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Pain Management. Dr. J.M. Roesner, DVM, DABVP Dr. Vanessa Lee, DVM. Ethics and Economics of Pain Management Pain Pathway and Strategies for Pain Reduction NSAIDS Tepoxalin Parting Thoughts. AVMA Position.

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pain management

Pain Management

Dr. J.M. Roesner, DVM, DABVP

Dr. Vanessa Lee, DVM

slide2
Ethics and Economics of Pain Management
  • Pain Pathway and Strategies for Pain Reduction
  • NSAIDS
  • Tepoxalin
  • Parting Thoughts
avma position
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 2001:218:1694)

untapped market
Untapped Market:

60% or more of DJD dogs are not treated or managed by a DVM.

(JAVMA 2002:221:215-222)

1 somatic
1. Somatic
  • Skin, musculoskeletal
  • Dull, aching, localizable
2 visceral
2. Visceral
  • Compression, distension, infiltration of pelvic, abdominal or thoracic organs
  • May be difficult to localize
3 neuropathic
3. Neuropathic
  • Nerve compression, damage infiltration, +/-hyperalgesia
  • Severe burning or tingling

(Tranquilly, Teton Press)

pain pathway continued
Pain Pathway Continued:

“First Pain” – A-delta, fast

“Second Pain” - C fibers, slow

Dorsal Root Ganglia – contains afferent cell bodies

pain pathway continued13
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

pain pathway continued14
Pain Pathway Continued:

3rd order neurons are within:

  • Medulla
  • Pons
  • Midbrain
  • Thalamus
  • Hypothalamus
  • Cerebral Cortex
pain pathway continued15
Pain Pathway Continued:

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

nociception
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.

pain recognition
Pain Recognition
  •  HR,  BP,  RR, peripheral vasoconstriction
  • Restless
  • Sedentary hunched
  •  Appetite
  • Purring, vocalization
  • Pain scores – VAS & NRS
preemptive analgesia
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
multimodal analgesia
Multimodal Analgesia
  • Synergistic
  • Decreased potential for adverse reactions
  • Effective
  • E.g NSAID   transduction
  • Local Block  stops transmission
  • Opiod and Alpha 2 agonist   modulation
multimodal analgesia22
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
inhibit transduction peripheral sensitization of nociceptors
Inhibit Transduction(peripheral sensitization of nociceptors)
  • Local anesthetics
  • Opiods
  • NSAIDs
  • Corticosteriods
inhibit transmission impulse conduction
Inhibit Transmission(impulse conduction)
  • Local anesthetics
  • Alpha 2 agonists
modulation of spinal pathway inhibit central sensitization
Modulation of Spinal Pathway(inhibit central sensitization)
  • Local anesthetics
  • Opiods
  • Alpha 2 agonists
  • Trycyclic antidepressants
  • Cholinesterase inhibitors
  • NMDA antagonists
  • NSAIDs
  • Anticonvulsants
inhibit perception
Inhibit Perception
  • General anesthetics
  • Opiods
  • Alpha 2 agonists
  • Benzodiazepams
  • Phenothiazines
epidural29
Epidural
  • Lidocaine Bupivicaine 1 ml/4.5 kg or 1 ml/3.5 kg for abdominal
  • Morphine
  • Fentanyl
  • Alpha 2 Agonists
  • Buprenorphine
cri s
CRI’s
  • Can overcome short +/- ½ limitations
  • Morphine, Ketamine, Butorphanol
  • Calculator programs available
transdermal
Transdermal
  • Fentanyl or lidoderm patches
  • Topical gabapentin
  • Emla cream
drugs to consider
Drugs to Consider:
  • Tramadol
  • Amatidine
  • Dextromethorphan
  • Gabapentin
  • IV lidocaine
butorphanol plumb 2005
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)
analgesic doses
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
buprenorphine plumb 2005
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
analgesic doses40
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)
fentanyl plumb 2005
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
tramadol plumb 2005
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
ketamine plumb 2005
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
analgesic doses44
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
amantidine plumb 2005
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
dextromethorphan
Dextromethorphan
  • NMDA antagonist, SSRI, antitussive
  • Conflicting pain data
  • Caution mixing with MAOI and SSRI (serotonin syndrome)
  • Doses: Dog: 1-2 mg/kg q 12h
gabapentin plumb 2005
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
analgesic dose
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
amitriptyline plumb 2005
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
lidocaine marc raffe personal communication
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
serotonin syndrome aspca poison control center personal communication
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)
serotonin syndrome symptoms
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)
serotonin syndrome treatment
Serotonin Syndrome Treatment
  • Cyproheptadine=non-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)
inflammation
Inflammation
  •  NF α, 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

