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, hydrocodone, oxycodone, and methadone. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia). Some studies on animals have also demonstrated this effect occurring after only a single high dose of opioids.[4]

Although tolerance and opioid-induced hyperalgesia both result in a similar need for dose escalation, they are nevertheless caused by two distinct mechanisms.[5] 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]

If an individual is taking opioids for a chronic non-cancer pain condition, and cannot achieve effective pain relief despite increases in dose, they may be experiencing opioid-induced hyperalgesia. In this case, they may benefit from complete withdrawal from opioid therapy. Many individuals report reduced pain levels when opioids are withdrawn.[6]

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.[7] 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]


  1. ^ Angst, Martin S.; Clark, J David (2006). "Opioid-induced Hyperalgesia". Anesthesiology 104 (3): 570–87. doi:10.1097/00000542-200603000-00025. PMID 16508405. 
  2. ^ Mao, Jianren (2002). "Opioid-induced abnormal pain sensitivity: Implications in clinical opioid therapy". Pain 100 (3): 213–7. doi:10.1016/S0304-3959(02)00422-0. PMID 12467992. 
  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. ^ 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. 
  5. ^ Chu, Larry F.; Angst, Martin S.; Clark, David (2008). "Opioid-induced Hyperalgesia in Humans". The Clinical Journal of Pain 24 (6): 479–96. doi:10.1097/AJP.0b013e31816b2f43. PMID 18574358. 
  6. ^ Wuitchik, M. & Feehan, GG: Opioid withdrawal versus opioid maintenance for persons with chronic non-cancer pain: The experience of the Canmore Pain Clinic. Rehab Review 2006; 2:19-21[verification needed]
  7. ^ Drdla, R.; Gassner, M.; Gingl, E.; Sandkühler, J. (2009). "Induction of Synaptic Long-Term Potentiation After Opioid Withdrawal". Science 325 (5937): 207–10. doi:10.1126/science.1171759. PMID 19590003.