Elevated inflammatory markers in response to prolonged sleep restriction are associated with increased pain experience in healthy volunteers

Abstract

Context: Sleep disturbances, pain, and inflammation co-occur in various medical conditions, but their interrelationships are poorly understood.

Objective: We investigated the effects of reduced sleep duration (by approximately 50%) to 4 h/night across 10 days, on peripherally circulating inflammatory mediators. In addition, we tested the prediction that degree of inflammation is quantitatively related to the extent to which pain is increased in response to prolonged sleep restriction.

Design: Randomized, 16 day controlled in-laboratory study conducted in GCRC.

Methods: Eighteen volunteers were randomly assigned to either 12 days of sleeping 8 h/night or 4 h/night. Participants rated mood and pain symptoms throughout experimental days. Urine was collected and blood was drawn frequently on the baseline day and after the 10th experimental day for 25 hours.

Outcome measures: Levels of plasma interleukin (IL)-6, serum C-reactive protein (CRP), plasma soluble tumor necrosis factor receptor p55 (sTNF-R p55), urinary levels of prostaglandin (PG) metabolites D2 and E2, subjective assessment of pain and tiredness-fatigue.

Results: IL-6 levels were elevated in the 4-h sleep condition over the 8-h sleep condition (P <0.05). CRP levels showed the same trend as IL-6, but did not differ significantly between groups (P = 0.11). Levels of sTNF-R p55 were unchanged in both groups. PG E2 and 11beta-F2alpha metabolite increased in 4-h sleepers, but did not differ significantly from the 8-h sleepers. Elevated IL-6 levels were strongly associated with increased pain ratings in response to sleep restriction (r = 0.67, P <0.01), and this association could not be explained by elevations in tiredness-fatigue.

Conclusion: Insufficient sleep quantity may facilitate and/or exacerbate pain through elevations of IL-6. In disorders where sleep disturbances are common, insufficient sleep quantity itself may establish and maintain its co-occurrence with pain and increased inflammation.

Figures

Figure 1

Percent change of urinary levels of PG E2 metabolite and the D2 metabolite 11β-PGF2α from baseline to the 11th day of sleeping either 8 h/night (grey bar, N=8) or 4 h/night (hatched bar, N=10). PGs were measured in 24-h urine collection. Values are presented and at percent change from baseline due to large inter-individual variability (see text for original values).

Figure 2

Change of plasma IL-6, serum CRP, and plasma sTNF-R p55 levels from baseline to the 11th day of sleeping either 8 h/night (grey bar, N=8) or 4 h/night (hatched bar, N=10 for IL-6, N=9 for sTNF-R p55). IL-6, CRP, and sTNF-R p55 were measured every 4 h and averaged across a 24-h period. Original values are presented, and statistics were based on log-transformed values. Asterisk indicates significant difference between sleep conditions.

Figure 3

Change of subjective reports of bodily discomfort and tiredness-fatigue from baseline to the 11th day of sleeping either 8 h/night (grey bar, N=8) or 4 h/night (hatched bar, N=10). Bodily discomfort and tiredness-fatigue were assessed every 2 h throughout the waking periods of the protocol and averages across a 24-h period. Original values are presented, and statistics were based on log-transformed values. Asterisk indicates significant difference between sleep conditions.

Figure 4

Correlation between change in IL-6 and change in bodily discomfort (left) and tiredness-fatigue (right) from baseline to the 11th day of sleep 4 h/night (▴) or 8 h/night (). Log-transformed data are presented.