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Neuropathic pain

Nature Reviews Disease Primers volume 3, Article number: 17002 (2017) Cite this article

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Abstract

Neuropathic pain is caused by a lesion or disease of the somatosensory system, including peripheral fibres (Aβ, Aδ and C fibres) and central neurons, and affects 7–10% of the general population. Multiple causes of neuropathic pain have been described and its incidence is likely to increase owing to the ageing global population, increased incidence of diabetes mellitus and improved survival from cancer after chemotherapy. Indeed, imbalances between excitatory and inhibitory somatosensory signalling, alterations in ion channels and variability in the way that pain messages are modulated in the central nervous system all have been implicated in neuropathic pain. The burden of chronic neuropathic pain seems to be related to the complexity of neuropathic symptoms, poor outcomes and difficult treatment decisions. Importantly, quality of life is impaired in patients with neuropathic pain owing to increased drug prescriptions and visits to health care providers, as well as the morbidity from the pain itself and the inciting disease. Despite challenges, progress in the understanding of the pathophysiology of neuropathic pain is spurring the development of new diagnostic procedures and personalized interventions, which emphasize the need for a multidisciplinary approach to the management of neuropathic pain.

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Figure 1: The peripheral and central changes induced by nerve injury or peripheral neuropathy.
Figure 2: Neuroanatomical distribution of pain symptoms and sensory signs in neuropathic pain conditions.
Figure 3: Schematic representation of the conditioned pain modulation.
Figure 4: Diagnosing neuropathic pain.
Figure 5: Subgrouping patients with peripheral neuropathic pain based on sensory signs.
Figure 6: Example interventional treatments for neuropathic pain.

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References

  1. Abbott, C. A., Malik, R. A., van Ross, E. R., Kulkarni, J. & Boulton, A. J. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K. Diabetes Care 34, 2220–2224 (2011).

    Google Scholar 

  2. Costigan, M., Scholz, J. & Woolf, C. J. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu. Rev. Neurosci. 32, 1–32 (2009). This review presents differences and commonalities among distinct chronic pain states.

    CAS  Google Scholar 

  3. Attal, N., Lanteri-Minet, M., Laurent, B., Fermanian, J. & Bouhassira, D. The specific disease burden of neuropathic pain: results of a French nationwide survey. Pain 152, 2836–2843 (2011).

    Google Scholar 

  4. Torrance, N., Smith, B. H., Bennett, M. I. & Lee, A. J. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J. Pain 7, 281–289 (2006).

    Google Scholar 

  5. Finnerup, N. B. et al. Neuropathic pain: an updated grading system for research and clinical practice. Pain 157, 1599–1606 (2016). This is an updated grading system to guide clinical diagnosis of neuropathic pain by illustrating the significance of confirmatory tests, the role of screening tools and potential uncertainties about anatomical pain distributions.

    CAS  Google Scholar 

  6. Dolgin, E. Fluctuating baseline pain implicated in failure of clinical trials. Nat. Med. 16, 1053 (2010).

    Google Scholar 

  7. Tuttle, A. H. et al. Increasing placebo responses over time in U.S. clinical trials of neuropathic pain. Pain 156, 2616–2626 (2015). This study explores factors explaining why novel analgesics that were designed to treat neuropathic pain failed.

    Google Scholar 

  8. van Hecke, O., Austin, S. K., Khan, R. A., Smith, B. H. & Torrance, N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 155, 654–662 (2014). This is one of the first attempts to review epidemiological studies of neuropathic pain in the general population; however, the heterogeneity of the studies precluded meta-analysis, indicating a need for standardized tools and diagnostic approaches.

    CAS  Google Scholar 

  9. Bouhassira, D. et al. Patient perspective on herpes zoster and its complications: an observational prospective study in patients aged over 50 years in general practice. Pain 153, 342–349 (2012).

    Google Scholar 

  10. Helgason, S., Petursson, G., Gudmundsson, S. & Sigurdsson, J. A. Prevalence of postherpetic neuralgia after a first episode of herpes zoster: prospective study with long term follow up. BMJ 321, 794–796 (2000).

    CAS  Google Scholar 

  11. Daousi, C. et al. Chronic painful peripheral neuropathy in an urban community: a controlled comparison of people with and without diabetes. Diabet. Med. 21, 976–982 (2004).

    CAS  Google Scholar 

  12. Davies, M., Brophy, S., Williams, R. & Taylor, A. The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care 29, 1518–1522 (2006).

    Google Scholar 

  13. Bouhassira, D., Letanoux, M. & Hartemann, A. Chronic pain with neuropathic characteristics in diabetic patients: a French cross-sectional study. PLoS ONE 8, e74195 (2013).

    CAS  Google Scholar 

  14. Jensen, M. P., Chodroff, M. J. & Dworkin, R. H. The impact of neuropathic pain on health-related quality of life: review and implications. Neurology 68, 1178–1182 (2007).

    Google Scholar 

  15. Solaro, C. et al. The prevalence of pain in multiple sclerosis: a multicenter cross-sectional study. Neurology 63, 919–921 (2004).

    CAS  Google Scholar 

  16. Osterberg, A., Boivie, J. & Thuomas, K. A. Central pain in multiple sclerosis — prevalence and clinical characteristics. Eur. J. Pain 9, 531–542 (2005).

    CAS  Google Scholar 

  17. Siddall, P. J., McClelland, J. M., Rutkowski, S. B. & Cousins, M. J. A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury. Pain 103, 249–257 (2003).

    Google Scholar 

  18. Klit, H., Finnerup, N. B., Andersen, G. & Jensen, T. S. Central poststroke pain: a population-based study. Pain 152, 818–824 (2011).

    Google Scholar 

  19. Rayment, C. et al. Neuropathic cancer pain: prevalence, severity, analgesics and impact from the European Palliative Care Research Collaborative-Computerised Symptom Assessment study. Palliat. Med. 27, 714–721 (2013).

    Google Scholar 

  20. Bennett, M. I. et al. Prevalence and aetiology of neuropathic pain in cancer patients: a systematic review. Pain 153, 359–365 (2012).

    Google Scholar 

  21. Bouhassira, D. & Attal, N. Diagnosis and assessment of neuropathic pain: the saga of clinical tools. Pain 152, S74–S83 (2011). This review describes the main clinical tools that are used for the screening and measurement of neuropathic pain, focusing on the potential value and limitation of each tool.

