Opioid-induced hyperalgesia

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Opioid-induced hyperalgesia[1] or opioid-induced abnormal pain sensitivity,[2] also called paradoxical hyperalgesia[3] is a phenomenon associated with the long-term use of opioids such as morphine[citation needed], hydrocodone[citation needed], oxycodone[citation needed], and methadone.[4][5] Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia)[citation needed]. Some studies on animals have also demonstrated this effect occurring after only a single high dose of opioids.[6]

Although tolerance and opioid-induced hyperalgesia both result in a similar need for dose escalation, they are nevertheless caused by two distinct mechanisms.[7] The similar net effect makes the two phenomena difficult to distinguish in a clinical setting. Under chronic opioid treatment, a particular individual's requirement for dose escalation may be due to tolerance (desensitization of antinociceptive mechanisms), opioid-induced hyperalgesia (sensitization of pronociceptive mechanisms), or a combination of both. Identifying the development of hyperalgesia is of great clinical importance since patients receiving opioids to relieve pain may paradoxically experience more pain as a result of treatment. Whereas increasing the dose of opioid can be an effective way to overcome tolerance, doing so to compensate for opioid-induced hyperalgesia may worsen the patient's condition by increasing sensitivity to pain while escalating physical dependence.[citation needed]

The phenomenon is common among palliative care patients following a too rapid escalation of opioid dosage.[8][9]

Mechanism of Action[edit]

The precise mechanisms underlying opioid-induced hyperalgesia are poorly understood. The sensitization of pronociceptive pathways in response to opioid treatment appears to involve several pathways. Research thus far has primarily implicated the abnormal activation of NMDA receptors in the CNS, and long-term potentiation of synapses between nociceptive C fibers and neurons in the spinal dorsal horn.[10] One possible strategy for treating hyperalgesia involves blocking activation of these receptors with NMDAR antagonists such as ketamine, dextromethorphan, or methadone (which has NMDAR antagonist properties in addition to being an opioid analgesic). Human studies examining the benefit of combining opioid treatment with NMDAR antagonism have yielded mixed results, and few conclusions can be drawn until larger studies are conducted. Targeting the NMDA receptors in areas of potential pathology (such as the dorsal horn of the spinal cord) is a challenge considering their widespread presence throughout the spinal cord and brain, and the profound psychotomimetic side effects associated with known NMDAR antagonists may limit their clinical potential as adjuvants to the treatment of pain. Gliosis due to the TLR4 agonist effects of opioids has also been implicated in both hyperalgesia and tolerance.[citation needed]


In examining the published studies on opioid-induced hyperalgesia (OIH), Reznikov et al criticize the methodologies employed on both humans and animals as being far-removed from the typical regimen and dosages of pain patients in the real world.[11] They also note that some OIH studies were performed on drug addicts in methadone rehabilitation programs, and that such results are very difficult to generalize and apply to medical patients in chronic pain. In contrast, a study of 224 chronic pain patients receiving 'commonly-used' doses of oral opioids, in more typical clinical scenarios, found that the opioid-treated patients actually experienced no difference in pain sensitivity when compared to patients on non-opioid treatments. The authors conclude that opioid-induced hyperalgesia may not be an issue of any significance for normal, medically-treated chronic pain patients at all.[11]

Opioid-induced hyperalgesia has also been criticized as overdiagnosed among chronic pain patients, due to poor differential practice in distinguishing it from the much more common phenomenon of opioid tolerance.[12] The misdiagnosis of common opioid tolerance (OT) as opioid-induced hyperalgesia (OIH) can be problematic as the clinical actions suggested by each condition can be contrary to each other. Patients misdiagnosed with OIH may have their opioid dose mistakenly decreased (in the attempt to counter OIH) at times when it is actually appropriate for their dose to be increased or rotated (as a counter to opioid tolerance).[12]

The suggestion that chronic pain patients who are diagnosed as experiencing opioid-induced hyperalgesia ought to be completely withdrawn from opioid therapy has also been met with criticism. This is not only because of the uncertainties surrounding the diagnosis of OIH in the first place,[11] but because of the viability of rotating the patient between different opioid analgesics over time. Opioid rotation is considered a valid alternative to the reduction or cessation of opioid therapy,[13] and multiple studies demonstrate the rotation of opioids to be a safe and effective protocol.[14][15][16]


