Opioids

Vivian Imbriotis | June 16, 2026

Opioids are agonists of opioid receptors used for analgesia.

  • These are GPCRs \(\to \ \downarrow\)cAMP \(\to\) open GIRK channels allowing K to flow out of cell \(\to\) hyperpolarize, inhibit L-type Ca channels \(\to\) hyperpolarization, impaired synaptic transmission
  • Different subtypes have different distributions \(\to\) different effects when agonised.
  • \(\mu\): analgesia, miosis, euphoria, pruritis, resp depression, \(\downarrow\)GI motility, urinary retention. Clustered in PAG \(\to\) descending inhibition of nociception.
  • \(\delta\): Analgesia, resp depression
  • \(\kappa\): Miosis, dysphoria, inhibition of ADH release

Sites of analgesia

  • Peripheral nociceptor: decreased firing in response to inflammatory mediators
  • Dorsal horn: decreased presynapic glutamate and substance P release (\(\because\ \downarrow Ca\)) + hyperpolarization of postsynapic membrane (\(\because\ \downarrow K\)) \(\to \ \downarrow\)ascending nociceptive transmission
  • Brainstem: \(\mu\) agonism in PAG, locus ceruleus, rostroventralmedial medulla \(\to\) descending inhibition
  • Cortex + limbic system: euphoria, \(\downarrow\)distress, \(\downarrow\)pain perception

Mechanism of tolerance

  • Continued agonism phosphorylates the receptor
  • \(\beta\)-Arrestins bind, decouple from adenylate cyclase, then endocytose and destroy receptors \(\to\) reduced agonist effect

Mechanism of respiratory depression

  • Agonise \(\mu\)R in Pre-Botzinger Complex of medulla
  • Decreased medullary reaction to hypercapnoea (shifts PaCO2 response curve to the right)
  • Decreased RR and tidal volumes \(\to\ \ \downarrow MV \ \to\) T2 respiratory failure
  • Early (systemic absorption, <2 hours), or late (poorly lipid-soluable intrathecal opioid e.g. morphine migrates to medulla by bulk CSF flow)

Mechanism of constipation

  • \(\mu\) and \(\kappa\) receptors in bowel
  • agonism increases SM tone \(\to\) decreases motility, increases sphincter tone
  • Slow transit \(\to\) Increased water absorption \(\to\) harder stool

Dose: 20mg PO oxy = 10mg IV oxy = 15mg IV morphine = 30mg OMEs

Mechanism: mu opioid agonism \(\to\) neuron hyperpolarizination, including in

Adverse effects: as general opioids (resp depression, constipation, urinary retention, myosis), plus mild crossreactivity at mast cell receptors \(\to\) histamine release \(\to\) vasodilation \(\to\) hypotension

A: 70% OBA (morphine OBA ~30% \(\because\) first pass \(\to\) oral endone more potent\). Intermediate onset.

D: Low lipid solubility. Crosses placenta and breast milk.

M: Interesting

  • 70% by CYP3A4 \(\to\) noroxycodone (less active)
  • 10% by CYP2D6 \(\to\) oxymorphone (much more active)
  • 20% excreted unchanged in urine

E: Metabolites renally excreted

Dose: 100mcg IV fentanyl \(\approx\) 10mg IV morphine

Mechanism: strong opioid agonist.

Adverse effects: As other opioids. No histamine release.

A: 30% oral (\(\because\) first pass), 70% subling/buccal. Rapid onset.

D: high lipid solubility (600x morphine). VdSS 4L/kg. Active uptake into lung \(\to\) sequestration.

M: CYP3A4 \(\to\) inactive.

E: Metabolites eliminated in urine. Bolus duration ~ 5 minutes (\(T_{\frac{1}{2} \alpha} = 2\)min), max CSHT can exceed 5 hours


Dose: Varies. PCA 1-2mg Q5mins. Oral dose = 3x IV dose. Intrathecal 100-300mcg.

Mechanism: strong opioid agonist.

Adverse effects: As other opioids, plus significant crossreactivity at mast cell receptors \(\to\) histamine release \(\to\) vasodilation \(\to\) hypotension; also pruritis.

A: 30% oral (\(\because\) first pass). Intermediate onset (takes ~20 minutes to cross BBB)

D: 3L/kg. Crosses placenta and breast milk. Poor CNS penetration (75% ionized, even unionized form has poor lipid solublity)

M: Glucuronidation (hepatic and renal!)

  • 80% to inactive M3G
  • 10% to more active M6G \(\to\) accumulates

E: Metabolites (active and inactive) eliminated in urine. T1/2 = 3 hours