Alcohol Consumption Modulates the Development of Chronic Pain in COVID-19 Patients: A Network Meta-Analysis

The mechanisms underlying the onset and progression of chronic pain in COVID-19 patients have been understudied. Using network meta-analysis, we previously demonstrated that alcohol augments COVID-19 symptoms and pathologies possibly by inducing a severe cytokine storm. We and others have also reported that acute alcohol consumption produces analgesic effects, while chronic alcohol consumption results in hyperalgesia and chronic pain. This study aimed to identify the influence of alcohol consumption and COVID-19 on pain. Using publicly available curated gene expression data sets of differentially expressed genes (DEGs) in the prefrontal cortex (PFC) and amygdala of COVID-19 patients, we employed a bioinformatics application, QIAGEN ingenuity pathway analysis (IPA), to identify the key signaling pathways, upstream regulators, and biological functions in these brain areas known to play a role in pain. Canonical pathway analysis revealed activation of the neuropathic pain pathway and signaling pathways involving the cytokine storm, S100 family, IL-6, and neuroinflammation. IPA's network builder was employed to construct a network map of shared molecules between alcohol and pain-related constructs (discomfort, neuropathic pain, and inflammatory pain). The simulation of alcohol consumption inhibited pain in this network map. To study the influence of COVID-19, we overlaid the DEGs from the PFC and amygdala onto these networks, mimicking alcohol consumption during SARS-CoV-2 infection. Upregulation of molecules in the amygdala and PFC predicted an increase in neuropathic pain, as well as an increase in inflammatory pain in the PFC. Our results suggest that while alcohol consumption directly inhibits pain, the presence of COVID-19 exaggerates impaired cytokine signaling, neuroinflammation, and neuropathic pain signaling in the CNS providing novel insights into the signaling pathways associated with chronic pain of the COVID-19 patients.