Sleep Disruption and Activation of Cellular Inflammation Mediate Heightened Pain Sensitivity: A Randomized Clinical Trial.

Sleep loss heightens pain sensitivity, but the pathways underlying this association are not known. Given that experimental sleep disruption induces increases in cellular inflammation as well as selective loss of slow wave, N3 sleep, this study examined whether these mechanisms contribute to pain sensitivity following sleep loss in healthy adults. This assessor-blinded, cross-over sleep condition, single-site, randomized clinical trial enrolled 95 healthy adults (mean [SD] age, 27.8 [6.4]; female, 44 [53.7%]). The two sleep conditions were two nights of undisturbed sleep (US) and two nights of sleep disruption or forced awakening (FA, eight pseudorandomly distributed awakenings, 200 minutes wake time during 8 hr sleep opportunity), administered in a cross-over design after two weeks of washout and in random order (FA-US; US-FA). Primary outcome was heat pain threshold (hPTH). Sleep architecture was assessed by polysomnography, and morning levels of cellular inflammation were evaluated by Toll-like receptor (TLR)-4 stimulated monocyte intracellular proinflammatory cytokine production. As compared to US, FA was associated with decreases in the amount of slow wave or N3 sleep (P<0.001); increases in TLR-4 stimulated production of interleukin-6 and tumor necrosis factor-α (P=0.03); and decreases in hPTH (P=0.02). A comprehensive causal mediation analysis found that FA had an indirect effect on hPTH via decreases in N3 sleep and subsequent increases in inflammation (estimate=-0.15; 95% confidence interval, -0.30 - -0.03; P<0.05) with the proportion mediated 34.9%. Differential loss of slow wave, N3 sleep and increases in cellular inflammation are important drivers of pain sensitivity following sleep disruption.