Pathways linking sleep, neuroimmune signaling and pain: an integrative approach

Abstract: Background and objectives: Neuroinflammation is implicated in the development and maintenance of persistent pain states, but there is limited data linking cerebrospinal fluid (CSF) inflammatory mediators with neurophysiological pain processes in humans. Study I aimed to investigate whether there are coherent changes in CSF inflammation associated with central sensitization (CS), and to evaluate potential differences in CSF levels of inflammatory mediators between osteoarthritis (OA) patients with disabling pain and pain-free controls. The overarching objective of study II was to longitudinally evaluate changes in pain neurophysiology and inflammatory mediators in CSF and plasma following THA.Pain and sleep interact bidirectionally; pain may lead to disturbed sleep, and sleep disturbance can cause pain and hyperalgesia. Preoperative sleep disturbance is associated with impaired acute postoperative pain control. Given the salient links between sleep and pain, study III aimed to evaluate whether treatments that target perioperative sleep may have salutary effects not only on sleep itself, but also on postoperative pain outcomes. The main objective of study IV and V was to examine the role of sleep disturbance in the development and long-term maintenance of postoperative pain after total hip arthroplasty (THA) and groin hernia repair. Additionally, study V assessed sex-differences related to chronic postherniorrhaphy inguinal pain (CPIP) and sleep quality.Results: Study I: Compared to controls (n=30), OA patients undergoing THA (n=52) had higher CSF levels of interleukin 8 (IL-8) (P=0.002), intercellular adhesion molecule 1 (P=0.007) and vascular cell adhesion molecule 1 (P=0.006), indicating neuroinflammation. OA patients with signs of CS had elevated CSF concentrations of Fms-related tyrosine kinase 1 (Flt-1) (P=0.044), interferon gamma-induced protein 10 (IP-10) (P=0.024) and monocyte chemoattractant protein 1 (MCP-1) (P=0.011).Study II: THA leads to long-term decreases in pain sensitivity, indicative of resolution of sensitization processes. Compared to preoperative, CSF and plasma levels of IP-10 increased (P=0.041 and P=0.006, respectively), whereas plasma IL-8 decreased (P=0.023). Alterations in inflammatory mediators were linked to changes in pressure pain sensitivity.Study III: Systematic review, 14 studies were included (9 melatonin, 5 zolpidem; 921 patients). Addition of perioperative melatonin or zolpidem may improve acute postoperative pain control, however, evidence is weak.Study IV: Poor preoperative sleep quality predicted increased immediate opioid treatment after THA, and impaired long-term postoperative pain control. Sleep disturbance was associated with reduced endogenous pain inhibitory capacity, and increased pressure pain sensitivity.Study V: In a register-based cohort study (n=2084), preoperative sleep problems predicted development of CPIP 12 months after surgery (aOR 1.76 (95%CI 1.26-2.46), P=0.001) and CPIP in the long-term (aOR 2.20 (95%CI 1.61-3.00), P<0.0001). Increased severity of CPIP was linked to poorer sleep and depression. Compared to men, women had higher rates of CPIP with negative impact on daily activities 12 months after surgery (14.6 vs 9.2%, P<0.0005), and moderate-severe CPIP in the long-term (3.1 vs 1.2%, P=0.003).Significance: Pain phenotype may be influenced by specific CSF neuroinflammatory profiles. Targeting of pathways underlying neuroinflammation and glia activation might alleviate persistent pain. Interventions which achieve even modest improvements in sleep might translate into meaningful clinical improvements in pain.