    Google Scholar 

  22. Bouhassira, D. et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 114, 29–36 (2005).

    Google Scholar 

  23. Bennett, M. The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and signs. Pain 92, 147–157 (2001).

    CAS  Google Scholar 

  24. Bouhassira, D., Lanteri-Minet, M., Attal, N., Laurent, B. & Touboul, C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 136, 380–387 (2008).

    Google Scholar 

  25. Freynhagen, R. et al. Screening of neuropathic pain components in patients with chronic back pain associated with nerve root compression: a prospective observational pilot study (MIPORT). Curr. Med. Res. Opin. 22, 529–537 (2006).

    Google Scholar 

  26. Borsook, D. Neurological diseases and pain. Brain 135, 320–344 (2012).

    Google Scholar 

  27. Watson, J. C. & Sandroni, P. Central neuropathic pain syndromes. Mayo Clin. Proc. 91, 372–385 (2016).

    Google Scholar 

  28. Stavros, K. & Simpson, D. M. Understanding the etiology and management of HIV-associated peripheral neuropathy. Curr. HIV/AIDS Rep. 11, 195–201 (2014).

    Google Scholar 

  29. Thakur, S., Dworkin, R. H., Haroun, O. M., Lockwood, D. N. & Rice, A. S. Acute and chronic pain associated with leprosy. Pain 156, 998–1002 (2015).

    Google Scholar 

  30. Freeman, R. Not all neuropathy in diabetes is of diabetic etiology: differential diagnosis of diabetic neuropathy. Curr. Diab. Rep. 9, 423–431 (2009). This article discusses common disorders in the differential diagnosis of peripheral neuropathy.

    Google Scholar 

  31. Yang, Y. et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J. Med. Genet. 41, 171–174 (2004).

    CAS  Google Scholar 

  32. Fertleman, C. R. et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron 52, 767–774 (2006).

    CAS  Google Scholar 

  33. Faber, C. G. et al. Gain of function Nav1.7 mutations in idiopathic small fiber neuropathy. Ann. Neurol. 71, 26–39 (2012).

    CAS  Google Scholar 

  34. Haroutounian, S. et al. Primary afferent input critical for maintaining spontaneous pain in peripheral neuropathy. Pain 155, 1272–1279 (2014).

    Google Scholar 

  35. Vaso, A. et al. Peripheral nervous system origin of phantom limb pain. Pain 155, 1384–1391 (2014).

    Google Scholar 

  36. Serra, J. et al. Microneurographic identification of spontaneous activity in C-nociceptors in neuropathic pain states in humans and rats. Pain 153, 42–55 (2012).

    CAS  Google Scholar 

  37. Kleggetveit, I. P. et al. High spontaneous activity of C-nociceptors in painful polyneuropathy. Pain 153, 2040–2047 (2012).

    CAS  Google Scholar 

  38. Tesfaye, S., Boulton, A. J. & Dickenson, A. H. Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes Care 36, 2456–2465 (2013).

    CAS  Google Scholar 

  39. Fields, H. L., Rowbotham, M. & Baron, R. Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol. Dis. 5, 209–227 (1998).

    CAS  Google Scholar 

  40. Woolf, C. J. Central sensitization: implications for the diagnosis and treatment of pain. Pain 152, S2–S15 (2011).

    Google Scholar 

  41. Baron, R., Hans, G. & Dickenson, A. H. Peripheral input and its importance for central sensitization. Ann. Neurol. 74, 630–636 (2013). This article presents the main mechanisms of pain states that begin with damage to the nerves in the periphery and lead to enhanced transmitter release within the spinal cord and central sensitization — emphasizing the need for multimodal approaches that target central sensitization and/or its peripheral drivers.

    Google Scholar 

  42. Patel, R. & Dickenson, A. H. Neuronal hyperexcitability in the ventral posterior thalamus of neuropathic rats: modality selective effects of pregabalin. J. Neurophysiol. 116, 159–170 (2016).

    CAS  Google Scholar 

  43. Peyron, R. Functional brain imaging: what has it brought to our understanding of neuropathic pain? A special focus on allodynic pain mechanisms. Pain 157, S67–S71 (2016).

    Google Scholar 

  44. Gagnon, M. et al. Chloride extrusion enhancers as novel therapeutics for neurological diseases. Nat. Med. 19, 1524–1528 (2013).

    CAS  Google Scholar 

  45. Tsuda, M., Beggs, S., Salter, M. W. & Inoue, K. Microglia and intractable chronic pain. Glia 61, 55–61 (2013).

    Google Scholar 

  46. Navratilova, E., Atcherley, C. W. & Porreca, F. Brain circuits encoding reward from pain relief. Trends Neurosci. 38, 741–750 (2015).

    CAS  Google Scholar 

  47. Bannister, K. & Dickenson, A. H. What the brain tells the spinal cord. Pain 157, 2148–2151 (2016).

    Google Scholar 

  48. Yarnitsky, D. Role of endogenous pain modulation in chronic pain mechanisms and treatment. Pain 156, S24–S31 (2015).

    Google Scholar 

  49. Lewis, G. N., Rice, D. A. & McNair, P. J. Conditioned pain modulation in populations with chronic pain: a systematic review and meta-analysis. J. Pain 13, 936–944 (2012).

    Google Scholar 

  50. Yarnitsky, D., Granot, M., Nahman-Averbuch, H., Khamaisi, M. & Granovsky, Y. Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain 153, 1193–1198 (2012). This article presents a new perspective of predicting drug responses in patients with painful diabetic neuropathy based on CPM mechanisms.

    CAS  Google Scholar 

  51. Wilder-Smith, O. H., Schreyer, T., Scheffer, G. J. & Arendt-Nielsen, L. Patients with chronic pain after abdominal surgery show less preoperative endogenous pain inhibition and more postoperative hyperalgesia: a pilot study. J. Pain Palliat. Care Pharmacother. 24, 119–128 (2010).

    Google Scholar 

  52. Petersen, K. K., Graven-Nielsen, T., Simonsen, O., Laursen, M. B. & Arendt-Nielsen, L. Preoperative pain mechanisms assessed by cuff algometry are associated with chronic postoperative pain relief after total knee replacement. Pain 157, 1400–1406 (2016).

    Google Scholar 

  53. Kosek, E. & Ordeberg, G. Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following, surgical pain relief. Pain 88, 69–78 (2000).

