- Email: [email protected]
Sleep in Fibromyalgia Patients: Subjective and Objective Findings
Sleep in Fibromyalgia Patients: Subjective and Objective Findings SUSAN M. HARDING, MD
ABSTRACT: Fibromyalgia (FM) patients report early morning awakenings, awakening feeling tired or unrefreshed, insomnia, as well as mood and cognitive disturbances; they may also experience primary sleep disorders including sleep apnea. Longitudinal studies have demonstrated the chronic nature of these disturbances in patients with FM. A distinct relationship exists between poor sleep quality and pain intensity. Polysomnographic findings during sleep in these patients include an alpha frequency rhythm, termed alpha-delta sleep anomaly, which is also seen in normal controls during stage 4 sleep deprivation; deep pain induced during sleep in normal controls also causes this anomaly. Sleep architecture is altered in FM patients showing an increase in stage 1, a reduction in delta sleep, and an increased number of arousals. Before prescribing pharmacologic compounds aimed at modifying sleep, adequate pain control and sleep habits should be achieved; tricyclic antidepressants, trazadone, zopiclone, and selective serotonin reuptake inhibitors, however, may be required. More research is needed to elucidate the cellular and molecular mechanisms involved in the sleep disturbances occurring in patients with FM. KEY INDEXING TERMS: Fibromyalgia; Sleep; Electroencephalography; Alpha-delta sleep. [Am J Med Sci 1998;315(6): 367-376.]
E
arly diagnostic criteria for fibromyalgia (FM) included abnormal sleep characteristics such as nonrestorative sleep and an electroencephalographic (EEG) finding during sleep called alpha in-
From the Sleep/Wake Disorders Center, University of Alabama at Birmingham, Birmingham, Alabama. Correspondence: Susan M. Harding, MD, UAB Sleep / Wake Disorders Center, University ofAlabama at Birmingham, 215 Tinsley Harrison Tower, Birmingham, AL 35294. Email: [email protected] THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
trusion in nonrapid eye movement (NREM) sleep, as well as tiredness and poor sleep.1,2 Although current American College of Rheumatology (ACR) diagnostic criteria, as outlined by Wolfe et aI, do not include sleep-related abnormalities, nonrestorative sleep is a major complaint of patients with FM.3 In this large multicenter study, 184 of 243 (76%) FM patients reported awakening feeling tired or unrefreshed. 3 With the current data, it is not possible to determine whether disturbed sleep is a cause or a consequence of FM. Nevertheless, it is clear that sleep disturbances are a prominent feature in FM, and that pain in FM may flare with the lack of sleep. This article will review subjective and objective sleep abnormalities described in this disorder and will briefly discuss strategies directed toward sleep improvement. Subjective Sleep Complaints in Fibromyalgia Patients
Nonrestorative sleep or waking feeling unrefreshed is a common complaint in patients with FM.4 They often describe their sleep as being so light that any noise may awaken them, or they may be so restless that they are conscious of dreaming or thinking during their sleeptime. These patients also tend to experience diffuse stiffness, aching, and fatigue, even when they have slept 6 to 8 hours; on the rare occasion when they awake feeling rested, they describe little discomfort or fatigue. 5 ,6 Patients complain of having insomnia and early morning awakenings and perceive their sleep to be of poor quality,7 whereas healthy controls generally report sleeping well and feeling well-rested, clear-headed and satisfied with their sleep upon awakening. 8 It has been reported that these mood and cognitive disturbances are associated with sleep abnormalities. 9 However, patients with other musculoskeletal disorders may also experience poor sleep and insomnia. For example, Hyyppa and Kronholm compared reports of sleep disturbances among 24 patients with FM, 60 patients with a variety of other musculoskeletal disorders (eg, sciatica, low back pain without sciatica, neck and shoulder syndrome, spondylarthrosis, rheumatoid arthritis) and 91 healthy controls.lO All of these patients, but none of the controls, reported poor sleep and insomnia. 10 367
Sleep in Fibromyalgia Patients
There may also be a relationship between poor sleep quality, pain intensity, and attention to pain in patients with FM. Affieck et al asked 50 women with FM to recall their ratings of subjective sleep quality, pain intensity, and attention to pain for 30 days using a palm-top computerY It was found that poor sleepers tended to report significantly more pain than women with a relatively high quality of sleep. Moreover, the ratings indicated that a night of poor sleep tended to be followed by a significantly more painful day and that a painful day tended to be followed by a night of poor sleep.11 This study supports the hypothesis that nonrestorative sleep may exacerbate pain in patients with FM. Primary sleep disorders, especially sleep apnea, and periodic leg movements of sleep (PLMS), may also be found in patients with FM, indicating that patients should be screened for these disorders. Indeed, May et al screened all new FM patients for sleep apnea and if there was a suspicion of sleep apnea, polysomnography was performed l2 ; approximately 2% of the women had sleep apnea as opposed to 44% of the men. 12 It was concluded that in men, FM may be a marker for sleep apnea. 12 Other studies, however, have not supported this association. Lario et aI, for example, examined overnight pulse oximetry and Epworth Sleepiness Scale (a measure of daytime hypersomnolence) in 28 women with FM and 15 controls l3 ; they found that patients with FM had small decreases in oxygen saturation compared to the control group, without a difference in Epworth Sleepiness Scale. 13 Similarly, Donald et al reported that FM was uncommon (approximately 3%) in patients with a primary complaint of disturbed sleep at a respiratory sleep disorders clinic,14 and Molony found that FM patients had the same frequency of sleep apnea as normal controls.15 Finally, Lario et al studied 30 patients with sleep apnea and found a reduction of sleep stages 3 and 4 with frequent arousals. 16 Despite the presence of sleep apnea and a sleep disturbance thought to be involved in the pathogenesis of FM, none of the patients displayed musculoskeletal manifestations of this disorder. 16 Thus, although sleep apnea is found in selected patients with FM, apnea does not appear to be responsible for FM symptoms. PLMS is another common sleep disorder affecting about 29% of people by age 50, regardless of whether or not they suffer from FM. 17,IB PLMS is characterized by partial flexion at the ankle, knee, and sometimes the hip, with the extension of the big toe, lasting between 0.5 and 5 seconds, usually occurring at 20- to 60-second intervals. 19 Thus, PLMS is common in FM, especially in older patients, but it is not necessary for the development of FM. Normal Sleep Stages and Architecture
The use of EEG techniques to investigate the sleeping brain reveals a wealth of electrical activity
368
in a seemingly passive body.20 Sleep is divided into NREM sleep and rapid eye movement (REM) sleep. In turn, NREM sleep is divided into stages 1, 2, 3, and 4, with slow delta waves comprising stages 3 and 4. 20,21 Polysomnography is a recording of sleep which evaluates its stages and architecture, and is used to investigate underlying pathology, including sleep apnea. Standard EEG electrode derivations are C3Al or C4-A2 (central location), and 01-A2 or 02-Al (occipital location).22 Electro-oculography (EOG) is used to monitor eye movements which are important during REM sleep. Chin electromyogram (EMG) reflects EMG tone throughout the night and decreases significantly during REM sleep with the onset of muscle atonia. Other physiologic monitors include electrocardiography and respiratory effort measurement and ventilation; EMG electrodes are also placed on the legs to monitor PLMS. 22 Sleep stages are determined by evaluating EEG, chin EMG, and EOG data. 21,22 An EEG recording with a person awake and eyes closed shows an alpha rhythm (8 to 13 cycles per second or Hertz, Hz). In stage 1 sleep, alpha activity disappears and slow activity in the theta and delta ranges (2-3 Hz) oflow voltage are present with occasional vertex waves (Figure 1).20,21 Stage 2 is characterized by the development of K complexes, sharp negative EEG waves followed by a high-voltage slow wave, and sleep spindles; sleep spindles are intermittent bursts of fast activity in the 11.5 to 15 Hz range lasting 0.5 to 1.5 seconds (Figure 1).20,21 Stages 3 and 4 are identified by high-voltage waves (>75 microvolts) in the delta range «2 Hz); stage 3 is present if more than 20%, but less than 50%, of the polysomnographic epic (a page of an EEG record equivalent to 30 seconds of recording at the speed of 10 mm/second) is occupied by slow delta wave activity. Stage 4 is defined by the presence of high-voltage slow delta waves prevailing over more than 50% of the epic; stages 3 and 4 are also known as delta sleep or slow wave sleep (Figure 1).20,21 REM sleep is characterized by a low-voltage desynchronized EEG pattern associated with absent muscle tone in the chin EMG and well-defined episodic rapid eye movements in the EOG (Figure 1).20,21 Sleep stages occur in 4 to 5 sleep cycles. A sleep cycle is a period of sleep composed of a NREM sleep episode (sleep stages 1, 2, 3, and 4) and the subsequent REM sleep episode, commonly lasting 90 minutes. The REM stage increases in length as the night progresses; delta sleep is prominent early in the evening and is usually not present beyond the second sleep cycle. If individuals are awakened during an early-morning REM stage, they may report having a dream. The distribution of sleep stages produces an architecture that is predictable in the normal adult population. Normal individuals are awake apJune 1998 Volume 315 Number 6
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B
Figure 1. Stages of sleep. All panels are shown in a sleep stage montage with left and right electrooculogram (LOC, ROC), central EEG lead (C3-A2), occipital EEG lead (OI-A2), and chin EMG. (A) Stage 1 NREM sleep, with the alpha EEG pattern disappearing by the first quarter of the page with development of theta range EEG. (B) Stage 2 NREM sleep with Kcomplexes and a sleep spindle on EEG leads. (C) Delta sleep (stage 4 NREM) with delta waves in the EEG leads. (D) REM sleep with rapid eye movements in EOG leads, and absent chin tone in the chin EMG.
