Baron Ralf
Sektion Neurologische Schmerzforschung und Therapie, Klinik für Neurologie, Christian-Albrechts-Universität Kiel, Schittenhelmstr. 10, 24105 Kiel, Germany.
Handb Exp Pharmacol. 2009(194):3-30. doi: 10.1007/978-3-540-79090-7_1.
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 alpha-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.
神经病理性疼痛综合征，即外周或中枢神经系统损伤或疾病后的疼痛，其临床特征为自发性疼痛（持续性、阵发性）和诱发性疼痛（痛觉过敏、感觉异常）。外周和中枢神经系统中多种不同的病理生理机制协同作用：在一些患者中，神经损伤会触发伤害性神经元的分子变化，使其变得异常敏感并产生病理性自发活动（钠通道和受体上调，例如香草酸瞬时受体电位1型受体、薄荷醇敏感的瞬时受体电位M8型受体或α受体）。这些现象可能导致自发性疼痛、刺痛感，以及热痛觉过敏、冷痛觉过敏和交感神经维持性疼痛。受损的大型非伤害性A纤维的自发活动可能导致感觉异常。所有这些变化也可能发生在由相邻死亡细胞释放的物质驱动的未受损神经元中，未来应予以更多关注。伤害性感受器的活动亢进进而会在脊髓和大脑中的处理神经元中诱发继发性变化（兴奋性增高）。这种中枢敏化会使机械感受性A纤维的输入被感知为疼痛（机械性感觉异常）。中枢下行疼痛调节系统（抑制性或易化性）的神经可塑性变化可能导致进一步的兴奋性增高。神经病理性疼痛是一个主要的神经学问题，过去神经科医生很大程度上忽视了对此类疼痛患者的治疗。神经病理性疼痛的药物治疗包括五大类口服药物（具有再摄取阻断作用的抗抑郁药、具有钠通道阻断作用的抗惊厥药、具有钙调节作用的抗惊厥药、曲马多和阿片类药物）以及几类用于治疗皮肤感觉异常和痛觉过敏患者的局部用药（辣椒素和局部麻醉药）。在许多情况下，早期联合使用作用于不同机制的化合物是有益的。目前现有的试验仅为特定病因提供了一般的疼痛缓解值，这在一定程度上可能解释了在神经病理性疼痛情况下未能获得完全疼痛缓解的原因。总体而言，神经病理性疼痛的治疗仍然不尽人意。因此，提出了一个新的假说概念，即基于潜在机制对疼痛进行分析。对疼痛产生机制的了解增加及其转化为症状和体征，未来可能有助于剖析每个患者中起作用的机制。如果将对神经病理性疼痛患者的系统临床检查和精确的表型特征与针对那些特定机制的药物选择相结合，最终应该能够为个体患者设计出最佳治疗方案。