    CAS  Google Scholar 

  54. Graven-Nielsen, T., Wodehouse, T., Langford, R. M., Arendt-Nielsen, L. & Kidd, B. L. Normalization of widespread hyperesthesia and facilitated spatial summation of deep-tissue pain in knee osteoarthritis patients after knee replacement. Arthritis Rheum. 64, 2907–2916 (2012).

    CAS  Google Scholar 

  55. Colloca, L. & Miller, F. G. Role of expectations in health. Curr. Opin. Psychiatry 24, 149–155 (2011).

    Google Scholar 

  56. Hall, K. T. et al. Conscientiousness is modified by genetic variation in catechol-O-methyltransferase to reduce symptom complaints in IBS patients. Brain Behav. 5, 39–44 (2015).

    Google Scholar 

  57. Kaptchuk, T. J. et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ 336, 999–1003 (2008).

    Google Scholar 

  58. Vase, L., Robinson, M. E., Verne, G. N. & Price, D. D. The contributions of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients. An empirical investigation. Pain 105, 17–25 (2003).

    Google Scholar 

  59. Vase, L., Skyt, I. & Hall, K. T. Placebo, nocebo, and neuropathic pain. Pain 157, S98–S105 (2016).

    Google Scholar 

  60. Petersen, G. L. et al. Placebo manipulations reduce hyperalgesia in neuropathic pain. Pain 153, 1292–1300 (2012).

    Google Scholar 

  61. Petersen, G. L. et al. Expectations and positive emotional feelings accompany reductions in ongoing and evoked neuropathic pain following placebo interventions. Pain 155, 2687–2698 (2014).

    Google Scholar 

  62. Colloca, L., Lopiano, L., Lanotte, M. & Benedetti, F. Overt versus covert treatment for pain, anxiety, and Parkinson's disease. Lancet Neurol. 3, 679–684 (2004).

    Google Scholar 

  63. Bennett, M. I. et al. Using screening tools to identify neuropathic pain. Pain 127, 199–203 (2007).

    Google Scholar 

  64. Freynhagen, R., Baron, R., Gockel, U. & Tolle, T. R. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr. Med. Res. Opin. 22, 1911–1920 (2006).

    Google Scholar 

  65. Bouhassira, D. et al. Development and validation of the Neuropathic Pain Symptom Inventory. Pain 108, 248–257 (2004).

    Google Scholar 

  66. 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. 11, 999–1005 (2012).

    Google Scholar 

  67. Cruccu, G. et al. EFNS guidelines on neuropathic pain assessment: revised 2009. Eur. J. Neurol. 17, 1010–1018 (2010).

    CAS  Google Scholar 

  68. Backonja, M. M. et al. Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus. Pain 154, 1807–1819 (2013).

    Google Scholar 

  69. Rolke, R. et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 123, 231–243 (2006).

    CAS  Google Scholar 

  70. Baron, R. et al. Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles. Pain 158, 261–272 (2017). This study shows how patients with neuropathic pain present with different expression patterns of sensory signs, which suggests various mechanisms of neuropathic pain generation.

    Google Scholar 

  71. Magerl, W. et al. Reference data for quantitative sensory testing (QST): refined stratification for age and a novel method for statistical comparison of group data. Pain 151, 598–605 (2010).

    Google Scholar 

  72. Haanpaa, M. et al. NeuPSIG guidelines on neuropathic pain assessment. Pain 152, 14–27 (2011).

    Google Scholar 

  73. Garcia-Larrea, L. Objective pain diagnostics: clinical neurophysiology. Neurophysiol. Clin. 42, 187–197 (2012).

    CAS  Google Scholar 

  74. Truini, A. et al. Pathophysiology of pain in postherpetic neuralgia: a clinical and neurophysiological study. Pain 140, 405–410 (2008).

    CAS  Google Scholar 

  75. Truini, A. et al. Differential involvement of A-delta and A-beta fibres in neuropathic pain related to carpal tunnel syndrome. Pain 145, 105–109 (2009).

    CAS  Google Scholar 

  76. Truini, A. et al. Mechanisms of pain in distal symmetric polyneuropathy: a combined clinical and neurophysiological study. Pain 150, 516–521 (2010).

    CAS  Google Scholar 

  77. Truini, A., Garcia-Larrea, L. & Cruccu, G. Reappraising neuropathic pain in humans — how symptoms help disclose mechanisms. Nat. Rev. Neurol. 9, 572–582 (2013).

    CAS  Google Scholar 

  78. Truini, A. et al. Trigeminal small-fibre function assessed with contact heat evoked potentials in humans. Pain 132, 102–107 (2007).

    CAS  Google Scholar 

  79. Hansen, N. et al. Amplitudes of pain-related evoked potentials are useful to detect small fiber involvement in painful mixed fiber neuropathies in addition to quantitative sensory testing — an electrophysiological study. Front. Neurol. 6, 244 (2015).

    Google Scholar 

  80. Tesfaye, S. et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33, 2285–2293 (2010).

    Google Scholar 

  81. Lauria, G. et al. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur. J. Neurol. 17, 903–912 (2010).

    CAS  Google Scholar 

  82. Nolano, M. et al. Cutaneous innervation of the human face as assessed by skin biopsy. J. Anat. 222, 161–169 (2013).

    Google Scholar 

  83. Truini, A. et al. Does the epidermal nerve fibre density measured by skin biopsy in patients with peripheral neuropathies correlate with neuropathic pain? Pain 155, 828–832 (2014). This study presents the advantages and limitations of using skin biopsy and epidermal nerve fibre density measurement for the diagnosis of neuropathic pain.

    CAS  Google Scholar 

  84. Papanas, N. & Ziegler, D. Corneal confocal microscopy: recent progress in the evaluation of diabetic neuropathy. J. Diabetes Investig. 6, 381–389 (2015).

    Google Scholar 

  85. Ziegler, D. et al. Early detection of nerve fiber loss by corneal confocal microscopy and skin biopsy in recently diagnosed type 2 diabetes. Diabetes 63, 2454–2463 (2014).

    Google Scholar 

  86. Tavakoli, M. et al. Corneal confocal microscopy: a novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy. Exp. Neurol. 223, 245–250 (2010).

