1. Opioid Pharmacology : New Insight and Clinical Relevance R4 Yi Seong-Min

2. 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, agonists-antagonists –Natural products, synthetic and semisynthetic compounds, peptides synthesized by neurone and other cell

3. 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

4. Opioid Receptors ( II )

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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