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W H AT ’ S N E W I N A N E S T H E S I A / A N A L G E S I A ?

LY S A P A M P O S N E R , D V M , D A C V A A

P R O F E S S O R O F A N E S T H E S I O L O G Y

1 - 2 0 1 8

CREDIBILITY FACTOR?

BS   Biochemistry DVM 8 yrs

DACVAA Faculty 2005Faculty

Anesthesiology Residency

PLAN?

• Introduce new products

• Introduce new ways to use established products

A N A LG E S I C S

R E V I E W O F PA I N PAT H W AY

CLASSIC 3-NEURON CHAIN MODEL OF NOCICEPTIVE PROCESSING (SOMATIC)

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Ganong; physiology

PERIPHERAL SENSITIZATION

CENTRAL SENSITIZATION / WIND-UP

• Dorsal horn of the spinal cord• Extreme or repeated activation• Mediated by glutamate

• Results in– Decreased threshold

– Expansion of receptive field

– Increased spontaneous firing

– Hyperalgesia/allodynia

– Spontaneous pain

PERCEPTION

• Must reach cortex to be perceived as pain

• If patient is unconscious/ anesthetized, they won’t “feel” pain but the entire pathway may be activated

• When consciousness returns, pain pathway will be in full activation

– With less descending modulation

L O C A L A N E S T H E T I C S

LOCAL ANESTHETICS

– Mechanism of action

• Sodium channels propagate action potential

• Local anesthetics block sodium channel

– Routes of administration

• Perineural

• IV

• Dermal

– Species Differences

• Sensitivity to toxicity

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LOCAL ANESTHETIC UPDATES: LIDOCAINE PATCHES

• Lidocaine Patches

– Little to no systemic absorption (dogs/cats)

– CAN be cut to size/area wanted

– Should be replaced daily

– Potential uses

• IVDD, bone pain, inflammatory

LOCAL ANESTHETIC UPDATES: LIDOCAINE CRI IN DOGS

• IV lidocaine in DOGS

• Systemic analgesia

• Antiinflammatory

• GI Prokinetic

• Dose of IV lidocaine in dogs:

– Loading: 1.0 mg/kg

– CRI: 25 mcg/kg/min

LOCAL ANESTHETIC UPDATE: NOCITA

• Long acting local anesthetic– Extended-release bupivacaine technology

– Multivesicular liposomes

• 72 hr duration

• Labeled for dogs following CCL surgery

• Dosage – 5.3 mg/kg (0.4 mL/kg)

– Infiltration injection into the tissue layers

• No data on perineural administration

– At the time of incisional closure

• Very effective

• Expensive

• Short shelf life once opened– Labeled for 4 hr once opened

LOCAL ANESTHETIC UPDATE: NOCITA

• Off label use

– Amputations

– Orthopedics (besided CCL)

– Soft tissue procedures

– Cats

• Caution?

– Infected wounds

– Patients with immune disturbances

N M D A A N TA G O N I S T S

DISSOCIATIVE ANESTHETICSK E TA M I N E / T I L E TA M I N E / P H E N C Y C L I D I N EA M A N TA D I N E

•NMDA (N-methyl-D-aspartate) antagonists

–NMDA receptors are excitatory receptors

•Dissociative anesthetic

–Thalamo-cortical and limbic systems

–Altered consciousness (at anesthetic doses)

–Catalepsy (at anesthetic doses)

–Amnesia (at anesthetic doses)

–Analgesia –at subanesthetic doses

•Ketamine

–Approved for use in cats and primates

•Tiletamine (part of the combination Telazol)

–Telazol approved for cats and dogs

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NMDA RECEPTOR ANTAGONISTS PAIN PATHWAYDORSAL HORN OF SPINAL CORD

• Dorsal horn of spinal cord

– Opioid receptors

– Alpha-2 receptors

– NMDA receptors

• Central sensitization

– Wind-up pain

NMDA ANTAGONISTS

• Mechanism of action– Antagonize activation of NMDA receptor

with glutamate at dorsal horn of spinal cord

– With extended inactivation can interrupt central sensitization

• >24 hr (days? weeks?)

– Ketamine, amantadine

– Chronic pain/ wounds/ burns

– Amputations

DISSOCIATIVES: WHAT’S NEW?

•At least 24 hr CRI needed to “break” windup cycle (in humans)

– Unclear how long dogs/cats

– Induction dose unlikely enough

• Injectable ketamine CRI

– At least 24 hr is recommended to alter/ prevent windup

•Oral amantadine

– At least 2-3 week trial

– Can use with NSAIDs, gabapentin, opioids, etc

NMDA ANTAGONISTS

• Ketamine: side effects– Anesthetic doses

• 5mg/kg induction dose

• Increased CV work

• Hallucinations/ behavioral effects

– Analgesic doses—few side effects• 5-10 mcg/kg/min (ketamine)

• Amantadine: side effects– Not reported

• 3-5mg/kg PO SID

C A L C I U M C H A N N E L B L O C K E R S

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CALCIUM CHANNEL BLOCKERS GABAPENTIN

• Mechanism of action

– Binds α2δ subunit-voltage gated calcium channels

• Upregulated in pain states

– May (?) interacts with NMDA receptors, protein kinase C, inflammatory cytokines

CALCIUM CHANNEL BLOCKERS (GABAPENTIN)• Side effects

– Somnolence

• Decreases with time

– Humans

• Rapid withdrawal associated with seizure risk

• Species Differences

– Administered in many species

– Little adverse effects

– Unknown dosing ideals

T R V P 1 R E C E P T O R A G O N I S T S

TRPVI RECEPTOR AGONISTS

• Mechanism of Action– Calcium channels

– Activated by

• Heat

• H+

• Capsaicin

• Resiniferatoxin (RTX)

– More on c-fibers (?)

