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Neuropathic Pain in Small Fiber Neuropathy

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Book cover Small Fiber Neuropathy and Related Syndromes: Pain and Neurodegeneration

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Abstract

Neuropathic pain is the most common and disabling symptom in small fiber neuropathy (SFN). It usually presents as a burning or tingling sensation in the distal limbs, accompanied by increased pain sensitivity, such as hyperalgesia or allodynia. Neuropathic pain in SFN may be a direct consequence of enhanced sensitivity in small myelinated Aδ and unmyelinated C fibers due to axonal degeneration or local inflammation. Damage to these nerve fibers facilitates the release of nerve growth factor or proinflammatory cytokines, which in turn activate nociceptive receptors expressed in sensory neurons, including voltage-gated sodium channels, transient receptor potential cation channel vanilloid type 1 (TRPV1) receptor, and glutamate receptors. Neuropathic pain may also be attributed to maladaptive plasticity in the central nervous system, where hypersensitivity in the spinal or cerebral nociceptive systems, also known as central sensitization, is induced by long-term peripheral overstimulations. In addition, sensory deafferentation due to peripheral denervation also contributes to the development of chronic central pain, where cortical reorganization or remodeling in the pain-processing areas sustains augmented nociceptive responses. Treatment of neuropathic pain in SFN is challenging. Pharmacological therapy is the major strategy to alleviate neuropathic pain in SFN. Possible choices of medications include antiepileptic drugs, antidepressants, and opioids. However, up to 40% of patients with neuropathic pain are refractory to pharmacological treatments. Nonpharmacological therapeutic strategies, e.g., stimulation of peripheral sensory nerves, the spinal cord, or the brain, may be considered as an alternative for patients who are nonresponsive or intolerable to medications. In recent years, noninvasive brain stimulation techniques including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have shown promising advances in pain treatment. These techniques may reset nociceptive processes in the brain by modulating synaptic plasticity in the pain-processing areas. Nevertheless, large randomized clinical trials are still warranted to evaluate the efficacy of these alternative treatment methods.

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References

  1. Hsieh ST. Pathology and functional diagnosis of small-fiber painful neuropathy. Acta Neurol Taiwanica. 2010;19:82–9.

    Google Scholar 

  2. Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. 2008;131:1912–25.

    Article  Google Scholar 

  3. Baron R, Forster M, Binder A. Subgrouping of patients with neuropathic pain according to pain-related sensory abnormalities: a first step to a stratified treatment approach. Lancet Neurol. 2012;11:999–1005.

    Article  Google Scholar 

  4. Truini A, Garcia-Larrea L, Cruccu G. Reappraising neuropathic pain in humans—how symptoms help disclose mechanisms. Nat Rev Neurol. 2013;9:572–82.

    Article  CAS  Google Scholar 

  5. Lin YH, Hsieh SC, Chao CC, Chang YC, Hsieh ST. Influence of aging on thermal and vibratory thresholds of quantitative sensory testing. J Peripher Nerv Syst. 2005;10:269–81.

    Article  Google Scholar 

  6. Hsieh PC, Tseng MT, Chao CC, Lin YH, Tseng WY, Liu KH, et al. Imaging signatures of altered brain responses in small-fiber neuropathy: reduced functional connectivity of the limbic system after peripheral nerve degeneration. Pain. 2015;156:904–16.

    Article  Google Scholar 

  7. Chao CC, Hsieh SC, Tseng MT, Chang YC, Hsieh ST. Patterns of contact heat evoked potentials (CHEP) in neuropathy with skin denervation: correlation of CHEP amplitude with intraepidermal nerve fiber density. Clin Neurophysiol. 2008;119:653–61.

    Article  Google Scholar 

  8. Chien HF, Tseng TJ, Lin WM, Yang CC, Chang YC, Chen RC, et al. Quantitative pathology of cutaneous nerve terminal degeneration in the human skin. Acta Neuropathol. 2001;102:455–61.

    CAS  PubMed  Google Scholar 

  9. Chiang MC, Lin YH, Pan CL, Tseng TJ, Lin WM, Hsieh ST. Cutaneous innervation in chronic inflammatory demyelinating polyneuropathy. Neurology. 2002;59:1094–8.

