Nocturnal sleep, daytime sleepiness and fatigue in fibromyalgia patients compared to rheumatoid arthritis patients and healthy controls: A preliminary study

Sleep Medicine 14 (2013) 109–115

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Original Article

Nocturnal sleep, daytime sleepiness and fatigue in fibromyalgia patients compared to rheumatoid arthritis patients and healthy controls: A preliminary study Timothy Roehrs a,c,⇑, Christina Diederichs a, Mazy Gillis a, Amanda J. Burger b, Rebecca A. Stout b, Mark A. Lumley b, Thomas Roth a,c a b c

Henry Ford Hospital, Sleep Disorders and Research Center, Detroit, 48202 MI, United States Department of Psychology, Wayne State University, School of Medicine, Detroit, 48202 MI, United States Department of Psychiatry and Behavioral Neurosciences, Wayne State University, School of Medicine, Detroit, 48202 MI, United States

a r t i c l e

i n f o

Article history: Received 3 May 2012 Received in revised form 17 September 2012 Accepted 19 September 2012 Available online 11 November 2012 Keywords: Nocturnal polysomnography MSLT Sleepiness Fibromyalgia Rheumatoid arthritis

a b s t r a c t Objective: Fibromyalgia (FM) and rheumatoid arthritis (RA) are pain disorders, both of which are associated with complaints of sleep disturbance, non-refreshing sleep, and daytime sleepiness and fatigue. Given the putative differential central versus peripheral nervous system involvement in these disorders, subjective and objective measures of nocturnal sleep, daytime sleepiness, fatigue and pain were compared between patient groups and to healthy controls (HC). Methods: Fifty women (18 with FM, 16 with RA, and 16 HC) completed an 8 h nocturnal polysomnogram (NPSG), Multiple Sleep Latency Test (MSLT) the following day, and self-reports of sleepiness, fatigue, and pain. Results: FM and RA patients were similar to each other and had less total sleep time than HC, primarily due to more wake after sleep onset. In an analysis of sleep and wake bouts, both patient groups had longer duration of wake bouts than HC. Nocturnal sleep was judged to be non-restorative for both patient groups. Although reporting the greatest subjective sleepiness and fatigue, FM patients had less objective (MSLT) daytime sleepiness than HC, whereas RA patients were intermediate in objective sleepiness. Unlike the RA and HC, FM patients also showed no association between their subjective and objective sleepiness. Conclusions: Women with FM have similar nocturnal sleep disturbance as those with RA, but FM patients report greater self-rated daytime sleepiness and fatigue than RA and HC, which did not correspond to the relatively low level of objectively determined daytime sleepiness of FM patients. These findings suggest a generalized hyperarousal state in FM. Ó 2012 Elsevier B.V. All rights reserved.

1. Introduction The first polysomnographic (PSG) study of fibromyalgia (FM) was performed in 1975 [1]. This early PSG study of FM reported intrusions of EEG alpha activity (a-EEG) in NREM sleep, which correlated positively with pain scores. This data led to the speculation that a-EEG is a marker of the musculoskeletal pain and mood symptoms of FM. Subsequently, there have been multiple reports indicating a correlation between a-EEG and FM pain [2–5]. While FM continues to be characterized by sleep disturbance and pain, the causal link between a-EEG and FM symptoms has not been substantiated. The presence and amount a-EEG is difficult to assess and quantify visually and the procedures and scoring rules for its visual assessment have yet to be established [6,7]. Automated, fast ⇑ Corresponding author. Address: Sleep Disorders and Research Center, Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, MI 48202, United States. Tel.: +1 313 916 5177; fax: +1 313 916 5167. E-mail address: [email protected] (T. Roehrs). 1389-9457/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2012.09.020