0l·A2
~~~~~~~~)~~~~~~~~ ChinIlMG
proximately 5% of the night; otherwise, they remain in Stage 1, 2% to 5% of the night; in Stage 2, 40% to 55% of the night; in Stage 3, 3% to 8% ofthe night; in Stage 4, 10% to 15% of the night; and in stage REM, 20% to 25% of the night. 20 Polysomnographic Alterations During Sleep in Patients With Fibromyalgia
Over the past 30 years, several investigators have monitored sleep in patients with FM to determine if altered sleep architecture or disruptive sleep causes symptoms of FM. Polysomnographic findings in patients with FM, relative to healthy individuals, include lower amounts of slow wave sleep corrected for age, REM sleep, and total sleep time as well as a higher number of arousals and awakenings, long awakenings (> 10 minutes), and an EEG pattern of alpha waves superimposed on sleep EEG. 23 Alpha waves (8-13 Hz) are associated with relaxed wakefulness (with eyes closed) and intrude upon the sleep EEG in patients with FM. This alpha-delta EEG anomaly has been implicated in the pathophysiology of this disorder. 24,25 Alpha Frequency Rhythm. Alpha-delta sleep is an abnormal sleep EEG rhythm characterized by alpha activity that is superimposed on delta waves of slow wave sleep stages 3 and 4 (Figure 2).26 This activity was first reported by Hauri and Hawkins in 1973 in nine psychiatric patients with somatic malaise and fatigue 27 ; subsequently, Moldofsky identified an alpha-delta sleep anomaly in patients with FM.24 THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Alpha sleep has been broadened to include alpha intrusion into all stages of NREM sleep28; this sleep anomaly is accompanied by indications of vigilance during sleep and the subjective experience of unrefreshing sleep.29 Moldofsky et al performed polysomnography on 10 drug-free patients with FM and measured musculoskeletal tenderness using a 20-pound dolorimeter4; all subjects showed an overnight increase in dolorimeter scores and seven showed an alpha rhythm intrusion during NREM sleep.24 In another study using normal controls, the alpha-delta sleep anomaly was observed coincidentally with auditory stimulation during phase 4 sleep deprivation.24 Furthermore, pharmacologic manipulation of EEG frequencies using chlorpromazine and L-tryptophan (both of which increase delta sleep) in patients with FM showed that the alpha-delta frequency was related to pain, energy, and mood30 ; the amount of alpha frequency during sleep correlated with an increase in overnight pain measures. 30 The investigators concluded that alpha frequency during sleep is an indicator of unrefreshing sleep.30 Branco et al also recognized the importance of alpha-delta sleep in patients with FM; they prospectively studied alpha and delta activity and the alphadelta ratio across sleep cycles in 14 normal controls and 10 patients with FM.31 Spectral analysis ofEEG and alpha and delta power were calculated for each sleep cycle. Nine of 10 patients exhibited the alpha369
Sleep in Fibromyalgia Patients
Figure 2. Alpha-delta sleep. Sleep stage montage showing electro-oculogram (EOG [LOC], EOG [ROG]), central EEG lead (C3-A2), occipital EEG lead (02-A1) and chin EMG lead. Alpha frequency EEG wave forms are superimposed on a background of delta activity seen in stage 4 NREM of sleep.
delta sleep anomaly, which appeared to increase exponentially through the night; this anomaly was not observed in any of the controls (Figure 3).31 These data suggest that alpha intrusion is an intrinsic feature of NREM sleep in patients with FM. Drewes et al also examined spectral EEG patterns in 12 women with FM and 14 control women32 ; patients with FM displayed more power in the higher frequency bands (alpha) and a decrease in the lower frequency
bands throughout all NREM sleep stages and all sleep cycles. This study supports Moldofsky's hypothesis that, when compared to healthy persons, FM patients experience less restorative32 sleep and that they have a high frequency of alpha intrusion in NREM sleep with decreased slow wave (delta) energy.33 Drewes's group also retrieved more information from the sleep EEG, using cluster analysis,34 which demonstrated a specific EEG pattern in patients
y NOR • 0,007 + O,0208x R. 0,91
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1.00
!
0.80
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!
I
. •
0,40
~
FMS
Figure 3. Progression ofthe alphadelta ratio across sleep cycles (c1c4). The fibromyalgia group (FMS) had more alpha intrusion in successive sleep cycles over the normal control group (NOR). (Reprinted with permission from Branco J, Atalaia A, Paiva T. J Rheumatol. 1994;21:1116.)