• “burning, itching, stinging” sensation

– Activate then desensitize nerve

TRPVI RECEPTOR AGONISTS

• Side effects

– First must “activate” then desensitize receptor

– Tingling up to pain

– Some treatments require anesthesia

A N E S T H ET I C S

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N E U R O S T E R O I D SA L F A X A L O N E

NEUROSTEROIDS: ALFAXALONE

•GABA is the primary inhibitory neurotransmitter

•Binds to specific site on GABA receptor– GABA enhancer/ agonist

•Structurally similar to steroids

–Does not bind to sex hormone, glucocorticoid or mineralocorticoid receptors

ALFAXALONENEUROSTEROID STRUCTURE

PROGESTERONE ALFAXALONE

NEUROSTEROIDS & VETERINARY MEDICINE

• Saffan

– Alfaxalone and alfadolone (3:1)

– Clinical trials and marketed in UK

– Hard to dissolve in water-based solutions

• Solubilized in Cremophor

– Reports from 1974 & 1980

• Allergic reactions (69% of cats!)

– Ear swelling to anaphylaxis

• Many dogs died from anaphylaxis

ALFAXAN®

ALFAXALONE

•Alfaxalone only

–Difficult to dissolve in water based solution

•Cyclodextrin ring

–Water soluble delivery

•Approved in USA

–Schedule IV controlled drug (USA)

–Labeled for dogs and cats, IV use

•Clear solution

–< 6 hr once opened

ALFAXALONE: DOSE AND SAFETY

DOGS

•~2mg/kg IV

•> 10 weeks age

•C-sections

•Safety at 10 x dose

CATS

•4-5 mg/kg IV

•> 4 weeks age

•C-sections

•Safety with 5x dose

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ALFAXALONE: PHYSIOLOGIC EFFECTS

•CV– CV depression similar or better than propofol

•Respiratory– Depression to apnea

•Analgesia– No analgesia

•Metabolism– Liver metabolism

ALFAXALONE: MISCELLANEOUS

• Induction and recovery not as smooth as propofol– Particularly as a solo agent

• Head bob, uncoordinated gait

• Does not cause tissue reaction if administered outside of vein or SQ– Product literature and Heit 2004

• Can us as a CRI (constant rate infusion)

• More expensive that propofol in USA

ALFAXALONE: WHAT'S NEW?

• Off Label Use– IM administration for sedation

– Not labeled for in USA, but is in Australia

– Volume is the limiting factor

– Dose

– Dogs: ~ 1 mg/kg (with opioid or midazolam)

– Cats: ~ 1-2 mg/kg (with opioid or midazolam)

• Indication– e.g. Fractious animal with CV disease

– e.g. Echo without dexmedetomidine/ketamine

ALFAXALONE: WHAT'S NEW?

• Off label, published, use in other species

– Ferrets

– Rabbits

– Turtles

– Reptiles

– Fish by immersion

QUESTIONS ON ALFAXALONE?

ET O M I D AT E

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ETOMIDATE

•Ultrashort non-barbiturate (imidazole compound)– Introduced in human anesthesia 1972

• Not approved for use in veterinary species

•Not scheduled in USA

•Propylene glycol vehicle (35%)– Long shelf life

– Pain on injection

– Can cause hemolysis with CRI

ETOMIDATE

• CV– NO CV EFFECTS

• HR, BP, SVR, CO

• CNS Effects– GABA enhancer

• Respiratory– Moderate depression

• Metabolism– Liver metabolism (+ propylene glycol)

• Decreases adrenal gland hormones

ETOMIDATE: ENDOCRINE EFFECTS

• Decreased adrenocortical activity – lasts, 2 - 6 hr

•Inhibits 11-B hydroxylase – cholesterol to cortisol

• Decreased adrenal stress response

•Multiple doses / CRI– hypoadrenocorticism

– +/- death (dogs and humans)

ETOMIDATE: MISCELLANEOUS

• Poor muscle relaxation

– Muscle rigidity, myoclonus, vocalization, opisthotonus

– Administer with muscle relaxant (e.g. benzodiazepine)

• Emesis

• Expensive (2015) (~ $5/ml)

– 4kg cat ~ $12.00

– 40kg dog ~ $100.00

WHAT’S NEW: ETOMIDATE?

• Available

• Non scheduled

• Fills particular patient needs Q U E S T I O N S ?