Analgesia

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 2

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 3

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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 pretreatment with e.g opioids 5

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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 7

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 8

Pharmacological treatment of pain • • •

Periphery-along axons-CNS Single treatment/polymodal Continuosly/ intermittently 1. 2. 3. 4. 5. 6.

Regional ane NSAIDs Opioids NMDA-receptor agonists Alpha-2-receptor agonists Other agents 9

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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 – –

•

Toxicity –

•

lipid solubility (bupivacaine > lidocaine) Adrenaline (1: 200,000): cave appendices convulsions, hypotension, ventricular arrhythmia and myocardial depression

Application –

Local infiltration, mucous membranes, eye, ear, around a nerve, intrapleurally, epidurally 12

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 13

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) 15

3. Opioids cont. – – – – – – –

Morphine Fentanyl: Leptanal®, Hypnorm® Sufentanil Burprenorphine: Temgesic® Sedation PO, SC, IM, IP Side effects: • •

respiratory depression, severe bradycardia, decreased gastric Less from delta agonists

HCl secretion

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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 17

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 19

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 21

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 22

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 23

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 25

Drug delivery • Oral delivery – – – –

Dosing Consumption Degradation NSAIDs • Aspirin • carprofen

– Opioids • buprenorphine

• Parenteral delivery – S/c, i/p, i/v, sublingual, rectal 26

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

ibuprofen

5 mg/kg SC or by mouth 24 hourly 30 mg/kg by mouth 24 hourly

lidocaine

15 mg/kg by mouth 24 hourly 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

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Use of local anaesthetics 1.

Topical, local infiltration, nerve block •

2.

Skin, eye, ear canal, epidurally, periost,

Reduction of anesthetic needs Post-operative analgesia Maximum dose for

3. 4. • •

lidocaine: 4mg/kg bupivacaine: 2mg/kg 28

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Fish anaeshthesia • MS-222 (tricaine)

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Use of NSAIDs 1. 2. 3. 4.

For mild-moderate pain Acute and chronic pain When opioids are contraindicated Preemptively before inhalation or injection anaeshetsia: carprofen 5. In combination with local anaesthetics or opioids for severe postoperative pain 6. Not in pregnant animals 31

Main use of opioids 1.

Preemptive analgesia and sedation – – –

2.

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 –

3.

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 33

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 35

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 36

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