0.20 ~.OO
370
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with FM compared to matched controls, independent of the classical sleep stages. 34 Consistent with the findings noted above, the spectral analysis showed that these FM patients displayed a decreased lower (delta) power and an increased power in higher (alpha) frequency bands. 34 In another study, Drewes et al evaluated the EEG response to painful stimuli applied to skin, muscles, and joints of 10 normal subjects during slow wave sleep.35 Muscle pain was induced by infusing 6% hypertonic saline to the quadriceps muscle, joint pain was induced by using a computer-controlled pneumatic stimulator placed over the second proximal interphalangeal joint, and cutaneous pain was stimulated by transmitting green-blue light from an argon laser to the skin. During muscle and joint stimulations, there was an arousal effect, observed with a decrease in delta (0.5-3.5 Hz) and an increase in alpha (8-10 Hz) activities. This effect, however, was not observed during the cutaneous stimulation. 35 This study shows that deep pain can alter sleep architecture, including an increase in alpha activity in normal controls. Perlis et al examined the relationships between alpha sleep and the perception of sleep, information processing, muscle tenderness, and arousability in 20 FM patients. 36 It was found that alpha sleep correlated with perceived shallow sleep and an increased tendency to display arousal in response to external stimuli. 36 Alpha activity, however, was not associated with enhanced long-term or short-term memory during sleep or with the myalgic symptoms ofFM. 36 This study nicely demonstrated that alpha sleep not only looks like a shallow form of sleep electrophysiologically, but is perceived as such phenomenologically. In turn, alpha sleep may predispose the individual to increased arousability and may be indirectly related to subjective complaints; a predisposure to arousal in response to auditory stimuli could lead to fragmented sleep and complaints of nonrestorative sleep. Not all investigators agree on the importance of the alpha EEG finding during sleep because it also occurs in normal individuals 8,37,38 and in patients with disorders such as rheumatoid arthritis and chronic fatigue syndrome. 39 ,4o In summary, the alpha EEG anomaly, although not specific to FM, correlates with the subjective feeling of nonrestorative sleep; this alpha rhythm is found in the vast majority of FM patients, and the amount of this rhythm correlates with objective measurements of pain. Decreasing the amount of this alpha rhythm results in improved pain measurements. Deep painful stimuli induced in normal controls during sleep also causes an increase in alpha activity. The biochemical and cellular processes that occur with this EEG finding are unknown and warrant further study. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Sleep Architecture Alterations and Arousals. Patients with FM perceive that their sleep is fragmented. In the clinical laboratory, polysomnograpic studies often exhibit prolonged sleep onset latencies (the time that it takes for a person to fall asleep after the lights are turned off), an increase in stage 1 sleep, and a reduction in slow wave (delta) sleep (stages 3 and 4).31,38 Many studies also have shown an increased number of arousals which fragment sleep (Figure 4).9,15 Table 1 summarizes sleep architecture data in FM patients and healthy controls. Consistent with the clinical findings noted above, the data reveals an increase in stage 1 sleep,8 a significant increase in wake time after sleep onset, and a reduction in stages 3 and 4 of NREM as well as in REM sleep (Figure 5).31 Although a small number of subjects were examined in these investigations (7 to 20 subjects), each study shows that patients with FM had either alterations in sleep stages or an increased number of arousals compared to controls. 8,9,15,31,38,39,41 The importance of adequate delta sleep is illustrated by a series of studies performed by Moldofsky's group, who hypothesized that a decrease in stage 4 sleep would be associated with musculoskeletal and mood symptoms. They examined six normal controls during two nights of undisturbed sleep, followed by three nights of stage 4 deprivation produced by auditory stimuli and two subsequent nights of undisturbed sleep.24 It was found that during stage 4 deprivation, three subjects experienced an overnight increase in dolorimeter scores (ie, increased tenderness), musculoskeletal symptoms, and mood disturbances comparable to those of "fibrositis" patients. 24 In contrast, remission of symptoms and a decrease in dolorimeter scores accompanied the return of undisturbed sleep.24 These findings provide further support of the relationship between delta sleep and musculoskeletal pain. 25 What may be even more significant than inadequate amounts of delta sleep is the frequency of arousals from sleep causing sleep fragmentation. 9,15 Molony et aI, for example, noted that patients with FM had three times more microarousals per hour (brief sleep interruptions lasting 5-19 seconds) than did control subjects. 15 These results support the notion that patients with FM have poor sleep quality with frequently interrupted sleep. Biochemical Findings Which May Contribute to Altered Sleep Architecture in Fibromyalgia Patients
Although studies show an association between disordered sleep and FM, current research has not elucidated how specific neurotransmitters and centrally located neurons which regulate sleep relate to nocturnal symptoms and EEG findings in these patients. Several studies have shown that patients with FM have a decrease in cerebrospinal fluid 371
Sleep in Fibromyalgia Patients
Figure 4. Sleep arousal. Sleep stage montage showing electro-oculogram (EOG [LOC], EOG [ROC]), central EEG lead (C3-A2), occipital EEG lead (Ol-A2), and chin EMG. An EEG arousal is noted with the occurrence of alpha activity in the EEG leads and an increase chin EMGtone.
(CSF) and blood serum levels of serotonin. 42 ,43 Jouvet et al noted that 5-hydroxytryptamine (5-HT), a serotonin precursor, is released at axonal nerve endings in the basal hypothalamus as a neurotransmitter during waking. Thus, it may act as a neurohormone and induce hypnogenic factors that are secondarily responsible for slow wave and REM sleep.44
Low doses of tricyclic antidepressant medications (eg, amitriptyline) which influence central nervous system serotonin metabolism have been found to be beneficial for sleep in patients with FM.45 Interestingly, Watson et al showed that amitriptyline reduced alpha-delta sleep from an average of 90 minutes to 63 minutes with improvement in nonrestor-
Table 1. Controlled Studies Evaluating Sleep Architecture in Fibromyalgia Patients Molony, 198615 Variable Total sleep time (min) Sleep efficiency (% of time) Sleep onset (min) REM onset (min) NREM 1 (%) NREM2 (%) NREM 3 and 4 (%) NREM3 (%) NREM4 (%) REM(%) Arousals (%) Arousal index (no.lh) Arousal from NREM 1 Mini arousalslhour Wake time after sleep onset (%) Alpha-NREM (%) Percent transitional stage
* P :5 0.05. FM = fibromyalgia patients; C
372
=
FM
C
(n = 7)
(n = 6)
183
177
37
15
Horne, 199138
Moldofsky, 198839 FM (n = 9) 389 89 21 79 3.6 56.7 14.1
FM
C (n
=
10)
369 89 20 103 9.8 53.9 12.2
9.4
9.3
17.4
16.4
3.0
1.6
7.1
8.7
3.3*
1.0* 8.0 2.4*
7.5 0.9*
25*
(n
= 11)
C (n
= 11)
441 93.3 29.0* 73.3 12.9 45.9
437 96.3 13.9* 105.9 10.1 45.2
11.8 4.4 21.3
11.1 4.1 20.6
15*
healthy control patients; REM
=
rapid eye movement; NREM
=
nonrapid eye movement. June 1998 Volume 315 Number 6
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50
In
Figure 5. Sleep parameters in fibromyalgia. The sleep variables for both groups are represented in percentages. The fibromyalgia group (FMS) had a higher value of wake time and a clear reduction in stages 3 NREM, 4 NREM, and REM sleep. (Adapted with permission from Branco J, Atalaia A, Paiva T. J RheumatoL 1994;21:1115.)
*
40
-
.% Wake
G,)
01
CIS (/)
Ili% 1NREM 11% 2NREM 1IIiil%3NREM O%4NREM IiiI%REM
30
C.
