Hyperalgesia (/ˌhaɪpərælˈdʒiːziə/or/-siə/; 'hyper' from Greek ὑπέρ (huper, “over”), '-algesia' from Greek algos, ἄλγος (pain)) is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptorsorperipheral nerves and can cause hypersensitivity to stimulus.
Prostaglandins E and F are largely responsible for sensitizing the nociceptors.[1] Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.[2]
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.[3] 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.
Long-term opioid (e.g. heroin, morphine) 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.[3][6][7] 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,[8][9][10] and blocking this receptor may therefore be a means of preventing the development of hyperalgesia.[11]
Stimulation of nociceptive fibers in a pattern consistent with that from inflammation switches on a form of amplification in the spinal cord, long term potentiation.[12] This occurs where the pain fibres synapse to pain pathway, the periaqueductal grey. Amplification in the spinal cord may be another way of producing hyperalgesia.
Simple bedside tests include response (pain intensity and character) to cotton swab, finger pressure, pinprick, cold and warm stimuli, e.g., metal thermo rollers at 20°C and 40°C, as well as mapping of the area of abnormality.[citation needed]
Quantitative sensory testing can be used to determine pain thresholds (decreased pain threshold indicates allodynia) and stimulus/response functions (increased pain response indicate hyperalgesia). Dynamic mechanical allodynia can be assessed using a cotton swab or a brush. A pressure algometer and standardized monofilaments or weighted pinprick stimuli are used for assessing pressure and punctate allodynia and hyperalgesia and a thermal tester is used for thermal testing.[15][16]
Hyperalgesia is similar to other sorts of pain associated with nerve irritation or 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,[17][18]Nonsteroidal anti-inflammatory drugs (NSAIDs),[19]glucocorticoids,[20]gabapentin[21]orpregabalin,[22]NMDA antagonists,[23][24][25] or atypical opioids such as tramadol.[26] Where hyperalgesia has been produced by chronic high doses of opioids, reducing the dose may result in improved pain management.[27] 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 trial and error. The use of a transcutaneous electrical nerve stimulation device has been shown to alleviate hyperalgesia.[28][29]
^Marchand F, Perretti M, McMahon SB (July 2005). "Role of the immune system in chronic pain". Nat. Rev. Neurosci. 6 (7): 521–32. doi:10.1038/nrn1700. PMID15995723. S2CID9660194.
^de Plater GM, Milburn PJ, Martin RL (March 2001). "Venom from the platypus, Ornithorhynchus anatinus, induces a calcium-dependent current in cultured dorsal root ganglion cells". J. Neurophysiol. 85 (3): 1340–45. doi:10.1152/jn.2001.85.3.1340. PMID11248005. S2CID2452708.
^DuPen A, Shen D, Ersek M (September 2007). "Mechanisms of opioid-induced tolerance and hyperalgesia". Pain Manag Nurs. 8 (3): 113–21. doi:10.1016/j.pmn.2007.02.004. PMID17723928.
^Mitra S (2018). "Opioid-induced hyperalgesia: pathophysiology and clinical implications". J Opioid Manag. 4 (3): 123–30. doi:10.5055/jom.2008.0017. PMID18717507.
^Okuda-Ashitaka E, Minami T, Matsumura S, et al. (February 2006). "The opioid peptide nociceptin/orphanin FQ mediates prostaglandin E2-induced allodynia, tactile pain associated with nerve injury". Eur. J. Neurosci. 23 (4): 995–1004. doi:10.1111/j.1460-9568.2006.04623.x. PMID16519664. S2CID39006891.
^Fu X, Zhu ZH, Wang YQ, Wu GC (January 2007). "Regulation of proinflammatory cytokines gene expression by nociceptin/orphanin FQ in the spinal cord and the cultured astrocytes". Neuroscience. 144 (1): 275–85. doi:10.1016/j.neuroscience.2006.09.016. PMID17069983. S2CID40500310.
^Maier SF, Wiertelak EP, Martin D, Watkins LR (October 1993). "Interleukin-1 mediates the behavioral hyperalgesia produced by lithium chloride and endotoxin". Brain Res. 623 (2): 321–24. doi:10.1016/0006-8993(93)91446-Y. PMID8221116. S2CID40529634.
^Haanpää M, Attal N, Backonja M, Baron R, Bennett M, Bouhassira D, Cruccu G, Hansson P, Haythornthwaite JA, Iannetti GD, Jensen TS, Kauppila T, Nurmikko TJ, Rice AS, Rowbotham M, Serra J, Sommer C, Smith BH, Treede RD (Jan 2001). "NeuPSIG guidelines on neuropathic pain assessment". Pain. 152 (1): 14–27. doi:10.1016/j.pain.2010.07.031. PMID20851519. S2CID2032474.
^Koppert W, Wehrfritz A, Körber N, et al. (March 2004). "The cyclooxygenase isozyme inhibitors parecoxib and paracetamol reduce central hyperalgesia in humans". Pain. 108 (1–2): 148–53. doi:10.1016/j.pain.2003.12.017. PMID15109518. S2CID33124447.
^Stubhaug A, Romundstad L, Kaasa T, Breivik H (October 2007). "Methylprednisolone and Ketorolac rapidly reduce hyperalgesia around a skin burn injury and increase pressure pain thresholds". Acta Anaesthesiol Scand. 51 (9): 1138–46. doi:10.1111/j.1399-6576.2007.01415.x. PMID17714578. S2CID20639496.
^Gottrup H, Juhl G, Kristensen AD, et al. (December 2004). "Chronic oral Gabapentin reduces elements of central sensitization in human experimental Hyperalgesia". Anesthesiology. 101 (6): 1400–08. doi:10.1097/00000542-200412000-00021. PMID15564948. S2CID15060257.
^Warncke T, Stubhaug A, Jørum E (August 1997). "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. 72 (1–2): 99–106. doi:10.1016/S0304-3959(97)00006-7. PMID9272793. S2CID1343794.
^De Kock MF, Lavand'homme PM (March 2007). "The clinical role of NMDA receptor antagonists for the treatment of postoperative pain". Best Pract Res Clin Anaesthesiol. 21 (1): 85–98. doi:10.1016/j.bpa.2006.12.006. PMID17489221.
^Klein T, Magerl W, Hanschmann A, Althaus M, Treede RD (January 2008). "Antihyperalgesic and analgesic properties of the N-methyl-D-aspartate (NMDA) receptor antagonist neramexane in a human surrogate model of neurogenic Hyperalgesia". Eur J Pain. 12 (1): 17–29. doi:10.1016/j.ejpain.2007.02.002. PMID17449306. S2CID2875679.
^Christoph T, Kögel B, Strassburger W, Schug SA (2007). "Tramadol has a better potency ratio relative to morphine in neuropathic than in nociceptive pain models". Drugs in R&D. 8 (1): 51–57. doi:10.2165/00126839-200708010-00005. PMID17249849. S2CID10268544.
