Taneja A, Della Pasqua O, Danhof M
Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Uxbridge, UK.
Eur J Clin Pharmacol. 2017 Oct;73(10):1219-1236. doi: 10.1007/s00228-017-2301-8. Epub 2017 Sep 11.
Despite an improved understanding of the molecular mechanisms of nociception, existing analgesic drugs remain limited in terms of efficacy in chronic conditions, such as neuropathic pain. Here, we explore the underlying pathophysiological mechanisms of neuropathic and inflammatory pain and discuss the prerequisites and opportunities to reduce attrition and high-failure rate in the development of analgesic drugs.
A literature search was performed on preclinical and clinical publications aimed at the evaluation of analgesic compounds using MESH terms in PubMed. Publications were selected, which focused on (1) disease mechanisms leading to chronic/neuropathic pain and (2) druggable targets which are currently under evaluation in drug development. Attention was also given to the role of biomarkers and pharmacokinetic-pharmacodynamic modelling.
Multiple mechanisms act concurrently to produce pain, which is a non-specific manifestation of underlying nociceptive pathways. Whereas these manifestations can be divided into neuropathic and inflammatory pain, it is now clear that inflammatory mechanisms are a common trigger for both types of pain. This has implications for drug development, as the assessment of drug effects in experimental models of neuropathic and chronic pain is driven by overt behavioural measures. By contrast, the use of mechanistic biomarkers in inflammatory pain has provided the pharmacological basis for dose selection and evaluation of non-steroidal anti-inflammatory drugs (NSAIDs).
A different paradigm is required for the identification of relevant targets and candidate molecules whereby pain is coupled to the cause of sensorial signal processing dysfunction rather than clinical symptoms. Biomarkers which enable the characterisation of drug binding and target activity are needed for a more robust dose rationale in early clinical development. Such an approach may be facilitated by quantitative clinical pharmacology and evolving technologies in brain imaging, allowing accurate assessment of target engagement, and prediction of treatment effects before embarking on large clinical trials.
尽管对伤害感受的分子机制有了更深入的了解，但现有的镇痛药在慢性疾病（如神经性疼痛）的疗效方面仍然有限。在此，我们探讨神经性疼痛和炎性疼痛的潜在病理生理机制，并讨论在镇痛药开发中减少损耗和高失败率的前提条件与机会。
在PubMed中使用医学主题词（MESH）对旨在评估镇痛化合物的临床前和临床出版物进行文献检索。选择的出版物聚焦于：（1）导致慢性/神经性疼痛的疾病机制；（2）目前在药物开发中正在评估的可成药靶点。同时也关注生物标志物的作用以及药代动力学 - 药效学建模。
多种机制同时作用产生疼痛，疼痛是潜在伤害感受通路的非特异性表现。虽然这些表现可分为神经性疼痛和炎性疼痛，但现在很清楚，炎症机制是这两种疼痛的常见触发因素。这对药物开发具有重要意义，因为在神经性和慢性疼痛实验模型中对药物效果的评估是由明显的行为指标驱动的。相比之下，炎性疼痛中机制性生物标志物的使用为非甾体抗炎药（NSAIDs）的剂量选择和评估提供了药理学基础。
识别相关靶点和候选分子需要一种不同的模式，即疼痛与感觉信号处理功能障碍的原因相关联，而非与临床症状相关联。在早期临床开发中，为了更合理地确定剂量，需要能够表征药物结合和靶点活性的生物标志物。定量临床药理学以及脑成像技术的不断发展可能有助于采用这种方法，从而在开展大型临床试验之前能够准确评估靶点参与情况并预测治疗效果。