Fourier transform computer analyses of a-EEG is also not without controversy [8]. Furthermore, the a-EEG NREM sleep anomaly is reported in other patient populations, as well as healthy controls (HC) [9–13]. In fact, some have argued that the non-specificity of the a-EEG marker is because a-EEG is a characteristic of sleep maintenance rather than disturbance [8–14]. Beyond the a-EEG anomaly, FM patients also have significantly longer sleep latencies than healthy controls (HC) [12]. They often have increased arousals and a greater number of transitions from one sleep stage to another [15] and lower amounts of slow wave sleep (corrected for age), REM, and total sleep time (TST) [16]. Shorter durations of stage 2 NREM sleep have also been reported, compared to healthy controls (HC) [17]. FM patients often report insomnia symptoms [2,4,18] and their reports of not getting enough sleep, disturbed sleep, and waking less rested are more frequent than in HC. Interestingly, they have better recall of their awakenings than controls [3]. Similar to FM, rheumatoid arthritis (RA) patients experience sleep disturbance and pain [7]. However, the sleep disturbance of

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RA has been characterized by fragmented sleep and increased wake caused by discrete, short arousals [19,20]. RA patients were also found to have multiple stage shifts and a higher occurrence as compared to HC of periodic leg movements, which also fragment sleep. [21,19]. Patients with RA often report daytime sleepiness and fatigue in association with their pain [22]. The Level of fatigue is an important symptom as it has been shown to correlate with dysfunction [23]. A recent study of RA showed that poor sleep quality was significantly correlated with mood disturbance, pain, fatigue and functional disability [24]. Studies of RA patients have also shown that hypnotic treatment (triazolam) of sleep disturbance can lead to a reduction in morning stiffness and daytime sleepiness [25]. In contrast, similar hypnotic treatment (zopiclone) only improves ‘‘tiredness’’ in FM patients [26]. FM is thought of to involve heightened sensitivity of all, in addition to pain, central nervous system sensory processing, or in abnormalities of the endocrine system [16], whereas RA is more frequently attributed to peripheral nervous system and immune system dysfunction [7]. The pain of FM is considered to be widespread involving all soft tissues [16], while that of RA is localized to the joints and surrounding tissue [7]. The similarity of symptoms, despite the difference between relative central and peripheral involvement and localization of pain in these two disorders, makes them valuable to compare to further understand the relation of nocturnal sleep to daytime sleepiness, fatigue and pain. The authors of a literature review on sleep in RA argued that current studies of chronic rheumatoid diseases are inconsistent in their findings and they encouraged the further systematic, objective study of sleep and daytime function [22]. We report on the relation between self-report measures and objective measures of nocturnal sleep (PSG) and daytime sleepiness (MSLT), as well as self-reported fatigue and pain in these two pain disorders. We compared the two pain disorders to each other and to healthy age and gender matched controls. Symptoms of sleepiness, fatigue, and pain are commonly reported in both disorders and are associated with reports of disturbed and nonrefreshing sleep. To our knowledge, no studies have compared objective measures of the sleep of FM to RA patients directly. In addition, there are no studies that have compared patients’ subjective and objective measures of sleepiness, as well as attempted to distinguish sleepiness from fatigue in these pain disorders.

2. Methods 2.1. Participants Participants were 50 women from southeastern Michigan who were recruited from local newspapers and physician referrals: 18 with FM, 16 with RA, and 16 healthy controls (HC) age-matched to the patients. Participants in the two pain groups were required to (a) have FM or RA as their primary pain condition (see below for the diagnostic procedures); (b) report a customary bedtime of midnight or earlier; and (c) report current pain severity of at least 4 on a scale of 1–10. Individuals were excluded from the study if they (a) met criteria for other pain conditions co-morbid with FM or RA; (b) had a primary sleep disorder, based on both history and screening PSG: (apnea/hypopnea and periodic leg movement index >10); (c) were taking medications that interfere with sleep (e.g., beta-blockers, steroids, etc., other medications were allowed.); (d) had current psychiatric problems as screened by the DSM-IV Axis I Disorders (SCID-I), or (e) were taking antidepressant medications. Healthy control participants had a customary bedtime of midnight or earlier and had no history of any pain condition or sleep-related complaint or disorder. There were no differences in age among the three groups, but African–Americans were overrep-

Table 1 Participant demographics by group. Demographics

FM (n = 18)

