NeuroPain lab, Lyon Centre for Neuroscience Inserm U1028, Lyon, France.
Pain Center Neurological Hospital (CETD), Hospices Civils de Lyon, Lyon, France.
Eur J Pain. 2021 Aug;25(7):1389-1428. doi: 10.1002/ejp.1768. Epub 2021 May 8.
As in other fields of medicine, development of new medications for management of neuropathic pain has been difficult since preclinical rodent models do not necessarily translate to the clinics. Aside from ongoing pain with burning or shock-like qualities, neuropathic pain is often characterized by pain hypersensitivity (hyperalgesia and allodynia), most often towards mechanical stimuli, reflecting sensitization of neural transmission.
We therefore performed a systematic literature review (PubMed-Medline, Cochrane, WoS, ClinicalTrials) and semi-quantitative meta-analysis of human pain models that aim to induce central sensitization, and generate hyperalgesia surrounding a real or simulated injury.
From an initial set of 1569 reports, we identified and analysed 269 studies using more than a dozen human models of sensitization. Five of these models (intradermal or topical capsaicin, low- or high-frequency electrical stimulation, thermode-induced heat-injury) were found to reliably induce secondary hyperalgesia to pinprick and have been implemented in multiple laboratories. The ability of these models to induce dynamic mechanical allodynia was however substantially lower. The proportion of subjects who developed hypersensitivity was rarely provided, giving rise to significant reporting bias. In four of these models pharmacological profiles allowed to verify similarity to some clinical conditions, and therefore may inform basic research for new drug development.
While there is no single "optimal" model of central sensitization, the range of validated and easy-to-use procedures in humans should be able to inform preclinical researchers on helpful potential biomarkers, thereby narrowing the translation gap between basic and clinical data.
Being able to mimic aspects of pathological pain directly in humans has a huge potential to understand pathophysiology and provide animal research with translatable biomarkers for drug development. One group of human surrogate models has proven to have excellent predictive validity: they respond to clinically active medications and do not respond to clinically inactive medications, including some that worked in animals but failed in the clinics. They should therefore inform basic research for new drug development.
与其他医学领域一样，由于临床前啮齿动物模型不一定能转化为临床应用，因此开发治疗神经性疼痛的新药一直很困难。除了持续性的灼痛或电击样疼痛外，神经性疼痛通常还表现为疼痛敏化（痛觉过敏和感觉异常），最常见于机械刺激，反映了神经传递的敏化。
因此，我们对旨在诱导中枢敏化并在真实或模拟损伤周围产生痛觉过敏的人类疼痛模型进行了系统的文献回顾（PubMed-Medline、Cochrane、WoS、ClinicalTrials）和半定量荟萃分析。
从最初的 1569 篇报告中，我们确定并分析了 269 项使用十几种人类敏化模型的研究。其中五种模型（皮内或局部辣椒素、低频或高频电刺激、热模型诱导的热损伤）被发现能可靠地诱导针刺二次痛觉过敏，并已在多个实验室中实施。然而，这些模型诱导动态机械感觉异常的能力要低得多。很少有报告提供发生过敏的受试者比例，导致报告存在严重偏倚。在这四种模型中，药理学特征允许验证与某些临床情况的相似性，因此可能为新药开发的基础研究提供信息。
虽然没有单一的“最佳”中枢敏化模型，但在人类中已经有一系列经过验证且易于使用的程序，这些程序应该能够为临床前研究人员提供有帮助的潜在生物标志物，从而缩小基础和临床数据之间的转化差距。
能够直接在人类身上模拟病理性疼痛的某些方面，具有巨大的潜力来理解病理生理学，并为动物研究提供可转化的药物开发生物标志物。一组人类替代模型已经被证明具有很好的预测有效性：它们对临床有效的药物有反应，对临床无效的药物没有反应，包括一些在动物中有效的但在临床上失败的药物。因此，它们应该为新药开发的基础研究提供信息。
