Data-Driven Path Analytic Modeling to Understand Underlying Mechanisms in COVID-19 Survivors Suffering from Long-Term Post-COVID Pain: A Spanish Cohort Study.

Pain can be present in up to 50% of people with post-COVID-19 condition. Understanding the complexity of post-COVID pain can help with better phenotyping of this post-COVID symptom. The aim of this study is to describe the complex associations between sensory-related, psychological, and cognitive variables in previously hospitalized COVID-19 survivors with post-COVID pain, recruited from three hospitals in Madrid (Spain) by using data-driven path analytic modeling. Demographic (i.e., age, height, and weight), sensory-related (intensity or duration of pain, central sensitization-associated symptoms, and neuropathic pain features), psychological (anxiety and depressive levels, and sleep quality), and cognitive (catastrophizing and kinesiophobia) variables were collected in a sample of 149 subjects with post-COVID pain. A Bayesian network was used for structural learning, and the structural model was fitted using structural equation modeling (SEM). The SEM model fit was excellent: RMSEA < 0.001, CFI = 1.000, SRMR = 0.063, and NNFI = 1.008. The only significant predictor of post-COVID pain was the level of depressive symptoms (ß=0.241, p = 0.001). Higher levels of anxiety were associated with greater central sensitization-associated symptoms by a magnitude of ß=0.406 (p = 0.008). Males reported less severe neuropathic pain symptoms (-1.50 SD S-LANSS score, p < 0.001) than females. A higher level of depressive symptoms was associated with worse sleep quality (ß=0.406, p < 0.001), and greater levels of catastrophizing (ß=0.345, p < 0.001). This study presents a model for post-COVID pain where psychological factors were related to central sensitization-associated symptoms and sleep quality. Further, maladaptive cognitions, such as catastrophizing, were also associated with depression. Finally, females reported more neuropathic pain features than males. Our data-driven model could be leveraged in clinical trials investigating treatment approaches in COVID-19 survivors with post-COVID pain and can represent a first step for the development of a theoretical/conceptual framework for post-COVID pain.

The Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) and PainDETECT Questionnaires in COVID-19 Survivors with Post-COVID Pain.

This study aimed to analyze correlations between Self-Report Leeds Assessment of Neuropathic Symptoms (S-LANSS) and PainDETECT with proxies of sensitization, pain-related, or psychological/cognitive variables in coronavirus disease, 2019 (COVID-19) survivors exhibiting post-COVID pain. Demographic, clinical, psychological, cognitive, sensitization-associated symptoms, and health-related quality of life were collected in 146 survivors with post-COVID pain. The PainDETECT and S-LANSS questionnaires were used for assessing neuropathic pain-related symptoms. Patients were assessed with a mean of 18.8 (SD 1.8) months after hospitalization. Both questionnaires were positively associated with pain intensity (p < 0.05), anxiety (PainDETECT p < 0.05; S-LANSS p < 0.01), sensitization-associated symptoms (p < 0.01), catastrophism (p < 0.01), and kinesiophobia (p < 0.01) and negatively associated with quality of life (PainDETECT p < 0.05; S-LANSS p < 0.01). Depressive levels were associated with S-LANSS (p < 0.05) but not with PainDETECT. The stepwise regression analyses revealed that 47.2% of S-LANSS was explained by PainDETECT (44.6%), post-COVID pain symptoms duration (1.7%), and weight (1.1%), whereas 51.2% of PainDETECT was explained by S-LANSS (44.6%), sensitization-associated symptoms (5.4%), and anxiety levels (1.2%). A good convergent association between S-LANSS and PainDETECT was found. Additionally, S-LANSS was associated with symptom duration and weight whereas PainDETECT was associated with sensitization-associated symptoms and anxiety levels, suggesting that the two questionnaires evaluate different aspects of the neuropathic pain spectrum in post-COVID pain patients.

Understanding Sensitization, Cognitive and Neuropathic Associated Mechanisms behind Post-COVID Pain: A Network Analysis.

This study aimed to describe a network including demographic, sensory-related, psychological/cognitive and other variables in individuals with post-COVID pain after hospitalization. Demographic (i.e., age, height, weight, months with symptoms), sensory-related (Central Sensitization Inventory -CSI-, Self-Report Leeds Assessment of Neuropathic Symptoms -S-LANSS-, PainDETECT), psychological/cognitive (Hospital Anxiety and Depression Scale -HADS-A/HADS-D-, Pain Catastrophizing Scale -PCS-, Tampa Scale for Kinesiophobia -TSK-11-) and other (sleep quality and health-related quality of life -EQ/5D/5L) variables were collected in 146 COVID-19 survivors with post-COVID pain. A network analysis was conducted to quantify the adjusted correlations between the modelled variables, and to assess their centrality indices (i.e., the connectivity with other symptoms in the network and the importance in the system modelled as network). The network revealed associations between sensory-related and psychological/cognitive variables. PainDETECT was associated with S-LANSS (ρ: 0.388) and CSI (ρ: 0.207). Further, CSI was associated with HADS-A (ρ: 0.269), TSK-11 (ρ: 0.165) and female gender (ρ: 0.413). As expected, HADS-A was associated with HADS-D (ρ: 0.598) and TSK-11 with PCS (ρ: 0.405). The only negative association was between sleep quality and EQ-5D-5L (ρ: -0.162). Gender was the node showing the highest strength, closeness, and betweenness centralities. In addition, CSI was the node with the second highest closeness and betweenness centralities, whereas HADS-D was the node with the second highest strength centrality. This is the first study applying a network analysis for phenotyping post-COVID pain. Our findings support a model where sensitization-associated symptoms, neuropathic phenotype, and psychological aspects are connected, reflecting post-COVID pain as a nociplastic pain condition. In addition, post-COVID pain is gender dependent since female sex plays a relevant role. Clinical implications of current findings, e.g., developing treatments targeting these mechanisms, are discussed.