Opioid Analgesics BMS2047 20-21 PDF

www.pbs.org Analgesics DR SARAH TRINDER [email protected] Outline What is pain? Nociceptive pathways Endogenous modulation of nociceptive pathways Pharmacological modulation of nociceptive pathways Pain ▪Subjective experience ▪Direct response to untoward event associated with tissue damage ▪Noc...

www.pbs.org Analgesics DR SARAH TRINDER [email protected] Outline What is pain? Nociceptive pathways Endogenous modulation of nociceptive pathways Pharmacological modulation of nociceptive pathways Pain ▪Subjective experience ▪Direct response to untoward event associated with tissue damage ▪Nociception – perception of noxious stimuli ▪Analgesics - ↓ distress associated with pain, not just antinociceptive www.menshealth.com Types of pain ▪Acute – excessive noxious stimulus → intense & unpleasant sensation ▪Chronic – aberrations of the normal physiological pathway → ▪ Hyperalgesia - ↑ pain but mild noxious stimulus ▪ Allodyria – pain evoked by non-noxious stimulus ▪ Spontaneous pain – no stimulus www.menshealth.com Nociceptive afferent pathway ▪Pain – impulse activity in small ø primary afferent fibres of peripheral nerves ▪ C and Aδ ▪ Have sensory endings ▪C fibres (unmyelinated) – polymodal nociceptive endings ▪ Convey dull diffuse burning pain ▪Aδ (myelinated) – convey sharp, well localised pain C fibre Aδ fibre Activation of nociceptive neurons From Rang & Dale’s Pharmacology 8th Ed. Dorsal horn Peripheral nerve terminal Nerve to brain ATP? Excitation Depolarisation Bradykinin Prostaglandin Inflammation SP Excitation Glu CGRP 5-HT SP – substance P CGRP – calcitonin gene-related peptide Modulation in the nociceptive pathway From Rang & Dale’s Pharmacology 8th Ed. Transmission of pain to higher centres Descending inhibitory controls A – amygdala IC – insular cortex H - hypothalamus PAG – periaqueductal grey RVM – rostroventral medulla SG – substantia gelantinosa From Rang & Dale’s Pharmacology 8th Ed. Analgesic drugs opioids Analgesic drugs ▪Opium – extract from poppy juice ▪ Contains morphine ▪Opioid receptors ▪ 4 receptors – μ, δ, κ & ORL ▪ All Gi/o ▪ Widely distributed in brain, spinal cord & peripheral sensory neurons ▪Endogenous ligands – endorphins www.pbs.org Mechanism of action 5HT/enkephalin neuron Neuron transmitting pain to brain Glu & SP Neuron from periphery Enkephalins Morphine ▪CNS ▪ Analgesia ▪ Euphoria ▪ Respiratory depression ▪ Depression of cough reflex ▪ Nausea & vomiting ▪ Pupillary constriction ▪GI tract ▪Other actions Tolerance & dependence ▪Tolerance ▪ ↑ed dose required to produce given pharmacological effect ▪ Drug rotation ▪ In part due to desensitisation of μ ▪Physical dependence ▪ When withdrawal causes adverse physiological effects ▪ Irritability & aggression ▪ Shakes & writhing ▪Codeine, tramadol, buprenorphine less likely to cause physical & psychological dependence Neuropathic pain ▪Neurological disease ▪ Unrelated to peripheral tissue injury ▪Associated with – ▪ Stroke, multiple sclerosis, peripheral diabetic neuropathy, shingles ▪Pathophysiology poorly understood ▪ What could it be due to? ▪Little response to conventional analgesics ▪ Opioid resistant? ▪ Analgesia vs side effects ▪ Unconventional analgesics? ▪ Antidepressants– downregulate α-adrenoceptors? ▪ Antiepileptics – reduced neuronal transmission Learning objectives ▪Describe and explain nociceptive pathways ▪Discuss endogenous modulation of nociceptive pathways ▪Discuss pharmacological modulation of nociceptive pathways