazolidin, Butatron,

Equipalazone

- Yes No

Ketoprofen Ketofen Orudis KT, Oruvail Yes Yes

Meloxicam Metacam Mobic Yes

Only labeled for a one-time dose. Others uses are off-

label.

Deracoxib Deramaxx - Yes No

Firocoxib Previcox Yes No

FlunixinBanamine, 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.

Side Effects

Decrease or increase in appetite or drinking habits

Vomiting Change in bowel

movements Diarrhea Black, tarry, or bloody stools

Change in behavior Decreased or increased

activity level Aggression

Jaundice Yellowing of gums Yellowing of skin Yellowing of whites of the

eyes Change in urination habits

Frequency Color Smell

Skin changes Redness Scabs Itching

Side effects usually surface 48-72 hours after starting NSAIDs.

Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

Counseling Points

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.

Opioids (Briefly) – Cats and Dogs

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

Keates HL, Cramond T, Smith MT. Intra-articular and periarticular opioid binding in inflamed tissue in experimental canine arthritis. Anesth Analg 89:409-415, 1999.

Side Effects

CNS depression Miosis Hypothermia Bradycardia Respiratory depression Constipation Commonly vomit

(especially with morphine)

CNS stimulation Mydriasis Sweating Tachycardia Panting Constipation May vomit

Dogs Cats

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, 1985:491-531.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 1982:267-296.

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.

Gabapentin

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

https://www.caymanchem.com/app/template/Product.vm/catalog/10008346

http://online.lexi.com.une.idm.oclc.org/lco/action/doc/retrieve/docid/patch_f/6961#f_pharmacology-and-pharmacokinetics

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;91:680-687.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), 235-248.

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.

Glucosamine & chondroitin

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.

Mechanism of Action

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.

Glucosamine Chondroitin Sulfate

Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

Dosing

Dosing is based on chondroitin component Dogs: 13-15 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.

Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

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

Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

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