G,) G,)
20
u; 0~
10
0 NOR
FMS Diagnostic Groups
ative sleep in five patients with FM.46 Together, these findings suggest that low CNS levels of serotonin in patients with FM may be partially responsible for decreases in delta sleep and therefore may predispose these patients to the development of the alpha EEG rhythm. Elevated cerebral spinal fluid levels of substance P have also been found in patients with FMY Substance P, a neuroactive peptide, is widely distributed throughout the nervous system and may contribute to arousals; however, additional evidence is needed to verify its role in sleep regulation. 48 Levels of insulin growth hormone-I (somatomedin C) are related to the production of growth hormone
(*p < .05)
(GH), which is primarily secreted during stage 4 of slow wave sleep. Somatomedin C levels are low in approximately one third of FM patients. 49 Bennett et al showed that the administration ofGH improved sleep in patients with FM compared to those receiving a placebo. 50 In examining regional cerebral blood flow (rCBF) to specific brain structures, Mountz et al used neuroimaging of normal control subjects and of patients with FM and showed that rCBF to the thalamus and caudate nucleus was decreased compared to that of control subjects. 51 Although these brain structures are involved in encoding and inhibiting pain transmission, studies in the cat have shown that ablation
Table 1 (continued). Branco, 199431
Jennum, 19939
FM
C
(n = 11)
(n = 11)
15.7 26.6*
13.1 40.3*
4.8 10.4* 9.5*
6.6 20.4* 19.5*
32.5*
5.7*
FM (n = 20)
C (n = 10)
348
358
15 107 5.5 57.6 15.5
24 131 6.8 58.7 16.9
17.5 3.9* 10.2*
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
16.8 1.1* 2.7*
Leventhal, 1995 41
Shaver, 19978
FM (n = 8)
C (n = 7)
82.1 21.1
90.2 19.1
88
91
5.0* 57.5 17.5
15.6* 48.1 14.2
14.4* 46.7
10.4* 46.8
5.8 1.7
7.6 4.9
18.5
22.1
7.5
7.1
20.8
13.6
FM (n = 11)
C (n = 11)
373
Sleep in Fibromyalgia Patients
of the thalamus leads to persistent and severe insomnia. 52,53,54 Also, clinical observations by Culebras et al have linked lesions in the dorsal medial nucleus of the thalamus with loss of growth hormone secretion during slow wave sleep. 55 This suggests that altered thalamic rCBF may be involved in the GH secretion abnormalities observed in patients with FM. Approach to the Management of Sleep in Fibromyalgia
Before considering the pharmacologic and nonpharmacologic interventions available for modifying . the disordered sleep that commonly afflicts patients with FM, it is of utmost importance to obtain a complete history to uncover the patient's sleeping habits, environment, disruptions, and sleep disorders. AB important as it may be to determine the presence of sleep apnea (loud snoring, witnessed apneic events, nocturnal choking, and daytime hypersomnolence) or PLMS, it also is critical to determine the patient's sleep environment (snoring partner, baby in the room, outside traffic), sleep/wake time cycle over the 24-hour day (same or different during weekdays and weekends), and practice of unhealthy behaviors (caffeine intake, smoking, alcohol), as well as to obtain a complete (current and past) pharmacologic history. By properly obtaining these data, some simple but valuable recommendations can be made that may significantly improve the patient's quality of sleep without resorting to pharmacologic agents. Such recommendations may include adhering to a regular sleep/wake schedule that is the same every day, including weekends, ensuring sufficient potential sleep time (ie, at least 7 or 8 hours per night), performing daily exercise (but not before going to bed or late in the evening), avoiding heavy meals before bedtime, relaxing prior to turning the lights out (eg, reading [but not with a bright light]), and eliminating physical disturbances such as noise, light, and poor temperature control (with earplugs and eye shades if necessary). Finally, the patient's medications should be reviewed and those compounds which affect sleep should be avoided if at all possible. Table 2 reviews important sleep management issues in FM patients. Several of the pharmacologic agents evaluated in FM patients have been tested specifically for their potential for improving sleep. The following compounds have been examined: chlorpromazine, amitriptyline, zopiclone, fluoxetine, and trazodone. 30,39,56-59 Moldofsky et al showed that chlorpromazine, which decreases alpha-delta frequencies, reduced pain and trigger point tenderness. 3o Gronblad et al reported that zopiclone increases delta sleep, improves subjective sleep quality, and decreases awakenings during the night; it should be noted, however, that patients in their study reported a 90% improvement in the quality of their 374
Table 2. Basic Issues to be Addressed in the Management of Sleep in Patients With Fibromyalgia 1. Presence of primary sleep disorders including sleep apnea and PLMS 2. Adequate sleep hygiene Sleep time Sleep environment Regular sleep/wake cycle Life-style habits (caffeine, smoking, alcohol, physical activity) Relaxation 3. Adequate pain management 4. Judicious use of pharmacologic agents Avoidance of those which may disrupt sleep narcotics cocaine clonidine beta blockers (lipophilic-propranolol) nicotine Use of those which may facilitate sleep Tricyclic antidepressants (eg, amitriptyline) Selective serotonin reuptake inhibitor (eg, fluoxetine) Other antidepressants (eg, trazodone) Chlorpromazine Zopiclone
PLMS = periodic leg movements of sleep.
sleep and that similar improvement was reported by more than 60% of patients on placebo, suggesting that zopiclone had only marginal effects. 56 Goldenberg and colleagues recently showed that treatment with both amitriptyline and fluoxetine resulted in significant improvement among FM patients in general sleep scores and appeared to be superior to either drug alone. 57 Other trials (Carette et al,45 Goldenbert8 ) have also noted self-reported sleep improvement using amitriptyline. Finally, Branco et al examined the effects of trazodone, an antidepressant with an inhibitory effect on 5-HT reuptake, on sleep architecture in 13 patients in a double-blind crossover placebo controlled trial. 59 Polysomnography was performed with spectral analysis before and after 2 months of placebo or trazodone 150 mg/day.59 Interestingly, trazodone almost doubled the amount of stage 3 and 4 sleep over basal and placebo levels, but there was no difference in sleep latency, sleep efficiency, or percentage of wake time; alpha activity was also reduced with trazodone. 59 The long-term effects of this medication on sleep architecture are unknown. There is a lack of well-controlled, randomized trials evaluating sleep parameters with medications. Medications which show promise in improving sleep quality include amitriptyline, fluoxetine, trazodone, and chlorpromazine. However, it is essential for future clinical trials to include evaluations of sleep architecture as well as self-reports of sleep quality. The medications' June 1998 Volume 315 Number 6
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role in restoring sleep architecture may be a link to clinical benefits. In conclusion, screening for primary sleep disorders, improving sleep hygiene, and pharmacologic management may improve sleep quality and symptoms in FM patients. Treatment strategies should be individualized to improve the patient's quality of life.
16. 17.
18.
Acknowledgments
The author is supported by a NHLBI Sleep Academic Award (5K07HL03633), and thanks Len Shigley, RPSGT, for editing Figures 1, 2, and 4, and Martin Robbins and Felicia M. Fields for their editorial assistance.
19. 20. 21.
References 1. Smythe HA, Moldofsky H. Two contributions to understanding "fibrositis" syndrome. Bull Rheum Dis. 1977;28: 928-31. 2. Yunus M, Masi AT, Calabro JJ, Miller KA, Feigenbaum SI. Primary fibromyalgia (fibrositis): clinical study of 50 patients with matched normal controls. Semin Arthritis Rheum. 1981;11:151-72. 3. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia: report of the multi-center criteria committee. Arthritis Rheum. 1990;33:160-72. 4. Campbell SM, Clark S, Tindall EA, Forehand ME, Bennett RM. Clinical characteristics of fibrositis I: a "blinded" controlled study of symptoms and tender points. Arthritis Rheum. 1983; 26:817 -25. 5. Moldofsky H. Sleep and fibrositis syndrome. Rheum Dis Clin North Am. 1989;15:91-103. 6. Wolfe F, Cathey MA. Prevalence of primary and secondary fibrositis. J Rheumatol. 1983; 10:965-68. 7. Schaefer KM. Sleep disturbances and fatigue in women with fibromyalgia and chronic fatigue syndrome. JOGNN. 1995; 24:229-33. 8. Shaver JLF, Lentz M, Landis CA, Heitkemper MM, Buchwald DS, Woods NF. Sleep, psychological distress, and stress arousal in women with fibromyalgia. Res Nurs Health. 1997;20:247-57. 9. Jennum P, Drewes AM, Andreasen A, Nielson KD. Sleep and other symptoms in primary fibromyalgia and in healthy controls. J Rheumatol. 1993;20:1756-9. 10. Hyyppa MT, Kronholm E. Nocturnal motor activity in fibromyalgia patients with poor sleep quality. J Psychosomatic Res. 1995;39:85-91. 11. Affleck G, Urrows S, Tennen H, Higgins P, Abeles M. Sequential daily relations of sleep, pain intensity, and attention to pain among women with fibromyalgia. Pain. 1996; 68:363-8. 12. May KP, West SG, Baker MR, Everett DW. Sleep apnea in male patients with the fibromyalgia syndrome. Am J Med. 1993;94:505-8. 13. Lario BA, Valdivielso JLA, Lopez JA, Soteres CM, Banuelos JLV, Cabello AM. Fibromyalgia syndrome: overnight falls in arterial oxygen saturation. Am J Med. 1996; 101:54-60. 14. Donald F, Esdaile JM, Kimoff JR, Fitzcharles M-A. Musculoskeletal complaints and fibromyalgia in patients attending a respiratory sleep disorders clinic. J Rheumatol. 1996;23:1612-6. 15. Molony RR, MacPeek DM, Schiffman PL, Frank M, Neubauer JA, Schwartzberg M et al. Sleep, sleep apnea, THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
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25. 26. 27. 28. 29. 30.
