Define opioid-induced hyperalgesia and how it may complicate management.

• A. A paradoxical decrease in pain sensitivity due to sustained opioid exposure
• B. Pain relief that increases with higher opioid doses
• C. A paradoxical increase in pain sensitivity due to sustained opioid exposure
• D. Tolerance to analgesia that reduces effect

Answer: (C)

Opioid-induced hyperalgesia is a paradoxical increase in pain sensitivity that develops with sustained or high-dose opioid exposure. Instead of the pain relief you’d expect from more opioid, the person experiences amplified pain or newly heightened sensitivity (including allodynia, where normally non-painful stimuli hurt). This is different from tolerance, where more opioid is needed to achieve the same relief; with hyperalgesia, higher opioid doses can worsen the pain.

Mechanistically, the pain amplification involves central sensitization in the spinal cord, activation of NMDA receptors, and glial-driven neuroinflammation that enhances nociceptive signaling and disrupts normal pain modulation. Clinically, OIH may present as pain spreading beyond the original injury and escalating despite rising opioid doses, which can be mistaken for tolerance.

Managing OIH focuses on reducing the opioid-related contribution to pain and using multimodal strategies. This often means tapering or rotating opioids, avoiding further dose escalation, and adding nonopioid analgesics and adjuvants (such as NSAIDs, acetaminophen, gabapentinoids, antidepressants), regional anesthesia, and nonpharmacologic therapies. NMDA receptor–mediated pathways can be targeted with agents like ketamine; methadone’s NMDA antagonism may help in some cases. Overall, recognizing OIH prevents unnecessary increases in opioid exposure and guides a shift toward strategies that dampen central sensitization while controlling pain.