RA (n = 16)

HC (n = 16)

Age yrs mean (±sd) Ethnicity n (%) Caucasian African–American Hispanic Undisclosed BMI mean (±sd)

48 (9)

52 (7)

47 (6)

15 (83) 2 (12) 0 (0) 1(5) 29.0 (5.2)

8 (50) 4 (25) 2 (12.5) 2(12.5) 28.1 (4.9)

6 (38) 9 (56) 0 (0) 1 (6) 26.9 (4.0)

FM = fibromyalgia patients, RA = rheumatoid arthritis patients and HC = healthy controls.

resented in the HC group and Caucasians in the FM group (see Table 1). All participants signed an IRB approved informed consent and were paid for their participation. 2.2. Procedures All participants made a screening visit to the Henry Ford Hospital Sleep Disorders and Research Center in Detroit, where they provided informed consent and completed screening procedures, including questionnaires assessing general health, sleep habits and disorders, fatigue and pain. Participants met with a physician and underwent a history and physical examination for the purpose of confirming their normal health status or for the two pain groups their pain diagnosis. To rule out psychiatric disorders in healthy controls and the two patient groups, the Diagnostic and Statistical Manual (DSM) of Mental Disorders’ Structured Interview [DSM-IV Axis I Disorders (SCID-I)] was used [27] and the Center for Epidemiological Studies-Depression (CES-D) scale was used to rule out current clinical depression [28]. The presence of insomnia in the two patient groups was assessed by the sleep habits and disorders questionnaire and defined by a positive response to any one of the three questions ‘‘Do you have difficulty falling asleep?, Do you have difficulty staying asleep?, and Do you experience non-refreshing sleep?’’ Healthy controls were required to respond negatively to all three questions. To confirm the diagnosis of FM, participants needed to have at least 11 of 18 tender points rated as painful when assessed with a standard procedure using a dolorimeter at a pressure of 64 kg [29]. All participants provided blood and urine samples to screen for the presence of diseases that may mimic FM or RA, including Hepatitis C, Epstein Barr, and thyroid dysfunction. Participants toured the sleep facility to familiarize them selves with the sleep lab environment and then scheduled their laboratory sleep nights. Participants were asked to abstain from use of pain medications (e.g., NSAIDs, opioids, other analgesics) for 1 week prior to initiating the first sleep study night. Participants completed two consecutive nights of laboratory sleep followed by one day of Multiple Sleep Latency Testing (MSLT). The first night served as a laboratory adaptation and sleep disorders screening night, and the second night provided an assessment of sleep parameters used in analyses. For each sleep night, participants arrived 2 h prior to their reported bedtime to complete check-in procedures and undergo electrode placement for standard 8 h NPSG [30]. Bedtimes were determined using the participant’s self-reported normal sleep schedule as confirmed by their sleep diaries. Overnight NPSG recordings consisted of continuous monitoring of two channels of EEG (C3-A2 and O2-A1), left and right EOG, and submental EMG. 2.3. Measures 2.3.1. Epworth Sleepiness Scale [ESS; 31,32] Baseline sleepiness was assessed with this 8 item scale, on which participants rate the likelihood of falling asleep over the last