    Article  Google Scholar 

  10. Chao CC, Tseng MT, Lin YJ, Yang WS, Hsieh SC, Lin YH, et al. Pathophysiology of neuropathic pain in type 2 diabetes: skin denervation and contact heat-evoked potentials. Diabetes Care. 2010;33:2654–9.

    Article  Google Scholar 

  11. Tseng MT, Chiang MC, Chao CC, Tseng WY, Hsieh ST. fMRI evidence of degeneration-induced neuropathic pain in diabetes: enhanced limbic and striatal activations. Hum Brain Mapp. 2013;34:2733–46.

    Article  Google Scholar 

  12. Holland NR, Stocks A, Hauer P, Cornblath DR, Griffin JW, McArthur JC. Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology. 1997;48:708–11.

    Article  CAS  Google Scholar 

  13. Kennedy WR, Said G. Sensory nerves in skin: answers about painful feet? Neurology. 1999;53:1614–5.

    Article  CAS  Google Scholar 

  14. Periquet MI, Novak V, Collins MP, Nagaraja HN, Erdem S, Nash SM, et al. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology. 1999;53:1641–7.

    Article  CAS  Google Scholar 

  15. Lindenlaub T, Sommer C. Epidermal innervation density after partial sciatic nerve lesion and pain-related behavior in the rat. Acta Neuropathol. 2002;104:137–43.

    Article  CAS  Google Scholar 

  16. Nolano M, Crisci C, Santoro L, Barbieri F, Casale R, Kennedy WR, et al. Absent innervation of skin and sweat glands in congenital insensitivity to pain with anhidrosis. Clin Neurophysiol. 2000;111:1596–601.

    Article  CAS  Google Scholar 

  17. Lauria G, Lombardi R. Skin biopsy in painful and immune-mediated neuropathies. J Peripher Nerv Syst. 2012;17(Suppl 3):38–45.

    Article  CAS  Google Scholar 

  18. Lai J, Hunter JC, Porreca F. The role of voltage-gated sodium channels in neuropathic pain. Curr Opin Neurobiol. 2003;13:291–7.

    Article  CAS  Google Scholar 

  19. Hong S, Wiley JW. Early painful diabetic neuropathy is associated with differential changes in the expression and function of vanilloid receptor 1. J Biol Chem. 2005;280:618–27.

    Article  CAS  Google Scholar 

  20. Hudson LJ, Bevan S, Wotherspoon G, Gentry C, Fox A, Winter J. VR1 protein expression increases in undamaged DRG neurons after partial nerve injury. Eur J Neurosci. 2001;13:2105–14.

    Article  CAS  Google Scholar 

  21. Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P, et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature. 2000;405:183–7.

    Article  CAS  Google Scholar 

  22. Ko MH, Hsieh YL, Hsieh ST, Tseng TJ. Nerve demyelination increases metabotropic glutamate receptor subtype 5 expression in peripheral painful mononeuropathy. Int J Mol Sci. 2015;16:4642–65.

    Article  CAS  Google Scholar 

  23. Marchand F, Perretti M, McMahon SB. Role of the immune system in chronic pain. Nat Rev Neurosci. 2005;6:521–32.

    Article  CAS  Google Scholar 

  24. Purwata TE. High TNF-alpha plasma levels and macrophages iNOS and TNF-alpha expression as risk factors for painful diabetic neuropathy. J Pain Res. 2011;4:169–75.

    Article  CAS  Google Scholar 

  25. Uçeyler N, Kafke W, Riediger N, He L, Necula G, Toyka KV, et al. Elevated proinflammatory cytokine expression in affected skin in small fiber neuropathy. Neurology. 2010;74:1806–13.

    Article  Google Scholar 

  26. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152:S2–15.

    Article  Google Scholar 

  27. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10:895–926.

    Article  Google Scholar 

  28. Baron R. Mechanisms of disease: neuropathic pain—a clinical perspective. Nat Clin Pract Neurol. 2006;2:95–106.

    Article  Google Scholar 

  29. von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron. 2012;73:638–52.

    Article  Google Scholar 

  30. Mendell LM, Wall PD. Responses of single dorsal cord cells to peripheral cutaneous unmyelinated fibres. Nature. 1965;206:97–9.

    Article  CAS  Google Scholar 

  31. Cook AJ, Woolf CJ, Wall PD, McMahon SB. Dynamic receptive field plasticity in rat spinal cord dorsal horn following C-primary afferent input. Nature. 1987;325:151–3.

