Our findings support a role for sleep disturbance and associated inflammatory processes in understanding bi-directional associations among pain and sleep. In adults with chronic low back pain, we found poorer subjective sleep quality to be associated with higher levels of the inflammatory cytokine IL-6. This association is especially noteworthy given the absence in our sample of common chronic back pain co-morbidities, such as heart disease, rheumatoid arthritis, or diabetes,36
that are characterized by inflammatory dysregulation and elevated IL-6.35, 37
Thus, we suspect our findings may underestimate the bi-directional associations among sleep, IL-6, and pain that may be particularly problematic for individuals with chronic pain co-morbidities and associated inflammatory burden.
Our evidence also suggests that sleep and IL-6 play a role in pain perceptions. Poorer sleep quality was associated with higher morning pain. IL-6 levels related only to affective pain ratings, and this association was mediated by sleep quality. To explore this relationship further, we examined associations among IL-6 and specific affective pain descriptors from the MPQ-SF. We found that higher IL-6 levels were strongly associated with higher ratings of current pain being “tiring/exhausting” (r
= .58, p
= .002), a relationship that was not attenuated by including sleep quality in the model. This finding suggests that individuals may attribute daytime fatigue to pain, rather than to its more likely source: sleep disturbance and concomitant increases in IL-6 levels. Inflammatory cytokines have multiple effects on the central nervous system, producing “sickness behaviors” that include both hyperalgesia and fatigue.26, 38
Misattribution of negative affect and fatigue to pain may lead to greater fear-avoidant behavior and disability,39
a prospect we did not address in this study but a possible avenue for future research.
As expected, depressive symptom scores were significantly higher among our CLBP group compared to controls.40
However, depression did not fully explain associations among IL-6 and sleep, and poor sleep quality remained a significant predictor of pain after adjusting for depressive symptoms. Given the strong associations between depression and insomnia, and depression and pain, depressed mood likely plays an important role in neurobiological pathways linking pain and sleep. Nevertheless, it is also probable that depression is neither necessary nor sufficient for persistent pain to be underpinned by sleep and inflammatory processes. Additionally, sickness behaviors, all of which can characterize clinical depression,41, 42
may be a consequence of pain and sleep-related inflammatory function. Longitudinal studies evaluating pain, sleep, mood, and inflammation are necessary to fully delineate the nature of these complex and bi-directional associations.
Our findings in the context of emerging literature on inflammation and pain, and sleep, suggest that the mechanisms underpinning increased IL-6 among chronic pain sufferers with sleep disturbance warrant scrutiny. Recent psychoneuroimmunological research suggests a role for inflammatory mediators in hyperalgesia, including exacerbated back pain,7, 11
possibly through direct effects of inflammatory cytokines on pain sensory pathways,10, 12, 43-45
These links, however, are not fully understood. Sleep disturbance, as a modulator of inflammation, may contribute to this process. Stress pathways may be involved as well.46
Notably, nociceptive stimulation can lead to inflammatory reactivity,47, 48
and, in a recent study, IL-6 responses were attenuated in individuals reporting less pain-related catastrophizing.49
Thus, pain-associated stress and anxiety may exacerbate pain through heightened inflammatory responses to nociception. Sleep disturbance, too, can modulate physiological stress reactivity.50, 51
Future research should assess both sleep disturbance and pain-related stress reactivity as a source of increased systemic inflammation in pain disorders.
Limitations of the current study include a small sample size and the inclusion of otherwise healthy and relatively young adults with chronic low back pain. Despite the small sample, we found significant associations among poorer sleep quality and higher IL-6. Further, inflammatory dysregulation increases with age, and higher IL-6 levels are associated with age-related sleep changes.22
Thus, the association we observed here between sleep disturbance and inflammation in younger to middle-aged adults with chronic pain may be particularly problematic for older adults with chronic pain. Controls showed the expected age-related increases in IL-6,34, 35
although the age and IL-6 correlation was non-significant (p
= .09). In contrast, for the CLBP group, age showed no association with IL-6 (p
= .48). The most parsimonious explanation is that there is no significant association within either group, which may be due to our smaller and younger sample. Alternatively, variation in sleep quality may play a more prominent role in inflammatory function among individuals with chronic pain than does chronological age.
Additional limitations include the use of a modified version of the PSQI to assess sleep quality during a single night, which has not been validated previously, and a single blood draw. Multiple assessments of IL-6 throughout the day on multiple days would allow for analysis of change and improved reliability. Whether venipuncture pain affected outcomes is also unknown. We did not have information on factors such as body mass index, estradiol levels, or 12-hour pre-blood draw diet (as this was not a fasting blood draw), any of which may have related to sleep,52, 53
or pain57, 58
in our sample. Whether these factors can explain our findings warrants future study. Nonetheless, our exclusion criteria do reduce the likelihood that relationships observed here are due to confounding by inflammatory-related conditions. Finally, we assessed fibromyalgia and inflammatory conditions characterized by episodic pain (e.g., rheumatoid arthritis), but we did not specifically inquire about all episodic pain conditions (e.g., migraine, mennorhagia). Thus, we cannot rule out the possibility that these conditions were present and influenced our findings.
In sum, the current findings suggest important roles for sleep disturbance and associated inflammatory processes in chronic pain that require further study. Notably, we have also found that improving sleep in adults with insomnia as a secondary co-morbidity to chronic pain leads to reductions in circulating IL-6.59
Adults with non-malignant, non-site specific chronic pain and insomnia who received a cognitive behavioral treatment (CBT) that included a sleep intervention component had significantly larger declines in IL-6 levels following treatment compared to a group receiving CBT without attention to sleep. These encouraging data underscore significant clinical implications of understanding pathways linking sleep, inflammation, and pain, and support explicit treatment of sleep problems in the management of chronic pain. Given the strong associations we observed between sleep and IL-6 in our study, these implications may indeed be similar in the context of chronic low back pain.