31. 32.
33. 34.
35.
36.
and the fibromyalgia syndrome. J Rheumatol. 1986; 13:797800. Lario BA, Teran J, Alonso JL, Alegre J, Arroyo I, Viejo JL. Lack of association between fibromyalgia and sleep apnea syndrome. Ann Rheum Dis. 1992;51:108-11. Bixler EO, Kales A, Vela-Bueno A, JA Jacoby, S Scarone, Soldatos CR. Nocturnal myoclonus and nocturnal myoclonic activity in the normal population. Res Comm Chern Pathol Pharmacol. 1982;36:129-40. Moldofsky H, Tullis C, Lue FA. Sleep related myoclonus in rheumatic pain modulation disorder (fibrositis syndrome). J Rheumatol. 1986;13:614-17. Coleman RM, Pollak CP, Weitzman ED. Periodic movements in sleep (nocturnal myoclonus): relation to sleep disorders. Ann Neurol. 1980;8:416-21. Culebras A. Biology of sleep. Clinical Handbook of Sleep Disorders. Boston: Butterworth-Heinemann; 1996:13-51. Rechtschaffen A, Kales A. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Los Angeles: Brain Information Service; 1968. Keenan SE. Polysomnographic technique. In: Chokroverty S, ed. Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects. Boston: ButterworthHeinemann; 1994:79-94. Shapiro CM, Devins GM, Hussain MRG. Sleep problems in patients with medical illness. Br Med J. 1993;306:1532-5. Moldofsky H, Scarisbrick P, England R, Smythe H. Musculoskeletal symptoms and non-REM sleep disturbance in patients with "fibrositis syndrome" and healthy subjects. Psychosomat Med. 1975;37:341-51. Moldofsky H, Scarisbrick P. Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation. Psychosomat Med. 1976;38:35-44. McNamara ME. Alpha sleep: a mini review and update. Clin Electroencephalogr. 1993; 24: 192 - 3. Hauri P, Hawkins D. Alpha-delta sleep. Electroencephalogr Clin Neurophysiol. 1973; 34:233-7. Scheuler W, Stinshoff D, Kubicki S. The alpha sleep pattern: different from other sleep patterns and effects ofhypnotics. Neuropsychobiology. 1983; 10:183-9. Anch AM, Lue FA, MacLean AW, Moldofsky H. Sleep physiology and psychological aspects of fibrositis (fibromyalgia) syndrome. Can J Exp Psychol. 1991;45:179-84. Moldofsky H, Lue FA. The relationship of alpha delta EEG frequencies to pain and mood in "fibrositis" patients with chlorpromazine and L-tryptophan. Electroencephalogr Clin Neurophysiol. 1980;50:71-80. Branco J, Atalaia A, Paiva T. Sleep cycles and alphadelta sleep in fibromyalgia syndrome. J Rheumatol. 1994; 21:1113-7. Drewes AM, Nielsen KD, Taagholt SJ, Bjerregard K, Svendsen L, Gade J. Sleep intensity in fibromyalgia: focus on the microstructure of the sleep process. Br J Rheumatol. 1995;34:629-35. Smythe HA. Studies of sleep in fibromyalgia: techniques, clinical significance, and future directions. Br J Rheumatol. 1995; 34:897 -900. Drewes AM, Gade J, Nielsen KD, Bjerregard K, Taagholt SJ, Svendsen L. Clustering of sleep electroencephalopathic patterns in patients with the fibromyalgia syndrome. Br J Rheumatol. 1995;34:1151-6. Drewes AM, Nielsen KD, Arendt-Nielsen L, BirketSmith L, Hansen LM. The effect of cutaneous and deep pain on the electroencephalogram during sleep: an experimental study. Sleep. 1997;20:632-40. Perlis ML, Giles DE, Bootzin RR, Dikman ZV, Fleming GM, Drummond SPA et al. Alpha sleep and information processing, perception of sleep, pain, and arousability in fibromyalgia. Int J Neurosci. 1997;89:265-80.
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37. Scheuler W, Stinhoff D, Kubrick S. The alpha-sleep pattern. Neuropsycholobiology. 1983; 10:183-9. 38. Horne JA, Shackell BS. Alpha-like EEG activity in nonREM sleep and the fibromyalgia (fibrositis) syndrome. Electroencephalogr Clin Neurophysiol. 1991; 79:271-6 39. Moldofsky H, Saskin P, Lue FA. Sleep and symptoms in fibrositis syndrome after a febrile illness. J Rheumatol. 1988; 15:1701-4. 40. Moldofsky H, Lue FA, Smythe H. Alpha EEG sleep and morning symptoms of rheumatoid arthritis. J Rheumatol. 1983; 10:373-9. 41. Leventhal L, Freundlich B, Lewis J, Gillen K, Henry J, Dinges D. Controlled study of sleep parameters in patients with fibromyalgia. J Clin Rheum. 1995; 1:110-3. 42. Russell IJ, Michalek JE, Vipario GA, Fletcher EM, Javors MA, Bowden, CA. Platelet 3H-imipramine uptake receptor density and serum serotonin levels in patients with fibromyalgiaifibrositis syndrome. J Rheumatol. 1992; 19:104-9. 43. Vaeroy H, Helle R, Forre 0, Kass E, Terenius L. Cerebrospinal fluid levels ofB-endorphin in patients with fibromyalgia (fibrositis syndrome). J Rheumatol. 1988; 15:1804-6. 44. Sallanon M, Buda C, Janin M, Jouvet M. Implication of serotonin in sleep mechanisms: induction, facilitation? In: Wauquier A, Monte JM, Gaillard JM, Radulovacki M, eds. Sleep: Neurotransmitters and Neuromodulators. New York: Raven Press; 1985:136. 45. Carette S, McCain GA, Bell DA, Fam AG. Evaluation of amitriptyline in primary fibrositis. Arthritis Rheum. 1986; 29:655-9. 46. Watson R, Liebmann KO, Jenson J. Alpha-delta sleep: EEG characteristics, incidence, treatment, psychological correlates in personality. Sleep Res. 1985; 14:226. 47. Vaeroy H, Helle R, Forre 0, Kass E, Terenius L. Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis. Pain. 1988;32:21-6. 48. Cooper JR, Bloom FE, Roth RH. The Biochemical Basis of Neuropharmacology. New York: Oxford University Press; 1986:362-6. 49. Bennett RM, Clark SR, Campbell SM, Burchkhardt CS.
376
50.
51.
52.
53. 54. 55. 56.
57.
