The role of biological sex in neurophysiological associations of patients with chronic osteoarthritis pain: a prospective cross-sectional study

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Keywords: Chronic pain; Confounding variable; Osteoarthritis; Pain; Sex.

Figure 1

DAG, Direct Acyclic Graph; QST, Quantitative Sensory Tests; PPT, Pain Pressure Threshold; CPM, Conditioned Pain Modulation; TMS, Transcranial Magnetic Stimulation; MEP, Motor-Evoked Potentials; SICI, Short Intracortical Inhibition; ICF, Intracortical Facilitation; EEG, Electroencephalography; VAS, Visual Analog Scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; HAD, Hospital Anxiety and Depression.

Figure 2

Effect modification by sex.