View source for Hyperalgesia

{{short description|Abnormally increased sensitivity to pain}}
{{distinguish|Hypoalgesia}}
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'''Hyperalgesia''' ({{IPAc-en|ˌ|h|aɪ|p|ər|æ|l|ˈ|dʒ|iː|z|i|ə}} or {{IPAc-en|-|s|i|ə}}; ''hyper'' from  Greek ὑπέρ (''huper'') 'over' + ''-algesia'' from Greek ἄλγος (algos) 'pain') is an abnormally increased sensitivity to [[pain]], which may be caused by damage to [[nociceptor]]s or [[peripheral nerves]] and can cause [[hypersensitivity]] to stimulus. [[Prostaglandin]]s E and F are largely responsible for sensitizing the nociceptors.<ref>{{Cite web|url=http://www.clinicalpharmacology-ip.com/Forms/Common/print.aspx?cpnum=303&sec=mondesc,monclas,monbran,monmech,monphar,monindi,monadmi,moncontr,monpreg,moninte,monadve,monivco,monsup,monmp&t=0|title=Clinical Pharmacology|website=www.clinicalpharmacology-ip.com|access-date=2017-06-25|archive-date=2019-12-10|archive-url=https://web.archive.org/web/20191210055921/http://www.clinicalpharmacology-ip.com/Forms/Common/print.aspx?cpnum=303&sec=mondesc,monclas,monbran,monmech,monphar,monindi,monadmi,moncontr,monpreg,moninte,monadve,monivco,monsup,monmp&t=0|url-status=dead}}</ref> Temporary increased sensitivity to pain also occurs as part of [[sickness behavior]], the [[evolutionary medicine|evolved]] response to infection.<ref  name="Hart">{{cite journal |doi=10.1016/S0149-7634(88)80004-6 |author=Hart BL |title=Biological basis of the behavior of sick animals |journal=Neurosci Biobehav Rev |volume=12 |issue=2 |pages=123–37 |year=1988 |pmid=3050629 |s2cid=17797005 }}</ref>

==Types==
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 in surrounding undamaged tissues.

More diffuse, functional hyperalgesia can occur in [[fibromyalgia]]. [[Opioid-induced hyperalgesia]] may develop as a result of long-term opioid use in the treatment of [[chronic pain]].<ref name="Chu">{{cite journal |vauthors=Chu LF, Angst MS, Clark D |title=Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations |journal=Clin J Pain |volume=24 |issue=6 |pages=479–96 |year=2008 |pmid=18574358 |doi=10.1097/AJP.0b013e31816b2f43 |s2cid=8489213 }}</ref> 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.

==Causes==
Hyperalgesia is induced by [[platelet-activating factor]] (PAF), which comes about in an [[inflammation|inflammatory]] or an [[allergy|allergic]] response. This seems to occur via immune cells interacting with the [[peripheral nervous system]] and releasing pain-producing chemicals ([[cytokine]]s and [[chemokine]]s).<ref>{{cite journal |vauthors=Marchand F, Perretti M, McMahon SB |title=Role of the immune system in chronic pain |journal=Nat. Rev. Neurosci. |volume=6 |issue=7 |pages=521–32 |date=July 2005 |pmid=15995723 |doi=10.1038/nrn1700|s2cid=9660194 }}</ref>

One unusual cause of focal hyperalgesia is [[platypus venom]].<ref>{{cite journal |vauthors=de Plater GM, Milburn PJ, Martin RL |title=Venom from the platypus, Ornithorhynchus anatinus, induces a calcium-dependent current in cultured dorsal root ganglion cells |journal=J. Neurophysiol. |volume=85 |issue=3 |pages=1340–45 |date=March 2001 |pmid=11248005 |doi=10.1152/jn.2001.85.3.1340 |s2cid=2452708 }}</ref>