    Article  CAS  Google Scholar 

  32. Torebjork HE, Lundberg LE, LaMotte RH. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol. 1992;448:765–80.

    Article  CAS  Google Scholar 

  33. Devor M. Ectopic discharge in Abeta afferents as a source of neuropathic pain. Exp Brain Res. 2009;196:115–28.

    Article  CAS  Google Scholar 

  34. Koltzenburg M, Lundberg LE, Torebjork HE. Dynamic and static components of mechanical hyperalgesia in human hairy skin. Pain. 1992;51:207–19.

    Article  CAS  Google Scholar 

  35. Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain. 1991;44:293–9.

    Article  CAS  Google Scholar 

  36. Luo C, Kuner T, Kuner R. Synaptic plasticity in pathological pain. Trends Neurosci. 2014;37:343–55.

    Article  CAS  Google Scholar 

  37. Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending facilitation. Trends Neurosci. 2002;25:319–25.

    Article  CAS  Google Scholar 

  38. Urban MO, Gebhart GF. Supraspinal contributions to hyperalgesia. Proc Natl Acad Sci U S A. 1999;96:7687–92.

    Article  CAS  Google Scholar 

  39. Wei F, Zhuo M. Potentiation of sensory responses in the anterior cingulate cortex following digit amputation in the anaesthetised rat. J Physiol. 2001;532:823–33.

    Article  CAS  Google Scholar 

  40. Fu Y, Han J, Ishola T, Scerbo M, Adwanikar H, Ramsey C, et al. PKA and ERK, but not PKC, in the amygdala contribute to pain-related synaptic plasticity and behavior. Mol Pain. 2008;4:26.

    Article  Google Scholar 

  41. Pedersen LH, Scheel-Kruger J, Blackburn-Munro G. Amygdala GABA-A receptor involvement in mediating sensory-discriminative and affective-motivational pain responses in a rat model of peripheral nerve injury. Pain. 2007;127:17–26.

    Article  CAS  Google Scholar 

  42. Vogt BA. Pain and emotion interactions in subregions of the cingulate gyrus. Nat Rev Neurosci. 2005;6:533–44.

    Article  CAS  Google Scholar 

  43. Derbyshire SW. Exploring the pain “neuromatrix”. Curr Rev Pain. 2000;4:467–77.

    Article  CAS  Google Scholar 

  44. Peyron R, Laurent B, Garcia-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin. 2000;30:263–88.

    Article  CAS  Google Scholar 

  45. Schweinhardt P, Glynn C, Brooks J, McQuay H, Jack T, Chessell I, et al. An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients. Neuroimage. 2006;32:256–65.

    Article  Google Scholar 

  46. Becerra L, Morris S, Bazes S, Gostic R, Sherman S, Gostic J, et al. Trigeminal neuropathic pain alters responses in CNS circuits to mechanical (brush) and thermal (cold and heat) stimuli. J Neurosci. 2006;26:10646–57.

    Article  CAS  Google Scholar 

  47. DaSilva AF, Becerra L, Pendse G, Chizh B, Tully S, Borsook D. Colocalized structural and functional changes in the cortex of patients with trigeminal neuropathic pain. PLoS One. 2008;3:e3396.

    Article  Google Scholar 

  48. Lauria G, Morbin M, Lombardi R, Capobianco R, Camozzi F, Pareyson D, et al. Expression of capsaicin receptor immunoreactivity in human peripheral nervous system and in painful neuropathies. J Peripher Nerv Syst. 2006;11:262–71.

    Article  CAS  Google Scholar 

  49. MacIver K, Lloyd DM, Kelly S, Roberts N, Nurmikko T. Phantom limb pain, cortical reorganization and the therapeutic effect of mental imagery. Brain. 2008;131:2181–91.

    Article  CAS  Google Scholar 

  50. Flor H. Maladaptive plasticity, memory for pain and phantom limb pain: review and suggestions for new therapies. Expert Rev Neurother. 2008;8:809–18.

    Article  Google Scholar 

  51. Chiang MC, Dutton RA, Hayashi KM, Lopez OL, Aizenstein HJ, Toga AW, et al. 3D pattern of brain atrophy in HIV/AIDS visualized using tensor-based morphometry. Neuroimage. 2007;34:44–60.