arachidonic acid cascade
Arachidonic Acid Cascade

PL

Stimulus  P1lipaseA2  

AA

/ \

LOX / \ COX

/ \

12HETE, 15HETE, LTA2 PGH2

/ \ 

/\ ¯ ¯ ¯  ¯ ¯ ¯ ¯ ¯ ¯ ¯ ¯ ¯

LTB4 LTC4, LTD4, LTE4 PGE2 PGD2 PGF2α PGI2 TXAα

(SRSA) (“PC”)

prostaglandin actions deleval et al 2002
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
leukotriene actions deleval et al 2002
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
sources
COX1

GI epithelium

Kidney

Platelets

Seminal Vesicles

COX2

Endothelial cells

Monocytes

Macrophage

Fibroblast

Synovial cells

Chondrocytes

Sources
leukotriene sources deleval et al 2002
Leukotriene Sources(deLeval et al, 2002)
  • PMN’s
  • Eosinophiles
  • Macrophage
  • Reticulocytes
  • Mast Cells
the old story cox2 inducible inflammatory cox1 constituative housekeeping
The Old Story:COX2 inducible inflammatory COX1 constituative housekeeping

INFORMATION TO CONSIDER:(Papich NAVC, 2004)

Invitro data for COX1:COX2 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.

thrombosis hennan et al circulation 2001 104 820 825
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
invitro selectivity data
Invitro Selectivity Data
  • E.g Carprofen COX1:COX2 =
    • 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)
5 lox and leukotrienes
5-LOX and Leukotrienes

 LT when block COX

(Gilroy et al EurJ Pharmacol, 1998)

potential alternative mechanism for nsaids
Potential Alternative Mechanism for NSAIDs

Stimulus  Cell Membrane

Transcription Factor 1kB

Nucleus

Nuclear Factor Kappa B

Gene Transcription

Cytokines

slide67
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
site specific pg inhibition wallace et al gastroenterology 1993
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.

slide69
May impact joint pathology positively by  LT
  • 1982 Palmoske and Brandt;

More significant joint lesions in humans on chronic high dose COX inhibitors.

other properties of tepoxalin deleval et al 2002
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
slide71
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)
7 day trials
7 Day Trials

ZubrinRimadyl

n=62, % improved n=60, % 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)

28 day efficacy study
28 day Efficacy Study
  • 84% of dogs improved
  • Incremental benefit if extend 14  28 days

(Technical Monograph Worldwide Symposium)

slide75
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
slide76
Medicolegal
    • Monitor bloodwork
    • Reminders
    • Decrease dose
vid in 7 day trial
VID in 7 day trial

Tepoxalin vs CarprofenZubrin vs Meloxicam

% dogs with 5.4 7.5 10.3 19.2

vomiting or

Diarrhea

n=82 n=77 n=107 n=99

safety studies
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
safety studies 6 months
SAFETY STUDIES: 6 Months
  • 20mg/kg n=8  no adverse effects
  • 100 mg/kg n=8  1 ulcer on gross
  • 300 mg/kg n=8  3 ulcers
safety studies 1 year
Safety Studies: 1 Year
  • 100 mg/ml n=8 
    • no renal hepatic or GI toxicity
  • 30 mg/kg n=8 
    • no renal hepatic or GI toxicity
  • 300 mg/kg n=8 
    • 2 dogs with GI erosions & small ulcers

(World Wide Symposium)

european study world wide symposium
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)