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Pain Classification and Opioid Physiology. A Review. Analgesic Ladder. Non-Opioid Non-Opioid + Adjuvant Analgesic Weak Opioid Weak Opioid + Adjuvant Analgesic Strong Opioid Strong Opioid + Adjuvant Analgesic. Mechanisms of Pain. Visceral Pain Pain from abdominal & thoracic viscera
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Analgesic Ladder • Non-Opioid • Non-Opioid + Adjuvant Analgesic • Weak Opioid • Weak Opioid + Adjuvant Analgesic • Strong Opioid • Strong Opioid + Adjuvant Analgesic
Mechanisms of Pain Visceral Pain • Pain from abdominal & thoracic viscera • Deep, squeezing, pressure. • Poorly localised. • Sometimes referred. • Liver, pancreas, lung
Mechanisms of Pain Somatic Pain • ‘Nociceptive’ • Pain from nerve endings in tissues & bones • Aching, gnawing. • Well localised. • eg Bone Metastases
Mechanisms of Pain Neuropathic Pain • Pain from nerve irritation/damage. • Flashing, sharp, electric, burning. • Often follows nerve pathway. • Plexus pain.
Pain Pathway NA 5HT Cortico-Spinal Spino-thalamic Receptors Peripheral Nerve
Synapse Peripheral Nerve Spinal Nerve Synaptic Cleft
Synapse Impulse Impulse Depolarisation
The Busy Gate Cortico-Spinal Sympathetic Other Spinothalamic
Opioid Receptors Mu - - Ca2+ - -
Receptors Excitatory receptors Mu To Spino- thalamic tract K/Ca Inhibitory receptors
Opioid Response Opioid level 100% % opioid receptor binding Opioid Dose
Opioid Response Opioid level Side Effects 100% Maximum opioid analgesia % opioid receptor binding Opioid Dose
Opioid Receptor Sites NA 5HT Cortico-Spinal Spino-thalamic Receptors Peripheral Nerve
Peripheral Action of Morphine Nociceptor Mu K/Ca Inflammatory cell
Receptors and Channels AMPA Short depolarisation “Fast” Sharp, pricking pain NMDA Enhance depolarisation Greater response to stimulus Response outlasts stimulus
Receptors Excitatory Receptors AMPA Mu To Spino- thalamic tract K/Ca
NMDA feedback To Spino- thalamic tract K/Ca NMDA receptors NMDA receptors
Receptor responses AMPA NMDA Stimulus Stimulus Impulses Impulses Time Time
Receptor co-operation C-fibre response NMDA NK 1-2 AMPA Stimulus number
NMDA Antagonists Very weak Paracetamol Weak Some NSAID’s Methadone Pethidine Valproate Amantidine
NMDA Antagonists Moderate Ketamine Dextromethorphan Strong Experimental Lethal
Opioid Response Opioid level % opioid receptor binding Opioid Dose
Opioid Receptor Sites NA 5HT Cortico-Spinal Spino-thalamic Receptors Peripheral Nerve
Receptors Excitatory Receptors AMPA Mu To Spino- thalamic tract K/Ca
Sodium Channels To Spino- thalamic tract K/Ca
Receptors 1. Cell body receives electrical impulse producing Mu receptor 3. Receptors next to synapse bind opioids which stop chemical transmission of impulse To Spino- thalamic tract K/Ca 2. Mu receptors migrate down nerve cell membrane Inhibitory receptors
Sodium Channel Blockers • Valproate • Gabapentin • Carbamazepine
Pain Pathway NA 5HT Cortico-Spinal Spino-thalamic Receptors Peripheral Nerve
Paracetamol NA 5HT Paracetamol acts here Cortico-Spinal Spino-thalamic Receptors Peripheral Nerve
NSAID’s NA 5HT NSAIDs acts here Cortico-Spinal Spino-thalamic Receptors Peripheral Nerve
Morphine NA 5HT 25% Morphine acts here Cortico-Spinal Spino-thalamic Receptors 5% 70% Peripheral Nerve
Neuropathic Pain • Has many mechanisms • Therefore illogical to expect one drug to work every time • Often need combination therapy
Pain Pathway NA 5HT Cortico-Spinal Spino-thalamic Receptors Peripheral Nerve
Opioid Receptors Mu - - Ca2+ - -
Opioid Response Opioid level % opioid receptor binding Opioid Dose
Side Effect Threshold High threshold Opioid level Opioid Dose
Side Effect Threshold Opioid level Low threshold Opioid Dose
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.
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.
Side Effect Threshold Methadone side effect threshold Opioid level Morphine side effect threshold Opioid Dose
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 Study Side Effects • Confusion 20 • Drowsiness 34 • Hallucinations 13 • Nausea 24 • Pruritis 2
Methadone Study • Case study - 68 patients • Resolution of adverse effects in 56 (82%) • Side effects same or changed in 12
Morphine/Methadone Conversion Average = 6.34