  1. ^ Angst, Martin S.; Clark, J David (2006). "Opioid-induced Hyperalgesia". Anesthesiology. 104 (3): 570–87. PMID 16508405. doi:10.1097/00000542-200603000-00025. 
  2. ^ Mao, Jianren (2002). "Opioid-induced abnormal pain sensitivity: Implications in clinical opioid therapy". Pain. 100 (3): 213–7. PMID 12467992. doi:10.1016/S0304-3959(02)00422-0. 
  3. ^ Lee, SH; Cho, SY; Lee, HG; Choi, JI; Yoon, MH; Kim, WM (2013). "Tramadol induced paradoxical hyperalgesia". Pain Physician. 16 (1): 41–4. PMID 23340532. 
  4. ^ Compton, P.; Charuvastra, V. C.; Ling, W. (2001-07-01). "Pain intolerance in opioid-maintained former opiate addicts: effect of long-acting maintenance agent". Drug and Alcohol Dependence. 63 (2): 139–146. ISSN 0376-8716. PMID 11376918. doi:10.1016/s0376-8716(00)00200-3. 
  5. ^ Compton, P.; Charuvastra, V. C.; Kintaudi, K.; Ling, W. (2000-10-01). "Pain responses in methadone-maintained opioid abusers". Journal of Pain and Symptom Management. 20 (4): 237–245. ISSN 0885-3924. PMID 11027904. doi:10.1016/s0885-3924(00)00191-3. 
  6. ^ Célèrier, E; Laulin, JP; Corcuff, JB; Le Moal, M; Simonnet, G (2001). "Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: A sensitization process". The Journal of Neuroscience. 21 (11): 4074–80. PMID 11356895. 
  7. ^ Chu, Larry F.; Angst, Martin S.; Clark, David (2008). "Opioid-induced Hyperalgesia in Humans". The Clinical Journal of Pain. 24 (6): 479–96. PMID 18574358. doi:10.1097/AJP.0b013e31816b2f43. 
  8. ^ Wilson GR, Reisfield GM (2003). "Morphine hyperalgesia: a case report". Am J Hosp Palliat Care. 20 (6): 459–61. PMID 14649563. doi:10.1177/104990910302000608. 
  9. ^ Vella-Brincat J, Macleod AD (2007). "Adverse effects of opioids on the central nervous systems of palliative care patients". J Pain Palliat Care Pharmacother. 21 (1): 15–25. PMID 17430825. doi:10.1080/J354v21n01_05. 
  10. ^ Drdla, R.; Gassner, M.; Gingl, E.; Sandkühler, J. (2009). "Induction of Synaptic Long-Term Potentiation After Opioid Withdrawal". Science. 325 (5937): 207–10. PMID 19590003. doi:10.1126/science.1171759. 
  11. ^ a b c Reznikov, Igor, Dorit Pud, and Elon Eisenberg. "Oral opioid administration and hyperalgesia in patients with cancer or chronic nonmalignant pain." British journal of clinical pharmacology 60.3 (2005): 311-318.
  12. ^ a b Chen, Lucy, et al. "Clinical interpretation of opioid tolerance versus opioid-induced hyperalgesia." Journal of opioid management 10.6 (2013): 383-393
  13. ^ Mitra, S. "Opioid-induced hyperalgesia: pathophysiology and clinical implications." Journal of opioid management 4.3 (2007): 123-130.
  14. ^ Fine PG (2004). "Opioid insights:opioid-induced hyperalgesia and opioid rotation". J Pain Palliat Care Pharmacother 18 (3): 75–9. doi:10.1080/J354v18n03_08 . PMID 15364634
  15. ^ Mercadante S, Arcuri E (2005). "Hyperalgesia and opioid switching". Am J Hosp Palliat Care 22 (4): 291–4. doi:10.1177/104990910502200411 . PMID 16082916
  16. ^ González-Barboteo, J., et al. "Effectiveness of opioid rotation in the control of cancer pain: The ROTODOL Study." Journal of opioid management 10.6 (2013): 395-403.