    Google Scholar 

  87. Smith, B. H. & Torrance, N. Epidemiology of neuropathic pain and its impact on quality of life. Curr. Pain Headache Rep. 16, 191–198 (2012).

    Google Scholar 

  88. Oxman, M. N. et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N. Engl. J. Med. 352, 2271–2284 (2005).

    CAS  Google Scholar 

  89. Schmader, K. E. et al. Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50–59 years. Clin. Infect. Dis. 54, 922–928 (2012).

    Google Scholar 

  90. Lal, H. et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N. Engl. J. Med. 372, 2087–2096 (2015). This randomized, placebo-controlled, phase III study evaluates the efficacy and safety of a herpes zoster virus subunit vaccine; the vaccine reduced the risk of herpes zoster infection similarly in adults across several age brackets.

    Google Scholar 

  91. Cunningham, A. L. et al. Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. N. Engl. J. Med. 375, 1019–1032 (2016).

    CAS  Google Scholar 

  92. Gewandter, J. S. et al. Research design considerations for chronic pain prevention clinical trials: IMMPACT recommendations. Pain 156, 1184–1197 (2015).

    Google Scholar 

  93. Dworkin, R. H. et al. Recommendations for the management of herpes zoster. Clin. Infect. Dis. 44, S1–S26 (2007).

    CAS  Google Scholar 

  94. Smith, A. G. et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care 29, 1294–1299 (2006).

    Google Scholar 

  95. Attal, N. et al. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur. J. Neurol. 13, 1153–1169 (2006).

    CAS  Google Scholar 

  96. Dworkin, R. H. et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132, 237–251 (2007).

    CAS  Google Scholar 

  97. Moulin, D. et al. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res. Manag. 19, 328–335 (2014).

    Google Scholar 

  98. Tan, T., Barry, P., Reken, S., Baker, M. & Guideline Development Group. Pharmacological management of neuropathic pain in non-specialist settings: summary of NICE guidance. BMJ 340, c1079 (2010).

    Google Scholar 

  99. Attal, N. et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur. J. Neurol. 17, 1113–e88 (2010).

    CAS  Google Scholar 

  100. Finnerup, N. B. & Attal, N. Pharmacotherapy of neuropathic pain: time to rewrite the rulebook? Pain Manag. 6, 1–3 (2016).

    Google Scholar 

  101. Finnerup, N. B. et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 14, 162–173 (2015). This systematic review updates the recommendations for the pharmacological management of neuropathic pain, emphasizing that modest efficacy, considerable placebo responses, heterogeneous diagnostic criteria and poor phenotypic profiling account for moderate trial outcomes and unmet needs of the patients.

    CAS  Google Scholar 

  102. Yalcin, I. et al. β2-Adrenoceptors are critical for antidepressant treatment of neuropathic pain. Ann. Neurol. 65, 218–225 (2009).

    CAS  Google Scholar 

  103. Luo, Z. D. et al. Upregulation of dorsal root ganglion α2δ calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J. Neurosci. 21, 1868–1875 (2001).

    CAS  Google Scholar 

  104. Vinik, A. I. et al. Capsaicin 8% patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral neuropathy: a randomised, 52-week, open-label, safety study. BMC Neurol. 16, 251 (2016).

    Google Scholar 

  105. Tesfaye, S. et al. Duloxetine and pregabalin: high-dose monotherapy or their combination? The “COMBO-DN study” — a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain 154, 2616–2625 (2013).

    CAS  Google Scholar 

  106. Binder, A. et al. Topical 5% lidocaine (lignocaine) medicated plaster treatment for post-herpetic neuralgia: results of a double-blind, placebo-controlled, multinational efficacy and safety trial. Clin. Drug Investig. 29, 393–408 (2009).

    CAS  Google Scholar 

  107. Demant, D. T. et al. Pain relief with lidocaine 5% patch in localized peripheral neuropathic pain in relation to pain phenotype: a randomised, double-blind, and placebo-controlled, phenotype panel study. Pain 156, 2234–2244 (2015).

    CAS  Google Scholar 

  108. Backonja, M. et al. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study. Lancet Neurol. 7, 1106–1112 (2008).

    CAS  Google Scholar 

  109. Burness, C. B. & McCormack, P. L. Capsaicin 8% patch: a review in peripheral neuropathic pain. Drugs 76, 123–134 (2016).

    CAS  Google Scholar 

  110. Attal, N. et al. Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 15, 555–565 (2016). This randomized, double-blind, placebo-controlled trial in peripheral neuropathic pain indicates that botulinum toxin A reduces pain intensity over 24 weeks compared with a placebo treatment.

    CAS  Google Scholar 

  111. Shackleton, T. et al. The efficacy of botulinum toxin for the treatment of trigeminal and postherpetic neuralgia: a systematic review with meta-analyses. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 122, 61–71 (2016).

    Google Scholar 

  112. Lakhan, S. E., Velasco, D. N. & Tepper, D. Botulinum toxin-A for painful diabetic neuropathy: a meta-analysis. Pain Med. 16, 1773–1780 (2015).

    Google Scholar 

  113. Ray W. A., Chung, C. P., Murray, K. T., Hall, K. & Stein, C. M. Prescription of long-acting opioids and mortality in patients with chronic noncancer pain. JAMA 315, 2415–2423 (2016).

    CAS  Google Scholar 

  114. Emery, E. C., Luiz, A. P. & Wood, J. N. Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief. Expert Opin. Ther. Targets 20, 975–983 (2016).

    CAS  Google Scholar 

  115. Rice, A. S. et al. EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial. Lancet 383, 1637–1647 (2014).

    CAS  Google Scholar 

  116. Chen, G., Park, C. K., Xie, R. G. & Ji, R. R. Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-beta secretion. J. Clin. Invest. 125, 3226–3240 (2015).

    Google Scholar 

  117. Braz, J. M. et al. Forebrain GABAergic neuron precursors integrate into adult spinal cord and reduce injury-induced neuropathic pain. Neuron 74, 663–675 (2012).

    CAS  Google Scholar 

  118. Cruccu, G. et al. EFNS guidelines on neurostimulation therapy for neuropathic pain. Eur. J. Neurol. 14, 952–970 (2007).

    CAS  Google Scholar 

  119. Dworkin, R. H. et al. Interventional management of neuropathic pain: NeuPSIG recommendations. Pain 154, 2249–2261 (2013).

