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:
- 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).
- 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.
- Mao J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain. 2000; 100:213-217.
- 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.
- Laird D, Lovel T. Paradoxical pain (letter). Lancet. 1993; 341:241.
- 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.
- 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.
Fast Facts and Concepts are edited by Sean Marks MD (Medical College of Wisconsin) and associate editor Drew A Rosielle MD (University of Minnesota Medical School), with the generous support of a volunteer peer-review editorial board, and are made available online by the Palliative Care Network of Wisconsin (PCNOW); the authors of each individual Fast Fact are solely responsible for that Fast Fact’s content. The full set of Fast Facts are available at Palliative Care Network of Wisconsin with contact information, and how to reference Fast Facts.
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