Pacheco-Barrios Kevin, Simis Marcel, de Melo Paulo S, Rebello-Sanchez Ingrid, Vasquez-Avila Karen, Franco Sara Barbosa, Gonzalez-Mego Paola, Battistella Linamara, Imamura Marta, Fregni Felipe
Neuromodulation Center and Center for Clinical Research Learning, Harvard Medical School, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Boston, USA; Universidad San Ignacio de Loyola, Vicerrectorado de Investigación, Unidad de Investigación para la Generación y Síntesis de Evidencias en Salud, Lima, Peru.
Universidade de São Paulo, Faculdade de Medicina, Hospital das Clinicas (HCFMUSP), São Paulo, SP, Brazil.
Braz J Anesthesiol. 2025 Jul-Aug;75(4):844639. doi: 10.1016/j.bjane.2025.844639. Epub 2025 May 16.
This study aims to explore the role of sex as a confounder and effect modifier in the associations of clinical outcomes, pain-related outcomes, and neurophysiological measurements in chronic knee OA pain subjects.
Sociodemographic, clinical, and neurophysiological data were extracted from 113 knee OA subjects with chronic pain. We performed exploratory multivariate regression models assessing the association of physiological outcomes (Quantitative Sensory Testing [QST], Electroencephalography [EEG], and Transcranial Magnetic Stimulation [TMS]) and clinical characteristics (pain, anxiety, and motor function). In each independent model we tested the role of biological sex as confounder and effect modifier (adding the interaction term).
Females reported higher pain intensity, lower quality of life, diminished pain thresholds, and less EEG alpha power compared to males. Sex negatively confounded the association between pain interference and pain intensity with pain threshold confounding (ranged between -19% to -125%). Moreover, sex acted as an effect modifier, predominantly influencing the relationship between pain interference and frontocentral alpha-delta power in EEG. Similarly, sex modified the association between pain interference and pain threshold. In females EEG and PPT variables explained less variability of pain interference compared to males.
Our study suggests that sex is a confounder and effect modifier mainly in the relationship between neurophysiological variables and pain-related outcomes in a chronic OA pain population. Females may have weaker associations between pain intensity and mechanistic outcomes (EEG and QST). Thus, the use of these biomarkers in females requires further optimization. We therefore reinforce the need for accounting for biological sex in the analysis, not only as a confounder, but as an effect modifier in further randomized trials and observational studies in the field of pain.
本研究旨在探讨性别作为混杂因素和效应修饰因素在慢性膝关节骨关节炎（OA）疼痛患者的临床结局、疼痛相关结局及神经生理学测量指标的关联中所起的作用。
从113例患有慢性疼痛的膝关节OA患者中提取社会人口统计学、临床及神经生理学数据。我们进行了探索性多变量回归模型，以评估生理指标（定量感觉测试[QST]、脑电图[EEG]和经颅磁刺激[TMS]）与临床特征（疼痛、焦虑和运动功能）之间的关联。在每个独立模型中，我们测试了生物学性别作为混杂因素和效应修饰因素的作用（加入交互项）。
与男性相比，女性报告的疼痛强度更高、生活质量更低、疼痛阈值更低且脑电图α波功率更小。性别对疼痛干扰与疼痛强度之间的关联产生负向混杂作用，同时伴有疼痛阈值的混杂（范围在-19%至-125%之间）。此外，性别作为效应修饰因素，主要影响疼痛干扰与脑电图额中央α-δ波功率之间的关系。同样，性别改变了疼痛干扰与疼痛阈值之间的关联。与男性相比，在女性中脑电图和疼痛阈值变量对疼痛干扰的变异性解释较少。
我们的研究表明，在慢性OA疼痛人群中，性别主要是神经生理学变量与疼痛相关结局之间关系的混杂因素和效应修饰因素。女性的疼痛强度与机制性指标（脑电图和QST）之间的关联可能较弱。因此，在女性中使用这些生物标志物需要进一步优化。我们因此强调在分析中不仅要将生物学性别作为混杂因素，而且要作为效应修饰因素加以考虑的必要性，这在疼痛领域的进一步随机试验和观察性研究中尤为重要。