58.
59.
Low levels of somatomedin C in patients with the fibromyalgia syndrome: a possible link between sleep and muscle pain. Arthritis Rheum. 1992;35:1113-6. Bennett RM, Clark SR, Burckhardt CS, Walczyk J. A double-blind placebo controlled study of growth hormone therapy in fibromyalgia (abstract). J Musculoskeletal Pain. 1995;3:110. Mountz JM, Bradley LA, Modell JG, Alexander RW, Triana-Alexander M, Aaron LA, et al. Fibromyalgia in women: abnormalities of regional cerebral blood flow in the thalamus and the caudate nucleus are associated with low pain threshold levels. Arthritis Rheum. 1995;38:926-38. Villablanca J. Role of the thalamus in sleep control: sleepwakefulness studies in chronic diencephalic and athalamic cats. In: Petre-Quadens 0, Schlag JD, eds. Basic Sleep Mechanisms. New York: Academic; 1974:51. Jurko MF, Andy OJ, Webster CL. Disorderal sleep patterns following thalamotomy. Clin Electroencephalogr. 1971; 2:213-7. Lugaresi E. The thalamus and insomnia. Neurology. 1992; 42(suppI6):28-33. Culebras A, Miller M. Dissociated patterns of nocturnal prolactin, cortisol and growth hormone secretion after stroke. Neurology. 1984;34:631-6. Gronblad M, Nykanen J, Konttinen Y, Jarvinen E, Helve T. Effect of zopiclone on sleep quality, morning stiffness, widespread tenderness and pain and general discomfort in primary fibromyalgic patients. Clin Rheumatol. 1993; 12: 186-91. Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmid C. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 1996;39:1852-9. Goldenberg DL, Felson DT, Dinerman H. A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia. Arthritis Rheum. 1986; 29:1371-7. Branco JC, Martini A, Palva T. Treatment of sleep abnormalities and clinical complaints in fibromyalgia with trazodone (abstract). Arthritis Rheum. 1996;39:591.
June 1998 Volume 315 Number 6
ABSTRACT: Fibromyalgia (FM) patients report early morning awakenings, awakening feeling tired or unrefreshed, insomnia, as well as mood and cognitive disturbances; they may also experience primary sleep disorders including sleep apnea. Longitudinal studies have demonstrated the chronic nature of these disturbances in patients with FM. A distinct relationship exists between poor sleep quality and pain intensity. Polysomnographic findings during sleep in these patients include an alpha frequency rhythm, termed alpha-delta sleep anomaly, which is also seen in normal controls during stage 4 sleep deprivation; deep pain induced during sleep in normal controls also causes this anomaly. Sleep architecture is altered in FM patients showing an increase in stage 1, a reduction in delta sleep, and an increased number of arousals. Before prescribing pharmacologic compounds aimed at modifying sleep, adequate pain control and sleep habits should be achieved; tricyclic antidepressants, trazadone, zopiclone, and selective serotonin reuptake inhibitors, however, may be required. More research is needed to elucidate the cellular and molecular mechanisms involved in the sleep disturbances occurring in patients with FM. KEY INDEXING TERMS: Fibromyalgia; Sleep; Electroencephalography; Alpha-delta sleep. [Am J Med Sci 1998;315(6): 367-376.]
E
arly diagnostic criteria for fibromyalgia (FM) included abnormal sleep characteristics such as nonrestorative sleep and an electroencephalographic (EEG) finding during sleep called alpha in-
From the Sleep/Wake Disorders Center, University of Alabama at Birmingham, Birmingham, Alabama. Correspondence: Susan M. Harding, MD, UAB Sleep / Wake Disorders Center, University ofAlabama at Birmingham, 215 Tinsley Harrison Tower, Birmingham, AL 35294. Email: [email protected] THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
trusion in nonrapid eye movement (NREM) sleep, as well as tiredness and poor sleep.1,2 Although current American College of Rheumatology (ACR) diagnostic criteria, as outlined by Wolfe et aI, do not include sleep-related abnormalities, nonrestorative sleep is a major complaint of patients with FM.3 In this large multicenter study, 184 of 243 (76%) FM patients reported awakening feeling tired or unrefreshed. 3 With the current data, it is not possible to determine whether disturbed sleep is a cause or a consequence of FM. Nevertheless, it is clear that sleep disturbances are a prominent feature in FM, and that pain in FM may flare with the lack of sleep. This article will review subjective and objective sleep abnormalities described in this disorder and will briefly discuss strategies directed toward sleep improvement. Subjective Sleep Complaints in Fibromyalgia Patients
Nonrestorative sleep or waking feeling unrefreshed is a common complaint in patients with FM.4 They often describe their sleep as being so light that any noise may awaken them, or they may be so restless that they are conscious of dreaming or thinking during their sleeptime. These patients also tend to experience diffuse stiffness, aching, and fatigue, even when they have slept 6 to 8 hours; on the rare occasion when they awake feeling rested, they describe little discomfort or fatigue. 5 ,6 Patients complain of having insomnia and early morning awakenings and perceive their sleep to be of poor quality,7 whereas healthy controls generally report sleeping well and feeling well-rested, clear-headed and satisfied with their sleep upon awakening. 8 It has been reported that these mood and cognitive disturbances are associated with sleep abnormalities. 9 However, patients with other musculoskeletal disorders may also experience poor sleep and insomnia. For example, Hyyppa and Kronholm compared reports of sleep disturbances among 24 patients with FM, 60 patients with a variety of other musculoskeletal disorders (eg, sciatica, low back pain without sciatica, neck and shoulder syndrome, spondylarthrosis, rheumatoid arthritis) and 91 healthy controls.lO All of these patients, but none of the controls, reported poor sleep and insomnia. 10 367
Sleep in Fibromyalgia Patients
There may also be a relationship between poor sleep quality, pain intensity, and attention to pain in patients with FM. Affieck et al asked 50 women with FM to recall their ratings of subjective sleep quality, pain intensity, and attention to pain for 30 days using a palm-top computerY It was found that poor sleepers tended to report significantly more pain than women with a relatively high quality of sleep. Moreover, the ratings indicated that a night of poor sleep tended to be followed by a significantly more painful day and that a painful day tended to be followed by a night of poor sleep.11 This study supports the hypothesis that nonrestorative sleep may exacerbate pain in patients with FM. Primary sleep disorders, especially sleep apnea, and periodic leg movements of sleep (PLMS), may also be found in patients with FM, indicating that patients should be screened for these disorders. Indeed, May et al screened all new FM patients for sleep apnea and if there was a suspicion of sleep apnea, polysomnography was performed l2 ; approximately 2% of the women had sleep apnea as opposed to 44% of the men. 12 It was concluded that in men, FM may be a marker for sleep apnea. 12 Other studies, however, have not supported this association. Lario et aI, for example, examined overnight pulse oximetry and Epworth Sleepiness Scale (a measure of daytime hypersomnolence) in 28 women with FM and 15 controls l3 ; they found that patients with FM had small decreases in oxygen saturation compared to the control group, without a difference in Epworth Sleepiness Scale. 13 Similarly, Donald et al reported that FM was uncommon (approximately 3%) in patients with a primary complaint of disturbed sleep at a respiratory sleep disorders clinic,14 and Molony found that FM patients had the same frequency of sleep apnea as normal controls.15 Finally, Lario et al studied 30 patients with sleep apnea and found a reduction of sleep stages 3 and 4 with frequent arousals. 16 Despite the presence of sleep apnea and a sleep disturbance thought to be involved in the pathogenesis of FM, none of the patients displayed musculoskeletal manifestations of this disorder. 16 Thus, although sleep apnea is found in selected patients with FM, apnea does not appear to be responsible for FM symptoms. PLMS is another common sleep disorder affecting about 29% of people by age 50, regardless of whether or not they suffer from FM. 17,IB PLMS is characterized by partial flexion at the ankle, knee, and sometimes the hip, with the extension of the big toe, lasting between 0.5 and 5 seconds, usually occurring at 20- to 60-second intervals. 19 Thus, PLMS is common in FM, especially in older patients, but it is not necessary for the development of FM. Normal Sleep Stages and Architecture
