Download - Pain Classification and Opioid Physiology
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Pain Classification and Opioid Physiology
A Review
Copyright Dr Andrew Dean
Analgesic LadderAnalgesic Ladder
• Non-Opioid• Non-Opioid + Adjuvant Analgesic• Weak Opioid• Weak Opioid + Adjuvant Analgesic• Strong Opioid• Strong Opioid + Adjuvant Analgesic
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Visceral Pain• Pain from abdominal & thoracic viscera• Deep, squeezing, pressure.• Poorly localised.• Sometimes referred.• Liver, pancreas, lung
Mechanisms of PainMechanisms of Pain
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Mechanisms of PainMechanisms of Pain
Somatic Pain• ‘Nociceptive’• Pain from nerve endings in tissues & bones• Aching, gnawing.• Well localised.• eg Bone Metastases
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Neuropathic Pain• Pain from nerve irritation/damage.• Flashing, sharp, electric, burning.• Often follows nerve pathway.• Plexus pain.
Mechanisms of PainMechanisms of Pain
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Pain Pathway
Receptors
Cortico-Spinal
Peripheral Nerve
Spino-thalamic
5HTNA
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Synapse
SpinalNerve
Peripheral Nerve
Synaptic Cleft
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Synapse
Impulse
Impulse
Depolarisation
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The Busy Gate
Cortico-Spinal
Sympathetic
Other
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Opioid Receptors
MuMu
CaCa2+2+
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Receptors
MuMu
K/CaK/CaTo
Spino-thalamic
tract
Excitatoryreceptors
Inhibitoryreceptors
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Opioid ResponseOpioid Response
Opioidlevel
Opioid Dose
% opioidreceptorbinding
100%
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Opioid ResponseOpioid Response
Opioidlevel
Opioid Dose
% opioidreceptorbinding
100%
Maximumopioid
analgesia
SideEffects
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Opioid Receptor Sites
Receptors
Cortico-Spinal
Peripheral Nerve
Spino-thalamic
5HTNA
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Peripheral Action of Morphine
MuMu
K/CaK/Ca
Nociceptor
Inflammatorycell
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Pain wind up
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Receptors and Channels
AMPA Short depolarisation “Fast” Sharp, pricking pain
NMDA Enhance
depolarisation Greater response to
stimulus Response outlasts
stimulus
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Receptors
MuMu
K/CaK/CaTo
Spino-thalamic
tract
ExcitatoryReceptors
AMPA
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NMDA feedback
K/CaK/CaTo
Spino-thalamic
tract
NMDAreceptors
NMDAreceptors
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Receptor responses
Impulses Impulses
AMPA NMDA
Stimulus Stimulus
Time Time
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Receptor co-operation
AMPANK 1-2
NMDAC-fibre
response
Stimulus number
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NMDA AntagonistsVery weak Paracetamol
Weak Some NSAID’s Methadone Pethidine Valproate Amantidine
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NMDA AntagonistsModerate Ketamine Dextromethorphan
Strong Experimental Lethal
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Opioid ResponseOpioid Response
Opioidlevel
Opioid Dose
% opioidreceptorbinding
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Opioid Receptor Sites
Receptors
Cortico-Spinal
Peripheral Nerve
Spino-thalamic
5HTNA
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Receptors
MuMu
K/CaK/CaTo
Spino-thalamic
tract
ExcitatoryReceptors
AMPA
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Sodium Channels
K/CaK/CaTo
Spino-thalamic
tract
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Receptors
K/CaK/CaTo
Spino-thalamic
tract
3. Receptors next to synapse bind opioids which stop chemical
transmission of impulse
Inhibitoryreceptors
1. Cell body receives
electrical impulse producing
Mu receptor
2. Mu receptors migrate down
nerve cell membrane
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Sodium Channel Blockers• Valproate• Gabapentin• Carbamazepine
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Pain Pathway
Receptors
Cortico-Spinal
Peripheral Nerve
Spino-thalamic
5HTNA
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Paracetamol
Receptors
Cortico-Spinal
Peripheral Nerve
Spino-thalamic
5HTNAParacetamol acts here
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NSAID’s
Receptors
Cortico-Spinal
Peripheral Nerve
Spino-thalamic
5HTNANSAIDs acts here
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Morphine
Receptors
Cortico-Spinal
Peripheral Nerve
Spino-thalamic
5HTNAMorphine acts here
5%
25%
70%
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Dorsal Horn
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Dorsal Horn
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Neuropathic Pain• Has many mechanisms• Therefore illogical to expect one drug to
work every time• Often need combination therapy
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Pain Pathway
Receptors
Cortico-Spinal
Peripheral Nerve
Spino-thalamic
5HTNA
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Opioid Receptors
MuMu
CaCa2+2+
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--
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Opioid ResponseOpioid Response
Opioidlevel
Opioid Dose
% opioidreceptorbinding
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Side Effect ThresholdSide Effect Threshold
Opioidlevel
Opioid Dose
High threshold
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Side Effect ThresholdSide Effect Threshold
Opioidlevel
Opioid Dose
Low threshold
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Methadone• Potent Mu agonist• NMDA receptor activity• No active metabolites
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Methadone• Formulation
– Oral liquid, tablets– Injection, SC, IM, IV
• Not predicable– Large inter-individual variation– 1-2 hours onset, lasts 6-12 hours– t 1/2 <120 hrs, Steady state 2-10 days.
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Methadone• Formulation
– Oral liquid, tablets– Injection, SC, IM, IV
• Not predicable– Large inter-individual variation– 1-2 hours onset, lasts 6-12 hours– t 1/2 <120 hrs, Steady state 2-10 days.
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Opioidlevel
Opioid Dose
Side Effect ThresholdSide Effect Threshold
Morphineside effect threshold
Methadoneside effect threshold
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Methadone Study• Retrospective• Case study - 68 patients• Morphine side effects• Co-analgesics unchanged• Opioid changed to methadone
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Methadone Study
Pain Types Somatic 28 Neuropathic 2 Visceral 11 SV 3 SN 22 SVN 1
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Methadone StudySide Effects• Confusion 20• Drowsiness 34• Hallucinations 13• Nausea 24• Pruritis 2
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Methadone Study
Case study - 68 patientsResolution of adverse effects in 56 (82%)Side effects same or changed in 12
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Morphine/Methadone Conversion
1 1
9
13
23
4
10
1 10
5
10
15
20
25
1 2 3 4 5 6 7 8 9 10 11 12
Conversion ratio
No
Peop
le
Average = 6.34
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Methadone Study
RatiosNeuropathic Pain• Ratio 7.06
Non-Neuropathic Pain• Ratio 5.78
Does this reflect NMDA antagonism?
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Dose RegimenDose Regimen• bd 57• tds 11
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Methadone Study
Conclusions• Methadone is a suitable alternative to
morphine for cancer pain• Suggested ratio Suggested regimen May be better for neuropathic pain
6:1bd
Consider threshold theory