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Explore the complex mechanisms of pain including visceral, somatic, and neuropathic types. Learn about the analgesic ladder, opioid response, receptors, and side effects. Discover the impact of opioids like morphine and methadone in pain management.
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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