Pain Management

1
Pain Management

• Dr. J.M. Roesner, DVM, DABVP
• Dr. Vanessa Lee, DVM

2

• Ethics and Economics of Pain Management
• Pain Pathway and Strategies for Pain Reduction
• NSAIDS
• Tepoxalin
• Parting Thoughts

3
AVMA Position

• Animal pain and suffering are clinically
  important conditions that adversely affect an
  animals quality of life. Drugs, technique or
  husbandry methods used to prevent and control
  pain must be tailored to individual animals.
• (JAVMA 20012181694)

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Untapped Market

• 60 or more of DJD dogs are not treated or
  managed by a DVM.
• (JAVMA 2002221215-222)

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Ethical Economics
6
Types of Pain
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1. Somatic

• Skin, musculoskeletal
• Dull, aching, localizable

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2. Visceral

• Compression, distension, infiltration of pelvic,
  abdominal or thoracic organs
• May be difficult to localize

9
3. Neuropathic

• Nerve compression, damage infiltration,
  /-hyperalgesia
• Severe burning or tingling

(Tranquilly, Teton Press)
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NMDA Receptor
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Pain Pathway
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Pain Pathway Continued

• First Pain A-delta, fast
• Second Pain - C fibers, slow
• Dorsal Root Ganglia contains afferent cell
  bodies

13
Pain Pathway Continued

• Dorsal Horn of Spinal Cord (2nd order Neurons)
• Site of Synapse of First Order Neurons
• A excitatory and inhibitory interneurons
• B propriospinal neurons (segmental reflex
  activity)
• C projecting neurons to supraspinal centers
  (midbrain, cortex)
• Spinothalamic, Spinocervical, Spinomesencephalic

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Pain Pathway Continued

• 3rd order neurons are within
• Medulla
• Pons
• Midbrain
• Thalamus
• Hypothalamus
• Cerebral Cortex

15
Pain Pathway Continued

• Descending inhibitory influences occur within
  cortex, thalamus, midbrain, rostral medulla and
  brain stem.

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Nociception

• A Transduction receptor translates physical
  energy into electrical energy
• B Transmission A delta and C fibers propagate
  impulses
• C Modulation endogenous descending analgesic
  systems (opiod, serotonergic and noradrenergic)
  inhibit stimuli processing in spinal dorsal horn
  cells.

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Pain Recognition

• ? HR, ? BP, ? RR, peripheral vasoconstriction
• Restless
• Sedentary hunched
• ? Appetite
• Purring, vocalization
• Pain scores VAS NRS

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• Pain has negative consequences on healing,
  morbidity mortality.

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• Assume an animal is painful if you would be in a
  similar circumstance.

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Preemptive Analgesia

• Rx Prior to stimulus
• Minimizes likelihood of chronic pain
• Pain is easier to prevent than to alleviate
  (windup)
• e.q. premed opiods, NSAIDS, Alpha 2 agonists,
  local blocks, epidurals

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Multimodal Analgesia

• Synergistic
• Decreased potential for adverse reactions
• Effective
• E.g NSAID ? ? transduction
• Local Block ? stops transmission
• Opiod and Alpha 2 agonist ? ? modulation

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Multimodal Analgesia

• Decreases nociceptor sensitization (inflammation)
• Decreases wind up (neuroplastic changes in cord)
• Decreases tachyphylaxis
• Decreases neuroendocrine response
• Decreases convalescent time
• Improves healing (perfusion)
• Improves immune function

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Sites of Drug Intervention in Pain Processing
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Inhibit Transduction(peripheral sensitization of
nociceptors)

• Local anesthetics
• Opiods
• NSAIDs
• Corticosteriods

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Inhibit Transmission(impulse conduction)

• Local anesthetics
• Alpha 2 agonists

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Modulation of Spinal Pathway(inhibit central
sensitization)

• Local anesthetics
• Opiods
• Alpha 2 agonists
• Trycyclic antidepressants
• Cholinesterase inhibitors
• NMDA antagonists
• NSAIDs
• Anticonvulsants

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Inhibit Perception

• General anesthetics
• Opiods
• Alpha 2 agonists
• Benzodiazepams
• Phenothiazines

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Epidural
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Epidural

• Lidocaine Bupivicaine 1 ml/4.5 kg or 1 ml/3.5 kg
  for abdominal
• Morphine
• Fentanyl
• Alpha 2 Agonists
• Buprenorphine

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Distal Radial/Ulnar Median Nerve Block
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Articular Blocks - Stifle
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Dental Blocks
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Intercostal Blocks
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CRIs

• Can overcome short /- ½ limitations
• Morphine, Ketamine, Butorphanol
• Calculator programs available