The use of EEG techniques to investigate the sleeping brain reveals a wealth of electrical activity
368
in a seemingly passive body.20 Sleep is divided into NREM sleep and rapid eye movement (REM) sleep. In turn, NREM sleep is divided into stages 1, 2, 3, and 4, with slow delta waves comprising stages 3 and 4. 20,21 Polysomnography is a recording of sleep which evaluates its stages and architecture, and is used to investigate underlying pathology, including sleep apnea. Standard EEG electrode derivations are C3Al or C4-A2 (central location), and 01-A2 or 02-Al (occipital location).22 Electro-oculography (EOG) is used to monitor eye movements which are important during REM sleep. Chin electromyogram (EMG) reflects EMG tone throughout the night and decreases significantly during REM sleep with the onset of muscle atonia. Other physiologic monitors include electrocardiography and respiratory effort measurement and ventilation; EMG electrodes are also placed on the legs to monitor PLMS. 22 Sleep stages are determined by evaluating EEG, chin EMG, and EOG data. 21,22 An EEG recording with a person awake and eyes closed shows an alpha rhythm (8 to 13 cycles per second or Hertz, Hz). In stage 1 sleep, alpha activity disappears and slow activity in the theta and delta ranges (2-3 Hz) oflow voltage are present with occasional vertex waves (Figure 1).20,21 Stage 2 is characterized by the development of K complexes, sharp negative EEG waves followed by a high-voltage slow wave, and sleep spindles; sleep spindles are intermittent bursts of fast activity in the 11.5 to 15 Hz range lasting 0.5 to 1.5 seconds (Figure 1).20,21 Stages 3 and 4 are identified by high-voltage waves (>75 microvolts) in the delta range «2 Hz); stage 3 is present if more than 20%, but less than 50%, of the polysomnographic epic (a page of an EEG record equivalent to 30 seconds of recording at the speed of 10 mm/second) is occupied by slow delta wave activity. Stage 4 is defined by the presence of high-voltage slow delta waves prevailing over more than 50% of the epic; stages 3 and 4 are also known as delta sleep or slow wave sleep (Figure 1).20,21 REM sleep is characterized by a low-voltage desynchronized EEG pattern associated with absent muscle tone in the chin EMG and well-defined episodic rapid eye movements in the EOG (Figure 1).20,21 Sleep stages occur in 4 to 5 sleep cycles. A sleep cycle is a period of sleep composed of a NREM sleep episode (sleep stages 1, 2, 3, and 4) and the subsequent REM sleep episode, commonly lasting 90 minutes. The REM stage increases in length as the night progresses; delta sleep is prominent early in the evening and is usually not present beyond the second sleep cycle. If individuals are awakened during an early-morning REM stage, they may report having a dream. The distribution of sleep stages produces an architecture that is predictable in the normal adult population. Normal individuals are awake apJune 1998 Volume 315 Number 6
Harding
B
Figure 1. Stages of sleep. All panels are shown in a sleep stage montage with left and right electrooculogram (LOC, ROC), central EEG lead (C3-A2), occipital EEG lead (OI-A2), and chin EMG. (A) Stage 1 NREM sleep, with the alpha EEG pattern disappearing by the first quarter of the page with development of theta range EEG. (B) Stage 2 NREM sleep with Kcomplexes and a sleep spindle on EEG leads. (C) Delta sleep (stage 4 NREM) with delta waves in the EEG leads. (D) REM sleep with rapid eye movements in EOG leads, and absent chin tone in the chin EMG.
0l·A2
~~~~~~~~)~~~~~~~~ ChinIlMG
proximately 5% of the night; otherwise, they remain in Stage 1, 2% to 5% of the night; in Stage 2, 40% to 55% of the night; in Stage 3, 3% to 8% ofthe night; in Stage 4, 10% to 15% of the night; and in stage REM, 20% to 25% of the night. 20 Polysomnographic Alterations During Sleep in Patients With Fibromyalgia
Over the past 30 years, several investigators have monitored sleep in patients with FM to determine if altered sleep architecture or disruptive sleep causes symptoms of FM. Polysomnographic findings in patients with FM, relative to healthy individuals, include lower amounts of slow wave sleep corrected for age, REM sleep, and total sleep time as well as a higher number of arousals and awakenings, long awakenings (> 10 minutes), and an EEG pattern of alpha waves superimposed on sleep EEG. 23 Alpha waves (8-13 Hz) are associated with relaxed wakefulness (with eyes closed) and intrude upon the sleep EEG in patients with FM. This alpha-delta EEG anomaly has been implicated in the pathophysiology of this disorder. 24,25 Alpha Frequency Rhythm. Alpha-delta sleep is an abnormal sleep EEG rhythm characterized by alpha activity that is superimposed on delta waves of slow wave sleep stages 3 and 4 (Figure 2).26 This activity was first reported by Hauri and Hawkins in 1973 in nine psychiatric patients with somatic malaise and fatigue 27 ; subsequently, Moldofsky identified an alpha-delta sleep anomaly in patients with FM.24 THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Alpha sleep has been broadened to include alpha intrusion into all stages of NREM sleep28; this sleep anomaly is accompanied by indications of vigilance during sleep and the subjective experience of unrefreshing sleep.29 Moldofsky et al performed polysomnography on 10 drug-free patients with FM and measured musculoskeletal tenderness using a 20-pound dolorimeter4; all subjects showed an overnight increase in dolorimeter scores and seven showed an alpha rhythm intrusion during NREM sleep.24 In another study using normal controls, the alpha-delta sleep anomaly was observed coincidentally with auditory stimulation during phase 4 sleep deprivation.24 Furthermore, pharmacologic manipulation of EEG frequencies using chlorpromazine and L-tryptophan (both of which increase delta sleep) in patients with FM showed that the alpha-delta frequency was related to pain, energy, and mood30 ; the amount of alpha frequency during sleep correlated with an increase in overnight pain measures. 30 The investigators concluded that alpha frequency during sleep is an indicator of unrefreshing sleep.30 Branco et al also recognized the importance of alpha-delta sleep in patients with FM; they prospectively studied alpha and delta activity and the alphadelta ratio across sleep cycles in 14 normal controls and 10 patients with FM.31 Spectral analysis ofEEG and alpha and delta power were calculated for each sleep cycle. Nine of 10 patients exhibited the alpha369
Sleep in Fibromyalgia Patients
Figure 2. Alpha-delta sleep. Sleep stage montage showing electro-oculogram (EOG [LOC], EOG [ROG]), central EEG lead (C3-A2), occipital EEG lead (02-A1) and chin EMG lead. Alpha frequency EEG wave forms are superimposed on a background of delta activity seen in stage 4 NREM of sleep.
delta sleep anomaly, which appeared to increase exponentially through the night; this anomaly was not observed in any of the controls (Figure 3).31 These data suggest that alpha intrusion is an intrinsic feature of NREM sleep in patients with FM. Drewes et al also examined spectral EEG patterns in 12 women with FM and 14 control women32 ; patients with FM displayed more power in the higher frequency bands (alpha) and a decrease in the lower frequency
bands throughout all NREM sleep stages and all sleep cycles. This study supports Moldofsky's hypothesis that, when compared to healthy persons, FM patients experience less restorative32 sleep and that they have a high frequency of alpha intrusion in NREM sleep with decreased slow wave (delta) energy.33 Drewes's group also retrieved more information from the sleep EEG, using cluster analysis,34 which demonstrated a specific EEG pattern in patients
y NOR • 0,007 + O,0208x R. 0,91
1.20
YFMS. . 0.112 + 0,2786x R. 0.81
1.00
!