    Google Scholar 

  120. Mekhail, N. A. et al. Retrospective review of 707 cases of spinal cord stimulation: indications and complications. Pain Pract. 11, 148–153 (2011).

    Google Scholar 

  121. Eldabe, S., Buchser, E. & Duarte, R. V. Complications of spinal cord stimulation and peripheral nerve stimulation techniques: a review of the literature. Pain Med. 17, 325–336 (2016).

    Google Scholar 

  122. Bhatia, A., Flamer, D. & Shah, P. S. Perineural steroids for trauma and compression-related peripheral neuropathic pain: a systematic review and meta-analysis. Can. J. Anaesth. 62, 650–662 (2015).

    Google Scholar 

  123. Cohen, S. P., Bicket, M. C., Jamison, D., Wilkinson, I. & Rathmell, J. P. Epidural steroids: a comprehensive, evidence-based review. Reg. Anesth. Pain Med. 38, 175–200 (2013).

    CAS  Google Scholar 

  124. Chou, R. et al. Epidural corticosteroid injections for radiculopathy and spinal stenosis: a systematic review and meta-analysis. Ann. Intern. Med. 163, 373–381 (2015).

    Google Scholar 

  125. Melzack, R. & Wall, P. D. Pain mechanisms: a new theory. Science 150, 971–979 (1965).

    CAS  Google Scholar 

  126. Yearwood, T. L., Hershey, B., Bradley, K. & Lee, D. Pulse width programming in spinal cord stimulation: a clinical study. Pain Physician 13, 321–335 (2010).

    Google Scholar 

  127. De Ridder, D., Plazier, M., Kamerling, N., Menovsky, T. & Vanneste, S. Burst spinal cord stimulation for limb and back pain. World Neurosurg. 80, 642–649.e1 (2013).

    Google Scholar 

  128. Russo, M. & Van Buyten, J. P. 10-kHz high-frequency SCS therapy: a clinical summary. Pain Med. 16, 934–942 (2015).

    Google Scholar 

  129. Manca, A. et al. Quality of life, resource consumption and costs of spinal cord stimulation versus conventional medical management in neuropathic pain patients with failed back surgery syndrome (PROCESS trial). Eur. J. Pain 12, 1047–1058 (2008).

    Google Scholar 

  130. Kumar, K. & Rizvi, S. Cost-effectiveness of spinal cord stimulation therapy in management of chronic pain. Pain Med. 14, 1631–1649 (2013).

    Google Scholar 

  131. Deer, T. R. et al. The appropriate use of neurostimulation: new and evolving neurostimulation therapies and applicable treatment for chronic pain and selected disease states. Neuromodulation Appropriateness Consensus Committee. Neuromodulation 17, 599–615 (2014).

    Google Scholar 

  132. North, R. B. et al. Spinal cord stimulation versus re-operation in patients with failed back surgery syndrome: an international multicenter randomized controlled trial (EVIDENCE study). Neuromodulation 14, 330–335 (2011).

    Google Scholar 

  133. Kumar, K. et al. Spinal cord stimulation versus conventional medical management for neuropathic pain: a multicentre randomised controlled trial in patients with failed back surgery syndrome. Pain 132, 179–188 (2007).

    Google Scholar 

  134. Simpson, E. L., Duenas, A., Holmes, M. W., Papaioannou, D. & Chilcott, J. Spinal cord stimulation for chronic pain of neuropathic or ischaemic origin: systematic review and economic evaluation. Health Technol. Assess. 13, 1–154 (2009).

    Google Scholar 

  135. Kumar, K. et al. The effects of spinal cord stimulation in neuropathic pain are sustained: a 24-month follow-up of the prospective randomized controlled multicenter trial of the effectiveness of spinal cord stimulation. Neurosurgery 63, 762–770 (2008).

    Google Scholar 

  136. Kemler, M. A., De Vet, H. C., Barendse, G. A., Van Den Wildenberg, F. A. & Van Kleef, M. The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: two years’ follow-up of the randomized controlled trial. Ann. Neurol. 55, 13–18 (2004).

    Google Scholar 

  137. de Vos, C. C. et al. Spinal cord stimulation in patients with painful diabetic neuropathy: a multicentre randomized clinical trial. Pain 155, 2426–2431 (2014).

    Google Scholar 

  138. Slangen, R. et al. Spinal cord stimulation and pain relief in painful diabetic peripheral neuropathy: a prospective two-center randomized controlled trial. Diabetes Care 37, 3016–3024 (2014).

    Google Scholar 

  139. Cruccu, G. et al. EAN guidelines on central neurostimulation therapy in chronic pain conditions. Eur. J. Neurol. 23, 1489–1499 (2016). These up-to-date guidelines on neurostimulation for neuropathic pain by the European Academy of Neurology indicate poor-to-moderate quality of evidence for non-invasive and invasive neurostimulation.

    CAS  Google Scholar 

  140. Campbell, C. M., Jamison, R. N. & Edwards, R. R. Psychological screening/phenotyping as predictors for spinal cord stimulation. Curr. Pain Headache Rep. 17, 307 (2013).

    Google Scholar 

  141. Campbell, C. M. et al. Dynamic pain phenotypes are associated with spinal cord stimulation-induced reduction in pain: a repeated measures observational pilot study. Pain Med. 16, 1349–1360 (2015).

    Google Scholar 

  142. Krames, E. S. The role of the dorsal root ganglion in the development of neuropathic pain. Pain Med. 15, 1669–1685 (2014).

    Google Scholar 

  143. Petersen, E. A. & Slavin, K. V. Peripheral nerve/field stimulation for chronic pain. Neurosurg. Clin. N. Am. 25, 789–797 (2014).

    Google Scholar 

  144. Liem, L. et al. One-year outcomes of spinal cord stimulation of the dorsal root ganglion in the treatment of chronic neuropathic pain. Neuromodulation 18, 41–48 (2015).

    Google Scholar 

  145. Sukul, V. V. & Slavin, K. V. Deep brain and motor cortex stimulation. Curr. Pain Headache Rep. 18, 427 (2014).

    Google Scholar 

  146. Moore, N. Z., Lempka, S. F. & Machado, A. Central neuromodulation for refractory pain. Neurosurg. Clin. N. Am. 25, 77–83 (2014).

