Dr Brian Stickle

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Pain
Physiology And Pharmacology

• Dr Brian Stickle
• Consultant Anaesthetist
• Acute Pain Team
• Department of Anaesthesia
• ARI

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Contents

• Physiology of Pain
• Recap
• Pharmacology
• Opiates
• NSAIDs (inc paracetamol)?
• Tramadol
• Modes / routes of drug delivery

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Definition
Pain is an unpleasant sensory and emotional
experience associated with actual or potential
tissue damage or described in terms of such
damage.

• International Association for the Study of Pain
• Implies emotional component.
• Pain can exist without tissue damage.

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Peripheral Modulation of Pain

• Tissue damage
• Release of inflammatory mediators
• Increased blood vessel permeability
• Swelling / Oedema
• Vasodilation
• Redness
• Stimulated inflammatory process
• Immune response white cell activation
• Phagocytosis
• Sensitisation of nerve endings
• Tenderness

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Peripheral modulation of pain
Tissue injury
Blood Vessel
Tissue
PGs, leukotrienes
Oedema
Plasma extravasation
Nerve terminal
Bradykinin
SP NKA CGRP
Mast cell
Spinal cord
Histamine
5HT
platelet
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Spinal ModulationGate Control Theory
Central control
Gate control System
-

Fast fibres touch / pressure

Action System
T
PAIN
SG
-
Slow pain fibres
-

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Descending control

• Motor System
• release of spinal cord reflexes
• loss of tonic descending control hyperreflexia
• Sensory System
• descending inhibitory systems
• stop pain transmission
• loss of inhibition pain
• transmission noradrenaline, 5HT

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Descending control
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Central Modulation of Pain

• Thalamic Gate
• opiates
• Peri-aqueductal grey matter
• opiate gating (? principal site of action)?
• switch on off neurones
• switch off on neurones

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Wind - Up

• Pain input into cord influences pain transmission
• NMDA mediated
• Increased sensitivity and increased transmission
• i.e. pain can be self amplifying

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Pre-emptive analgesia

• Block nociceptive input into cord blocks
  wind-up
• Experimental evidence good
• No evidence in humans
• No good trials in humans (yet)?
• ? How much stimulation required
• Other factors ?

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Analgesic Drugs
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NSAIDs

• Non Steroidal Anti-Inflammatory Drugs
• willow bark - salicin
• Cyclo-oxygenase inhibitors
• Sole therapy for mild/moderate pain
• Combination therapy balanced analgesia

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COX inhibition and NSAIDs

• ? Most likely mechanism for NSAID-mediated
  analgesia.
• Selective COX-2 inhibitors should produce
  analgesia with fewer adverse effects.

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NSAID Side effects

• Respiratory
• aspirin sensitive asthma
• GI
• peptic ulceration stomach duodenum
• Renal
• removes vasodilatory prostaglandins
• precipitate ARF in susceptible Patients
• impaired renal blood flow
• dehydration
• impaired renal function
• other nephrotoxic therapies

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Paracetamol

• The most under-rated drug in the BNF
• Stickle, B.R. 1996 (and loads of times since)?
• Inhibits central COX
• BUT - role of central COX unclear
• Analgesic
• Antipyretic
• No peripheral effects
• No toxicity in therapeutic doses (?)?

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Opiates Sites of action

• Central
• PAGM
• Switch off on cells
• Switch on off cells
• Spinal
• Gating function Inhibits release of
  neurotransmitters involved in pain transmission
• Peripheral
• receptors only active in inflammatory states

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Opiate Side Effects

• Side effects
• Respiratory depression
• antagonised by pain
• all opiates the same at equianalgesic doses
• risk small if properly titrated
• CVS
• vasodilatation, bradycardia, myocardial
  depression
• CNS
• sedation, euphoria, dysphoria, NV, miosis
• GU/GI
• urinary retention, decreased GI motility, spasm
  of sphincter of Oddi

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Tramadol

• Weak µ agonist (1/6000 v morphine)?
• selective µ agonist
• pure agonist activity
• 30 of effect antagonised by naloxone
• Noradrenaline reuptake inhibitor
• 5-HT reuptake inhibitor
• Non-controlled drug

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Descending control
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Tramadol

• Advantages
• lack of respiratory depression
• less sedative vs morphine
• ? less N V
• less GI SFX
• non-controlled drug
• oral preparation effective
• Disadvantages
• slightly less potent vs morphine
• slower onset times
• cost

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Ketamine

• NMDA receptor antagonist
• NMDA receptors shown to have role in development
  of hyperalgesia
• Blockade of NMDA receptors may prevent
  development of opioid tolerance
• Established opioid sparing effect

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Ketamine

• General anaesthetic agent
• Doses typically 1-2mg/kg
• Atypical
• Preserves CVS / resp function
• Airway reflexes / patency generally preserved
• Analgesic
• Bronchodilator
• Famous side effects
• Hallucinations

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Ketamine

• Analgesic at low doses
• 10 of anaesthetic doses
• LOADS of studies
• Cochrane review
• It works
• 30-50 reduction in opiate doses
• Reduced PONV

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Ketamine

• How to give it?
• Single dose ?
• Continuous infusion ?
• Added to PCA X
• Epidurally ? ?

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Ketamine Side effects?

• Doses low
• Tolerability good in all trials
• Reduced PONV pruritis
• Some increased sedation
• Low incidents of hallucination / vivid dreaming

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Ketamine

• Proven adjuvant in opioid tolerance in chronic
  and cancer pain
• Poorly studied in acute pain
• But
• Significant reduction in opioid requirements in
  positive studies
• Anecdotally effective

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Choice of drug(s)?

