Sleep disturbances are associated with increased pain, disease activity, depression, and anxiety in ankylosing spondylitis: a case-control study

Sleep quality

Sleep during the month preceding the evaluation was examined by using the PSQI, which includes 19 questions completed by the subject. These 19 items were broken down into the following seven components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disorders, use of hypnotics, and daytime dysfunction. Sleep latency is assessed by two questions rated according to time to fall asleep. Sleep duration by one question rated 4 on a Likert scale from >7 to <5 hours, and sleep efficiency by hours asleep divided by total of hours in bed. Use of hypnotics and poor daytime functioning are rated by a 4-point Likert scale (not during the past month, less than once per week, once or twice per week, 3 or more times per week). Sleep disorders were assessed with nine questions focused on waking up in the middle of the night or early in the morning, getting up to go to the toilet, difficulty breathing properly, coughing or snoring loudly, being too cold, being too hot, having nightmares, experiencing pain, or other reasons for disturbed sleep. Each question is rated with a 4-point Likert scale (not during the past month, less than once per week, once or twice per week, 3 or more times per week). Subjective sleep is evaluated with one question rated by a 4-point Likert scale from very good to very bad. The seven components were each scored from 0 (no difficulty) to 3 (severe difficulty), and summed, to give an overall score ranging from 0 to 21. Participants were dichotomized into a poor-sleep group if the PSQI was >7.0 and a good-sleep group if the PSQI was ≤7.0 [22].

Depressive symptoms

The depression levels of the patients were evaluated by using the SDS. This scale consists of 20 questions that examine the somatic, affective, and psychological symptoms associated with depression. Each question is scored between 1 and 4 (rarely, sometimes, frequently, and always). The total score varies between 20 and 80. Higher scores reflected more-severe depression. A score of 50 to 69 shows the existence of depression, and a score of 70 or higher means extreme depression [23].

Anxiety symptoms

The revised SAS was used to evaluate the level of anxiety-related symptoms during the last week before the survey. This self-administered test has 20 questions, with 15 items worded toward increasing anxiety levels and five questions worded toward decreasing anxiety levels. Each question was scored on a scale of 1 to 4 (rarely, sometimes, frequently, and always). The scores ranged between 20 and 80. A score of 50 to 69 shows the existence of anxiety, and a score of 70 or higher means extreme anxiety [24].

Data analysis

Descriptive statistics were used for assessing the parameters related to disease. The differences in terms of variables that are studied in patients who are grouped as experiencing poor sleep and good sleep, according to the PSQI, were evaluated with independent sample Mann-Whitney U test and a t test. The relations between the sleep and the other evaluation parameters were examined with Spearman rank correlation analysis. Hierarchic multiple regression analysis was chosen to analyze the contribution of demographic, medical, and psychological variables to sleep disturbances. Stepwise multiple regression analysis was designed to find the most powerful predictor of sleep disturbances. Statistical analysis was performed by using SPSS 17.0, and the level of significance was set at P < 0.05.

Patient characteristics

Of the 318 AS patients who agreed to participate in this study, 314 (98.7%) returned their completed questionnaires, and four patients were no longer interested and/or had no time to participate.

Sleep-disturbances parameters

Mann-Whitney U test and t test

Bivariate associations

Characteristics of sleep in AS patients

Significant sleep disturbance was much more common in AS patients than in the control group. PSQI is a standard index for assessing sleep quality and is widely used in both clinical settings and public health practice. The prevalence of poor sleep was 35.4%, and the mean total PSQI score was 6.62 ± 3.62 in participants, compared with 22.9% and 5.50 ± 2.51, respectively, in the control group. This prevalence was lower than those reported, 54.1% and 64.5% of sleep disturbance, respectively, in other studies of AS patients [20, 25].

Among seven components of PSQI, the most prominent component of sleep disturbances was daytime dysfunction. In total, 57.6% of participants reported various degrees of daytime dysfunction, including excessive daytime sleepiness, fatigue, and changes in mood. In another study in patients with AS [20], 66.4% experienced severe fatigue, and a positive relation was established between fatigue and sleep problems. These changes are reflected in patient reports of difficulty in concentrating, increased forgetfulness, an inability to make decisions, and falling asleep at the wheel of a motor vehicle. Those with moderate to severe cases of the disorder are at a higher risk of having a motor vehicle accident and may also have difficulties at work or school [26].

Another prominent component of PSQI was use of sleep medication. Despite the high incidence of sleep disturbance in AS patients, they rarely use hypnotics. The main reasons for impairment of chronic sleep disturbance were not paid attention to by patients, such as daytime sleepiness, fatigue, negative mood, and recognition [8–13]. Moreover, patients worry that long-term use of sleep medication could increase the risks of development of tolerance and dependence. Intervention for and prevention of sleep disturbances are becoming increasingly important. Recent studies [27, 28] concluded that nonpharmacologic interventions are clinically effective for sleep disturbance, including sleep-hygiene education, bright-light therapy, and cognitive and behavioral therapies.

Sleep and pain

Pain is one of the most common symptoms of AS. However, it is a chicken-and-egg problem to determine the direction of causation between pain and sleep disturbance. Some studies [29–31] demonstrated an apparent bidirectionality in the relation between pain causing sleep dysfunction and sleep dysfunction aggravating pain. This cross-sectional study demonstrates a strong association between not only sleep disturbance and pain (nocturnal pain, total back pain), but also the components of PSQI (subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disorders, use of sleep medications, daytime dysfunction) and pain in AS patients.