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Transdermal

• Fentanyl or lidoderm patches
• Topical gabapentin
• Emla cream

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Drugs to Consider

• Tramadol
• Amatidine
• Dextromethorphan
• Gabapentin
• IV lidocaine

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Butorphanol (Plumb 2005)

• Kappa agonist, mu antagonist, sigma agonist
• NOT adequate for severe pain
• NOT adequate for bone pain
• Controlled (C-IV)
• Short duration of analgesia (best in CRI, has a
  ceiling effect)

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Analgesic Doses

• D 0.1-1.0 mg/kg (SQ, IM, IV)
• C 0.1-1.0 mg/kg (SQ, IM, IV)
• H 0.1 (SQ, IM, IV)
• Ferret 0.05-0.1 mg/kg (SQ, IM, IV)
• Rabbit, Rodent 0.4 mg/kg (IV, SQ, IM)
• Avian 2-4 mg/kg

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Buprenorphine (Plumb 2005)

• Partial mu agonist, weak kappa antagonist
• Long duration
• Sublingual and buccal use in cats
• Scheduled C-III
• May decrease analgesia from pure mu agonists
  (controversial, may be species dependent)
• Contra indicated in patients on MAOI
• Ceiling effect

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Analgesic Doses

• D 0.005-0.03 mg/kg (IV, SQ, IM)
• C 0.005-0.03 mg/kg (IV, SQ, IM or buccal
• Ferret 0.01-0.05 mg/kg (IV, SQ, IM)
• H 0.004-0.02 mg/kg (IV, SQ, IM)
• Rabbit 0.02-0.05 mg/kg (IV, SQ, IM)
• Rodent 0.1-0.05 mg/kg (IV, SQ, IM)

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Fentanyl (Plumb 2005)

• Pure mu agonist
• CRI or patch
• Class C-II
• Alters amylase and lipase
• Do not combo with MAOI
• Some variation in patch absorption with
  individual and site
• Dosing see pg. 328 Plumb

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Tramadol (Plumb 2005)

• Mu agonist, SSRI, decreases norepinephrin
  reuptake
• Caution with combo in SSRI, MAOI, TCA, SAME,
  digoxin
• Synergistic with NSAIDS
• Naloxone does not fully reverse
• Inexpensive, unscheduled
• Analgesic doses PO D 1-4mg/kg q 8-12
  C 4 mg/kg q 12
• Injectable form available in Europe

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Ketamine (Plumb 2005)

• NMDA receptor antagonist, dissociative anesthetic
  
• Decreases wind up in spinal cord processing of
  pain
• Doses are lower for analgesia than anesthesia
• Adverse effects are less than when used as an
  anesthetic, but still present
• Use as adjunct with narcotics

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Analgesic Doses

• D 0.1-1 mg/kg PO,IM, SQ q 4-6 h CRI 0.1-0.3
  mg/kg h
• C 0.1-1 mg/kg IM,SQ q 4-6 h CRI
  0.1-0.3 mg/kg h
• Exotic Species-little analgesic data extrapolate
  from anesthetic doses
  

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Amantidine (Plumb 2005)

• NMDA receptor antagonist, antiviral
• Oral, inexpensive, gel cap
• Use as an adjunct in pain management (especially
  with opioids, NSAIDS)
• Drug interactions TMS, quinidine, thiazide,
  diuretics, triamterene, CNS stimulants,
  anticholinergics
• Analgesic Doses D 1.25-4 mg/kg PO q 12-24 h,
  C 3 mg/kg PO q 24h

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Dextromethorphan

• NMDA antagonist, SSRI, antitussive
• Conflicting pain data
• Caution mixing with MAOI and SSRI (serotonin
  syndrome)
• Doses Dog 1-2 mg/kg q 12h

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Gabapentin (Plumb 2005)

• Analgesic, anticonvulsant, psychiatric Rx
• Oral, fairly expensive
• Adjunct in management of chronic pain
• Mechanism unknown
• Drug interactions antacids decrease absorption,
  may increase AUC when combined with morphine or
  hydrocodone
• False positive for protein on urine multistix

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Analgesic Dose

• D 3 mg/kg PO q 24 h
• C 3 mg/kg PO q 24 h
• Anectdotal can be used in transdermal prep
  applied to trigger points for fibromyalgia and
  migraines in man

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Amitriptyline (Plumb 2005)

• Tricyclic antidepressant
• Mechanism unclear blocks amine pump (increase
  NE, serotonin), sedation, anticholinergic
• Adjunct in chronic pain, antipuritic
• Caution in patients with seizures, MAOIs,
  glaucoma, thyroid disease, cardiac or metabolic
  disease
• May alter blood glucose levels
• Analgesic Doses D 1-2 mg/kg PO q 12-24h C
  0.5-2 mg/kg PO q 24 h

