Hyperalgesia Explained

Hyperalgesia should not be confused with Hypoalgesia.

Hyperalgesia

Hyperalgesia (or ; '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 nociceptors or peripheral 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]

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:

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.

Causes

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).[4]

One unusual cause of focal hyperalgesia is platypus venom.[5]

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.

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.[2] [13] [14]

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°C and 40°C, as well as mapping of the area of abnormality.

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]

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 antidepressants,[17] [18] Nonsteroidal anti-inflammatory drugs (NSAIDs),[19] glucocorticoids,[20] gabapentin[21] or pregabalin,[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]

See also

Notes and References

  1. Web site: Clinical Pharmacology. www.clinicalpharmacology-ip.com. 2017-06-25. 2019-12-10. 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. dead.
  2. 10.1016/S0149-7634(88)80004-6 . Hart BL . Biological basis of the behavior of sick animals . Neurosci Biobehav Rev . 12 . 2 . 123–37 . 1988 . 3050629 . 17797005 .
  3. Chu LF, Angst MS, Clark D . Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations . Clin J Pain . 24 . 6 . 479–96 . 2008 . 18574358 . 10.1097/AJP.0b013e31816b2f43 . 8489213 .
  4. Marchand F, Perretti M, McMahon SB . Role of the immune system in chronic pain . Nat. Rev. Neurosci. . 6 . 7 . 521–32 . July 2005 . 15995723 . 10.1038/nrn1700. 9660194 .
  5. de Plater GM, Milburn PJ, Martin RL . Venom from the platypus, Ornithorhynchus anatinus, induces a calcium-dependent current in cultured dorsal root ganglion cells . J. Neurophysiol. . 85 . 3 . 1340–45 . March 2001 . 11248005 . 10.1152/jn.2001.85.3.1340 . 2452708 .
  6. DuPen A, Shen D, Ersek M . Mechanisms of opioid-induced tolerance and hyperalgesia . Pain Manag Nurs . 8 . 3 . 113–21 . September 2007 . 17723928 . 10.1016/j.pmn.2007.02.004 .
  7. Mitra S . Opioid-induced hyperalgesia: pathophysiology and clinical implications . J Opioid Manag . 4 . 3 . 123–30 . 2018 . 18717507 . 10.5055/jom.2008.0017 .
  8. Okuda-Ashitaka E, Minami T, Matsumura S, etal . The opioid peptide nociceptin/orphanin FQ mediates prostaglandin E2-induced allodynia, tactile pain associated with nerve injury . Eur. J. Neurosci. . 23 . 4 . 995–1004 . February 2006 . 16519664 . 10.1111/j.1460-9568.2006.04623.x . 39006891 .
  9. 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 . 144 . 1 . 275–85 . January 2007 . 17069983 . 10.1016/j.neuroscience.2006.09.016 . 40500310 .
  10. Chen Y, Sommer C . Activation of the nociceptin opioid system in rats. Sensory neurons produce antinociceptive effects in inflammatory pain: involvement of inflammatory mediators . J. Neurosci. Res. . 85 . 7 . 1478–88 . May 2007 . 17387690 . 10.1002/jnr.21272. 10161/13662 . 41843938 . free .
  11. 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 . Eur. J. Pharmacol. . 510 . 3 . 223–28 . March 2005 . 15763246 . 10.1016/j.ejphar.2005.01.033 .
  12. Ikeda H, Stark J, Fischer H, etal . Synaptic amplifier of inflammatory pain in the spinal dorsal horn . Science . 312 . 5780 . 1659–62 . June 2006 . 16778058 . 10.1126/science.1127233 . 2006Sci...312.1659I . 20540556 .
