Companion Animal Pain Management – Cats and Dogs Cory 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 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

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

Head held down or hidden 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 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.

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 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 http://archive.ispub.com/journal/the-internet-journal-of-toxicology/volume-6-number-2/acetaminophen-poisoning-case-report.article-g02.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 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. 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 Acetylcysteine: Replenish hepatic stores of glutathione Oxygen: Counteract methemoglobinemia and anemia http://www.ansci.cornell.edu/plants/toxcat/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. 6th Edition.

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: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. Primarily relief of minor musculoskeletal pain (arthritis) 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 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; 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. 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 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.

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 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. 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

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.

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 48-72 hours after starting NSAIDs. Plumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.

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.

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 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 89:409-415, 1999.

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, 1985:491-531. 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 Is GABA inhibitory or excitatory? Inhibitory 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 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.

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. 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.

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.

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