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2 weeks in different situations, on a scale of 0 (‘‘no chance of dozing’’) to 3 (‘‘high chance of dozing’’). The ESS has been shown to be reliable and valid in previous studies with both clinical and general population samples [31,32]. This scale has also been shown to adequately discriminate between those with sleep disorders and the general population [33]. A score P10 on the ESS is considered an indication of excessive daytime sleepiness. 2.3.2. Fatigue Assessment Instrument [FAI; 34] Baseline fatigue was assessed with this 29 item scale, which yields a fatigue severity subscale score; items are rated from 1–7, (completely disagree to completely agree) and thus higher scores indicate greater fatigue. In validation assessments, 81% of medical patients scored >4 and 89% of healthy controls <4 [34]. The FAI has demonstrated adequate reliability and validity [35]. 2.3.3. Daytime mood and symptom measures Before each test of the MSLT, participants rated their current experience of sleepiness, fatigue and pain on separate 1–10 Likert scales, with a rating of 1 indicating ‘‘not at all sleepy’’ (‘‘no fatigue,’’ ‘‘no pain’’), and 10 indicating ‘‘as sleepy as I have ever been’’ (‘‘as fatigued as I have ever been,’’ or ‘‘most intense pain imaginable’’). 2.3.4. Profile of Mood States Fatigue-Inertia Scale [POMS; 36] The POMS is an adjective checklist which measures six factor analytically, derived mood states [36]. Participants completed the POMS 30 minutes before their scheduled bedtime on the second laboratory sleep night, and again within 30 minutes of waking the next morning. 2.3.5. Nocturnal sleep parameters Recordings from the second laboratory NPSG were scored for standard sleep stages by scorers who maintained a 90% scoring reliability and were unaware of participants’ group membership [30]. Sleep stages as well as latency to stage 1, latency to persistent sleep, wake after sleep onset, and total sleep time were analyzed. In addition, sleep–wake bout analyses of the PSG were conducted. It is becoming clear that visual scoring of brief EEG arousals, such as applied to assess sleep fragmentation, does not completely characterize sleep continuity because arousal scoring defines the arousal, but not its consequence (i.e., rapid versus delayed return to sleep). Sleep and wake bout duration analyses quantify the number and duration of contiguous 30-second epochs of sleep or wake, using the standard R & K definitions of sleep assigned to a given epoch (stage 1, 2, 3/4 and REM) or wake. The number of sleep and wake bouts are by definition the same, but the duration of a given wake or sleep bout can vary independently. At the first epoch of wake (i.e., at lightsout), the number of contiguous wake epochs is calculated which determines wake bout 1 duration. The first epoch of sleep that has terminated wake bout 1, initiates the duration count of sleep bout 1, which is terminated by the first epoch of wake and initiates the duration count of wake bout 2, etc. This calculation of wake and sleep bout durations continues over the total 960 epochs of the standard 8-h PSG. 2.4. Multiple Sleep Latency Test (MSLT) On the day following the second laboratory sleep night, participants completed a clinical MSLT, with naps scheduled at 9:15, 11:15, 13:15, 15:15, and 17:15 h. Each test of the MSLT was conducted according to the standard protocol [37]. Participants were placed in bed in quiet, darkened rooms and instructed to close their eyes, relax, and fall asleep. Each test was concluded after 20 minute of continuous wake or 20 minute after one 30 second epoch of any sleep stage. Latency to sleep onset was scored as minutes to the first epoch of sleep or 20 minute if sleep did not occur.

We averaged the latencies for the five tests to generate a single latency value. 2.5. Statistical analysis Univariate single factor ANOVAs were computed for each dependent variable. The between groups factor was diagnosis (FM, RA, and HC). Tukey’s B post hoc tests were conducted as appropriate to test for specific between group differences. Where distributions deviated greatly from normal, non-parametric Kruskal–Wallis analyses were conducted. In addition, to better understand how each group perceives their sleepiness and fatigue, correlations were conducted within each of the three study groups between baseline self-rated fatigue (FAI) and self-rated sleepiness (ESS), as well as between self-rated sleepiness (ESS) and objective sleepiness (MSLT). Differences between groups in these correlations were tested with Fisher’s r to z test. An alpha level of 0.05 was used for determining significance. 3. Results 3.1. Baseline group comparisons Table 2 presents the self-report measures at baseline, before and after sleep, and the following day during the MSLT for the three groups. Analyses revealed no significant differences among the FM, RA, and HC groups in baseline sleepiness on the ESS (F = 2.06, p = 0.14). No group showed mean ESS scores indicative of excessive daytime sleepiness. In contrast, analyses revealed significant differences between the groups for baseline fatigue severity on the FAI (F = 31.72, p < 0.001). Post hoc tests demonstrated that the FM group reported greater levels of fatigue compared to the RA group, which in turn demonstrated greater levels of fatigue compared to the HC group. At baseline 82% of the FM patients complained of insomnia and 75% of the RA patients complained of insomnia. Across the two patient groups (FM and RA) there was no difference in screening PSG total sleep time between those reporting insomnia 6.6 ± 0.92 h and those without insomnia 6.7 ± 0.75 h. Similarly, within each patient group total sleep times did not differ between those with and without insomnia. 3.2. Polysomnography (PSG) Means and standard deviations for the PSG variables in each group are presented in Table 3. Analyses revealed significant differences between the groups on total sleep time (F = 3.95, p < 0.05).

