Opioid-induced hyperalgesia: pathophysiology and clinical implications

J Opioid Manag. 2008 May-Jun;4(3):123-30. doi: 10.5055/jom.2008.0017.


Background: Opioid-induced hyperalgesia (OIH) refers to a phenomenon whereby opioid administration results in a lowering of pain threshold, clinically manifest as apparent opioid tolerance, worsening pain despite accelerating opioid doses, and abnormal pain symptoms such as allodynia.

Aim: The current review, while providing a clinically oriented updated overview on the pathophysiology of OIH, focuses predominantly on evidence-based clinical and management aspects of this important and often baffling phenomenon.

Method: Online and manual search using key words such as opioid-induced hyperalgesia, opioid-induced abnormal pain sensitivity, opioid hyperalgesia, opioid-induced paradoxical pain, or opioid-induced abnormal pain, followed by full-text access and further crossreferencing.

Results: The underlying pathophysiology of this phenomenon, although still unclear, appears to be related to an opioid-induced imbalance between the internal antinociceptive and pronociceptive systems. Clinical differentiation of an apparent opioid tolerance state includes OIH. Once diagnosed or provisionally considered, treatment strategies could include opioid dose reduction, opioid rotation, use of agents with NMDA receptor antagonism, and a properly timed coxib.

Conclusion: Despite initial skepticism and reservations, the phenomenon of OIH in humans is now accepted a clinical reality and a challenge faced by anesthesiologists, intensivists, pain specialists, and other workers in a diverse range of settings from perioperative care to palliative care medicine.

Publication types

  • Review

MeSH terms

  • Adrenergic alpha-2 Receptor Agonists
  • Adrenergic alpha-Agonists / therapeutic use
  • Analgesics, Non-Narcotic / therapeutic use
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / adverse effects*
  • Analgesics, Opioid / therapeutic use
  • Humans
  • Hyperalgesia / chemically induced*
  • Hyperalgesia / diagnosis
  • Hyperalgesia / physiopathology*
  • Hyperalgesia / therapy
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Terminology as Topic


  • Adrenergic alpha-2 Receptor Agonists
  • Adrenergic alpha-Agonists
  • Analgesics, Non-Narcotic
  • Analgesics, Opioid
  • Receptors, N-Methyl-D-Aspartate