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Hyperalgesia

January 13, 2023

Not to be confused with Hypoalgesia.

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]

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.[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]

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

References

  1. ^ "Clinical Pharmacology". www.clinicalpharmacology-ip.com. Retrieved 2017-06-25.
  2. ^ a b 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. S2CID 17797005.
  3. ^ a b 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. S2CID 8489213.
  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. S2CID 9660194.
  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): 1340–45. doi:10.1152/jn.2001.85.3.1340. PMID 11248005. S2CID 2452708.
  6. ^ 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. PMID 17723928.
  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.
  8. ^ 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. PMID 16519664. S2CID 39006891.
  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. S2CID 40500310.
  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. S2CID 41843938.
  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): 223–28. doi:10.1016/j.ejphar.2005.01.033. PMID 15763246.
  12. ^ Ikeda H, Stark J, Fischer H, et al. (June 2006). "Synaptic amplifier of inflammatory pain in the spinal dorsal horn". Science. 312 (5780): 1659–62. Bibcode:2006Sci...312.1659I. doi:10.1126/science.1127233. PMID 16778058. S2CID 20540556.
  13. ^ Kelley KW, Bluthé RM, Dantzer R, et al. (February 2003). "Cytokine-induced sickness behavior". Brain Behav. 17 (Suppl 1): S112–18. doi:10.1016/S0889-1591(02)00077-6. PMID 12615196. S2CID 25400611.
  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): 321–24. doi:10.1016/0006-8993(93)91446-Y. PMID 8221116. S2CID 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 (Jan 2001). "NeuPSIG guidelines on neuropathic pain assessment". Pain. 152 (1): 14–27. doi:10.1016/j.pain.2010.07.031. PMID 20851519. S2CID 2032474.
  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. S2CID 25011309.
  17. ^ Sindrup SH, Otto M, Finnerup NB, Jensen TS (June 2005). "Antidepressants in the treatment of neuropathic pain". Basic Clinical Pharmacology Toxicology. 96 (6): 399–409. doi:10.1111/j.1742-7843.2005.pto_96696601.x. PMID 15910402.
  18. ^ Matsuzawa-Yanagida K, Narita M, Nakajima M, et al. (July 2008). "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. doi:10.1038/sj.npp.1301590. PMID 17957217.
  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. S2CID 33124447.
  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. S2CID 20639496.
  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): 1400–08. doi:10.1097/00000542-200412000-00021. PMID 15564948. S2CID 15060257.
  22. ^ Chizh BA, Göhring M, Tröster A, Quartey GK, Schmelz M, Koppert W (February 2007). "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. doi:10.1093/bja/ael344. PMID 17251214.
  23. ^ 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. PMID 9272793. S2CID 1343794.
  24. ^ 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. PMID 17489221.
  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. S2CID 2875679.
  26. ^ 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. PMID 17249849. S2CID 10268544.
  27. ^ Vorobeychik Y, Chen L, Bush MC, Mao J (September 2008). "Improved opioid analgesic effect following opioid dose reduction". Pain Med. 9 (6): 724–27. doi:10.1111/j.1526-4637.2008.00501.x. PMID 18816332.
  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): 492–99. doi:10.1007/s11926-008-0080-z. PMC 2746624. PMID 19007541.
  29. ^ Sluka, KA; Chandran, P (November 2002). "Enhanced reduction in hyperalgesia by combined administration of clonidine and TENS". Pain. 100 (1–2): 183–90. doi:10.1016/s0304-3959(02)00294-4. PMID 12435471. S2CID 12117342.

External links

January 13, 2023
hyperalgesia, confused, with, hypoalgesia, hyper, from, greek, ὑπέρ, huper, over, algesia, from, greek, algos, ἄλγος, pain, abnormally, increased, sensitivity, pain, which, caused, damage, nociceptors, peripheral, nerves, cause, hypersensitivity, stimulus, pro. Not to be confused with Hypoalgesia Hyperalgesia ˌ h aɪ p er ae l ˈ dʒ iː z i e or s i e hyper from Greek ὑper huper over algesia from Greek algos ἄlgos 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 HyperalgesiaSpecialtyNeurology Contents 1 Types 2 Causes 3 Diagnosis 4 Treatment 5 See also 6 References 7 External linksTypes EditHyperalgesia 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 EditHyperalgesia 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 EditSimple 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 Treatment EditHyperalgesia 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 EditAllodyniaReferences Edit Clinical Pharmacology www clinicalpharmacology ip com Retrieved 2017 06 25 a b 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 S2CID 17797005 a b 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 S2CID 8489213 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 S2CID 9660194 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 PMID 11248005 S2CID 2452708 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 PMID 17723928 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 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 PMID 16519664 S2CID 39006891 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 S2CID 40500310 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 S2CID 41843938 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 PMID 15763246 Ikeda H Stark J Fischer H et al June 2006 Synaptic amplifier of inflammatory pain in the spinal dorsal horn Science 312 5780 1659 62 Bibcode 2006Sci 312 1659I doi 10 1126 science 1127233 PMID 16778058 S2CID 20540556 Kelley KW Bluthe RM Dantzer R et al February 2003 Cytokine induced sickness behavior Brain Behav 17 Suppl 1 S112 18 doi 10 1016 S0889 1591 02 00077 6 PMID 12615196 S2CID 25400611 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 PMID 8221116 S2CID 40529634 Haanpaa 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 S2CID 2032474 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 S2CID 25011309 Sindrup SH Otto M Finnerup NB Jensen TS June 2005 Antidepressants in the treatment of neuropathic pain Basic Clinical Pharmacology Toxicology 96 6 399 409 doi 10 1111 j 1742 7843 2005 pto 96696601 x PMID 15910402 Matsuzawa Yanagida K Narita M Nakajima M et al July 2008 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 doi 10 1038 sj npp 1301590 PMID 17957217 Koppert W Wehrfritz A Korber 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 S2CID 33124447 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 S2CID 20639496 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 PMID 15564948 S2CID 15060257 Chizh BA Gohring M Troster A Quartey GK Schmelz M Koppert W February 2007 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 doi 10 1093 bja ael344 PMID 17251214 Warncke T Stubhaug A Jorum 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 PMID 9272793 S2CID 1343794 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 PMID 17489221 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 S2CID 2875679 Christoph T Kogel 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 amp D 8 1 51 57 doi 10 2165 00126839 200708010 00005 PMID 17249849 S2CID 10268544 Vorobeychik Y Chen L Bush MC Mao J September 2008 Improved opioid analgesic effect following opioid dose reduction Pain Med 9 6 724 27 doi 10 1111 j 1526 4637 2008 00501 x PMID 18816332 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 99 doi 10 1007 s11926 008 0080 z PMC 2746624 PMID 19007541 Sluka KA Chandran P November 2002 Enhanced reduction in hyperalgesia by combined administration of clonidine and TENS Pain 100 1 2 183 90 doi 10 1016 s0304 3959 02 00294 4 PMID 12435471 S2CID 12117342 External links Edit Retrieved from https en wikipedia org w index php title Hyperalgesia amp oldid 1095529720, wikipedia, wiki, book, books, library,

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