Table 2 Means and standard deviations by group for self-report measures. FM Baseline assessments Epworth 8.83 (4.5) sleepiness Fatigue instrument 5.05 (1.2)

RA

HC

ANOVA p level

6.00 (3.7)

6.66 (3.0)

NS

3.57 (1.3)

1.82 (0.7)

p < 0.001

Fatigue before and after sleep POMS fatigue PM 51.12 (7.4) POMS fatigue AM 50.18 (7.4) Change PM–AM 0.94 (5.5)

46.92 (7.8) 45.31 (8.3) 1.00 (5.9)

39.78 (4.0) 39.00 (5.3) 1.33 (4.7)

p < 0.001 p < 0.001 NS

Daytime ratings Likert sleepiness Likert fatigue Likert pain

2.63 (1.2) 2.35 (0.9) 2.45 (0.8)

1.99 (0.8) 1.58 (0.5) 1.1 (0.2)

p < 0.05 p < 0.001 p < 0.001

3.5 (1.9) 3.83 (2.2) 4.4 (1.8)

FM = Fibromyalgia patients, RA = Rheumatoid Arthritis patients, HC = Healthy Controls, POMS = Profile of Mood States.

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Table 3 Means and standard deviations by group for PSG measures. FM (n = 18)

RA (n = 16)

HC (n = 16)

Total sleep time (h) Latency to persistent sleep (min) Latency to stage 1 (min) Wake after sleep onset (min) Stage 1 (%) Stage 2 (%) Stage 3–4 (%) REM Lat REM (%)

6.72 (0.15)* 23.72 (4.82) 14.39 (2.82) 64.3 (8.13)* 8.65 (.93) 60.32 (1.6) 9.45 (1.88) 99.2 (14.0) 21.57 (1.54)

6.66 (0.18)* 20.78 (3.57) 15.56 (3.69) 70.7 (9.94)* 7.98 (.75) 61.81 (1.69) 9.91 (1.40) 93.9 (13.2) 20.29 (1.79)

7.21 (0.10) 14.13 (3.35) 7.22 (1.35) 40.2 (5.59) 8.06 (.79) 63.11 (2.17) 10.27 (1.92) 120 (15.9) 17.92 (1.58)

FM = fibromyalgia patients, RA = rheumatoid arthritis patients and HC = healthy controls, data are means ± (SD). * =p < 0.05 versus HC.

Mean Sleep Latency (Min)

