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Neuraxial opioids: mechanism

Spinal activity: analgesia produced by agonism of mu-opioid receptors in the grey matter of the dorsal horn of the spinal cord, principally laminae II.

Spinal selectivity: liposolubility is inversely proportional to their spinal selectivity, which is higher for the most water-soluble drug, morphine, than for other more lipophilic drugs, such as fentanyl and sufentanil Lipophilic drugs (Fentanyl) diffuse intravascularly quickly and then reach brainstem via systemic circulation. Hydrophilic drugs (morphine) remain in CSF and circulate with CSF to brainstem receptors over 12-24 hours.

Epidural vs Intrathecal: opioids in the epidural space have farther to diffuse to reach target site. Epidural space contains fat and epidural venous plexus, which can absorb opioids or divert them to systemic circulation, respectively. Therefore, dosing for epidural administration is higher than for intrathecal.

All intrathecally administered opioids can produce brainstem-mediated side effects (euphoria, respiratory depression) due to vascular reabsorption to systemic circulation, but only hydrophilic opioids (morphine) produce these effects via spread within the CSF. This spread can take up to 12 hours to reach brainstem.


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  2. Bernards CM. Understanding the physiology and pharmacology of epidural and intrathecal opioids. Best Pract Res Clin Anaesthesiol. 2002 Dec;16(4):489-505. Link