    Google Scholar 

  147. Lefaucheur, J. P. Cortical neurostimulation for neuropathic pain: state of the art and perspectives. Pain 157, S81–S89 (2016). In this paper, various types of stimulation, including EMCS, rTMS and anodal tDCS, are discussed as therapeutic strategies when neuropathic pain is lateralized and stimulation is applied to the motor cortex contralateral to the pain side.

    Google Scholar 

  148. Lefaucheur, J. P. et al. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clin. Neurophysiol. 128, 56–92 (2016).

    Google Scholar 

  149. Keifer, O. P. Jr, Riley, J. P. & Boulis, N. M. Deep brain stimulation for chronic pain: intracranial targets, clinical outcomes, and trial design considerations. Neurosurg. Clin. N. Am. 25, 671–692 (2014).

    Google Scholar 

  150. Prager, J. et al. Best practices for intrathecal drug delivery for pain. Neuromodulation 17, 354–372 (2014).

    Google Scholar 

  151. Bolash, R. & Mekhail, N. Intrathecal pain pumps: indications, patient selection, techniques, and outcomes. Neurosurg. Clin. N. Am. 25, 735–742 (2014).

    Google Scholar 

  152. Deer, T. R. et al. Polyanalgesic Consensus Conference — 2012: recommendations to reduce morbidity and mortality in intrathecal drug delivery in the treatment of chronic pain. Neuromodulation 15, 467–482 (2012).

    Google Scholar 

  153. Pope, J. E., Deer, T. R., Bruel, B. M. & Falowski, S. Clinical uses of intrathecal therapy and its placement in the pain care algorithm. Pain Pract. 16, 1092–1106 (2016).

    Google Scholar 

  154. Dobson, J. L., McMillan, J. & Li, L. Benefits of exercise intervention in reducing neuropathic pain. Front. Cell Neurosci. 8, 102 (2014).

    Google Scholar 

  155. Kluding, P. M. et al. The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy. J. Diabetes Compl. 26, 424–429 (2012).

    Google Scholar 

  156. Smart, K. M., Wand, B. M. & O'Connell, N. E. Physiotherapy for pain and disability in adults with complex regional pain syndrome (CRPS) types I and II. Cochrane Database Syst. Rev. 2, CD010853 (2016).

    Google Scholar 

  157. Thieme, H., Morkisch, N., Rietz, C., Dohle, C. & Borgetto, B. The efficacy of movement representation techniques for treatment of limb pain — a systematic review and meta-analysis. J. Pain 17, 167–180 (2016).

    Google Scholar 

  158. Eccleston, C. & Crombez, G. Worry and chronic pain: a misdirected problem solving model. Pain 132, 233–236 (2007).

    Google Scholar 

  159. DOLORisk. Objectives. DOLORiskhttp://dolorisk.eu/project/objectives (2015).

  160. Williams, A. C., Eccleston, C. & Morley, S. Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst. Rev. 11, CD007407 (2012).

    Google Scholar 

  161. Eccleston, C. et al. Psychological therapies (internet-delivered) for the management of chronic pain in adults. Cochrane Database Syst. Rev. 2, CD010152 (2014).

    Google Scholar 

  162. Eccleston, C., Hearn, L. & Williams, A. C. Psychological therapies for the management of chronic neuropathic pain in adults. Cochrane Database Syst. Rev. 10, CD011259 (2015). This systematic review indicates a lack of evidence on the efficacy and safety of psychological interventions for chronic neuropathic pain.

    Google Scholar 

  163. Moore, A., Derry, S., Eccleston, C. & Kalso, E. Expect analgesic failure; pursue analgesic success. BMJ 346, f2690 (2013).

    Google Scholar 

  164. Otis, J. D. et al. A randomized controlled pilot study of a cognitive-behavioral therapy approach for painful diabetic peripheral neuropathy. J. Pain 14, 475–482 (2013).

    Google Scholar 

  165. Eccleston, C. Embodied: The Psychology of Physical Sensation (Oxford Univ. Press, 2016).

    Google Scholar 

  166. Eccleston, C., Tabor, A., Edwards, R. T. & Keogh, E. Psychological approaches to coping with pain in later life. Clin. Geriatr. Med. 32, 763–771 (2016).

    Google Scholar 

  167. Morley, S., Williams, A. & Eccleston, C. Examining the evidence about psychological treatments for chronic pain: time for a paradigm shift? Pain 154, 1929–1931 (2013).

    Google Scholar 

  168. Duggan, G. B. et al. Qualitative evaluation of the SMART2 self-management system for people in chronic pain. Disabil. Rehabil. Assist. Technol. 10, 53–60 (2015).

    Google Scholar 

  169. Meyer-Rosberg, K. et al. Peripheral neuropathic pain — a multidimensional burden for patients. Eur. J. Pain 5, 379–389 (2001).

    CAS  Google Scholar 

  170. Gordh, T. E. et al. Gabapentin in traumatic nerve injury pain: a randomized, double-blind, placebo-controlled, cross-over, multi-center study. Pain 138, 255–266 (2008).

    CAS  Google Scholar 

  171. Ahroni, J. H. & Boyko, E. J. Responsiveness of the SF-36 among veterans with diabetes mellitus. J. Diabetes Compl. 14, 31–39 (2000).

    CAS  Google Scholar 

  172. Van Acker, K. et al. Prevalence and impact on quality of life of peripheral neuropathy with or without neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatients clinics. Diabetes Metab. 35, 206–213 (2009).

    CAS  Google Scholar 

  173. Torrance, N. et al. Estimating the burden of disease in chronic pain with and without neuropathic characteristics: does the choice between the EQ-5D and SF-6D matter? Pain 155, 1996–2004 (2014). This study presents the advantage of using EQ-5D over SF-6D for estimating the burden of chronic pain in those with or without neuropathic clinical characteristics.

    Google Scholar 

  174. Geelen, C. C., Kindermans, H. P., van den Bergh, J. P. & Verbunt, J. A. Perceived physical activity decline as a mediator in the relationship between pain catastrophizing, disability, and quality of life in patients with painful diabetic neuropathy. Pain Pract.http://dx.doi.org/10.1111/papr.12449 (2016).

  175. Backonja, M. et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 280, 1831–1836 (1998).

    CAS  Google Scholar 

  176. Rowbotham, M., Harden, N., Stacey, B., Bernstein, P. & Magnus-Miller, L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 280, 1837–1842 (1998).

