Presentation on theme: "Companion Animal Pain Management – Cats and Dogs"— Presentation transcript:
1 Companion Animal Pain Management – Cats and Dogs Cory Theberge, PhD UNE College of PharmacyMPA Spring Conference CE 2015
2 Learning ObjectivesIdentify the physiological characteristics of cats and dogs that affect pain medication absorption, metabolism, and excretionRecognize the indications, side effects, and counseling points of pain management treatment options in cats and dogsRecall veterinary-label medications used for cat and dog pain management
3 Outline Background Feline Glucoronidation/APAP OTC Pain Medications Prescribing for Cats and DogsDietary PreferencesCat Pain PostureFeline Glucoronidation/APAPOTC Pain MedicationsNSAIDsOpiods (Brief Section)GabapentinGlucosamine 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 labelVeterinary OTC products used in any way not on the FDA- approved labelAll human prescription and OTC drugsAll compounded drugsWhen 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 omnivorousUrinary pH varies, depends on the amount of protein consumedCats are obligate carnivoresCats eat meat as their main source of protein.Grain-free dietA 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 = catHead held down or hiddenEyes squintedHunched back
8 Cats Are Glucuronyl Transferase-Deficient Cats are deficient in the liver enzyme glucuronyl transferaseMany medications undergo glucuronidation metabolismGlucuronidation is a major route of elimination of acetaminophen
9 Acetaminophen (APAP) Doses: Dogs: mg/kg PO q12hBeneficial for dogs with renal dysfunctionContraindicated in catsDogs: may be combined with codeine, hydrocodone, or tramadol for moderate painPlumb DC Veterinary Drug Handbook. Seventh Edition. Pages 6-7.
10 Cats and Acetaminophen (APAP) Cats can’t breakdown APAP by glucuronidationAPAP 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 overOnce the glutathione stores have been depleted, NAPIQ accumulates, producing adverse effectsTOXIC
12 What happens if a cat takes APAP? MethemoglobinemiaElevated methemoglobinThe hemoglobin has a decreased ability to bind free oxygenThe hemoglobin has an increased affinity for bound oxygen.This leads to an overall reduced ability of the red blood cell to release oxygen to tissuesResults in tissue hypoxiaHemolytic anemiaHepatic necrosisFacial and paw swellingHematuriaJaundiceMethemoglobinemiametHb = ferric [Fe3+] rather than ferrous [Fe2+] hemoglobin in the blood.The hemoglobin has a decreased ability to bind free oxygenBut…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 charcoalAcetylcysteinePrecursor to glutathioneOxygen therapyAscorbic acid for methemoglobinemiaAcetylcysteine:Replenish hepatic stores of glutathioneOxygen:Counteract methemoglobinemia and anemiaAhrens 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 MorphineTestosteroneOxazepamZidovudineBilirubinMany NSAIDsAcetaminophenNot meloxicamCarbamazepineValproic AcidCodeineLamotrigineLorazepamTemazepamKing C, Rios G, Green M, Tephly T (2000). "UDP-glucuronosyltransferases". Curr. Drug Metab. 1 (2): 143–61. doi: / PMID
17 Cats and Aspirin Aspirin elimination: Some glucuronidationSome eliminated unchanged in the urineSince cats are deficient in glucuronyl transferase, they can only eliminate the aspirin renallyCats have relatively acidic urineAspirin (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 lengthsCat: 25 – 45 hoursDog: 8 – 9 hoursHuman: 3 hoursIf aspirin is prescribed, the dosing interval is extended to hours to avoid accumulation.Doses:Dog: 10 mg/kg PO q12hCat: 10 mg/kg PO q48-72hFink-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 ToxicitySymptoms: Depression, vomiting, anorexia, hyperthermia, increased respiratory rateEffectsHyperpyrexiaAcid-base disturbancesDehydration (from vomiting and sweating)TreatmentGastric lavage, activated charcoal, or dialysisSodium bicarbonateRaises the urinary pH and therefore increases aspirin excretionIV fluidsRespiratory 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 functionIV fluids—corrects metabolic acidosis and dehydrationAhrens F. Pharmacology: The National Veterinary Medical Series. Blackwell Publishing: Ames, Iowa; PagesPlumb 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 bleedingDark, tarry stoolHematemesisPlumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.
21 Naproxen Not indicated for cats Use in dogs is discouraged Reports of GI ulcers and perforationMay be overly sensitive to the adverse effectsNephritisNephrotic syndromeIncreased liver enzymesOnly give one NSAID at a timeNever give with corticosteroidsWatch for signs of bleedingUse has declined due to the development of newer, less GI- toxic NSAIDsApproved for use in horses onlyNephrotic 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 bleedingPlumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.
