Hyperalgesia

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 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]

Not to be confused with Hypoalgesia.
Hyperalgesia
SpecialtyNeurology 

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 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.

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]

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See also

References
  1. "Clinical Pharmacology". www.clinicalpharmacology-ip.com. Retrieved 2017-06-25.
  2. Hart BL (1988). "Biological basis of the behavior of sick animals". Neurosci Biobehav Rev. 12 (2): 123–37. doi:10.1016/S0149-7634(88)80004-6. PMID 3050629.
  3. Chu LF, Angst MS, Clark D (2008). "Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations". Clin J Pain. 24 (6): 479–96. doi:10.1097/AJP.0b013e31816b2f43. PMID 18574358.
  4. 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. PMID 15995723.
  5. 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): 1340–5. doi:10.1152/jn.2001.85.3.1340. PMID 11248005.
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  7. Mitra S (2018). "Opioid-induced hyperalgesia: pathophysiology and clinical implications". J Opioid Manag. 4 (3): 123–30. doi:10.5055/jom.2008.0017. PMID 18717507.
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  9. 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. PMID 17069983.
  10. Chen Y, Sommer C (May 2007). "Activation of the nociceptin opioid system in rats. Sensory neurons produce antinociceptive effects in inflammatory pain: involvement of inflammatory mediators" (PDF). J. Neurosci. Res. 85 (7): 1478–88. doi:10.1002/jnr.21272. hdl:10161/13662. PMID 17387690.
  11. 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): 223–8. doi:10.1016/j.ejphar.2005.01.033. PMID 15763246.
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  14. 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): 321–4. doi:10.1016/0006-8993(93)91446-Y. PMID 8221116.
  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 (Jan 2001). "NeuPSIG guidelines on neuropathic pain assessment". Pain. 152 (1): 14–27. doi:10.1016/j.pain.2010.07.031. PMID 20851519.
  16. Jensen TS, Finnerup NB (Sep 2014). "Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms". Lancet Neurol. 13 (9): 924–35. doi:10.1016/S1474-4422(14)70102-4. PMID 25142459.
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  19. 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. PMID 15109518.
  20. 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. PMID 17714578.
  21. 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): 1400–8. doi:10.1097/00000542-200412000-00021. PMID 15564948.
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  25. 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. PMID 17449306.
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  27. Vorobeychik Y, Chen L, Bush MC, Mao J (September 2008). "Improved opioid analgesic effect following opioid dose reduction". Pain Med. 9 (6): 724–7. doi:10.1111/j.1526-4637.2008.00501.x. PMID 18816332. Archived from the original on 2013-01-05.
  28. DeSantana, JM; Walsh, DM; Vance, C; Rakel, BA; Sluka, KA (December 2008). "Effectiveness of transcutaneous electrical nerve stimulation for treatment of hyperalgesia and pain". Current Rheumatology Reports. 10 (6): 492–9. doi:10.1007/s11926-008-0080-z. PMC 2746624. PMID 19007541.
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