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.<ref name="Chu"/><ref>{{cite journal |vauthors=DuPen A, Shen D, Ersek M |title=Mechanisms of opioid-induced tolerance and hyperalgesia |journal=Pain Manag Nurs |volume=8 |issue=3 |pages=113–21 |date=September 2007 |pmid=17723928 |doi=10.1016/j.pmn.2007.02.004 }}</ref><ref>{{cite journal |author=Mitra S |title=Opioid-induced hyperalgesia: pathophysiology and clinical implications |journal=J Opioid Manag |volume=4 |issue=3 |pages=123–30 |year=2018 |pmid=18717507 |doi=10.5055/jom.2008.0017 }}</ref> 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 the [[nociceptin receptor]],.<ref>{{cite journal  |vauthors=Okuda-Ashitaka E, Minami T, Matsumura S, etal |title=The opioid peptide nociceptin/orphanin FQ mediates prostaglandin E2-induced allodynia, tactile pain associated with nerve injury |journal=Eur. J. Neurosci. |volume=23 |issue=4 |pages=995–1004 |date=February 2006 |pmid=16519664 |doi=10.1111/j.1460-9568.2006.04623.x |s2cid=39006891 }}</ref><ref>{{cite journal |vauthors=Fu X, Zhu ZH, Wang YQ, Wu GC |title=Regulation of proinflammatory cytokines gene expression by nociceptin/orphanin FQ in the spinal cord and the cultured astrocytes |journal=Neuroscience |volume=144 |issue=1 |pages=275–85 |date=January 2007 |pmid=17069983 |doi=10.1016/j.neuroscience.2006.09.016 |s2cid=40500310 }}</ref><ref>{{cite journal |vauthors=Chen Y, Sommer C |title=Activation of the nociceptin opioid system in rats. Sensory neurons produce antinociceptive effects in inflammatory pain: involvement of inflammatory mediators |journal=J. Neurosci. Res. |volume=85 |issue=7 |pages=1478–88 |date=May 2007 |pmid=17387690 |doi=10.1002/jnr.21272 |hdl=10161/13662 |s2cid=41843938 |url=https://dukespace.lib.duke.edu/dspace/bitstream/10161/13662/1/Chen_et_al-2007-Journal_of_Neuroscience_Research.pdf |hdl-access=free }}{{Dead link|date=August 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> Blocking this receptor may therefore be a means of preventing the development of hyperalgesia.<ref>{{cite journal |vauthors=Tamai H, Sawamura S, Takeda K, Orii R, Hanaoka K |title=Anti-allodynic and anti-hyperalgesic effects of nociceptin receptor antagonist, JTC-801, in rats after spinal nerve injury and inflammation |journal=Eur. J. Pharmacol. |volume=510 |issue=3 |pages=223–28 |date=March 2005 |pmid=15763246 |doi=10.1016/j.ejphar.2005.01.033 }}</ref>

Stimulation of nociceptive fibers in a pattern consistent with that from [[inflammation]] switches on a form of [[Amplifier|amplification]] in the [[spinal cord]], [[long term potentiation]].<ref>{{cite journal  |vauthors=Ikeda H, Stark J, Fischer H, etal |title=Synaptic amplifier of inflammatory pain in the spinal dorsal horn |journal=Science |volume=312 |issue=5780 |pages=1659–62 |date=June 2006 |pmid=16778058 |doi=10.1126/science.1127233 |bibcode=2006Sci...312.1659I |s2cid=20540556 |url=https://semanticscholar.org/paper/647289f4d21940e6db340c88d923a62674361817 }}</ref> This occurs where the pain fibres synapse to the pain pathway, the [[periaqueductal grey]]. Amplification in the spinal cord may be another way of producing hyperalgesia.