22 OTC Cat and Dog Summary Drug Dog Cat Aspirin (only buffered or EC) Yes With foodShort-term use onlyNoOnly by vet. One 325mg tab is 8x the recommended dose for an 8-lb cat.AcetaminophenUp to 15mg/kg PO TIDOne 500mg tab is lethal to a 10-lb cat.IbuprofenNaproxen SodiumOnly by vetAPAP 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 toxicityNSAID therapy and organ toxicity must be monitored by veterinarians.NSAIDs are poorly tolerated by catsIf 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.
26 Background Used for analgesic and anti-inflammatory properties MOA Inhibit COX enzymesVariable effects on:Gastric mucosal liningPlatelet functionRenal function and regulationMany NSAIDs are metabolized in the liver by glucuronidation (Not for cats!)Meloxicam undergoes oxidation
27 Butazolidin, Butatron, Equipalazone GenericVet-LabeledHuman-LabeledDogCatCarprofenRimadyl, Vetprofen-YesOnly for post-op painEtodolacEtogesicLodineNoPhenylbutazoneButazolidin, Butatron, EquipalazoneKetoprofenKetofenOrudis KT, OruvailMeloxicamMetacamMobicOnly labeled for a one-time dose. Others uses are off-label.DeracoxibDeramaxxFirocoxibPrevicoxFlunixinBanamine, and many othersOnly 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 habitsJaundiceVomitingYellowing of gumsChange in bowel movementsYellowing of skinDiarrheaYellowing of whites of the eyesBlack, tarry, or bloody stoolsChange in urination habitsChange in behaviorFrequencyDecreased or increased activity levelColorSmellAggressionSkin changesRednessScabsItchingSide 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.EtodolacDecreases T4 in some dogsLess impact on bleeding times than other NSAIDsA one-day wash-out period is recommended when discontinuing carprofen and switching to another NSAID.
31 Mechanism Of Action Three opioid receptors: μ, δ, κ Raise the pain thresholdDecrease the perception of painAct at the dorsal horn of the spinal cord and several other brain areasOpioids inhibit postsynaptic nociceptive projection neuronsMay inhibit release of substance P presynapticallyOpioids generally have less bioavailability in dogs than in humansNociceptive = of, relating to, or denoting pain arising from the stimulation of nerve cellsSubstance PNeuropeptideThe 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 depressionMiosisHypothermiaBradycardiaRespiratory depressionConstipationCommonly vomit (especially with morphine)CNS stimulationMydriasisSweatingTachycardiaPantingConstipationMay vomitMiosis = pupil constrictionMydriasis = pupil dilationJaffe 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 dogsDog dosing is often greater than cat dosingMorphineTramadolDDI: Meperidine plus MAOIs = Serotonin SyndromeTylenol 3 OK for Dogs, NOT for CatsPharmacists should be alert to owners seeking opiates for diversionLumb 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.
35 Mechanism of Action What is gabapentin? A GABA molecule covalently bound to a lipophilic cyclohexane ringDesigned to be a GABA agonist, but does not bind to GABAA or GABAB receptorsBlocks voltage-dependent calcium channelsModulates excitatory neurotransmitter release that participates in nociceptionIs GABA inhibitory or excitatory? Inhibitoryhttps://www.caymanchem.com/app/template/Product.vm/catalog/
36 Gabapentin Uses in animals Incisional painArthritisReduces “wind-up” painGood for chronic pain management in dogs and catsTypically not used for adaptive painDon’t use the xylitol-containing human-labeled liquid in dogsMao 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 withdrawalTitrate dose to minimize these side effects.Plumb, DC. Plumb’s Veterinary Drug Handbook. 6th edition.
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 hyaluronanRegulates the synthesis of collagen and proteoglycans in cartilageMild anti-inflammatory effects due to its ability to scavenge free radicalsChondrocytes 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 tractInhibits destructive enzymes in joint fluid and cartilageStimulates the production of glycosaminoglycans and proteoglycans in joint cartilageThrombi formation in microvasculature may be reducedShellfish 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 qodCats: 15-20mg/kg PO qd or qodMany 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 effectsFlatulenceStool softeningClinical improvement may take 2-6 weeks.Chondroitin sulfate is extremely hygroscopicStore in tight containers at room temperatureAvoid storing in direct sunlightAdministrationPets can be pilledTabletsGiven with a treatCrumbled and mixed with foodCapsulesPulled apart and sprinkled over foodWet or moist food works bestWrapped in foodHygroscopic = Tends to absorb moisture from the airPlumb DC. Plumb’s Veterinary Drug Handbook. 6th Edition.
43 SummaryHuman-label OTC NSAIDs should not be used without a veterinary RxDosing cats with aspirin or human OTC NSAIDs is not common and not recommendedA variety of animal-label NSAIDs are availableOpiate side effects and dosing are distinctly different between cats and dogsNutraceuticals glucosamine and chondroitin are used in cats and dogs as adjunctive pain therapy for OA