  13. 10.1016/S0889-1591(02)00077-6 . Kelley KW, Bluthé RM, Dantzer R, etal . Cytokine-induced sickness behavior . Brain Behav. . 17 . Suppl 1. S112–18 . February 2003 . 12615196 . 25400611 .
  14. 10.1016/0006-8993(93)91446-Y . Maier SF, Wiertelak EP, Martin D, Watkins LR . Interleukin-1 mediates the behavioral hyperalgesia produced by lithium chloride and endotoxin . Brain Res. . 623 . 2 . 321–24 . October 1993 . 8221116 . 40529634 .
  15. 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 . NeuPSIG guidelines on neuropathic pain assessment . Pain . 152 . 1 . 14–27 . Jan 2001 . 20851519. 10.1016/j.pain.2010.07.031 . 2032474 .
  16. Jensen TS, Finnerup NB . Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. . Lancet Neurol . 13 . 9 . 924–35. Sep 2014 . 25142459 . 10.1016/S1474-4422(14)70102-4 . 25011309 .
  17. Sindrup SH, Otto M, Finnerup NB, Jensen TS . Antidepressants in the treatment of neuropathic pain . Basic & Clinical Pharmacology & Toxicology . 96 . 6 . 399–409 . June 2005 . 15910402 . 10.1111/j.1742-7843.2005.pto_96696601.x . free .
  18. Matsuzawa-Yanagida K, Narita M, Nakajima M, etal . Usefulness of antidepressants for improving the neuropathic pain-like state and pain-induced anxiety through actions at different brain sites . Neuropsychopharmacology . 33 . 8 . 1952–65 . July 2008 . 17957217 . 10.1038/sj.npp.1301590. free .
  19. Koppert W, Wehrfritz A, Körber N, etal . The cyclooxygenase isozyme inhibitors parecoxib and paracetamol reduce central hyperalgesia in humans . Pain . 108 . 1–2 . 148–53 . March 2004 . 15109518 . 10.1016/j.pain.2003.12.017 . 33124447 .
  20. 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 Anaesthesiol Scand . 51 . 9 . 1138–46 . October 2007 . 17714578 . 10.1111/j.1399-6576.2007.01415.x. 20639496 .
  21. Gottrup H, Juhl G, Kristensen AD, etal . Chronic oral Gabapentin reduces elements of central sensitization in human experimental Hyperalgesia.. Anesthesiology . 101 . 6 . 1400–08 . December 2004 . 15564948 . 10.1097/00000542-200412000-00021. 15060257.
  22. 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 . Br J Anaesth . 98 . 2 . 246–54 . February 2007 . 17251214 . 10.1093/bja/ael344 . free .
  23. 10.1016/S0304-3959(97)00006-7 . 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 . 72 . 1–2 . 99–106 . August 1997 . 9272793 . 1343794 .
  24. 10.1016/j.bpa.2006.12.006 . De Kock MF, Lavand'homme PM . The clinical role of NMDA receptor antagonists for the treatment of postoperative pain . Best Pract Res Clin Anaesthesiol . 21 . 1 . 85–98 . March 2007 . 17489221 .
  25. 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. . Eur J Pain . 12 . 1 . 17–29 . January 2008 . 17449306 . 10.1016/j.ejpain.2007.02.002 . 2875679 .
  26. 10.2165/00126839-200708010-00005 . 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 . 8 . 1 . 51–57 . 2007 . 17249849 . 10268544 .
  27. Vorobeychik Y, Chen L, Bush MC, Mao J . Improved opioid analgesic effect following opioid dose reduction. . Pain Med . 9 . 6 . 724–27 . September 2008 . 18816332 . 10.1111/j.1526-4637.2008.00501.x . free .
  28. DeSantana. JM. Walsh. DM. Vance. C. Rakel. BA. Sluka. KA. Effectiveness of transcutaneous electrical nerve stimulation for treatment of hyperalgesia and pain.. Current Rheumatology Reports. December 2008. 10. 6. 492–99. 19007541. 2746624. 10.1007/s11926-008-0080-z.
  29. Sluka. KA. Chandran. P. Enhanced reduction in hyperalgesia by combined administration of clonidine and TENS.. Pain. November 2002. 100. 1–2. 183–90. 12435471. 10.1016/s0304-3959(02)00294-4. 12117342.

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