    CAS  Google Scholar 

  177. Ogawa, K., Fujikoshi, S., Montgomery, W. & Alev, L. Correlation between pain response and improvements in patient-reported outcomes and health-related quality of life in duloxetine-treated patients with diabetic peripheral neuropathic pain. Neuropsychiatr. Dis. Treat. 11, 2101–2107 (2015).

    CAS  Google Scholar 

  178. Duarte, R. V., Andronis, L., Lenders, M. W. & de Vos, C. C. Quality of life increases in patients with painful diabetic neuropathy following treatment with spinal cord stimulation. Qual. Life Res. 25, 1771–1777 (2016).

    Google Scholar 

  179. Dworkin, R. H. et al. Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations. Pain 153, 1148–1158 (2012).

    CAS  Google Scholar 

  180. Gewandter, J. S. et al. Research designs for proof-of-concept chronic pain clinical trials: IMMPACT recommendations. Pain 155, 1683–1695 (2014).

    Google Scholar 

  181. Dworkin, R. H. et al. Assay sensitivity and study features in neuropathic pain trials: an ACTTION meta-analysis. Neurology 81, 67–75 (2013).

    CAS  Google Scholar 

  182. Farrar, J. T. et al. Effect of variability in the 7-day baseline pain diary on the assay sensitivity of neuropathic pain randomized clinical trials: an ACTTION study. Pain 155, 1622–1631 (2014).

    Google Scholar 

  183. Attal, N. et al. Assessing symptom profiles in neuropathic pain clinical trials: can it improve outcome? Eur. J. Pain 15, 441–443 (2011).

    Google Scholar 

  184. Finnerup, N. B. & Jensen, T. S. Mechanisms of disease: mechanism-based classification of neuropathic pain — a critical analysis. Nat. Clin. Pract. Neurol. 2, 107–115 (2006).

    Google Scholar 

  185. Campbell, C. M. et al. Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. Pain 153, 1815–1823 (2012).

    CAS  Google Scholar 

  186. Demant, D. T. et al. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study. Pain 155, 2263–2273 (2014).

    CAS  Google Scholar 

  187. Dworkin, R. H., McDermott, M. P., Farrar, J. T., O'Connor, A. B. & Senn, S. Interpreting patient treatment response in analgesic clinical trials: implications for genotyping, phenotyping, and personalized pain treatment. Pain 155, 457–460 (2014). This article indicates within-patient variation and treatment-by-patient interaction as two sources of variance that contribute to differences between patients in responding to efficacious analgesic treatments.

    Google Scholar 

  188. Edwards, R. R. et al. Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations. Pain 157, 1851–1871 (2016). This article proposes core phenotyping domains to estimate the likelihood to experience pain relief. Recommended measures for each domain include psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes and response to pharmacological challenge.

    CAS  Google Scholar 

  189. Bennett, D. L. & Woods, C. G. Painful and painless channelopathies. Lancet Neurol. 13, 587–599 (2014). This paper provides an introduction to the discovery of genetic variants that can alter the individual perception of pain, including the inactivating mutations in SCN9A, resulting in congenital insensitivity to pain. Furthermore, other genetic variations that contribute to risk or severity of more complex pain phenotypes are presented.

    CAS  Google Scholar 

  190. Waxman, S. G. et al. Sodium channel genes in pain-related disorders: phenotype–genotype associations and recommendations for clinical use. Lancet Neurol. 13, 1152–1160 (2014).

    CAS  Google Scholar 

  191. Cregg, R., Cox, J. J., Bennett, D. L., Wood, J. N. & Werdehausen, R. Mexiletine as a treatment for primary erythromelalgia: normalization of biophysical properties of mutant L858F NaV1.7 sodium channels. Br. J. Pharmacol. 171, 4455–4463 (2014).

    CAS  Google Scholar 

  192. Yang, Y. et al. Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a NaV1.7 mutant channel. Nat. Commun. 3, 1186 (2012).

    Google Scholar 

  193. Geha, P. et al. Pharmacotherapy for pain in a family with inherited erythromelalgia guided by genomic analysis and functional profiling. JAMA Neurol. 73, 659–667 (2016).

    Google Scholar 

  194. Cao, L. et al. Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia. Sci Transl Med. 8, 335ra56 (2016).

    Google Scholar 

  195. Krause, S. J. & Backonja, M. M. Development of a neuropathic pain questionnaire. Clin. J. Pain 19, 306–314 (2003).

    Google Scholar 

  196. Portenoy, R. Development and testing of a neuropathic pain screening questionnaire: ID Pain. Curr. Med. Res. Opin. 22, 1555–1565 (2006).

    Google Scholar 

  197. Bierhaus, A. et al. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat. Med. 18, 926–933 (2012).

    CAS  Google Scholar 

  198. Burma, N. E., Leduc-Pessah, H., Fan, C. Y. & Trang, T. Animal models of chronic pain: advances and challenges for clinical translation. J. Neurosci. Res.http://dx.doi.org/10.1002/jnr.23768 (2016).

  199. Okun, A. et al. Hedonic and motivational responses to food reward are unchanged in rats with neuropathic pain. Pain 157, 2731–2738 (2016).

    Google Scholar 

  200. Patel, R. & Dickenson, A. H. Mechanisms of the gabapentinoids and alpha 2 delta-1 calcium channel subunit in neuropathic pain. Pharmacol. Res. Perspect. 4, e00205 (2016).

    Google Scholar 

  201. Dias, Q. M. et al. The effect of intrathecal gabapentin on neuropathic pain is independent of the integrity of the dorsolateral funiculus in rats. Life Sci. 91, 837–842 (2012).

    CAS  Google Scholar 

  202. Rauck, R. et al. Intrathecal gabapentin to treat chronic intractable noncancer pain. Anesthesiology 119, 675–686 (2013).

    Google Scholar 

  203. Nir, R. R. & Yarnitsky, D. Conditioned pain modulation. Curr. Opin. Support. Palliat. Care 9, 131–137 (2015).

    Google Scholar 

  204. Valeriani, M., Pazzaglia, C., Cruccu, G. & Truini, A. Clinical usefulness of laser evoked potentials. Neurophysiol. Clin. 42, 345–353 (2012).

