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Opioid Pharmacology : New Insight and Clinical Relevance R4 Yi Seong-Min • Opioid – Compound with morphine-like activity • Opiate – Substance extracted from opium – Exudate of seed pod of Papaver somniferum – True opiate – morphine, codeine • Mordern definition of opioid – Molecule that interact with opioid receptor • Opioid compound – Opioid receptor agoninsts, antagonists, agonistsantagonists – Natural products, synthetic and semisynthetic compounds, peptides synthesized by neurone and other cell Opioid Receptors ( I ) • Five classes of opioid receptor – , , , , receptor • Subtype of , , receptor • Structural characteristics – Typical G-protein-coupled receptor • • • • • Seven hydrophobic region Three intracellular loops Three extracellular loops Intracellular carboxy-terminal tail Extracellular amino-terminal tail Opioid Receptors ( II ) Opioid Receptors ( III ) • Most of available opioid analgesics – Act at -opioid receptor • Activation of -opioid receptor → analgesia, euphoria, respiratory depress, nausea, vomiting, decreased gastrointestinal motility, tolerance, dependence • -, -opioid receptor agonist – Produce analgesia – Not cause respiratory depression or to decease GI motility → Analgesia without -opioid side effect Opioid Receptors ( IV ) • -opioid receptor agonist – Produce dysphoria and hallucination – Focus • Not cross BBB, act only at pph -opioid receptor • Morphine – , , receptor activation • Fentanyl, sufentanyl – More selective -receptor agonist – High effective analgesia Endogenous Opioid Peptides • Pain modulation in brain – Endogenous Opioid Peptide : opioid-like pharmacologic activity • Cleaved from three primary precursor protein ( proopiomelanocortin, proenkephalin, prodynorphine) • Methionine-enkephalin and leucine-enkephalin Cellular Action of opioid • Opioid action on neuron – Presynaptic nerve terminal • Inhibit voltage-sensitive calcium channel → inhibit release neurotransmitter ( substance P and glutamate) – Postsynaptic neuron • Opening potassium channel → hyperpolarize Anatomic Site of Opioid Actions ( I ) • Opioid receptor – In ascending pain pathway • pph. nerve terminal, dorsal horn of spinal cord, thalamus ※ dorsal horn of spina cord opioid agonist – 1. inhibit release of excitatory neurotransmitter from primary afferent neuron 2. Directly inhibit second-order pain transmission neuron Anatomic Site of Opioid Actions ( II ) • Opioid receptor – In descending pain-modulating pathway • Midbrain periaqueductal gray area, rostral ventromedial medulla, locus ceruleus • Opioid : activate descending pathway by inhibiting inhibitory interneurons →inhibit spinal pain transmisssion Clincal Use of Opioid • Adjunct to general anesthesia – Reduce hemodynamic response to intubation and surgical stimuli, amount of general anesthetic agent, coughing on emergence – Analgesia during early postoperative period • High risk case – High dose opioid anesthesia ∵ not decrease myocardial contractility • Opioid as analgegics – Systemically, epidurally, intrathecally apply – Moderate to severe acute pain, chronic cancer pain – Not recommended for chronic benign pain ∵ tolerance and dependence Opioid Side Effect ( I ) • Respiratory depression – Most dangerous opioid side effect – Brain stem respiratory control mechanism : inhibited – Increased in arterial carbon dioxide pressure • Caused by decreased respiratory rate, decreased tidal volume • Nausea and vomiting Opioid Side Effect ( II ) • Constipation – Direct action on local enteric nerve system and effect on central nerve system in large intestine → resting tone increase, and propulsive peristaltic wave decrease → increase absorption of water from feces → constipation • Other side effect – Euphoria, sedation, miosis, truncal rigidity, biliary spasm, urinary retention, tolerance, dependence Tolerance and Dependence ( I ) • Opioid dependence – 1. Tolerance to analgesic or side effect of opioid 2. Specific withdrawal or abstinence syndrome resulting from physiologic dependence 3. Craving for drug from psychological dependence • Interaction between pain and opioid tolerance – Not develop tolerance for active, ongoing pain – Tolerant to analgesic effect for new pain, such as postoperative pain Tolerance and Dependence ( II ) • Repeated administration → lead to physiologic dependence → result in withdrawal or abstinence syndrome – Management • Careful tapering of drug with mild symptom ※ administration opioid antagonist undergeneral anesthesia – Controversial method • Addiction – For painful medical condition → very low iatrogenic addiction risk New Routes of Administration of Opioid ( I ) • Oral, IM, SC, IV, epidural, intrathecal, transdermal, transmucosal route • Intranasal route – – – – Dry power or dissolved in water or saline Preoperative sedation in children Well tolerated, not irritating Intranasal diamorphine • More acceptable than IM morphine • Time to maximum plasma concentration : less than 5 minutes – Meperidine • Bitter burning taste in 20% of patients New Routes of Administration of Opioid ( II ) • Iontophoresis – Alternative to transdermal administration – In past, limitation • Hydrolysis of water, generation of hydrogen ions →decrease drug delivery rate, tissue acidosis and burn, electrode dissolution – Advantage over transdermal administration • Overcome prolonged time required for activity ( 120 minutes vs. 14 hours ) • Rapid offset of opioid action • Delivery rate : adjusted • Allow delivery of drug that cannot be absorbed transdermally : morphine Newer Opioid Analgesics ( I ) • Remifentanil – -opioid receptor agonist – Ester side chain • Necessary for opioid activity • Hydrolysis by esterases – Short elimination half-life : 9.5 minutes – Rapid equilibrate between central compartment and action site – Terminated by metabolism – Blood concentration • Related linearly to infusion rate • Unrelated to duration of infusion – Pharmacokinetics • Not altered by liver dis., renal dis., pseudocholinesterase deficiency Newer Opioid Analgesics ( II ) • Tramadol – Analgesic action mechanism • Not fully understood • Weak affinity for -opioid receptor • Inhibition of norepinephrine reuptake → 2-adrenoreceptor activation → act synergistically with tramadol’s opioid receptor activation → analgesia – Advantage • Less respiratory depression, nausea, vomiting, constipation • Rapid psychomotor recovery – Moderate pain treatment : as effective as morphine – Severe pain treatment : less effective than morphine Peripherally Acting Opioid • Opioid receptor – outside central nerve system – Peripherally acting opioid agonist → analgesia without CNS side effect • Loperamide – – – – -opioid receptor agonist Not cross blood-brain barrier Treatment : inflammation-induced hyperalgesia Relieve diarrhea • Peripherally acting opioid antagonist ( methylnaltrexone ) – Systemically administered opioid agonist → reverse pph. side effect Opioid Interactions with Other Analgesics • Goal of using analgesics in combination – Achieve superior analgesia – Reduce dose of each drug – Minimizing side effect • NSAID – Synergistical action with systemic opioid to produce analgesia • Local anesthetics and opioid – Synergistical pain relief when intrathecal or epidural administration Opioid and Neuropathic Pain • Neuropathic pain – Less responsive to opioid than other pain – Opioid resistance of neuropathic pain • Mechanism : not completely clear – Cholecystokinin and dysnorphine • Antiopioid activity • Increase in spinal cord or dorsal root ganglion • Ch. benign pain patient – Cholecystokinin antagonist proglumide → enhance analgesic activity of opioid