18

Sleep Variables

16

*p<.01 vs HC *

14 12 10 8 6 4 2 0 FM

Post hoc tests revealed that the FM and RA groups had significantly lower total sleep times than HCs. Significant differences between groups were observed in wake after sleep onset (WASO) (F = 3.82, p 6 0.05), with the FM and RA groups spending significantly more time awake when compared in post hoc tests to the HC group. Analysis revealed no significant differences among the FM, RA, and HC groups on the PSG measures latency to stage 1 sleep (F = 2.52, p = 0.09); latency to persistent sleep (F = 2.23, p = 0.12); latency to REM (F = 0.76, p = 0.47); percent stage one sleep (F = 0.20, p = 0.82); percent stage two sleep (F = 0.60, p = 0.55); percent stage three–four (F = 0.56, p = 0.51); and percent REM sleep (F = 1.29, p = 0.28). Analyses of the PSG compared durations of sleep and wake bouts throughout the night. There were no differences among the three groups in sleep bout duration. However, there was a significant difference in the average wake bout duration (Kruskal–Wallis T = 7.09, p < .029) with both patient groups having longer wake bouts relative to HC, but not each other (FM = 5.9 ± 5.6 min, RA = 6.0 ± 6.1 min, HC = 2.9 ± 1.7 min). The number of wake bouts was numerically lower in both patients groups, but not significantly so (FM = 34.5 ± 11.3, RA = 35.7 ± 8.9, HC = 38.1 ± 10.7). 3.3. POMS fatigue before and after nocturnal sleep Analysis of POMS fatigue revealed significant differences between the groups on fatigue 30 minute prior to sleep (F = 12.24, p < 0.001). Post hoc tests demonstrated that the FM and RA groups did not differ from each other, but both groups reported significantly greater fatigue prior to sleep compared to the HC group. Similarly, on the morning following sleep, the FM and RA groups continued to report significantly greater fatigue upon wakening compared to the HC group (F = 6.60, p < 0.001). The change in fatigue from night to morning did not differ among groups (FM: 0.93 ± 5.5; RA: 1.00 ± 5.9; HC: 1.33 ± 4.7, greater positive scores reflect less fatigue in the morning). 3.4. MSLT: Mean Daily Sleep Latency Fig. 1 presents the average daily sleep latency for the three groups on the MSLT. The FM group was significantly less sleepy (i.e., more alert) compared to the HC group, while the RA group did not differ from either the FM or HC group in mean daily sleep latency, (F = 6.18, p < 0.01). 3.5. Self-reported daytime sleepiness, fatigue, and pain Participants completed the Likert scale assessments of sleepiness, fatigue, and pain prior to each MSLT test and scores on each test were averaged across the five tests. Analysis of mean subjec-

RA

HC

Fig. 1. Multiple Sleep Latency Test scores in the groups (mean of five tests). FM = Fibromyalgia patients, RA = Rheumatoid Arthritis patients and HC = Healthy Controls.

tive sleepiness revealed significant differences between the three groups on overall subjective sleepiness, (F = 4.00, p < 0.05). Post hoc tests revealed that the FM group reported significantly greater sleepiness compared to the HC group, while the RA group did not differ from either group in their overall report of sleepiness. Analysis of average subjective Likert fatigue revealed significant differences among the three groups on fatigue, (F = 8.41, p < 0.001). Post hoc tests revealed that participants in the FM group reported significantly greater fatigue compared to the RA and HC groups. Analysis of average subjective Likert pain revealed significant differences among the three groups on pain, (F = 27.50, p < 0.001). Post hoc tests revealed that participants in the FM group reported significantly greater pain compared to the RA group who, in turn, reported greater subjective pain compared to the HC group. 3.6. Correlations of MSLT to self-rated fatigue and sleepiness Fig. 2 presents the correlation between baseline fatigue severity (FAI) and baseline self-rated sleepiness (ESS) in the two patient groups (Panel A) and the healthy controls (Panel B). There was a significant positive correlation between fatigue and sleepiness ratings among the FM patients (r = 0.48, p < 0.05), whereas in the RA (r = 0.16, NS) and HC group, (r = 0.04, NS) these scores were not correlated. These correlation coefficients did not differ using the Fisher z test. Finally, Fig. 3 shows the correlations between selfrated sleepiness (ESS) and objective sleepiness (MSLT) for the two patient groups (Panel A) and HC (Panel B). ESS and MSLT scores were significantly inversely correlated in HC (r = 0.63, p < 0.02), whereas the correlation was lower and not significant in the RA group (r = 0.35, NS) and absent in the FM group (r = 0.01, NS). The correlation coefficient in HC differed significantly from that of the FM patients (p < 0.03) using the Fisher z test. 3.7. Summary of significant group comparison results To summarize the findings of this study, as shown in Table 4, FM patients have similar levels of insomnia as RA patients. Although patients’ sleepiness was not different from controls according to their self-report (ESS), fatigue severity (FAI) was greater in FM than in RA patients, which was higher than in HC. Regarding their sleep FM and RA both had less TST, more WASO, and longer wake bout durations than HC. Both patient group’s subjective fatigue (POMS) was greater than HC in the evening before

