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Mechanisms of Disease: neuropathic pain—a clinical perspective

Abstract

Neuropathic pain syndromes—pain after a lesion or disease of the peripheral or central nervous system—are clinically characterized by spontaneous and evoked types of pain, which are underpinned by various distinct pathophysiological mechanisms in the peripheral and central nervous systems. In some patients, the nerve lesion triggers molecular changes in nociceptive neurons, which become abnormally sensitive and develop pathological spontaneous activity. Inflammatory reactions of the damaged nerve trunk can induce ectopic nociceptor activity, causing spontaneous pain. The hyperactivity in nociceptors induces secondary changes in processing neurons in the spinal cord and brain, so that input from mechanoreceptive A-fibers is perceived as pain. Neuroplastic changes in the central pain modulatory systems can lead to further hyperexcitability. The treatment of neuropathic pain is still unsatisfactory, and a new hypothetical concept has been 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 might eventually allow a dissection of the mechanisms that operate in each patient. If a precise clinical phenotypic characterization of the neuropathic pain is combined with a selection of drugs that act on those mechanisms, it should ultimately be possible to design optimal treatments for individuals. This review discusses the conceptual framework of the novel mechanism-based classification, encouraging the reader to see neuropathic pain as a clinical entity rather than a compilation of single disease states.

Key Points

  • Neuropathic pain syndromes are chronic pain disorders caused by lesion or disease of the parts of the nervous system that normally signal pain

  • A disease- and anatomy-based system is often insufficient to classify neuropathic pain conditions, and analysis on the basis of underlying mechanisms provides an alternative approach

  • Molecular mechanisms that underlie the sensitization of primary afferent nociceptors include upregulation of voltage-gated sodium channels and various receptor proteins, and the release of growth factors from degenerating nerve fibers

  • As a consequence of peripheral nociceptor hyperactivity, dramatic secondary changes occur in the spinal cord dorsal horn, and there is also evidence of sensitization of neurons in the brain

  • A single symptom may be generated by several different mechanisms, so a specific symptom profile might be required to predict the underlying mechanism

  • By combining a systematic clinical examination and a precise phenotypic characterization with a selection of drugs that act on particular mechanisms, it should be possible to design optimal treatments for individual patients

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Figure 1: Proposed model for the relationship between neuropathic pain mechanisms and clinical symptoms and signs, and possible targets for therapeutic interventions.
Figure 2: Mechanisms of peripheral and central sensitization in neuropathic pain.

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Acknowledgements

R Baron is supported by the Deutsche Forschungsgemeinschaft (DFG Ba 1921), the German Ministry of Research and Education, German Research Network on Neuropathic Pain (BMBF, 01EM01/04) and an unrestricted educational grant from Pfizer, Germany.

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Ralf Baron has acted as a consultant for Grünenthal, Mundipharma, Schwarz-Pharma, Bayer Health Care, Life Science Vision and Novartis in Germany, and Allergan and Renovis in the US. He has also acted as a consultant and has received research funding from Pfizer Pharma GmbH, Germany.

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Baron, R. Mechanisms of Disease: neuropathic pain—a clinical perspective. Nat Rev Neurol 2, 95–106 (2006). https://doi.org/10.1038/ncpneuro0113

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