Neuropathic Pain: A Clinical Perspective
Neuropathic pain syndromes, i.e., pain after a lesion or disease of the peripheral or central nervous system, are clinically characterized by spontaneous pain (ongoing, paroxysms) and evoked types of pain (hyperalgesia, allodynia). A variety of distinct pathophysiological mechanisms in the peripheral and central nervous system operate in concert: In some patients the nerve lesion triggers molecular changes in nociceptive neurons that become abnormally sensitive and develop pathological spontaneous activity (upregulation of sodium channels and receptors, e.g., vanilloid TRPV1 receptors, menthol-sensitive TRPM8 receptors, or α-receptors). These phenomena may lead to spontaneous pain, shooting pain sensations, as well as heat hyperalgesia, cold hyperalgesia, and sympathetically maintained pain. Spontaneous activity in damaged large nonnociceptive A-fibers may lead to paresthesias. All these changes may also occur in uninjured neurons driven by substances released by adjacent dying cells and should receive more attention in the future. The hyperactivity in nociceptors in turn induces secondary changes (hyperexcitability) in processing neurons in the spinal cord and brain. This central sensitization causes input from mechanoreceptive A-fibers to be perceived as pain (mechanical allodynia). Neuroplastic changes in the central descending pain modulatory systems (inhibitory or facilitatory) may lead to further hyperexcitability. Neuropathic pain represents a major neurological problem and treatment of patients with such pain has been largely neglected by neurologists in the past. The medical management of neuropathic pain consists of five main classes of oral medication (antidepressants with reuptake blocking effect, anticonvulsants with sodium-blocking action, anticonvulsants with calcium-modulating actions, tramadol, and opioids) and several categories of topical medications for patients with cutaneous allodynia and hyperalgesia (capsaicin and local anesthetics). In many cases an early combination of compounds effecting different mechanisms is useful. At present existing trials only provide general pain relief values for specific causes, which in part may explain the failure to obtain complete pain relief in neuropathic pain conditions. In general, the treatment of neuropathic pain is still unsatisfactorily. Therefore, a new hypothetical concept was proposed in which pain is analyzed on the basis of underlying mechanisms. The increased knowledge of pain-generating mechanisms and their translation into symptoms and signs may in the future allow a dissection of the mechanisms that operate in each patient. If a systematic clinical examination of the neuropathic pain patient and a precise phenotypic characterization is combined with a selection of drugs acting against those particular mechanisms, it should ultimately be possible to design optimal treatments for the individual patient.
KeywordsNeuropathy Pathophysiology Assessment Treatment
This work was supported by the Deutsche Forschungsgemeinschaft (DFG Ba 1921/1-2), the German Ministry of Research and Education within the German Research Network on Neuropathic Pain (BMBF, 01EM01/04), and an unrestricted educational grant from Pfizer (Germany).
- Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG (2006) An SCN9A channelopathy causes congenital inability to experience pain. Nature 444:894–898PubMedCrossRefGoogle Scholar
- Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, Bushnell MC, Farrar JT, Galer BS, Haythornthwaite JA, Hewitt DJ, Loeser JD, Max MB, Saltarelli M, Schmader KE, Stein C, Thompson D, Turk DC, Wallace MS, Watkins LR, Weinstein SM (2003) Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 60:1524–1534PubMedCrossRefGoogle Scholar
- Dworkin RH, O'Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ, Portenoy RK, Rice AS, Stacey BR, Treede RD, Turk DC, Wallace MS (2007) Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132:237–251PubMedCrossRefGoogle Scholar
- Goldberg YP, MacFarlane J, MacDonald ML, Thompson J, Dube MP, Mattice M, Fraser R, Young C, Hossain S, Pape T, Payne B, Radomski C, Donaldson G, Ives E, Cox J, Younghusband HB, Green R, Duff A, Boltshauser E, Grinspan GA, Dimon JH, Sibley BG, Andria G, Toscano E, Kerdraon J, Bowsher D, Pimstone SN, Samuels ME, Sherrington R, Hayden MR (2007) Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations. Clin Genet 71:311–319PubMedCrossRefGoogle Scholar
- Gracely RH, Lynch SA, Bennett GJ (1992) Painful neuropathy: altered central processing maintained dynamically by peripheral input. Pain 51:175–194. Erratum (1993) Pain 52: 251–253Google Scholar
- Guilbaud G, Benoist JM, Levante A, Gautron M, Willer JC (1992) Primary somatosensory cortex in rats with pain-related behaviours due to a peripheral mononeuropathy after moderate ligation of one sciatic nerve: neuronal responsivity to somatic stimulation. Exp Brain Res 92:227–245PubMedCrossRefGoogle Scholar
- Mogil JS, Miermeister F, Seifert F, Strasburg K, Zimmermann K, Reinold H, Austin JS, Bernardini N, Chesler EJ, Hofmann HA, Hordo C, Messlinger K, Nemmani KV, Rankin AL, Ritchie J, Siegling A, Smith SB, Sotocinal S, Vater A, Lehto SG, Klussmann S, Quirion R, Michaelis M, Devor M, Reeh PW (2005) Variable sensitivity to noxious heat is mediated by differential expression of the CGRP gene. Proc Natl Acad Sci USA 102:12938–12943PubMedCrossRefGoogle Scholar
- Pleger B, Tegenthoff M, Schwenkreis P, Janssen F, Ragert P, Dinse HR, Volker B, Zenz M, Maier C (2004) Mean sustained pain levels are linked to hemispherical side-to-side differences of primary somatosensory cortex in the complex regional pain syndrome I. Exp Brain Res 155:115–119PubMedCrossRefGoogle Scholar
- Rolke R, Baron R, Maier C, Tolle TR, Treede RD, Beyer A, Binder A, Birbaumer N, Birklein F, Botefur IC, Braune S, Flor H, Huge V, Klug R, Landwehrmeyer GB, Magerl W, Maihofner C, Rolko C, Schaub C, Scherens A, Sprenger T, Valet M, Wasserka B (2006) Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 123:231–43PubMedCrossRefGoogle Scholar
- Zambreanu L, Wise RG, Brooks JC, Iannetti GD, Tracey I (2005) A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging. Pain 114:397–407Google Scholar