Fisher Amy S, Lanigan Michael T, Upton Neil, Lione Lisa A
Transpharmation Ltd., The London Bioscience Innovation Centre, London, United Kingdom.
School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom.
Front Pharmacol. 2021 Feb 8;11:614990. doi: 10.3389/fphar.2020.614990. eCollection 2020.
For patients suffering with chronic neuropathic pain the need for suitable novel therapies is imperative. Over recent years a contributing factor for the lack of development of new analgesics for neuropathic pain has been the mismatch of primary neuropathic pain assessment endpoints in preclinical vs. clinical trials. Despite continuous forward translation failures across diverse mechanisms, reflexive quantitative sensory testing remains the primary assessment endpoint for neuropathic pain and analgesia in animals. Restricting preclinical evaluation of pain and analgesia to exclusively reflexive outcomes is over simplified and can be argued not clinically relevant due to the continued lack of forward translation and failures in the clinic. The key to developing new analgesic treatments for neuropathic pain therefore lies in the development of clinically relevant endpoints that can translate preclinical animal results to human clinical trials. In this review we discuss this mismatch of primary neuropathic pain assessment endpoints, together with clinical and preclinical evidence that supports how bidirectional research is helping to validate new clinically relevant neuropathic pain assessment endpoints. Ethological behavioral endpoints such as burrowing and facial grimacing and objective measures such as electroencephalography provide improved translatability potential together with currently used quantitative sensory testing endpoints. By tailoring objective and subjective measures of neuropathic pain the translatability of new medicines for patients suffering with neuropathic pain will hopefully be improved.
对于患有慢性神经性疼痛的患者而言,迫切需要合适的新型疗法。近年来,用于神经性疼痛的新型镇痛药研发缺乏的一个促成因素是临床前试验与临床试验中主要神经性疼痛评估终点的不匹配。尽管在各种机制上持续出现正向转化失败的情况,但反射性定量感觉测试仍然是动物神经性疼痛和镇痛的主要评估终点。将疼痛和镇痛的临床前评估仅局限于反射性结果过于简单化,而且由于持续缺乏正向转化以及临床试验中的失败,可以认为其与临床无关。因此,开发用于神经性疼痛的新型镇痛疗法的关键在于开发能够将临床前动物实验结果转化为人体临床试验的临床相关终点。在本综述中,我们讨论了主要神经性疼痛评估终点的这种不匹配,以及支持双向研究如何有助于验证新的临床相关神经性疼痛评估终点的临床和临床前证据。诸如打洞和面部 grimacing 等行为学行为终点以及诸如脑电图等客观测量方法与目前使用的定量感觉测试终点一起提供了更高的转化潜力。通过调整神经性疼痛的客观和主观测量方法,有望提高用于患有神经性疼痛患者的新药的可转化性。 (注:原文中“facial grimacing ”原文未翻译,推测是个特定专业术语,此处保留原文,可根据实际情况补充准确译文)
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