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Panel A: FM & RA

Panel A: FM & RA n=33

7

20

MSLT Scores

FAI Severity Scores

6 5 4 3 2

FM

1 0

n=28

25

5

10

15

10

0

20

FM: r= -.007, NS RA: r= -.351, NS 0

5

10

n=16

n=14

25

r = -.630; p<.02

r = .042, NS

3.5

20

3

MSLT Scores

FAI Severity Scores

20

Panel B: HC

Panel B: HC

2.5 2 1.5

15 10 5

1 0.5 0

15

ESS Scores

ESS Scores

4

RA

FM

5

RA

FM: r = .480; p<.05 RA: r = .160, NS 0

15

0 0

2

4

6

8

10

12

0

2

4

14

ESS Scores Fig. 2. Correlation of fatigue and sleepiness scores in patients (Panel A) and healthy controls (Panel B) FM = Fibromyalgia Patients, RA = Rheumatoid Arthritis patients and HC = Healthy Controls, FAI = Fatigue Assessment Instrument, EES = Epworth Sleepiness Scale regression line for FM patients.

6

8

10

12

14

ESS Scores Fig. 3. Correlation of sleepiness scores and MSLT scores in patients (Panel A) and healthy controls (Panel B) FM = Fibromyalgia patients, RA = Rheumatoid Arthritis patients and HC = Healthy Controls ESS = Epworth Sleepiness Scale.

Table 4 Summary of significant study results.

their nighttime sleep, as well as in the morning after sleep suggesting that sleep was not restorative for the patients. During the day, objective measures on the MSLT showed FM patients were less sleepy than HC, while RA were intermediate to HC and FM patients. Results from the daytime Likert scale ratings showed that FM had greater sleepiness than HC, while RA patient’s ratings did not differ from HC and FM. Also FM patients rated their fatigue and pain higher than RA, while RA rated their fatigue similar to HC and their pain higher than HC. 4. Discussion This is the first study comparing FM and RA patients to each other and to HC on objective and subjective measures of sleep, daytime sleepiness, fatigue and pain. Two major findings of this study stand out: (1) the unusually high MSLT scores, that is high alertness of FM patients relative to RA patients despite a comparable degree of disturbed nocturnal sleep and (2) the absence of a correlation between self-ratings of sleepiness and the objective MSLT measure of sleepiness in the FM group. Elevated MSLT scores coupled with low nocturnal sleep efficiencies, have been reported in patients with primary insomnia [38]. The patients of the present study were not specifically recruited to have insomnia complaints, but at least three quarters of the FM and RA patients reported insomnia. In primary insomniacs this pattern of findings, high MSLT despite unusually short sleep times, has been interpreted as reflecting a state of hyperarousal. Among healthy normals, sleep restricted to 6.5 h would be associated with next-day MSLT daily sleep latencies of approximately 8 minutes or less. A number of other physiological measures

Measures

Group comparisons

Baseline assessments Fatigue assessment

FM > RA > HC

Physiologic measures of nocturnal sleep and daytime sleepiness NPSG TST FM = RA < HC NPSG WASO FM = RA > HC Sleep bout duration FM = RA > HC MSLT FM > HC; FM = RA, RA = HC Fatigue before and after sleep POMS fatigue PM POMS fatigue AM

FM = RA > HC FM = RA > HC

Daytime ratings Likert sleepiness Likert fatigue Likert pain

FM > HC; FM = RA, RA = HC FM > RA + HC FM > RA > HC

FM = fibromyalgia patients, RA = rheumatoid arthritis patients, HC = healthy controls, POMS = Profile of Mood States. Group comparisons reflect the post hoc test results following significant ANOVA main effects of group.

