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ICD-9 782.0
OMIM [1]
DiseasesDB 30788
MedlinePlus [2]
eMedicine /
MeSH {{{MeshNumber}}}

Hyperalgesia is a somatosensory disorder an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.[1]


Hyperalgesia can be experienced in focal, discrete areas, or as a more diffuse, body-wide form. Conditioning studies have established that it is possible to experience a learned hyperalgesia of the latter, diffuse form. The focal form is typically associated with injury, and is divided into two subtypes:

  • Primary hyperalgesia describes pain sensitivity that occurs directly in the damaged tissues.
  • Secondary hyperalgesia describes pain sensitivity that occurs in surrounding undamaged tissues.

Opioid-induced hyperalgesia may develop as a result of long-term opioid use in the treatment of chronic pain.[2] Various studies of humans and animals have demonstrated that primary or secondary hyperalgesia can develop in response to both chronic and acute exposure to opioids. This side effect can be severe enough to warrant discontinuation of opioid treatment.


Hyperalgesia is induced by platelet-activating factor (PAF) which comes about in an inflammatory or an allergic response. This seems to occur via immune cells interacting with the peripheral nervous system and releasing pain-producing chemicals (cytokines and chemokines).[3]

One unusual cause of focal hyperalgesia is platypus venom.[4]

Long term opioid (e.g. heroin, oxycodone) users and those on high-dose opioid medications for the treatment of chronic pain, may experience hyperalgesia and experience pain out of proportion to physical findings, which is a common cause for loss of efficacy of these medications over time.[2][5][6] As it can be difficult to distinguish from tolerance, opioid-induced hyperalgesia is often compensated for by escalating the dose of opioid, potentially worsening the problem by further increasing sensitivity to pain. Chronic hyperstimulation of opioid receptors results in altered homeostasis of pain signalling pathways in the body with several mechanisms of action involved, one major pathway being through stimulation of the nociceptin receptor,[7][8][9] and blocking this receptor may therefore be a means of preventing the development of hyperalgesia.[10]

Stimulation of pain fibres in a pattern consistent with that from inflammation switches on a form of amplification in the spinal cord, long term potentiation.[11] This occurs where the pain fibres synapse to pain pathway, the periaqueductal grey. Amplification in the spinal cord may thus be another way of producing hyperalgesia.

The release of proinflammatory cytokines such as Interleukin-1 by activated leukocytes triggered by lipopolysaccharides, endotoxins and other signals of infection also increases pain sensitivity as part of sickness behavior, the evolved response to illness.[1][12][13]


Hyperalgesia is similar to other sorts of pain associated with nerve damage such as allodynia and neuropathic pain, and consequently may respond to standard treatment for these conditions, using various drugs such as SSRI or tricyclic antidepressants,[14][15] non-steroidal antiinflammatory drugs,[16] glucocorticoids,[17] gabapentin[18] or pregabalin,[19] NMDA antagonists,[20][21][22] or atypical opioids such as tramadol.[23] Where hyperalgesia has been produced by chronic high doses of opioids, reducing the dose may result in improved pain management.[24] However as with other forms of nerve dysfunction associated pain, treatment of hyperalgesia can be clinically challenging, and finding a suitable drug or drug combination that is effective for a particular patient may require a certain amount of trial and error.