50
Lidocaine (Marc Raffe personal communication)

• Local anesthetic, CRI useful in analgesia,
  antiarrythmic
• Do not use lidocaine with epinephrine IV
• Cats may be more sensitive to CNS depression
• Emla cream
• Dose CRI Dog 2 mg/kg/hour
• MLK Protocol Morphine 0.1 mg/kg/h, Medetomidine
  1 mcg/kg/h, Lidocaine 2 mg/kg/h, Ketamine 0.2
  mg/kg/h

51
Serotonin Syndrome (ASPCA Poison Control Center
personal communication)

• Causes
• Drugs that increase synthesis (L trytophan
  I-5HT)
• Drugs that increase presynaptic release (MAO
  inhibitors, cocaine, amphetamine)
• Drugs that inhibit uptake into presynaptic
  neurons (SSRI, tricyclics, amphetamine, cocaine,
  dextromethorphan, meperidine)
• Drugs that inhibit metabolism (MAO inhibitors)
• Drugs that act as serotonin agonists (buspirone,
  sumatryptin, LSD)

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Serotonin Syndrome Symptoms

• Myoclonus
• Mental aberration
• Agitation (can also be sedate)
• Hyperreflexia
• Tremors
• Diarrhea
• Atoxia
• Hyperthermia
• Man-3 of above (ASPCA Poison Control Center
  personal communication)

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Serotonin Syndrome Treatment

• Cyproheptadinenon-selective serotonin antagonist
• Dogs 1.1 mg/kg
• Cats 2-4 mg/kg
• Can be given PO or as an enema in saline
• Support (fluids, antidiarrheals, cooling etc.)
• Propranolol if tachycardic (Personal
  Communication ASPCA Poison Control Center)

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Inflammation

• ? NF a, ILI from cells at site
• ? Eselecin on endoth cell
• L selectin on PMN intermittantly binds E P
  selectin on endoth
• PMN rolling on endoth
• Beta 2 CD 11/CD r8 integrin on PMN binds ICAM1
  Icam2 on endoth
• Emigrate PMN through entothelium
• Chemotaxins C5a LT ect help direct emigration

55
A new class of NSAIDs Dual inhibitors(ZUBRIN?)
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Arachidonic Acid Cascade
PL Stimulus ? P1lipaseA2 ?
? AA / \ LOX
/ \ COX /
\ 12HETE, 15HETE, LTA2
PGH2 / \
? /
\ ? ?
? ? ? LTB4 LTC4, LTD4, LTE4 PGE2
PGD2 PGF2a PGI2 TXAa (SRSA)
(PC)
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Prostaglandin Actions(deLeval et al, 2002)

• PG, PC ? Vasodilate
• TXA2 ? vasconstriction
• PC(PGI2) ? ? platelet aggregation
• TXA2 ? ? platelet aggregation
• PG, TX ? ? vascular permeability ? edema
• PG ? contract longitudinal GI muscle, relax
  circular
• PG ? contract uterine smooth muscle
• PG ? ? RBF, stimulate diuress

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Leukotriene Actions(deLeval et al, 2002)

• ? PMN margination
• ? endothelial permeability
• Chemotatic
• ? egress WBC from tissue
• Contract respiratory smooth muscle
• Species variable contraction on GI muscle
• ? acid secretion (rabbit)
• Vasoconstrictive
• Stimulate bone reabsorbtion

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Sources

• COX1
• GI epithelium
• Kidney
• Platelets
• Seminal Vesicles

• COX2
• Endothelial cells
• Monocytes
• Macrophage
• Fibroblast
• Synovial cells
• Chondrocytes

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Leukotriene Sources (deLeval et al, 2002)

• PMNs
• Eosinophiles
• Macrophage
• Reticulocytes
• Mast Cells

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The Old Story COX2 inducible inflammatory COX1
constituative housekeeping

• INFORMATION TO CONSIDER (Papich NAVC, 2004)
• Invitro data for COX1COX2 does not always
  reflect in vivo, species
• Both COX1 and COX2 must be inhibited in man to
  produce analgesia.
• COX2 selective drugs have similar rates of GI
  side effects as non selective.
• Concentration at site of action may be different
  than that of in vitro systems and drug may
  reflect different selectivity at that
  concentration.
• COX2 products are essential for GI ulcer healing.