(e.g., elevated levels of catecholamines, increased metabolic rate, and increased heart rate) have confirmed the hypothesized hyperarousal of insomnia [38]. This apparent hyperarousal in FM patients, as reflected in the MSLT, is parallel to the hypothesized central hypersensitization of sensory processing in FM [39], or the proposed stress intolerance and pain hypersensitivity model [40]. The present data suggest the sensitization of FM may extend beyond sensory processing to a general hyperarousal. In contrast, the RA patients of this study who had similarly shortened and disturbed nocturnal sleep as the FM patients

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showed MSLT scores that were intermediate to those of HC and FM patients and did not differ from HC and FM patients. As Fig. 3 Panel A shows the distribution of MSLT scores between FM and RA patients differed only slightly. Six of the FM patients had MSLTs >15 minutes and four of the RA patients had scores >15 minutes. No FM patients had MSLT scores <5 minutes, while three of the RA patients had such low scores. Larger patient samples will be necessary to determine whether RA and FM patients differ in MSLT and what is the possible clinical significance of such differences among patients. Further, it would be important to determine the repeatability of these MSLT observations within a given patient. The correlation analysis indicated that FM patients do not differentiate well between sleepiness and fatigue, while RA and HC do. This may have both theoretical and practical implications. FM is more closely tied than RA to stressful life experiences and emotional dysregulation, as such the ability to identify, label and differentiate among subjective states may be more impaired in FM than in RA. Such difficulty seems consistent with the theory of stress intolerance of FM [40]. A practical implication pertains to patient safety. Studies have shown there is heightened risk of automobile accidents in self-report and simulated driving assessments of patients with excessive sleepiness. A recent study in southeastern Michigan showed that a MSLT (<5 minutes) was predictive of Department of Motor Vehicle documented automobile crashes in the general population [41]. Thus, it might be particularly important to help patients with FM recognize and distinguish their level of sleepiness. Unlike some of the previous studies that have shown increased stage 1 and reduced stage 3–4 in FM and RA patients compared to HC [16], the two patient groups did not differ in sleep stages from the HC of this study. The patients and healthy controls were middle-aged with 8–10% of stage 3–4 sleep, which is well within the expected range. The most prominent nocturnal sleep disturbances of the two patient groups were greater WASO and longer duration wake bouts compared to the HC and the two patient groups did not differ on these measures. The longer wake duration of the two patient groups is an ‘‘insomnia-like’’ finding. We did not find, as hypothesized, greater sleep fragmentation in the RA patients compared to the FM patients [42]. That is the number of awakenings did not differ between groups nor did the percent of stage 1 sleep, which is also reflective of sleep fragmentation. The absence of differential findings with regard to the sleep of FM versus RA patients, compared to previous studies, may reflect similarity in pain and disability severity among the patients in our study. Both patient groups had to report current pain and disability. One would expect greater symptom severity to be associated with more complete awakenings from sleep, as opposed to a lightening of sleep, which would be shown as reduced slow wave sleep and increased stage 1 sleep. Our inability to find differential sleep disturbance patterns between the two patients groups may also be due to the fact that at least three quarters of each patient group had insomnia complaints. The co-morbid insomnia may have masked any differential sleep disturbance between the patient groups.

5. Limitations This study has several limitations. First, the sample size for the three groups were relatively small and larger samples may have yielded clearer differences, particularly between FM and RA patients. Second, the samples studied were free of a host of potential confounds, such as depression, other psychiatric disorders, substance use, and many medications, including antidepressants, that can alter sleep parameters. Although eliminating these confounds

is a strength of this study and enhances the validity of the results, it limits generalization to the larger population of patients with FM or RA, many of whom are depressed or taking medications and, therefore, were excluded from this study. Third, the three groups differed somewhat in racial composition; however, we know of no ethnicity/race differences in sleep that might account for the observed group differences noted in this study. Fourth, we did not determine whether the insomnia was an independent diagnosis and pre-dated the pain condition, or started substantially later, or whether the insomnia and pain condition overlapped in onset, suggesting a single disorder. Fifth, we had no assessment of the degree to which the patients felt their sleep was disrupted by pain. Sixth, the study included a large number of variables and comparisons and the risk of experiment-wise type 1 errors was increased. Finally, we examined only women, so we do not know whether these results apply to men with these pain conditions. Given these limitations we consider this study preliminary and our findings will need replication in larger samples. Conflict of Interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2012.09.020.

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