Mechanisms of Disease: neuropathic pain - a clinical perspective

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.