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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 Pharmacological treatment of
pain
• Periphery-along axons-CNS
• Single treatment/polymodal
• Continuosly/
intermittently
1. Regional ane
2. NSAIDs
3. Opioids
4. NMDA-receptor agonists
5. Alpha-2-receptor agonists
6. Other agents
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 1. Regional anesthesia
• Lidocaine (lignocaine): Xylocain®
• Bupivacaine: Marcain ®
• Tricaine: MS-222®
• Preoperatively and
postoperatively
• Underuse in small species
• Na+channels

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 1. Regional anesthesia cont.
• Sensory, motor and sympathetic nerves
• Duration
– lipid solubility (bupivacaine > 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
– mu> delta> 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® 18
 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 24
 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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Drug Mouse Rat Guinea pig

morphine 2-5 mg/kg SC, 2-5 mg/kg SC 2-5 mg/kg SC

4 hourly 4 hourly 4 hourly

butorphanol 1-2 mg/kg SC 1-2mg/kg SC 2 mg/kg SC

4 hourly 4 hourly

buprenorphine 0.05-0.1 mg/kg SC 8-12 0.01-0.05 mg/kg SC or IV 0.05 mg/kg SC

hourly 0.1-0.25 mg/kg by mouth 8-12 hourly
8-12 hourly

carprofen 5 mg/kg SC or by mouth 5 mg/kg SC or by mouth

24 hourly 24 hourly

ketoprofen 5 mg/kg SC or by mouth

24 hourly

ibuprofen 30 mg/kg by mouth 15 mg/kg by mouth

24 hourly 24 hourly

lidocaine 4 mg/kg or 0.4 ml/kg of a 1% solution

bupivacaine 1-2 mg/kg or 0.4-0.8 ml/kg of a 0.25% solution

amitriptyline 1.2-5 mg/kg SC or IP 1-10 mg/kg SC or IP

3-12 hourly 3-12 hourly

imipramine 2.3 mg/kg SC or IP 10 mg/kg SC or IP

12-24 hourly 12-24 hourly
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 Use of local anaesthetics
1. Topical, local
infiltration, nerve
block
• Skin, eye, ear canal,
epidurally, periost,
2. Reduction of
anesthetic needs
3. Post-operative
analgesia
4. 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

1. For mild-moderate pain

2. Acute and chronic pain
3. When opioids are contraindicated
4. Preemptively before inhalation or
injection anaeshetsia: carprofen
5. In combination with local anaesthetics or
opioids for severe postoperative pain
6. Not in pregnant animals
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 Main use of opioids
1. Preemptive analgesia and sedation
– Before inhalation anesthesia
– Before pentobarbital aneshtesia
– Not before other injectables
2. Intraoperative pain relief (fentanyl)
– With pentobarbital for acute
experiments in pigs
– Pig cardiac protocols
– Rodent anesthesia
– Hypnorm® (fluanisone + fentanyl)
3. 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
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• Local analgesia
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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