I: Pain and Analgesics

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I Pain and Analgesics

• Pain an unpleasant sensory and emotional
  experience with actual or potential tissue damage
  or described in terms of such damage
  (International Association for the Study of Pain,
  1979)
• Analgesia absence of pain

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Pain pathways

• Specialized receptors free nerve endings
• Stimulation
• Mechanical damage
• Extreme temperature
• Chemical irritation
• Two types of neurons
• A-delta first pain, sharp
• C second pain, dull
• Four distinct processes
• Transduction, transmission, modulation,
  perception

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Tissue damage

• Release of chemical substances and enzymes
  (mediators) that alter the activity and
  sensitivity of sensory neurons
• Prostaglandins, leukotriens sensitization of
  receptors
• Bradykinin and PGs stimulate the neurons
  directly
• Histamine pain, itching
• Result
• increase in nociceptor activity
• Hyperalgesia
• Neurogenic edema

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Dorsal horn

• Wind-up
• neurotransmittors causing enhanced excitability
  and sensitization of dorsal horn cells
• Persistent changes
• Cause of allodynia (touch becomes pain)
• Prevented by pre-treatment with e.g opioids

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Perception

• Somatosensory cortex, cingulate cortex
• Sensory discrimination
• Emotional response
• fear, anxiety and panic
• subjective experience
• Reticular formation
• Increased arousal
• Emotional response
• Somatic and autonomic motor reflexes
• Induction of biological and behavioural changes

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Perception cont.

• Higher vertebrates
• Anatomical components for perception of pain
• From the last third of embryonic development
• Primitive vertebrates
• Fish, reptiles, amphibians
• avoidance or escape behavior
• poorly developed cerebral cortex

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Pain modulation

• Efferent pathways modify afferent nociceptive
  information
• Motor cortex, hypothalamus, midbrain (PAG),
  medulla (NRM)
• Periphery, spinal cord, supraspinal
• Norepinephrine, serotonin, endorphines,
• GABA, glycin
• Failure of inhibition neuropathic pain

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Pharmacological treatment of pain

• Periphery-along axons-CNS
• Single treatment/polymodal
• Continuosly/
• intermittently
• Regional ane
• NSAIDs
• Opioids
• NMDA-receptor agonists
• Alpha-2-receptor agonists
• Other agents

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1. Regional anesthesia

• Lidocaine (lignocaine) Xylocain
• Bupivacaine Marcain
• Tricaine MS-222
• Preoperatively and postoperatively
• Underuse in small species
• Nachannels

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1. Regional anesthesia cont.

• Sensory, motor and sympathetic nerves
• Duration
• lipid solubility (bupivacaine gt lidocaine)
• Adrenaline (1 200,000) cave appendices
• Toxicity
• convulsions, hypotension, ventricular
  arrhythmia and myocardial depression
• Application
• Local infiltration, mucous membranes, eye, ear,
  around a nerve, intrapleurally, epidurally

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2. NSAIDs

• Non-steroidal anti-inflammatory drugs
• Reduce synthesis of PGs
• Cox inhibitors (cyclooxygenase)
• Diminish nociceptor activation
• Block peripheral sensitization
• Antipyretic
• Anti-hyperalgesic
• No sedation

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2. NSAIDs cont.

• Salicylates (aspirin)
• Ketoprofen Romefen
• Carprofen Rimadyl
• PO, SC, IM
• Gastrointestinal ulceration and renal
  function disturbances,
  embryotoxic, prolong bleeding

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3. Opioids

• Spinal cord
• Decreasing neurotransmitter release
• Blocking postsynaptic receptors
• Activating inhibitory pathways
• Receptor subtypes
• mugt deltagt kappa
• Supraspinal analgesia
• Peripheral analgesia (prevent nociceptor
  sensitization)

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3. Opioids cont.

• Morphine
• Fentanyl Leptanal, Hypnorm
• Sufentanil
• Burprenorphine Temgesic
• Sedation
• PO, SC, IM, IP
• Side effects
• respiratory depression, severe
  bradycardia, decreased gastric HCl
  secretion
• Less from delta agonists

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4. NMDA-receptor antagonists

• Spinal cord receptors
• Repetitive c-fiber activation
• Central hyperalgesia
• Not effective against acute inflammatory pain
• Effective against prolonged inflammatory pain
• Neuropathic and cancer pain
• Abolish the wind-up phenomenon
• Work in synergy with opioids
• Ketamine, tiletamine

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5. Alpha-2-agonists

• Xylaxine Rompun
• Medetomidine Domitor
• Receptors in the spinal cord and brain
• Activated by descending noradrenergic pathways
• Inhibit pre-synaptic calcium influx and
  neurotransmitter release
• IM, SC, IP, IV
• sedation, analgesia, muscle relaxation and
  anxiolysis
• Side effects
• Initial hypertension
• Hypotension
• Bradycardia
• Decreased cardiac output
• Depress insulin release
• Diuresis
• Hypothermia
• Specific antagonist atipamezole
  Antisedan

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6. Other agents

• Sedatives and tranquillizers
• Diazepam, acepromazine, fluanisone
• Relieve anxiety, decrease stress
• Minimal respiratory and cardiovascular effects
• Hypotension, hypothermia
• GABA (enhancement), dopamine (blockade)
• Antagonist (flumazenil)
• SC, IM, IV
• Tricyclic antidepressants
• Amintryptilline

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II Pain management

• Prevention preemptive approach
• Recognition of pain
• Choice of substance
• Drug dose and duration

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Do animals experience pain?

