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, agonists-antagonists– Natural products, synthetic and semisynthetic compounds, p

eptides 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, v

omiting, decreased gastrointestinal motility, tolerance, dependence

-, -opioid receptor agonist– Produce analgesia– Not cause respiratory depression or to decease GI m

otility→ 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 pharmacol

ogic 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 stimu

li, 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 cent

ral 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, uri

nary 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 postoperati

ve 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, electrod

e 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 : m

orphine

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 produc

e 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