    Article  Google Scholar 

  52. Friston KJ, Buechel C, Fink GR, Morris J, Rolls E, Dolan RJ. Psychophysiological and modulatory interactions in neuroimaging. Neuroimage. 1997;6:218–29.

    Article  CAS  Google Scholar 

  53. Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, et al. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76:1758–65.

    Article  CAS  Google Scholar 

  54. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005;118:289–305.

    Article  CAS  Google Scholar 

  55. Moore A, Wiffen P, Kalso E. Antiepileptic drugs for neuropathic pain and fibromyalgia. JAMA. 2014;312:182–3.

    Article  CAS  Google Scholar 

  56. Hansson PT, Attal N, Baron R, Cruccu G. Toward a definition of pharmacoresistant neuropathic pain. Eur J Pain. 2009;13:439–40.

    Article  Google Scholar 

  57. Morozumi S, Kawagashira Y, Iijima M, Koike H, Hattori N, Katsuno M, et al. Intravenous immunoglobulin treatment for painful sensory neuropathy associated with Sjogren’s syndrome. J Neurol Sci. 2009;279:57–61.

    Article  CAS  Google Scholar 

  58. Kawagashira Y, Watanabe H, Oki Y, Iijima M, Koike H, Hattori N, et al. Intravenous immunoglobulin therapy markedly ameliorates muscle weakness and severe pain in proximal diabetic neuropathy. J Neurol Neurosurg Psychiatry. 2007;78:899–901.

    Article  CAS  Google Scholar 

  59. White PF, Li S, Chiu JW. Electroanalgesia: its role in acute and chronic pain management. Anesth Analg. 2001;92:505–13.

    Article  CAS  Google Scholar 

  60. Hamza MA, White PF, Craig WF, Ghoname ES, Ahmed HE, Proctor TJ, et al. Percutaneous electrical nerve stimulation: a novel analgesic therapy for diabetic neuropathic pain. Diabetes Care. 2000;23:365–70.

    Article  CAS  Google Scholar 

  61. Oyibo SO, Breislin K, Boulton AJ. Electrical stimulation therapy through stocking electrodes for painful diabetic neuropathy: a double blind, controlled crossover study. Diabet Med. 2004;21:940–4.

    Article  CAS  Google Scholar 

  62. Jacobs MJ, Jorning PJ, Joshi SR, Kitslaar PJ, Slaaf DW, Reneman RS. Epidural spinal cord electrical stimulation improves microvascular blood flow in severe limb ischemia. Ann Surg. 1988;207:179–83.

    Article  CAS  Google Scholar 

  63. Tesfaye S, Watt J, Benbow SJ, Pang KA, Miles J, MacFarlane IA. Electrical spinal-cord stimulation for painful diabetic peripheral neuropathy. Lancet. 1996;348:1698–701.

    Article  CAS  Google Scholar 

  64. Miyazaki Y, Koike H, Akane A, Shibata Y, Nishiwaki K, Sobue G. Spinal cord stimulation markedly ameliorated refractory neuropathic pain in transthyretin Val30Met familial amyloid polyneuropathy. Amyloid. 2011;18:87–90.

    Article  Google Scholar 

  65. Fregni F, Freedman S, Pascual-Leone A. Recent advances in the treatment of chronic pain with non-invasive brain stimulation techniques. Lancet Neurol. 2007;6:188–91.

    Article  Google Scholar 

  66. Hallett M. Transcranial magnetic stimulation and the human brain. Nature. 2000;406:147–50.

    Article  CAS  Google Scholar 

  67. Ziemann U. TMS induced plasticity in human cortex. Rev Neurosci. 2004;15:253–66.

    Article  Google Scholar 

  68. Tamura Y, Okabe S, Ohnishi T, NS D, Arai N, Mochio S, et al. Effects of 1-Hz repetitive transcranial magnetic stimulation on acute pain induced by capsaicin. Pain. 2004;107:107–15.

    Article  Google Scholar 

  69. Graff-Guerrero A, Gonzalez-Olvera J, Fresan A, Gomez-Martin D, Mendez-Nunez JC, Pellicer F. Repetitive transcranial magnetic stimulation of dorsolateral prefrontal cortex increases tolerance to human experimental pain. Brain Res Cogn Brain Res. 2005;25:153–60.

