Opioid-Induced Hyperalgesia

  • Winifred G Teuteberg MD

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Background     Opioid-induced hyperalgesia is a clinical phenomenon, characterized by increasing in pain in patients who are receiving increasing doses of opioids.  This Fast Fact reviews the clinical findings and treatment options.  See also Fast Fact #215 on opioid poorly-responsive pain.

Clinical features of opioid hyperalgesia:

  • History
    • Increasing sensitivity to pain stimuli (hyperalgesia).
    • Worsening pain despite increasing doses of opioids.
    • Pain that becomes more diffuse, extending beyond the distribution of pre-existing pain.
    • Can occur at any dose of opioid, but more commonly with high parenteral doses of morphine or hydromorphone and/or in the setting of renal failure.
  • Physical Examination
    • Pain elicited from ordinarily non-painful stimuli, such as stroking skin with cotton (allodynia)
    • Presence of other opioid hyperexcitability effects: myoclonus, delirium or seizures (see Fast Facts #57,58).

Proposed mechanisms:

  • Toxic effect of opioid metabolites (e.g. morphine-3-glucuronide or hydromorphone-3-glucronide).
  • Central sensitization as a result of opioid-related activation of N-methyl-D-asparate (NMDA) receptors in the central nervous system.
  • Increase in spinal dynorphin activity.
  • Enhanced descending facilitation from the rostral ventromedial medulla.
  • Activation of intracellular protein kinase C.


  • Reduce or discontinue the current opioid.
  • Change opioid to one with less risk of neurotoxic effects: fentanyl or methadone (see Fast Fact #75).
  • Add an infusion of a non-opioid NMDA receptor antagonist such as ketamine (see Fast Fact #132).
  • Add a non-opioid adjuvant such as gabapentin, baclofen, acetaminophen or an NSAID.
  • Initiate epidural, intrathecal, regional or local anesthesia and taper/discontinue systemic opioids.
  • Increase hydration if clinically appropriate.

Conclusion     Opioids can lead to a paradoxical increase in pain. Opioid-induced hyperalgesia should be considered in any patient with increasing pain that is not responding to increasing opioids.  Referral to pain/palliative care professionals is appropriate to help develop a management strategy. 


  1. Mao J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain.  2000; 100:213-217.
  2. Portenoy RK, Forbes K, Lussier D, Hanks G. Difficult pain problems: an integrated approach.  In: Doyle D, Hanks G, Cherny N, Calman K, eds.  Oxford Textbook of Palliative Medicine. 3rd ed. New York, NY: Oxford University Press; 2004: p439.
  3. Laird D, Lovel T. Paradoxical pain (letter). Lancet. 1993; 341:241.
  4. Walker SM, Cousins MJ. Reduction in hyperalgesia and intrathecal morphine requirements by low-dose ketamine infusion (letter). J Pain Symptom Manage. 1997; 14:129-133.
  5. Carroll IR, et al. Management of perioperative pain in patients chronically consuming opioids. Reg Anesth Pain Med. 2004; 29:576-591.

Version History:  This Fast Fact was originally edited by David E Weissman MD and published in September 2005. Version re-copy-edited in April 2009; then again in July 2015.