The importance of central sensitization for clinical trials of disease modifying osteoarthritis drugs (DMOADs)

David A Walsh , Daniel F McWilliams
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Abstract

Osteoarthritis (OA) pain is associated with structural changes in the joint, which are usually quantified by imaging techniques. It is anticipated that structural disease modifying OA drugs (DMOADs) would reduce the burden of OA pain. However, nociceptive pain is moderated by the central nervous system. Central sensitization, increased activity in central nervous system neurones in response to a standard nociceptive input, is one reason why disease modification might not effectively relieve OA pain. Central sensitization may result from facilitated central neuronal activity, or inadequate inhibition by endogenous analgesic mechanisms. It changes the experience of pain: its severity, distribution and qualities, and its emotional and cognitive dimensions. Central sensitization can be a barrier to analgesic benefit from treatments directed at joint structure, and central pain processing can obscure analgesic benefit from structural modification in randomised controlled trials. Indices of central pain hypersensitivity might reflect central sensitization in humans. They include self-report questionnaires such as the Central Aspects of Pain (CAP) and short form Central Sensitization Inventory (CSI-9), and quantitative sensory testing (QST) modalities of Pressure Pain detection Thresholds distant to the affected joint, Temporal Summation, and Conditioned Pain Modulation. Understanding, measuring, managing and adjusting for central pain hypersensitivity should increase the power of clinical trials to demonstrate that DMOADs not only improve joint imaging outcomes, but also improve pain, the predominant clinical problem of OA.
中枢致敏对疾病调节性骨关节炎药物临床试验的重要性
骨关节炎(OA)疼痛与关节的结构改变有关,通常通过成像技术进行量化。预计结构疾病修饰性OA药物(DMOADs)将减轻OA疼痛的负担。然而,痛觉性疼痛是由中枢神经系统调节的。中枢致敏,即中枢神经系统神经元对标准伤害性输入的反应活动增加,是疾病改良可能无法有效缓解OA疼痛的原因之一。中枢致敏可能是由中枢神经元活动促进或内源性镇痛机制抑制不足引起的。它改变了痛苦的体验:它的严重程度、分布和质量,以及它的情感和认知维度。在随机对照试验中,中枢致敏可能是针对关节结构治疗的镇痛效果的障碍,中枢疼痛处理可能会掩盖结构改变带来的镇痛效果。中枢性疼痛超敏反应的指标可能反映了人类的中枢性致敏。它们包括自我报告问卷,如疼痛的中心方面(CAP)和简短的中央敏感化量表(CSI-9),以及距离受影响关节的压力疼痛检测阈值、时间总和和条件疼痛调节的定量感觉测试(QST)模式。对中枢性疼痛超敏反应的理解、测量、管理和调整应该增加临床试验的力量,以证明dmoad不仅改善关节成像结果,而且改善疼痛,OA的主要临床问题。
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Osteoarthritis imaging
Osteoarthritis imaging Radiology and Imaging
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