A patient on chronic high-dose opioids for cancer pain is switched from morphine to methadone due to opioid-induced hyperalgesia (OIH). The mechanism of OIH involves:

• A Down-regulation of mu-opioid receptors on peripheral nociceptors, requiring higher doses to achieve the same analgesic effect
• B Opioid-induced upregulation of substance P receptors in the dorsal horn, increasing nociceptive transmission
• C Increased prostaglandin E2 synthesis by activated opioid receptors on spinal cord microglia
• D Opioid metabolite (morphine-3-glucuronide) and NMDA receptor sensitisation leading to central sensitisation and paradoxical pain amplification ✓

Explanation

Opioid-induced hyperalgesia is a paradoxical state where prolonged opioid use sensitises nociceptive pathways, lowering the pain threshold. The major mechanisms include: (1) accumulation of morphine-3-glucuronide (M3G — an inactive metabolite at mu receptors that is an NMDA receptor antagonist-reversal ligand activating anti-analgesic spinal pathways); and (2) opioid-driven glutamate-NMDA receptor sensitisation, activation of spinal dynorphin (which releases calcitonin gene-related peptide), and glial activation. Methadone is preferred because it is a concurrent NMDA receptor antagonist (blocking OIH) in addition to being a mu-opioid agonist. mu-receptor downregulation causes tolerance, not OIH.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.