    Article  Google Scholar 

  70. Nguyen JP, Nizard J, Keravel Y, Lefaucheur JP. Invasive brain stimulation for the treatment of neuropathic pain. Nat Rev Neurol. 2011;7:699–709.

    Article  CAS  Google Scholar 

  71. Galhardoni R, Correia GS, Araujo H, Yeng LT, Fernandes DT, Kaziyama HH, et al. Repetitive transcranial magnetic stimulation in chronic pain: a review of the literature. Arch Phys Med Rehabil. 2015;96:S156–72.

    Article  Google Scholar 

  72. Onesti E, Gabriele M, Cambieri C, Ceccanti M, Raccah R, Di Stefano G, et al. H-coil repetitive transcranial magnetic stimulation for pain relief in patients with diabetic neuropathy. Eur J Pain. 2013;17:1347–56.

    Article  CAS  Google Scholar 

  73. Qiu YQ, Hua XY, Zuo CT, Li T, Zheng MX, Shen YD, et al. Deactivation of distant pain-related regions induced by 20-day rTMS: a case study of one-week pain relief for long-term intractable deafferentation pain. Pain Physician. 2014;17:E99–105.

    PubMed  Google Scholar 

  74. Maarrawi J, Peyron R, Mertens P, Costes N, Magnin M, Sindou M, et al. Motor cortex stimulation for pain control induces changes in the endogenous opioid system. Neurology. 2007;69:827–34.

    Article  CAS  Google Scholar 

  75. de Andrade DC, Mhalla A, Adam F, Texeira MJ, Bouhassira D. Neuropharmacological basis of rTMS-induced analgesia: the role of endogenous opioids. Pain. 2011;152:320–6.

    Article  Google Scholar 

  76. Lefaucheur JP, Drouot X, Menard-Lefaucheur I, Keravel Y, Nguyen JP. Motor cortex rTMS restores defective intracortical inhibition in chronic neuropathic pain. Neurology. 2006;67:1568–74.

    Article  CAS  Google Scholar 

  77. Filmer HL, Dux PE, Mattingley JB. Applications of transcranial direct current stimulation for understanding brain function. Trends Neurosci. 2014;37:742–53.

    Article  CAS  Google Scholar 

  78. Kim YJ, Ku J, Kim HJ, Im DJ, Lee HS, Han KA, et al. Randomized, sham controlled trial of transcranial direct current stimulation for painful diabetic polyneuropathy. Ann Rehabil Med. 2013;37:766–76.

    Article  Google Scholar 

  79. Portilla AS, Bravo GL, Miraval FK, Villamar MF, Schneider JC, Ryan CM, et al. A feasibility study assessing cortical plasticity in chronic neuropathic pain following burn injury. J Burn Care Res. 2013;34:e48–52.

    Article  Google Scholar 

  80. DosSantos MF, Love TM, Martikainen IK, Nascimento TD, Fregni F, Cummiford C, et al. Immediate effects of tDCS on the mu-opioid system of a chronic pain patient. Front Psychiatry. 2012;3:93.

    PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, National Yang-Ming University, Taipei, Taiwan

    Ming-Chang Chiang

  2. Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan

    Paul-Chen Hsieh

  3. Department of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan

    Sung-Tsang Hsieh

  4. Center of Precision Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

    Sung-Tsang Hsieh

  5. Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan

    Sung-Tsang Hsieh

  6. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

    Sung-Tsang Hsieh

  7. Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan

    Sung-Tsang Hsieh

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  1. Ming-Chang Chiang
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Editors and Affiliations

  1. Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan

    Sung-Tsang Hsieh

  2. Department of Neurology, Imperial College London, Hammersmith Hospital, London, UK

    Praveen Anand

  3. Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Christopher H. Gibbons

  4. Neurologische Klinik, Universitätsklinikum Würzburg , Würzburg, Germany

    Claudia Sommer

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Chiang, MC., Hsieh, PC., Hsieh, ST. (2019). Neuropathic Pain in Small Fiber Neuropathy. In: Hsieh, ST., Anand, P., Gibbons, C., Sommer, C. (eds) Small Fiber Neuropathy and Related Syndromes: Pain and Neurodegeneration. Springer, Singapore. https://doi.org/10.1007/978-981-13-3546-4_14

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