• No direct evidence
• Subtle behavioural responses
• Complex learning to avoid noxious stimuli
• Self-administration of analgesics in chronic pain
  conditions
• Response to analgesics
• Assessment central

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Why treat pain?

• Legal and ethical reason
• Beneficial for the animal
• Beneficial for reserach
• Rapid return to normal function
• A higher survival rate
• Counteract physiological changes
• Thoracic and abdominal pain affect ventilation
• Reduction in food and water consumption

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Recognition of pain

• Prey animals mask pain
• Nocturnal species
• Signs to look for
• General appearance and condition
• Attitude, posture and movements
• Interactions with cage mates
• Reactions to manipulation
• Food and water consumption
• Production of faeces and urine
• Species-typical signs of pain and distress
• Procedure-specific signs

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Pain during anaesthesia

• No consciousness-no pain perception (acute
  experiment)
• Sensory nerve activity and sensitization still
  possible
• Avoid unnecessary postoperative pain!
• Recognition of pain during surgery
• Spontanous movements
• Movemenets in reaction to nociceptive stimulation
• Respiration and puls frequency
• Blood pressure
• Withdrawal reflexes

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Postoperative pain

• Peripheral sensitization
• Central sensitization
• Amplification of pain sensation
• Surgery
• Inflammatory pain
• Neuropathic pain
• Prevention by preemptive analgesia

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Drug delivery

• Oral delivery
• Dosing
• Consumption
• Degradation
• NSAIDs
• Aspirin
• carprofen
• Opioids
• buprenorphine
• Parenteral delivery
• S/c, i/p, i/v, sublingual, rectal

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Use of local anaesthetics

• Topical, local infiltration, nerve block
• Skin, eye, ear canal, epidurally, periost,
• Reduction of anesthetic needs
• Post-operative analgesia
• Maximum dose for
• lidocaine 4mg/kg
• bupivacaine 2mg/kg

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Fish anaeshthesia

• MS-222 (tricaine)

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Use of NSAIDs

• For mild-moderate pain
• Acute and chronic pain
• When opioids are contraindicated
• Preemptively before inhalation or injection
  anaeshetsia carprofen
• In combination with local anaesthetics or opioids
  for severe postoperative pain
• Not in pregnant animals

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Main use of opioids

• Preemptive analgesia and sedation
• Before inhalation anesthesia
• Before pentobarbital aneshtesia
• Not before other injectables
• Intraoperative pain relief (fentanyl)
• With pentobarbital for acute experiments in pigs
• Pig cardiac protocols
• Rodent anesthesia
• Hypnorm (fluanisone fentanyl)
• Postoperative pain relief
• Buprenorphine (Temgesic) after Hypnorm or
  ketamine combinations
• Peak duration after 30min

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Management of postoperative pain

• Preemptive analgesia
• Good surgical technique
• Sterile technique
• Supportive therapy
• Soft food
• Long drinking nipples
• Soft bedding
• Warm environment
• Avoid social isolation

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Management of postoperative pain cont.

• Minor procedures
• single dose of an opioid or NSAID sufficient
  (preoperatively when possible)
• More invasive surgery
• Continue treatment for up to 24-36h
• After major surgery
• Continue analgesic administration for
• 36-72 hours
• Combination therapy
• Opioid
• NSAID
• Local analgesia

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Examples of analgesic treatment

• Implantation of brain canula rat
• Preemptive buprenorphine 0,05mg/kg
• Isoflurane anestesia
• Local infiltration with bupivacaine
• Ovarioectomy mouse
• Ketamine/medetomidine ane
• Buprenorphine towards the end of the procedure

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Examples of analgesic treatment cont.

• Arthrodesis lumbar spine rabbit
• Preemptive carprofen
• EMLA cream ear
• Induction of aneasthesia with propofol
• Maintainance with isoflurane anesthesia
• Local infiltration with bupivacaine
• Buprenorphine before recovery
• Feeding with baby food (carrot, apple)
• Fluids i/v
• Continuation of bup for 24-48h and NSAID for 72
  or more h

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IF MAJOR SURVIVAL SURGERY IS PLANNED- DISCUSS THE
ANAESTHETIC PROTOCOL WITH THE VETERINARIAN IN
CHARGE
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