Department of Orthopedics, University Medical Centre Utrecht, Heidelberglaan 100, 3508 GA Utrecht, the Netherlands.
Department of Anesthesiology, University Medical Centre Utrecht, Heidelberglaan 100, 3508 GA Utrecht, the Netherlands.
Bone. 2020 May;134:115272. doi: 10.1016/j.bone.2020.115272. Epub 2020 Feb 13.
Skeletal pathologies are often accompanied by bone pain, which has negative effects on the quality of life and functional status of patients. Bone pain can be caused by a wide variety of injuries and diseases including (poorly healed) fractures, bone cancer, osteoarthritis and also iatrogenic by skeletal interventions. Orthopedic interventions are considered to be the most painful surgical procedures overall. Two major groups of medication currently used to attenuate bone pain are NSAIDs and opioids. However, these systemic drugs frequently introduce adverse events, emphasizing the need for alternative therapies that are directed at the pathophysiological mechanisms underlying bone pain. The periosteum, cortical bone and bone marrow are mainly innervated by sensory A-delta fibers and C-fibers. These fibers are mostly present in the periosteum rendering this structure most sensitive to nociceptive stimuli. A-delta fibers and C-fibers can be activated upon mechanical distortion, acidic environment and increased intramedullary pressure. After activation, these fibers can be sensitized by inflammatory mediators, phosphorylation of acid-sensing ion channels and cytokine receptors, or by upregulation of transcription factors. This can result in a change of pain perception such that normally non-noxious stimuli are now perceived as noxious. Pathological conditions in the bone can produce neurotrophic factors that bind to receptors on A-delta fibers and C-fibers. These fibers then start to sprout and increase the innervation density of the bone, making it more sensitive to nociceptive stimuli. In addition, repetitive painful stimuli cause neurochemical and electrophysiological alterations in afferent sensory neurons in the spinal cord, which leads to central sensitization, and can contribute to chronic bone pain. Understanding the pathophysiological mechanisms underlying bone pain in different skeletal injuries and diseases is important for the development of alternative, targeted pain treatments. These pain mechanism-based alternatives have the potential to improve the quality of life of patients suffering from bone pain without introducing undesirable systemic effects.
骨骼病理学通常伴随着骨痛，这会对患者的生活质量和功能状态产生负面影响。骨痛可由多种损伤和疾病引起，包括（愈合不良的）骨折、骨癌、骨关节炎，也可由骨骼介入引起医源性骨痛。骨科介入被认为是总体上最痛苦的手术程序。目前用于减轻骨痛的两类主要药物是 NSAIDs 和阿片类药物。然而，这些全身药物经常会引起不良反应，这强调了需要替代疗法，这些疗法针对的是骨痛的病理生理机制。骨膜、皮质骨和骨髓主要由感觉 A-δ纤维和 C-纤维支配。这些纤维主要存在于骨膜中，使该结构对伤害性刺激最敏感。A-δ纤维和 C-纤维可在机械扭曲、酸性环境和骨髓内压增加时被激活。激活后，这些纤维可被炎症介质、酸感应离子通道和细胞因子受体的磷酸化，或转录因子的上调而敏化。这会导致疼痛感知的改变，使得正常的非伤害性刺激现在被感知为伤害性刺激。骨骼中的病理状况会产生神经营养因子，这些因子与 A-δ纤维和 C-纤维上的受体结合。这些纤维随后开始发芽并增加骨骼的神经支配密度，使其对伤害性刺激更加敏感。此外，重复的疼痛刺激会导致脊髓中的传入感觉神经元发生神经化学和电生理学改变，导致中枢敏化，并可能导致慢性骨痛。了解不同骨骼损伤和疾病中骨痛的病理生理机制对于开发替代的、靶向的疼痛治疗方法很重要。这些基于疼痛机制的替代方法有可能改善患有骨痛的患者的生活质量，而不会引入不良的全身效应。
