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Pain Management

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Title: 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)

4
Untapped Market
  • 60 or more of DJD dogs are not treated or
    managed by a DVM.
  • (JAVMA 2002221215-222)

5
Ethical Economics
6
Types of Pain
7
1. Somatic
  • Skin, musculoskeletal
  • Dull, aching, localizable

8
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)
10
NMDA Receptor
11
Pain Pathway
12
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

14
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.

16
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.

17
Pain Recognition
  • ? HR, ? BP, ? RR, peripheral vasoconstriction
  • Restless
  • Sedentary hunched
  • ? Appetite
  • Purring, vocalization
  • Pain scores VAS NRS

18
  • Pain has negative consequences on healing,
    morbidity mortality.

19
  • Assume an animal is painful if you would be in a
    similar circumstance.

20
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

21
Multimodal Analgesia
  • Synergistic
  • Decreased potential for adverse reactions
  • Effective
  • E.g NSAID ? ? transduction
  • Local Block ? stops transmission
  • Opiod and Alpha 2 agonist ? ? modulation

22
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

23
Sites of Drug Intervention in Pain Processing
24
Inhibit Transduction(peripheral sensitization of
nociceptors)
  • Local anesthetics
  • Opiods
  • NSAIDs
  • Corticosteriods

25
Inhibit Transmission(impulse conduction)
  • Local anesthetics
  • Alpha 2 agonists

26
Modulation of Spinal Pathway(inhibit central
sensitization)
  • Local anesthetics
  • Opiods
  • Alpha 2 agonists
  • Trycyclic antidepressants
  • Cholinesterase inhibitors
  • NMDA antagonists
  • NSAIDs
  • Anticonvulsants

27
Inhibit Perception
  • General anesthetics
  • Opiods
  • Alpha 2 agonists
  • Benzodiazepams
  • Phenothiazines

28
Epidural
29
Epidural
  • Lidocaine Bupivicaine 1 ml/4.5 kg or 1 ml/3.5 kg
    for abdominal
  • Morphine
  • Fentanyl
  • Alpha 2 Agonists
  • Buprenorphine

30
Distal Radial/Ulnar Median Nerve Block
31
Articular Blocks - Stifle
32
Dental Blocks
33
Intercostal Blocks
34
CRIs
  • Can overcome short /- ½ limitations
  • Morphine, Ketamine, Butorphanol
  • Calculator programs available

35
Transdermal
  • Fentanyl or lidoderm patches
  • Topical gabapentin
  • Emla cream

36
Drugs to Consider
  • Tramadol
  • Amatidine
  • Dextromethorphan
  • Gabapentin
  • IV lidocaine

37
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)

38
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

39
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

40
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)

41
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

42
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

43
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

44
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

45
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

46
Dextromethorphan
  • NMDA antagonist, SSRI, antitussive
  • Conflicting pain data
  • Caution mixing with MAOI and SSRI (serotonin
    syndrome)
  • Doses Dog 1-2 mg/kg q 12h

47
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

48
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

49
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)

52
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)

53
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)

54
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?)
56
Arachidonic Acid Cascade
PL Stimulus ? P1lipaseA2 ?
? AA / \ LOX
/ \ COX /
\ 12HETE, 15HETE, LTA2
PGH2 / \
? /
\ ? ?
? ? ? LTB4 LTC4, LTD4, LTE4 PGE2
PGD2 PGF2a PGI2 TXAa (SRSA)
(PC)
57
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

58
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

59
Sources
  • COX1
  • GI epithelium
  • Kidney
  • Platelets
  • Seminal Vesicles
  • COX2
  • Endothelial cells
  • Monocytes
  • Macrophage
  • Fibroblast
  • Synovial cells
  • Chondrocytes

60
Leukotriene Sources (deLeval et al, 2002)
  • PMNs
  • Eosinophiles
  • Macrophage
  • Reticulocytes
  • Mast Cells

61
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.

62
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

63
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)

64
5-LOX and Leukotrienes
  • ? LT when block COX
  • (Gilroy et al EurJ Pharmacol, 1998)

65
Potential Alternative Mechanism for NSAIDs
  • Stimulus ? Cell Membrane
  • ?
  • Transcription Factor 1kB
  • ?
  • Nucleus
  • ?
  • Nuclear Factor Kappa B
  • ?
  • Gene Transcription
  • ?
  • Cytokines

66
TEPOXALIN
67
  • 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.

69
  • 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

71
  • 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)

72
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)

73
28 day Efficacy Study
  • 84 of dogs improved
  • Incremental benefit if extend 14 ? 28 days
  • (Technical Monograph Worldwide Symposium)

74
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

77
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

78
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

80
No chemical change in hepatic or renal
biochemical parameters in any of the above.
81
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)

82
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)
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