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

“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:

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

(JAVMA 2002:221:215-222)

“Ethical Economics”

Types of Pain

1. Somatic

Skin, musculoskeletal Dull, aching, localizable

2. Visceral

Compression, distension, infiltration of pelvic, abdominal or thoracic organs

May be difficult to localize

3. Neuropathic

Nerve compression, damage infiltration, +/-hyperalgesia

Severe burning or tingling

(Tranquilly, Teton Press)

NMDA Receptor

Pain Pathway

Pain Pathway Continued:

“First Pain” – A-delta, fast

“Second Pain” - C fibers, slow

Dorsal Root Ganglia – contains afferent cell bodies

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 Continued:

3rd order neurons are within:

Medulla Pons Midbrain Thalamus Hypothalamus Cerebral Cortex

Pain Pathway Continued:

Descending inhibitory influences occur within cortex, thalamus, midbrain,

rostral medulla and brain stem.

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

HR, BP, RR, peripheral vasoconstriction

Restless Sedentary hunched Appetite Purring, vocalization Pain scores – VAS & NRS

Pain has negative consequences on healing, morbidity &

mortality.

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

circumstance.

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

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

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

Sites of Drug Intervention in Pain Processing

Inhibit Transduction(peripheral sensitization of nociceptors)

Local anesthetics Opiods NSAIDs Corticosteriods

Inhibit Transmission(impulse conduction)

Local anesthetics Alpha 2 agonists

Modulation of Spinal Pathway(inhibit central sensitization)

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

Inhibit Perception

General anesthetics Opiods Alpha 2 agonists Benzodiazepams Phenothiazines

Epidural

Epidural

Lidocaine Bupivicaine 1 ml/4.5 kg or 1 ml/3.5 kg for abdominal

Morphine Fentanyl Alpha 2 Agonists Buprenorphine

Distal Radial/Ulnar & Median Nerve Block

Articular Blocks - Stifle

Dental Blocks

Intercostal Blocks

CRI’s

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

Transdermal

Fentanyl or lidoderm patches Topical gabapentin Emla cream

Drugs to Consider:

Tramadol Amatidine Dextromethorphan Gabapentin IV lidocaine

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

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)

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 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)

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)

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)

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 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)

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

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)

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

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)

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)

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)

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 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 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

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 entotheliumChemotaxins C5a LT ect help direct emigration

A new class of NSAIDs… Dual inhibitors

(ZUBRIN)

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)

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)

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

PMN’s Eosinophiles Macrophage Reticulocytes Mast Cells

Leukotriene Sources (deLeval et al, 2002)

The Old Story:COX2 inducible inflammatoryCOX1 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)

COX2 PGI2(PC) vasodilation and decreased platelet aggregation

COX1 TxA2 increased aggregation ie COX2 inhibition may be prothrombotic

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

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

Potential Alternative Mechanism for NSAIDs

Stimulus Cell Membrane

Transcription Factor 1kB Nucleus

Nuclear Factor Kappa B Gene Transcription Cytokines

TEPOXALIN

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)

PGE2 levels in gastric mucosa, liver & blood of rats was not decreased.

PGE2 levels at sites of inflammation were decreased.

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)

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

expression

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

Zubrin Rimadyln=62, % improved n=60, % improved

Ambulation 92 81Weight Bearing 84 80Pain on palpation 86 87Pain on movement 82 81General attitude 88 80Owner evaluation 94 92DVM evaluation 95 90

Similar results with Meloxicam Multicenter european studies. (World Wide Symposium, Technical Monograph)

28 day Efficacy Study

84% of dogs improved Incremental benefit if extend 14 28

days(Technical Monograph Worldwide Symposium)

Safety/SIDE EFFECTS

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

Medicolegal Monitor bloodwork Reminders Decrease dose

VID in 7 day trial

Tepoxalin vs Carprofen Zubrin 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

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

20mg/kg n=8 no adverse effects 100 mg/kg n=8 1 ulcer on gross 300 mg/kg n=8 3 ulcers

No chemical change in hepatic or renal biochemical

parameters in any of the above.

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)

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)