Pain Classification and Opioid Physiology

Copyright Dr Andrew Dean

Pain Classification and Opioid Physiology

A Review


Analgesic LadderAnalgesic Ladder

• Non-Opioid• Non-Opioid + Adjuvant Analgesic• Weak Opioid• Weak Opioid + Adjuvant Analgesic• Strong Opioid• Strong Opioid + Adjuvant Analgesic


Visceral Pain• Pain from abdominal & thoracic viscera• Deep, squeezing, pressure.• Poorly localised.• Sometimes referred.• Liver, pancreas, lung

Mechanisms of PainMechanisms of Pain



Somatic Pain• ‘Nociceptive’• Pain from nerve endings in tissues & bones• Aching, gnawing.• Well localised.• eg Bone Metastases


Neuropathic Pain• Pain from nerve irritation/damage.• Flashing, sharp, electric, burning.• Often follows nerve pathway.• Plexus pain.



Pain Pathway

Receptors

Cortico-Spinal

Peripheral Nerve

Spino-thalamic

5HTNA


Synapse

SpinalNerve

Peripheral Nerve

Synaptic Cleft


Synapse

Impulse

Impulse

Depolarisation


The Busy Gate

Cortico-Spinal

Sympathetic

Other


Opioid Receptors

MuMu

CaCa2+2+

--

----

--


Receptors

MuMu

K/CaK/CaTo

Spino-thalamic

tract

Excitatoryreceptors

Inhibitoryreceptors


Opioid ResponseOpioid Response

Opioidlevel

Opioid Dose

% opioidreceptorbinding

100%



Opioidlevel

Opioid Dose


100%

Maximumopioid

analgesia

SideEffects


Opioid Receptor Sites

Receptors

Cortico-Spinal

Peripheral Nerve

Spino-thalamic

5HTNA


Peripheral Action of Morphine

MuMu

K/CaK/Ca

Nociceptor

Inflammatorycell


Pain wind up


Receptors and Channels

AMPA Short depolarisation “Fast” Sharp, pricking pain

NMDA Enhance

depolarisation Greater response to

stimulus Response outlasts

stimulus


Receptors

MuMu

K/CaK/CaTo

Spino-thalamic

tract

ExcitatoryReceptors

AMPA


NMDA feedback

K/CaK/CaTo

Spino-thalamic

tract

NMDAreceptors

NMDAreceptors


Receptor responses

Impulses Impulses

AMPA NMDA

Stimulus Stimulus

Time Time


Receptor co-operation

AMPANK 1-2

NMDAC-fibre

response

Stimulus number


NMDA AntagonistsVery weak Paracetamol

Weak Some NSAID’s Methadone Pethidine Valproate Amantidine


NMDA AntagonistsModerate Ketamine Dextromethorphan

Strong Experimental Lethal



Opioidlevel

Opioid Dose



Opioid Receptor Sites

Receptors

Cortico-Spinal

Peripheral Nerve

Spino-thalamic

5HTNA


Receptors

MuMu

K/CaK/CaTo

Spino-thalamic

tract

ExcitatoryReceptors

AMPA


Sodium Channels

K/CaK/CaTo

Spino-thalamic

tract


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


Sodium Channel Blockers• Valproate• Gabapentin• Carbamazepine


Pain Pathway

Receptors

Cortico-Spinal

Peripheral Nerve

Spino-thalamic

5HTNA


Paracetamol

Receptors

Cortico-Spinal

Peripheral Nerve

Spino-thalamic

5HTNAParacetamol acts here


NSAID’s

Receptors

Cortico-Spinal

Peripheral Nerve

Spino-thalamic

5HTNANSAIDs acts here


Morphine

Receptors

Cortico-Spinal

Peripheral Nerve

Spino-thalamic

5HTNAMorphine acts here

5%

25%

70%


Dorsal Horn


Neuropathic Pain• Has many mechanisms• Therefore illogical to expect one drug to

work every time• Often need combination therapy


Pain Pathway

Receptors

Cortico-Spinal

Peripheral Nerve

Spino-thalamic

5HTNA


Opioid Receptors

MuMu

CaCa2+2+

--

----

--



Opioidlevel

Opioid Dose



Side Effect ThresholdSide Effect Threshold

Opioidlevel

Opioid Dose

High threshold



Opioidlevel

Opioid Dose

Low threshold


Methadone• Potent Mu agonist• NMDA receptor activity• No active metabolites


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.


Opioidlevel

Opioid Dose


Morphineside effect threshold

Methadoneside effect threshold


Methadone Study• Retrospective• Case study - 68 patients• Morphine side effects• Co-analgesics unchanged• Opioid changed to methadone


Methadone Study

Pain Types Somatic 28 Neuropathic 2 Visceral 11 SV 3 SN 22 SVN 1


Methadone StudySide Effects• Confusion 20• Drowsiness 34• Hallucinations 13• Nausea 24• Pruritis 2


Methadone Study

Case study - 68 patientsResolution of adverse effects in 56 (82%)Side effects same or changed in 12


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


Methadone Study

RatiosNeuropathic Pain• Ratio 7.06

Non-Neuropathic Pain• Ratio 5.78

Does this reflect NMDA antagonism?


Dose RegimenDose Regimen• bd 57• tds 11


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

Pain Classification and Opioid Physiology

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