Endocannabinoids and Related Lipids in Chronic Pain : Analytical and Clinical Aspects

In Europe, approximately one in five adults experience chronic pain, pain that lasts more than three months. Chronic pain is a significant problem not only for those people suffering from chronic pain but also for society. The prevalence of chronic pain is higher in women and lower socioeconomic groups. Although chronic pain often originates in a specific site, it may eventually spread to several sites, transforming into chronic widespread pain (CWP), a condition evident in about 10% of the adult population. Approximately 1.2-5.4% are classified with fibromyalgia (FM). In addition to CWP, common symptoms of FM include, stiffness, fatigue, sleep disturbances, and cognitive dysfunction and common co-morbidities include depression and anxiety. Although FM/CWP has been reported to alter both central and peripheral nociceptive mechanisms, no objective biomarkers have been found that correlate with CWP/FM and no standard examinations such as blood test, X-ray or computed tomography can provide support for a diagnosis. Because there are no objective biomarkers that correlate with the pathophysiological processes associated with CWP/FM, this debilitating disease is difficult to diagnose and ultimately treat. However, there are some promising therapeutic targets for chronic pain with inter alia analgesic, anti-inflammatory, and stress modulating properties: the endocannabinoids (ECs) arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) and their related lipids oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA). This thesis investigates whether ECs and the related N-acylethanolamines (NAEs) can be used as potential biomarkers for CWP/FM. Specifically, the studies compared the peripheral and systemic levels of ECs and NAEs in 121 women with CWP/FM and in 137 healthy controls in two different cohorts. In addition, the correlation between lipid levels and common pain characteristics such as intensity, sensitivity, and duration were investigated. The EC and related lipid levels were measured using liquid chromatography in combination with tandem mass spectrometry. Multivariate data analysis was used for biomarker evaluation. Compared to the healthy controls, the CWP/FM patients had significantly higher concentrations of OEA, PEA, and SEA in muscle and plasma (p ≤ 0.05) and significantly higher 2-AG in plasma (p ≤ 0.01). These results may indicate that NAEs, are mobilized differently in painful muscles compared with pain free muscles. Moreover, increased systemic levels of NAEs and 2-AG in patients might be signs of ongoing low-grade inflammation in CWP/FM. These findings contribute to a better understanding of how peripheral and systemic factors maintain and activate chronic pain. Although the investigated lipids have statistically significant effects but biologically uncertain role in the clinical manifestations of CWP/FM. Thus plasma lipids are not a good biomarker for CWP/FM. Nevertheless, increased lipid levels indicate a metabolic asymmetry in CWP/FM, a finding that could serve as a basis for more research on pain management