• Patient Factors
• severity
• site
• patient requirements
• co-existing illness / disease
• available routes
• Other factors
• facilities
• equipment
• staff
• time

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Balanced Analgesia

• Concept of combination therapy
• Advantages
• Reduction in SFX
• minimising doses, synergy
• Improved analgesia
• Disadvantages
• Multiplication of SFX
• Cost
• Polypharmacy

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Balanced Analgesia
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Modes of delivery

• Regular(bd, tds, qds)?
• PRN
• (Patient receives NONE)?
• Slow release
• Infusion
• PCA
• IV, Epidural

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Hierarchical Mx
Increasing Pain severity

• Severe
• NSAIDs
• Tramadol
• Opiates
• PCA
• Epidural

• Mild
• Oral analgesia
• NSAIDs
• Weak opiates

• Moderate
• NSAIDs
• Tramadol
• Opiates
• IM/PCA

Increasing potency combinations
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Balanced analgesia ?
Opiate
Plus
(maybe)?
As required
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Balanced analgesia - really
NSAID Paracetamol
Regularly
And
As required opiate
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Balanced analgesia regimes
Weak Oral Opioid Codeine 30 60 mg 6 hrly
Dihydrocodeine 30mg 6 hrly
Mild pain Minor surgery
All Patients
Adjuvant Analgesic Regular Paracetamol and/or
NSAID
SC, IM or Oral morphine
Mod pain Intermed surgery
PCAS Morphine / Epidural
Severe pain Major surgery
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Routes of delivery

• Oral
• Rectal
• Subcutaneous
• Transdermal
• Intramuscular
• Intravenous
• Epidural
• Intra-spinal

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IM Morphine
Effective Plasma Concentration
Morphine concentration
3 hours
Time
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Intermittent subcut / IM
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PCA Morphine
Effective Plasma Concentration
Morphine concentration
Time
bolus 1mg
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Sustained release oral opiate
Effective Plasma Concentration
Plasma morphine concentration
4
8
12
Time
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Sustained release supplement
Effective Plasma Concentration
Plasma morphine concentration
4
8
12
Time
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?
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Summary

• Pain pathway vulnerable at a number of points
• Peripheral sensitisation primary problem
• Transmission can be modulated spinally and
  centrally
• Combination therapy
• Maximises analgesia
• Minimises side effects

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Local Anaesthesia and Epidural Blocks
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Balanced Analgesia
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Local Anaesthetics

• Lignocaine, bupivacaine, prilocaine.
• Sodium channel blockers
• Pharmacologically filthy !!!
• Prevent propagation of action potential
• LA molecules must pass into axon to block sodium
  channel from within.

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Local anaesthetics
Na
depolarisation
Na
un-ionised ionised
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LA Differential Blockade

• Due to differential penetration into different
  nerve types
• Myelinated, thick fibres Relatively spared
• Motor fibres spared (relatively)?
• Pain fibres blocked easily (luckily)?

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Local anaesthetics

• Limiting factor in use is toxicity
• Toxicity - high plasma levels
• Intravenous injection
• Absorption gt rate of metabolism high plasma
  levels
• ??vasoconstrictors - reduce blood flow, reduce
  absorption.
• Toxicity depends on-
• dose used
• rate of absorption
• patient weight
• drug ( bupivacaine gt lignocaine gt prilocaine )?

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Regional local anaesthesia

• Retain awareness / consciousness
• Lack of global effects of systemic analgesics
• Derangement of CVS physiology
• proportional to size of anaesthetised area
• Relative sparing of respiratory function

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Regional local anaesthesia

• Local anaesthesia
• Field blocks
• hernia repair
• Plexus blocks
• Limb blocks
• e.g. femoral N sciatic N
• Central neural (neuraxial) block
• epidural
• spinal

Increasing physiological impact
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Spinal canal
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Postoperative epidural analgesia

• Proven benefit in certain groups of patients
• ? Proven benefit for certain ops
• High incidence of minor CVS side effects
• Low incidence of major CNS side effects
• Haematoma / abscess

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Epidural advantages

• Gold standard analgesia
• Improved co-operation with physiotherapy /
  nursing staff
• Avoid systemic opiates
• Less sedation
• Less interference with resp function

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Epidural opiates

• Act on spinal cord
• Improve quality of analgesia
• Relative lack of systemic effects
• But-
• Pruritis
• High incidence of respiratory depression when
  combined with systemic opiates.

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Epidural infusions

• Short half life of LA / opiate in epidural space
  (3-4 hours)?
• Repeated top ups
• less stable block
• breakthrough pain
• Infusion
• requires kit
• Rate can be variable (sliding scale)?
• Tachyphlaxis

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Physiology of neuraxial block CVS
Venodilation
MAP CO SVR
Arteriolar vasodilation
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Signs and symptoms of local anaesthetic toxicity

• Circumoral and lingual numbness and tingling
• Light-headedness
• Tinnitus, visual disturbances
• Muscular twitching
• Drowsiness
• Cardiovascular depression
• Convulsions
• Coma
• Cardiorespiratory arrest

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Scenario 1

• 26 y/o asthmatic man
• Appx. Given IM Morphine 10mg 4 hourly. Pain
  scores 3-4

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Scenario 2

• 80 y/o lady. No sig PMH.
• Hemiarthroplasty. No analgesia prescribed.
  Spinal anaesthetic wearing off. Not PU'd.

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Scenario 3

• 56 y/o man. Metastatic lung Ca.
• Pathological femur. IM Nail
• Normally has MXL 150mg

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Scenario 4

• 75 y/o lady. L hemi-colectomy.
• PCA Morphine. Sedated .
• Pain scores 3-4 (when awake !!)?

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Scenario 5

• 65 y/o lady. Longstanding pain in right hip.
• Takes paracetamol occasionally codeine 30mg
  prn.
• Pain worsening recently interfering with daily
  living