Hyperalgesia (/ˌhaɪpərælˈdʒiːziə/ or/-siə/;hyper from Greek ὑπέρ (huper) 'over' +-algesia from Greek ἄλγος (algos) 'pain') is an abnormally increased sensitivity topain, which may be caused by damage tonociceptors orperipheral nerves and can causehypersensitivity to stimulus.Prostaglandins E and F are largely responsible for sensitizing the nociceptors.[1] Temporary increased sensitivity to pain also occurs as part ofsickness behavior, theevolved 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 alearned 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 in surrounding undamaged tissues.
More diffuse, functional hyperalgesia can occur infibromyalgia.Opioid-induced hyperalgesia may develop as a result of long-term opioid use in the treatment ofchronic 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; this 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, with one major pathway being through stimulation of thenociceptin receptor,.[8][9][10] 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 frominflammation switches on a form ofamplification in thespinal cord,long term potentiation.[12] This occurs where the pain fibres synapse to the pain pathway, theperiaqueductal 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 indicatesallodynia) and stimulus/response functions (increased pain response indicates 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 to evaluate pressure and punctate allodynia and hyperalgesia, and a thermal tester is used for thermal testing.[15][16]
^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.
^Tamai H, Sawamura S, Takeda K, Orii R, Hanaoka K (March 2005). "Anti-allodynic and anti-hyperalgesic effects of nociceptin receptor antagonist, JTC-801, in rats after spinal nerve injury and inflammation".Eur. J. Pharmacol.510 (3):223–28.doi:10.1016/j.ejphar.2005.01.033.PMID15763246.
^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.