    CAS  Google Scholar 

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Acknowledgements

L.C. acknowledges support from the UMB and the National Institute of Dental and Craniofacial Research (NIDCR) at the US NIH (R01DE025946). A.H.D. and D.L.B. acknowledge support from the Wellcome Trust Pain Consortium. R.B. acknowledges support from the European Union Project No. 633491: DOLORisk, IMI Europain, the German Federal Ministry of Education and Research (ERA_NET NEU-RON/IM-PAIN Project) and the German Research Network on Neuropathic Pain, NoPain system biology and the German Research Foundation. R.B. also acknowledges support from the German Federal Ministry of Education and Research (BMBF), the ERA_NET NEURON/IM-PAIN Project (01EW1503), the German Research Network on Neuropathic Pain (01EM0903), NoPain system biology (0316177C) and the German Research Foundation (DFG). D.Y. acknowledges support from the Israel Science Foundation, European Horizons 2020 and the US Department of Defense. S.N.R. acknowledges support from the NIH (NS26363).

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Authors and Affiliations

  1. Department of Pain and Translational Symptom Science, School of Nursing and Department of Anesthesiology School of Medicine, University of Maryland, 655 West Lombard Street, Baltimore, 21201, Maryland, USA

    Luana Colloca & Taylor Ludman

  2. INSERM, Unit 987, Ambroise Paré Hospital, UVSQ, Boulogne Billancourt, France

    Didier Bouhassira

  3. Department of Neurology, Division of Neurological Pain Research and Therapy, Klinik fur Neurologie Christian-Albrechts-Universität Kiel, Kiel, Germany

    Ralf Baron

  4. Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK

    Anthony H. Dickenson

  5. Department of Neurology, Rambam Health Care Campus, Technion Faculty of Medicine, Haifa, Israel

    David Yarnitsky

  6. Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Roy Freeman

  7. Department of Neurology and Psychiatry, Sapienza University, Rome, Italy

    Andrea Truini

  8. Pain Evaluation and Treatment Centre of Hôpital Ambroise Paré, Paris, France

    Nadine Attal

  9. Department of Clinical Medicine — The Danish Pain Research Center, Aarhus University, Aarhus, Denmark

    Nanna B. Finnerup

  10. Centre for Pain Research, University of Bath, Bath, UK

    Christopher Eccleston

  11. Department of Clinical and Health Psychology, Ghent University, Ghent, Belgium

    Christopher Eccleston

  12. Division of Pain Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    Eija Kalso

  13. Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK

    David L. Bennett

  14. Department of Anesthesiology, School of Medicine and Dentistry, University of Rochester, Rochester, New York, USA

    Robert H. Dworkin

  15. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Srinivasa N. Raja

Authors
  1. Luana Colloca
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  2. Taylor Ludman
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  3. Didier Bouhassira
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  4. Ralf Baron
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  6. David Yarnitsky
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  8. Andrea Truini
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  9. Nadine Attal
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  10. Nanna B. Finnerup
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Contributions

Introduction (L.C. and T.L.); Epidemiology (D.B.); Mechanisms/pathophysiology (A.H.D., L.C., D.Y. and R.F.); Diagnosis, screening and prevention (R.B., A.T. and R.H.D.); Management (N.A., N.B.F., S.N.R. and C.E.); Quality of life (E.K.); Outlook (R.H.D. and D.L.B.); Overview of the Primer (L.C.).

Corresponding author

Correspondence to Luana Colloca.

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Competing interests

L.C. has received lecture honoraria (Georgetown University and Stanford University) and has acted as speaker or consultant for Grünenthal and Emmi Solution. R.B. is an industry member of AstraZeneca, Pfizer, Esteve, UCB Pharma, Sanofi Aventis, Grünenthal, Eli Lilly and Boehringer Ingelheim; has received lecture honoraria from Pfizer, Genzyme, Grünenthal, Mundipharma, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai, Lilly, Boehringer Ingelheim, Astellas, Desitin, Teva Pharma, Bayer-Schering, MSD and Seqirus; and has served as a consultant for Pfizer, Genzyme, Grünenthal, Mundipharma, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai, Lilly, Boehringer Ingelheim Pharma, Astellas, Desitin, Teva Pharma, Bayer-Schering, MSD, Novartis, Bristol-Myers Squibb, Biogen idec, AstraZeneca, Merck, AbbVie, Daiichi Sankyo, Glenmark Pharmaceuticals, Seqirus, Genentech, Galapagos NV and Kyowa Hakko Kirin. A.H.D. has acted as speaker or consultant forSeqirus, Grünenthal, Allergan and Mundipharma. D.B. has acted as a consultant for Grünenthal, Pfizer and Indivior. D.L.B. has acted as a consultant for Abide, Eli Lilly, Mundipharma, Pfizer and Teva. D.Y. received a lecture honorarium from Pfizer and holds equity in BrainsGate and Theranica. R.F. has acted as an advisory board member for Abide, Astellas, Biogen, Glenmark, Hydra, Novartis and Pfizer. A.T. has received research funding, lecture honoraria and acted as speaker or consultant for Mundipharma, Pfizer, Grünenthal and Angelini Pharma. N.A. has received honoraria for participation in advisory boards or speaker bureau by Astellas, Teva, Mundipharma, Johnson and Johnson, Novartis and Sanofi Pasteur MSD. N.B.F. has received honoraria for participation in advisory boards from Teva Pharmaceuticals, Novartis and Grünenthal, and research support from EUROPAIN Investigational Medicines Initiative (IMI). E.K. has served on the advisory boards of Orion Pharma and Grünenthal, and received lecture honoraria from Orion Pharma and AstraZeneca. R.H.D. has received research grants and contracts from the US FDA and the US NIH, and compensation for activities involving clinical trial research methods from Abide, Aptinyx, Astellas, Boston Scientific, Centrexion, Dong-A, Eli Lilly, Glenmark, Hope, Hydra, Immune, Novartis, NsGene, Olatec, Phosphagenics, Quark, Reckitt Benckiser, Relmada, Semnur, Syntrix, Teva, Trevena and Vertex. S.N.R. has received a research grant from Medtronic Inc. and honoraria for participation in advisory boards of Allergan, Daiichi Sankyo, Grünenthal USA Inc. and Lexicon Pharmaceuticals. C.E. and T.L. declare no competing interests.

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Colloca, L., Ludman, T., Bouhassira, D. et al. Neuropathic pain. Nat Rev Dis Primers 3, 17002 (2017). https://doi.org/10.1038/nrdp.2017.2

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