Next-generation precision medicine for pain.

Chronic pain remains a massive problem in society in general, and in mental health patients in particular, being strongly bi-directionally connected to mental health. Lack of widespread use of objective information has hampered treatment and prevention efforts. Pain is a spectrum of severity, from transient vague discomfort to chronic excruciating incapacitation. Blood biomarkers that track pain severity can provide a window into the biology of pain, as well as could help with assessment and treatment. A previous study by us was positive. Here we describe new studies we conducted trans-diagnostically in psychiatric patients, starting with the whole genome, to expand the identification, prioritization, validation and testing of blood gene expression biomarkers for pain. We carried out two separate studies, on two different platforms, microarrays and RNA sequencing, using for each study a multiple independent cohorts design. This ensured biological and technical reproducibility. We then focused at the end on biomarkers that were convergent and reproducible between the two studies. We found new as well as previously known biomarkers that were predictive of high pain states, and of future emergency department visits related to them, using cross-sectional and longitudinal approaches. Using a polyevidence score, the overall top decreased in expression biomarker ("pain-suppressor gene") was CD55, a gene that suppresses the complement cascade and cell damage. The top increased biomarker ("algogene") was ANXA1, a gene that is an effector of glucocorticoid-mediated responses and regulator of the inflammatory processes. The top biological pathways were related to cellular response to TNF and to neuroinflammation. The top upstream regulator was TNF. Top therapeutic matches overall were the medications lithium and ketamine, as well as the nutraceuticals omega-3 fatty acids and magnesium. Drug repurposing bioinformatic analyses also identified the potential of carvedilol, sirolimus, budesonide, berbamine, and quetiapine, as well as of medications already used to treat pain such as amyleine, sulindac, sufentanil, carbamazepine, and meclofenamic acid, that serve as de facto positive controls. Additionally, we show how personalized patient reports for doctors would look like based on blood biomarkers testing, to aid with objective assessment of severity and risk, as well with individualized matching to medications and nutraceuticals. Given the fact that pain disorders are highly prevalent, can severely affect quality of life, and even lifespan, there is an urgent need for insights and tools such as the ones we have developed to be applied to and improve clinical diagnosis, treatment, and prevention options.