  1. 1.0 1.1 Hart, B. L. (1988) "Biological basis of the behavior of sick animals". Neurosci Biobehav Rev. 12: 123-137. PMID 3050629
  2. 2.0 2.1 Chu LF, Angst MS, Clark D. Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations. Clinical Journal of Pain. 2008 Jul-Aug;24(6):479-96. PMID 18574358
  3. Marchand, F., Perretti, M., & McMahon, S. B. (2005). Role of the immune system in chronic pain. Nature Reviews Neuroscience, 6, 521-532.
  4. de Plater GM, Milburn PJ, Martin RL. Venom from the platypus, Ornithorhynchus anatinus, induces a calcium-dependent current in cultured dorsal root ganglion cells. Journal of Neurophysiology. 2001 Mar;85(3):1340-5. PMID 11248005
  5. DuPen A, Shen D, Ersek M. Mechanisms of opioid-induced tolerance and hyperalgesia. Pain Management Nursing. 2007 Sep;8(3):113-21. PMID 17723928
  6. Mitra S. Opioid-induced hyperalgesia: pathophysiology and clinical implications. Journal of Opioid Management. 2008 May-Jun;4(3):123-30. PMID 18717507
  7. Okuda-Ashitaka E, Minami T, Matsumura S, Takeshima H, Reinscheid RK, Civelli O, Ito S. The opioid peptide nociceptin/orphanin FQ mediates prostaglandin E2-induced allodynia, tactile pain associated with nerve injury. European Journal of Neuroscience. 2006 Feb;23(4):995-1004. PMID 16519664
  8. Fu X, Zhu ZH, Wang YQ, Wu GC. Regulation of proinflammatory cytokines gene expression by nociceptin/orphanin FQ in the spinal cord and the cultured astrocytes. Neuroscience. 2007 Jan 5;144(1):275-85. PMID 17069983
  9. Chen Y, Sommer C. Activation of the nociceptin opioid system in rat sensory neurons produces antinociceptive effects in inflammatory pain: involvement of inflammatory mediators. Journal of Neuroscience Research. 2007 May 15;85(7):1478-88. PMID 17387690
  10. Tamai H, Sawamura S, Takeda K, Orii R, Hanaoka K. Anti-allodynic and anti-hyperalgesic effects of nociceptin receptor antagonist, JTC-801, in rats after spinal nerve injury and inflammation. European Journal of Pharmacology. 2005 Mar 14;510(3):223-8. PMID 15763246
  11. Ikeda, H., Stark, J., Fischer, H., Wagner, M., Drdla, R., Jäger, T., et al. (2006). Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science, 312, 1659-1662.
  12. Kelley, K. W., Bluthe, R. M., Dantzer, R., Zhou, J. H., Shen, W. H., Johnson, R. W. Broussard, S. R. (2003) "Cytokine-induced sickness behavior". Brain Behav Immun. 17 Suppl 1: S112-118 PMID 12615196
  13. Maier, S. F., Wiertelak, E. P., Martin, D. Watkins, L. R. (1993) "Interleukin-1 mediates the behavioral hyperalgesia produced by lithium chloride and endotoxin". Brain Res. 623: 321-324. PMID 8221116
  14. Sindrup SH, Otto M, Finnerup NB, Jensen TS. Antidepressants in the treatment of neuropathic pain. Basic and Clinical Pharmacology and Toxicology. 2005 Jun;96(6):399-409. PMID 15910402
  15. Matsuzawa-Yanagida K, Narita M, Nakajima M, Kuzumaki N, Niikura K, Nozaki H, Takagi T, Tamai E, Hareyama N, Terada M, Yamazaki M, Suzuki T. Usefulness of antidepressants for improving the neuropathic pain-like state and pain-induced anxiety through actions at different brain sites. Neuropsychopharmacology. 2008 Jul;33(8):1952-65. PMID 17957217
  16. Koppert W, Wehrfritz A, Körber N, Sittl R, Albrecht S, Schüttler J, Schmelz M. The cyclooxygenase isozyme inhibitors parecoxib and paracetamol reduce central hyperalgesia in humans. Pain. 2004 Mar;108(1-2):148-53. PMID 15109518
  17. Stubhaug A, Romundstad L, Kaasa T, Breivik H. Methylprednisolone and ketorolac rapidly reduce hyperalgesia around a skin burn injury and increase pressure pain thresholds. Acta Anaesthesiologica Scandinavica. 2007 Oct;51(9):1138-46. PMID 17714578
  18. Gottrup H, Juhl G, Kristensen AD, Lai R, Chizh BA, Brown J, Bach FW, Jensen TS. Chronic oral gabapentin reduces elements of central sensitization in human experimental hyperalgesia. Anesthesiology. 2004 Dec;101(6):1400-8. PMID 15564948
  19. Chizh BA, Göhring M, Tröster A, Quartey GK, Schmelz M, Koppert W. Effects of oral pregabalin and aprepitant on pain and central sensitization in the electrical hyperalgesia model in human volunteers. British Journal of Anaesthesia. 2007 Feb;98(2):246-54. PMID 17251214
  20. Warncke T, Stubhaug A, Jørum E. Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-induced secondary hyperalgesia in man: a double-blind, cross-over comparison with morphine and placebo. Pain. 1997 Aug;72(1-2):99-106. PMID 9272793
  21. De Kock MF, Lavand'homme PM. The clinical role of NMDA receptor antagonists for the treatment of postoperative pain. Best Practice and Research. Clinical Anaesthesiology. 2007 Mar;21(1):85-98. PMID 17489221
  22. Klein T, Magerl W, Hanschmann A, Althaus M, Treede RD. Antihyperalgesic and analgesic properties of the N-methyl-D-aspartate (NMDA) receptor antagonist neramexane in a human surrogate model of neurogenic hyperalgesia. European Journal of Pain. 2008 Jan;12(1):17-29. PMID 17449306
  23. Christoph T, Kögel B, Strassburger W, Schug SA. Tramadol has a better potency ratio relative to morphine in neuropathic than in nociceptive pain models. Drugs in R & D. 2007;8(1):51-7. PMID 17249849
  24. Vorobeychik Y, Chen L, Bush MC, Mao J. Improved opioid analgesic effect following opioid dose reduction. Pain Medicine. 2008 Sep;9(6):724-7. PMID 18816332

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