COMPANION ANIMAL PAIN MANAGEMENT CATS AND DOGS Cory

COMPANION ANIMAL PAIN MANAGEMENT – CATS AND DOGS Cory Theberge, Ph. D 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 p. H 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 p. H is relatively acidic. Differences in urinary p. H 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 squinted Hunched back http: //www. yogajournal. com/poses/2468 http: //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) Doses: � Dogs: 10 -15 mg/kg PO q 12 h 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.

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 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 NOT TOXIC http: //archive. ispub. com/journal/the-internet-journal-of-toxicology/volume-6 -number-2/acetaminophen-poisoning-case-report. articleg 02. fs. jpg

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 -overview Plumb 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 methemoglobinemia http: //www. ansci. cornell. edu/plants/toxcat. html Ahrens 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. 6 th 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 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 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 q 12 h � Cat: 10 mg/kg PO q 48 -72 h http: //pharmacistsletter. therapeuticresearch. com/ce/cecourse. aspx? pc=12 -221&fromce=021811. Fink-Gremmels J. (2008) Implications of hepatic cytochrome P 450 -related biotransformation processes in veterinary sciences. Eur J Pharmacol 585: 502 -509. Plumb DC Veterinary Drug Handbook. Seventh Edition. Pages 83 -6.

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 p. H and therefore increases aspirin excretion � IV fluids 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.

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. 6 th 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. 6 th Edition.

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 325 mg tab is 8 x the recommended dose for an 8 -lb cat. Acetaminoph en Yes Up to 15 mg/kg PO TID No One 500 mg tab is lethal to a 10 -lb cat. Ibuprofen No No Naproxen Sodium No Only by vet No http: //pets. webmd. com/cats/guide/safe-cat-pain-medications http: //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. 6 th Edition.

Never recommend OTC 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 antiinflammatory 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 Phenylbutazo ne Butazolidin, Butatron, Equipalazone - Yes No Ketoprofen Ketofen Orudis KT, Oruvail 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 Banamine, Only for horses and cattle. Flunixin and many (Remember EPM? ) others This table does not include NSAID ophthalmic preparations, such as bromfenac and flurbip Plumb DC. Plumb’s Veterinary Drug Handbook. Seventh Edition.

Side Effects Jaundice Decrease or increase in appetite or drinking habits � Yellowing of gums Vomiting � Yellowing of skin � Yellowing of whites of the Change in bowel movements � � Diarrhea Black, tarry, or bloody stools eyes � Change in behavior � � Decreased or increased activity level Aggression 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. 6 th 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 T 4 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 Dogs CNS depression Miosis Hypothermia Bradycardia Respiratory depression Constipation Commonly vomit (especially with morphine) Cats CNS stimulation Mydriasis Sweating Tachycardia Panting Constipation May vomit Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: Gilman AG, Goodman LS, Rall TW, eds. The Pharmacologic Basis of Therapeutics, 7 th ed. New York: Macmillan, 1985: 491 -531. Booth NH. Neuroleptanalgesics, narcotic analgesics, and analgesic antagonists. In: Booth NH, Mc. Donald LE, eds. Veterinary Pharmacology and Therapeutics, 5 th 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. 4 th ed. Edited by William J. Tranquilli, John C. Thurmon, and Kurt A. Grimm. Plumb DC. Plumb’s Veterinary Drug Handbook. 6 th 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/catal og/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. 6 th 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 Titrate dose to Dizziness minimize these *Sedation* side effects. Peripheral edema Abrupt discontinuation leads to withdrawal Plumb, DC. Plumb’s Veterinary Drug Handbook. 6 th 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. 6 th Edition.

Mechanism of Action Glucosamine 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 Plumb DC. Plumb’s Veterinary Drug Handbook. 6 th Edition. Chondroitin Sulfate • • 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.

Dosing is based on chondroitin component �Dogs: 13 -15 mg/kg PO qd or qod �Cats: 15 -20 mg/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. 6 th 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 Plumb DC. Plumb’s Veterinary Drug Handbook. 6 th Edition. 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

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