The release of [[proinflammatory cytokine]]s such as [[interleukin-1]] by activated [[leukocytes]] triggered by [[lipopolysaccharides]], [[endotoxin]]s and other signals of [[infection]] also increases pain sensitivity as part of [[sickness behavior]], the [[evolutionary medicine|evolved response]] to illness.<ref name="Hart"/><ref>{{cite journal |doi=10.1016/S0889-1591(02)00077-6  |vauthors=Kelley KW, Bluthé RM, Dantzer R, etal |title=Cytokine-induced sickness behavior |journal=Brain Behav. |volume=17 |issue=Suppl 1|pages=S112–18 |date=February 2003 |pmid=12615196 |s2cid=25400611 }}</ref><ref>{{cite journal |doi=10.1016/0006-8993(93)91446-Y |vauthors=Maier SF, Wiertelak EP, Martin D, Watkins LR |title=Interleukin-1 mediates the behavioral hyperalgesia produced by lithium chloride and endotoxin |journal=Brain Res. |volume=623 |issue=2 |pages=321–24 |date=October 1993 |pmid=8221116 |s2cid=40529634 }}</ref>

==Medical associations==
Hyperalgesia is associated with [[fibromyalgia]] syndrome.

==Diagnosis==
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&nbsp;°C and 40&nbsp;°C, as well as mapping of the area of abnormality.{{citation needed|date=June 2022}}

Quantitative sensory testing can be used to determine pain thresholds (decreased pain threshold indicates [[allodynia]]) 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.<ref>{{cite journal |vauthors=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 |title=NeuPSIG guidelines on neuropathic pain assessment |journal=Pain |volume=152 |issue=1 |pages=14–27 |date=Jan 2001 |pmid=20851519|doi=10.1016/j.pain.2010.07.031 |s2cid=2032474 }}</ref><ref>{{cite journal |vauthors=Jensen TS, Finnerup NB |title=Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. |journal=Lancet Neurol |volume=13 |issue=9 |pages=924–35|date=Sep 2014 |pmid=25142459 |doi=10.1016/S1474-4422(14)70102-4 |s2cid=25011309 }}</ref>

