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.

Therapies:

• 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. 

References

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.