These findings are consistent with a previous study [32] showing an association between sleep disturbance and clinical pain severity among RA patients. The mechanism of interaction between sleep disturbance and pain, so far not determined, could be understood with two factors. First, from the perspective of neurobiology, sleep disruption, fragmentation, or restriction produces hyperalgesia and can interfere with analgesic treatments involving opioidergic and serotonergic mechanisms of action [33–36]. Second, from the perspective of psychology, sleep disturbance lowers the pain threshold and amplifies the pain signals, resulting in increased attention to pain, and more negative pain-focused emotions and cognitions [3]. Thus, patients experience increased pain by hyperalgesia, reduced activity levels, and further disrupted sleep in a positive-feedback-loop pattern.

Sleep and disease activity

A close relation exists between sleep quality and disease activity in AS patients. In the current study, analyses were performed between patients who were good and poor sleepers; poor-sleep patients had significantly higher levels of morning stiffness, BASDAI, ESR, and CRP compared with good sleepers (P < 0.05). These findings indicate that sleep quality of AS patients is closely related to disease activity. CRP could directly and/or indirectly affect sleep quality. Some evidence [37–40] stems from studies that indicate that poor sleep is associated with inflammatory responses, indicated by increased CRP. Okun et al. [40] evaluated cross-sectional relations between self-reported sleep and three inflammatory markers (interleukin-6, tumor necrosis factor-α, and CRP) in community-dwelling nonpregnant women. Findings showed that poor sleep continuity and quality were related to high levels of CRP. Furthermore, Lee et al. [2] examining the association between disease activity, sleep, and pain sensitivity in rheumatoid arthritis, found that CRP was strongly associated with the pain threshold. Speculating from this result, we suspect that the CRP could indirectly affect sleep quality via a decreased pain threshold.

Tumor necrosis factor (TNF) plays an important role in AS and sleep regulation. Several observations [41, 42] strongly implicated TNF in the pathogenesis of AS, and elevated serum levels of TNF correlate with disease activity [43]. TNF-inhibitor therapies, such as thalidomide [44], etanercept [45], and infliximab [46], have been demonstrated to be effective in the treatment of AS. Moreover, TNF-α has been determined to be an important sleep-promoting substance [47, 48]. Chennaoui et al. [47] reported that total sleep deprivation in young healthy men is associated with significant sleepiness, decrements in psychomotor performance, and increased secretion of the proinflammatory cytokine TNF-α. The similar results of sleep deprivation led to elevated levels of TNF-α had been obtained in another experiment [48]. In turn, many of the symptoms induced by sleep loss (for example, sleepiness, fatigue, poor cognition, and enhanced sensitivity to pain) can be elicited by injection of exogenous IL-1 or TNF [49]. Further study was done recently by Rudwaleit et al. [50], and the results indicated that the TNF inhibitor, adalimumab, improved sleep and sleep quality in patients with active AS.

Sleep and depression

Sleep problems were the chief complaints of depression and anxiety; early awakening is the main disturbance of a depression disorder; and difficulty falling asleep is present in anxiety disorder. In the present study, analyses were performed between patients who were good and poor sleepers. Poor-sleep patients had significantly higher levels of SDS scores compared with good sleepers.

Sleep disturbances in relation to a depressed mood have been examined in the general population. Sayar et al. [51] reported that pain intensity, anxiety, and depression correlated significantly with poorer sleep quality. At the multivariate level, depression was found to be the only significant factor correlating with the quality of sleep, and the model explained 34% of the variance. In 2005, Costa et al. [52] compared systemic lupus erythematosus patients with healthy controls and insomniacs and concluded that only depressed mood was a significant independent determinant of global sleep quality.

The relation between sleep complaints and depressed mood is consistent with findings from another study of SLE [4]. Hultgren et al. [19] reported that depression was independently associated with three of the sleep parameters (quality, duration, and efficiency), whereas perceived stress contributed to global sleep quality. In this study, the association between depression and sleep disturbances was evident and significant on bivariate analysis, but did not remain significant on logistic regression analyses.

Sleep and anxiety

To our knowledge, this is the first study to examine anxiety correlates of sleep problems in AS. Poor-sleep patients had significantly higher levels of SAS scores compared with those of good sleepers. Bivariate analyses indicated a significant relation between anxiety and sleep disturbances. The relation of sleep and anxiety, rarely has been studied separately, apparently less than that of sleep and depression. A number of studies [53–55] indicated that sleep problems usually were associated with depression and anxiety. However, anxiety was divided into trait-anxiety and state-anxiety in a study by Augner [56], who reported that subjective sleep quality was strongly negatively correlated with trait-anxiety, which is ingrained in a person's personality. Further study might indicate whether state-anxiety, characterized as a temporary change in a person's emotional state due to an outside factor, is correlated with sleep quality.

Statistical contribution in predicting sleep disturbances

A number of studies [13, 57–60] indicated that poor sleep or insomnia or both are risk factors for major depression. Gregory et al. [57] reported that sleep problems predict symptoms of depression at 10 years. Riemann et al. [59] also reported that insomnia symptoms for a period of more than 2 weeks predict an increased risk for developing depression within the following 3 years. A few studies [13, 60, 61], usually included in surveys of sleep and depression, found that poor sleep or insomnia could predict anxiety. In turn, little research exists on the role of depression and/or anxiety in sleep disturbances. In our hierarchic multiple regression analysis, the medical and psychological variables contributed significantly to the variance in sleep-disturbances scores, adding an additional 23.9% to the overall R ² beyond that accounted for by demographic variables (R ² , 8.5%), resulting in a final R ² of 42.6%. Multiple stepwise regression analysis revealed that anxiety was the maximal statistical contribution in predicting sleep disturbances. It is worth mentioning that Jansson and Lindblom [11] conducted a population-based study providing prospective evidence that individuals liable to anxiety may be at particularly high risk of postevent sleep disturbances, at least during the first months after the event.