==Treatment==
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 antidepressant]]s,<ref>{{cite journal |vauthors=Sindrup SH, Otto M, Finnerup NB, Jensen TS |title=Antidepressants in the treatment of neuropathic pain |journal=Basic & Clinical Pharmacology & Toxicology |volume=96 |issue=6 |pages=399–409 |date=June 2005 |pmid=15910402 |doi=10.1111/j.1742-7843.2005.pto_96696601.x |doi-access=free }}</ref><ref>{{cite journal  |vauthors=Matsuzawa-Yanagida K, Narita M, Nakajima M, etal |title=Usefulness of antidepressants for improving the neuropathic pain-like state and pain-induced anxiety through actions at different brain sites |journal=Neuropsychopharmacology |volume=33 |issue=8 |pages=1952–65 |date=July 2008 |pmid=17957217 |doi=10.1038/sj.npp.1301590|doi-access=free }}</ref> [[nonsteroidal anti-inflammatory drugs]] (NSAIDs),<ref>{{cite journal  |vauthors=Koppert W, Wehrfritz A, Körber N, etal |title=The cyclooxygenase isozyme inhibitors parecoxib and paracetamol reduce central hyperalgesia in humans |journal=Pain |volume=108 |issue=1–2 |pages=148–53 |date=March 2004 |pmid=15109518 |doi=10.1016/j.pain.2003.12.017 |s2cid=33124447 }}</ref> [[glucocorticoids]],<ref>{{cite journal |vauthors=Stubhaug A, Romundstad L, Kaasa T, Breivik H |title=Methylprednisolone and Ketorolac rapidly reduce hyperalgesia around a skin burn injury and increase pressure pain thresholds |journal=Acta Anaesthesiol Scand |volume=51 |issue=9 |pages=1138–46 |date=October 2007 |pmid=17714578 |doi=10.1111/j.1399-6576.2007.01415.x|s2cid=20639496 }}</ref> [[gabapentin]]<ref>{{cite journal  |vauthors=Gottrup H, Juhl G, Kristensen AD, etal |title=Chronic oral Gabapentin reduces elements of central sensitization in human experimental Hyperalgesia.|journal=Anesthesiology |volume=101 |issue=6 |pages=1400–08 |date=December 2004 |pmid=15564948 |doi=10.1097/00000542-200412000-00021|s2cid=15060257}}</ref> or [[pregabalin]],<ref>{{cite journal |vauthors=Chizh BA, Göhring M, Tröster A, Quartey GK, Schmelz M, Koppert W |title=Effects of oral pregabalin and aprepitant on pain and central sensitization in the electrical hyperalgesia model in human volunteers |journal=Br J Anaesth |volume=98 |issue=2 |pages=246–54 |date=February 2007 |pmid=17251214 |doi=10.1093/bja/ael344 |doi-access=free }}</ref> [[NMDA antagonist]]s,<ref>{{cite journal |doi=10.1016/S0304-3959(97)00006-7 |vauthors=Warncke T, Stubhaug A, Jørum E |title=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.|journal=Pain |volume=72 |issue=1–2 |pages=99–106 |date=August 1997 |pmid=9272793 |s2cid=1343794 }}</ref><ref>{{cite journal |doi=10.1016/j.bpa.2006.12.006 |vauthors=De Kock MF, Lavand'homme PM |title=The clinical role of NMDA receptor antagonists for the treatment of postoperative pain |journal=Best Pract Res Clin Anaesthesiol |volume=21 |issue=1 |pages=85–98 |date=March 2007 |pmid=17489221 }}</ref><ref>{{cite journal |vauthors=Klein T, Magerl W, Hanschmann A, Althaus M, Treede RD |title=Antihyperalgesic and analgesic properties of the N-methyl-D-aspartate (NMDA) receptor antagonist neramexane in a human surrogate model of neurogenic Hyperalgesia. |journal=Eur J Pain |volume=12 |issue=1 |pages=17–29 |date=January 2008 |pmid=17449306 |doi=10.1016/j.ejpain.2007.02.002 |s2cid=2875679 }}</ref> and atypical opioids like [[tramadol]].<ref>{{cite journal |doi=10.2165/00126839-200708010-00005 |vauthors=Christoph T, Kögel B, Strassburger W, Schug SA |title=Tramadol has a better potency ratio relative to morphine in neuropathic than in nociceptive pain models |journal=Drugs in R&D |volume=8 |issue=1 |pages=51–57 |year=2007 |pmid=17249849 |s2cid=10268544 }}</ref> When hyperalgesia has been produced by chronic high doses of opioids, reducing the dose may result in improved pain management.<ref>{{cite journal |vauthors=Vorobeychik Y, Chen L, Bush MC, Mao J |title=Improved opioid analgesic effect following opioid dose reduction. |journal=Pain Med |volume=9 |issue=6 |pages=724–27 |date=September 2008 |pmid=18816332 |doi=10.1111/j.1526-4637.2008.00501.x |doi-access=free }}</ref> 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.<ref>{{cite journal|last1=DeSantana|first1=JM|last2=Walsh|first2=DM|last3=Vance|first3=C|last4=Rakel|first4=BA|last5=Sluka|first5=KA|title=Effectiveness of transcutaneous electrical nerve stimulation for treatment of hyperalgesia and pain.|journal=Current Rheumatology Reports|date=December 2008|volume=10|issue=6|pages=492–99|pmid=19007541|pmc=2746624|doi=10.1007/s11926-008-0080-z}}</ref><ref>{{cite journal|last1=Sluka|first1=KA|last2=Chandran|first2=P|title=Enhanced reduction in hyperalgesia by combined administration of clonidine and TENS.|journal=Pain|date=November 2002|volume=100|issue=1–2|pages=183–90|pmid=12435471|doi=10.1016/s0304-3959(02)00294-4|s2cid=12117342}}</ref>

==See also==
* [[Allodynia]]
* [[Hypoalgesia]]

==References==
{{Reflist}}

== External links ==
{{Medical resources
|  DiseasesDB     = 30788
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|  ICD9           = {{ICD9|782.0}}
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|  MeshID         = D006930
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{{Pain}}
{{Skin and subcutaneous tissue symptoms and signs}}

[[Category:Pain]]
[[Category:Symptoms and signs: Skin and subcutaneous tissue]]