Opioid-induced hyperalgesia (OIH) is a paradoxical phenomenon seen with high-dose opioid therapy. Its proposed mechanisms include:

• A Increased mu-receptor expression causing over-stimulation
• B Accumulation of morphine-6-glucuronide causing respiratory depression mistaken for pain
• C Central sensitisation via NMDA receptor activation by dynorphin, anti-opioid peptides, and glial activation; desensitisation of descending inhibitory pathways ✓
• D Peripheral sensitisation from prostaglandin E2 release triggered by opioids

Explanation

OIH is a state of nociceptive sensitisation paradoxically caused by opioid exposure itself, manifesting as increased pain sensitivity despite adequate or escalating opioid doses. Proposed mechanisms include: activation of NMDA receptors by released dynorphin (an endogenous kappa-opioid/NMDA co-activator); downregulation of descending noradrenergic inhibitory pathways; central glial activation releasing pro-nociceptive cytokines (TNF-alpha, IL-1); and mu-receptor uncoupling/desensitisation. OIH is distinguished from tolerance (dose escalation works) by the fact that reducing the opioid dose or rotating to a different opioid actually improves pain. Adding low-dose ketamine (NMDA antagonist) or buprenorphine may help.

Reference: Morgan & Mikhail's Clinical Anesthesiology, 6th ed.

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Written and medically reviewed by the StethoPrep medical team.