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Thrombosis (Hennan et al circulation 2001, 104,
820-825)

• COX2 ? PGI2(PC) ? vasodilation and decreased
  platelet aggregation
• COX1 ? TxA2 ? increased aggregation ie COX2
  inhibition may be prothrombotic

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Invitro Selectivity Data

• E.g Carprofen COX1COX2
• 129 (Canine Enzyme system, Rickets et al 1998)
• 1.0 (sheep, rodent, Vane et al, 1995)
• 1.75 (canine macrophate, Kay-Mungford, 2000)
• No effect either COX1 or COX2 (Bryant et al, 2003)

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5-LOX and Leukotrienes

• ? LT when block COX
• (Gilroy et al EurJ Pharmacol, 1998)

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Potential Alternative Mechanism for NSAIDs

• Stimulus ? Cell Membrane
• ?
• Transcription Factor 1kB
• ?
• Nucleus
• ?
• Nuclear Factor Kappa B
• ?
• Gene Transcription
• ?
• Cytokines

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TEPOXALIN
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• Parent drug, LOX inhibition, 3-5 hours
• Active metabalite COX inhibition, 24 hours
• No accumulation
• Reaches therapeutic levels in 1-2 hours in human
  knee
• Feeding enhances absorption
• ODT

68
Site Specific PG Inhibition(Wallace et al
Gastroenterology, 1993)

• PGE2 levels in gastric mucosa, liver blood of
  rats was not decreased.
• PGE2 levels at sites of inflammation were
  decreased.

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• May impact joint pathology positively by ? LT
• 1982 Palmoske and Brandt
• More significant joint lesions in humans on
  chronic high dose COX inhibitors.

70
Other properties of Tepoxalin(deLeval et al,
2002)

• Inhibits IL6 in astrocytes
• Inhibits IL1 in vitro human synovium
• Inhibits Mac1 Eselectin expression
• Inhibits NF kappa beta activation rgene expression

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• PO tepoxalin in man ?? PGE2 and lT in
  osteoarthritis knee (Willburger et al, 1998)
• PO tepoxalin in dogs ?? PGE2 and LT B4 in knee
  model (Schering Plough Data on file)
• PO tepoxalin in rats ? PMN number adherence and
  diapedesis (Kirchner PG, LT and EFA, 1997)

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7 Day Trials

• Zubrin Rimadyl
• n62, improved n60, improved
• Ambulation 92 81
• Weight Bearing 84 80
• Pain on palpation 86 87
• Pain on movement 82 81
• General attitude 88 80
• Owner evaluation 94 92
• DVM evaluation 95 90
• Similar results with Meloxicam Multicenter
  european studies. (World Wide Symposium,
  Technical Monograph)

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28 day Efficacy Study

• 84 of dogs improved
• Incremental benefit if extend 14 ? 28 days
• (Technical Monograph Worldwide Symposium)

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Safety/SIDE EFFECTS
75

• GI
• Direct chemical vs PG medication
• Differential COX2 inhibition
• COX2 products needed for ulcer healing
• LT mediate ulceration
• Renal
• COX2 constituative in kidney
• (Rossa et all, 1999)
• PG mediated ischemic necrosis
• Hepatic
• Any NSAID has potential for idiosyncratic response

76

• Medicolegal
• Monitor bloodwork
• Reminders
• Decrease dose

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VID in 7 day trial

• Tepoxalin vs Carprofen Zubrin vs
  Meloxicam
• dogs with 5.4 7.5 10.3 19.2
• vomiting or
• Diarrhea
• n82 n77 n107
  n99

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SAFETY STUDIES

• 28 days, 32 dogs, up to 300mg/kg ?
• No adverse effects
• No drug accumulation
• 13 weeks, 6 dogs, 100mg/kg ?
• No adverse effects
• 13 weeks, 6 dogs, 300mg/kg ?
• ? protein, albumin, Ca, PCV in 1 dog
• Small pyloric ulcer in 1 dog
• 13 weeks, 6 dogs, 20mg/kg ?
• No adverse effects

79
SAFETY STUDIES 6 Months

• 20mg/kg n8 ? no adverse effects
• 100 mg/kg n8 ? 1 ulcer on gross
• 300 mg/kg n8 ? 3 ulcers

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No chemical change in hepatic or renal
biochemical parameters in any of the above.
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Safety Studies 1 Year

• 100 mg/ml n8 ?
• no renal hepatic or GI toxicity
• 30 mg/kg n8 ?
• no renal hepatic or GI toxicity
• 300 mg/kg n8 ?
• 2 dogs with GI erosions small ulcers
• (World Wide Symposium)

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European Study (World Wide Symposium)

• 9/02 4/03 data, 1294 cases, 134 DVMs
• Acute or chronic musculoskeletal disease
• 10 mg/kg SID x 1-4 weeks
• Questionnaire completed by DVM
• 82 good or excellent response
• Concomitant disease in 23.3
• Adverse events
• 3.9 emesis
• 2.2 diarrhea
• 0.9 anorexia
• 0.6 lethargy
• 0.23 severe event (hemorrhagic diarrhea ect)