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I: Pain and Analgesics:

1 I: Pain and Analgesi cs 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

Pain pathways:

2 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

Tissue damage:

3 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:

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

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

Perception cont.:

8 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

Pharmacological treatment of pain:

9 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:

11 1. Regional anesthesia Lidocaine (lignocaine): Xylocain® Bupivacaine: Marcain ® Tricaine: MS-222® Preoperatively and postoperatively Underuse in small species Na + channels

1. Regional anesthesia cont.:

12 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 1. Regional anesthesia cont.

2. NSAIDs:

13 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

2. NSAIDs cont.:

14 Salicylates (aspirin) Ke toprofen: Romefen® Carprofen: Rimadyl ® PO, SC, IM Gastrointestinal ulceration and renal function disturbances, embryotoxic, prolong bleeding 2. NSAIDs cont.

3. Opioids:

15 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)

3. Opioids cont.:

16 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 3. Opioids cont.

4. NMDA-receptor antagonists:

17 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

5. Alpha-2-agonists :

18 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® 5. Alpha-2-agonists

6. Other agents:

19 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

II: Pain management:

20 II: Pain management Prevention: preemptive approach Recognition of pain Choice of substance Drug dose and duration

Do animals experience pain?:

21 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

Why treat pain?:

22 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

Recognition of pain:

23 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

Pain during anaesthesia:

24 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

Postoperative pain:

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

Drug delivery:

26 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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27 Drug Mouse Rat Guinea pig morphine 2-5 mg/kg SC, 4 hourly 2-5 mg/kg SC 4 hourly 2-5 mg/kg SC 4 hourly butorphanol 1-2 mg/kg SC 4 hourly 1-2mg/kg SC 4 hourly 2 mg/kg SC buprenorphine 0.05-0.1 mg/kg SC 8-12 hourly 0.01-0.05 mg/kg SC or IV 0.1-0.25 mg/kg by mouth 8-12 hourly 0.05 mg/kg SC 8-12 hourly carprofen 5 mg/kg SC or by mouth 24 hourly 5 mg/kg SC or by mouth 24 hourly ketoprofen 5 mg/kg SC or by mouth 24 hourly ibuprofen 30 mg/kg by mouth 24 hourly 15 mg/kg by mouth 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 3-12 hourly 1-10 mg/kg SC or IP 3-12 hourly imipramine 2.3 mg/kg SC or IP 12-24 hourly 10 mg/kg SC or IP 12-24 hourly

Use of local anaesthetics:

28 U se 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:

30 Fish anaeshthesia MS-222 (tricaine)

Use of NSAIDs:

31 U se 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

Main use of opioids:

32 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

Management of postoperative pain:

33 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

Management of postoperative pain cont. :

34 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 Management of postoperative pain cont.

Examples of analgesic treatment:

35 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

Examples of analgesic treatment cont. :

36 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 Examples of analgesic treatment cont.

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