0.80
•
0.80
!
I
. •
0,40
~
FMS
Figure 3. Progression ofthe alphadelta ratio across sleep cycles (c1c4). The fibromyalgia group (FMS) had more alpha intrusion in successive sleep cycles over the normal control group (NOR). (Reprinted with permission from Branco J, Atalaia A, Paiva T. J Rheumatol. 1994;21:1116.)
0.20 ~.OO
370
June 1998 Volume 315 Number 6
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with FM compared to matched controls, independent of the classical sleep stages. 34 Consistent with the findings noted above, the spectral analysis showed that these FM patients displayed a decreased lower (delta) power and an increased power in higher (alpha) frequency bands. 34 In another study, Drewes et al evaluated the EEG response to painful stimuli applied to skin, muscles, and joints of 10 normal subjects during slow wave sleep.35 Muscle pain was induced by infusing 6% hypertonic saline to the quadriceps muscle, joint pain was induced by using a computer-controlled pneumatic stimulator placed over the second proximal interphalangeal joint, and cutaneous pain was stimulated by transmitting green-blue light from an argon laser to the skin. During muscle and joint stimulations, there was an arousal effect, observed with a decrease in delta (0.5-3.5 Hz) and an increase in alpha (8-10 Hz) activities. This effect, however, was not observed during the cutaneous stimulation. 35 This study shows that deep pain can alter sleep architecture, including an increase in alpha activity in normal controls. Perlis et al examined the relationships between alpha sleep and the perception of sleep, information processing, muscle tenderness, and arousability in 20 FM patients. 36 It was found that alpha sleep correlated with perceived shallow sleep and an increased tendency to display arousal in response to external stimuli. 36 Alpha activity, however, was not associated with enhanced long-term or short-term memory during sleep or with the myalgic symptoms ofFM. 36 This study nicely demonstrated that alpha sleep not only looks like a shallow form of sleep electrophysiologically, but is perceived as such phenomenologically. In turn, alpha sleep may predispose the individual to increased arousability and may be indirectly related to subjective complaints; a predisposure to arousal in response to auditory stimuli could lead to fragmented sleep and complaints of nonrestorative sleep. Not all investigators agree on the importance of the alpha EEG finding during sleep because it also occurs in normal individuals 8,37,38 and in patients with disorders such as rheumatoid arthritis and chronic fatigue syndrome. 39 ,4o In summary, the alpha EEG anomaly, although not specific to FM, correlates with the subjective feeling of nonrestorative sleep; this alpha rhythm is found in the vast majority of FM patients, and the amount of this rhythm correlates with objective measurements of pain. Decreasing the amount of this alpha rhythm results in improved pain measurements. Deep painful stimuli induced in normal controls during sleep also causes an increase in alpha activity. The biochemical and cellular processes that occur with this EEG finding are unknown and warrant further study. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Sleep Architecture Alterations and Arousals. Patients with FM perceive that their sleep is fragmented. In the clinical laboratory, polysomnograpic studies often exhibit prolonged sleep onset latencies (the time that it takes for a person to fall asleep after the lights are turned off), an increase in stage 1 sleep, and a reduction in slow wave (delta) sleep (stages 3 and 4).31,38 Many studies also have shown an increased number of arousals which fragment sleep (Figure 4).9,15 Table 1 summarizes sleep architecture data in FM patients and healthy controls. Consistent with the clinical findings noted above, the data reveals an increase in stage 1 sleep,8 a significant increase in wake time after sleep onset, and a reduction in stages 3 and 4 of NREM as well as in REM sleep (Figure 5).31 Although a small number of subjects were examined in these investigations (7 to 20 subjects), each study shows that patients with FM had either alterations in sleep stages or an increased number of arousals compared to controls. 8,9,15,31,38,39,41 The importance of adequate delta sleep is illustrated by a series of studies performed by Moldofsky's group, who hypothesized that a decrease in stage 4 sleep would be associated with musculoskeletal and mood symptoms. They examined six normal controls during two nights of undisturbed sleep, followed by three nights of stage 4 deprivation produced by auditory stimuli and two subsequent nights of undisturbed sleep.24 It was found that during stage 4 deprivation, three subjects experienced an overnight increase in dolorimeter scores (ie, increased tenderness), musculoskeletal symptoms, and mood disturbances comparable to those of "fibrositis" patients. 24 In contrast, remission of symptoms and a decrease in dolorimeter scores accompanied the return of undisturbed sleep.24 These findings provide further support of the relationship between delta sleep and musculoskeletal pain. 25 What may be even more significant than inadequate amounts of delta sleep is the frequency of arousals from sleep causing sleep fragmentation. 9,15 Molony et aI, for example, noted that patients with FM had three times more microarousals per hour (brief sleep interruptions lasting 5-19 seconds) than did control subjects. 15 These results support the notion that patients with FM have poor sleep quality with frequently interrupted sleep. Biochemical Findings Which May Contribute to Altered Sleep Architecture in Fibromyalgia Patients
Although studies show an association between disordered sleep and FM, current research has not elucidated how specific neurotransmitters and centrally located neurons which regulate sleep relate to nocturnal symptoms and EEG findings in these patients. Several studies have shown that patients with FM have a decrease in cerebrospinal fluid 371
Sleep in Fibromyalgia Patients
Figure 4. Sleep arousal. Sleep stage montage showing electro-oculogram (EOG [LOC], EOG [ROC]), central EEG lead (C3-A2), occipital EEG lead (Ol-A2), and chin EMG. An EEG arousal is noted with the occurrence of alpha activity in the EEG leads and an increase chin EMGtone.
(CSF) and blood serum levels of serotonin. 42 ,43 Jouvet et al noted that 5-hydroxytryptamine (5-HT), a serotonin precursor, is released at axonal nerve endings in the basal hypothalamus as a neurotransmitter during waking. Thus, it may act as a neurohormone and induce hypnogenic factors that are secondarily responsible for slow wave and REM sleep.44
Low doses of tricyclic antidepressant medications (eg, amitriptyline) which influence central nervous system serotonin metabolism have been found to be beneficial for sleep in patients with FM.45 Interestingly, Watson et al showed that amitriptyline reduced alpha-delta sleep from an average of 90 minutes to 63 minutes with improvement in nonrestor-
Table 1. Controlled Studies Evaluating Sleep Architecture in Fibromyalgia Patients Molony, 198615 Variable Total sleep time (min) Sleep efficiency (% of time) Sleep onset (min) REM onset (min) NREM 1 (%) NREM2 (%) NREM 3 and 4 (%) NREM3 (%) NREM4 (%) REM(%) Arousals (%) Arousal index (no.lh) Arousal from NREM 1 Mini arousalslhour Wake time after sleep onset (%) Alpha-NREM (%) Percent transitional stage
* P :5 0.05. FM = fibromyalgia patients; C
372
=
FM
C
(n = 7)
(n = 6)
183
177
37
15
Horne, 199138
Moldofsky, 198839 FM (n = 9) 389 89 21 79 3.6 56.7 14.1
FM
C (n
=
10)
369 89 20 103 9.8 53.9 12.2
9.4
9.3
17.4
16.4
3.0
1.6
7.1
8.7
3.3*
1.0* 8.0 2.4*
7.5 0.9*
25*
(n
= 11)
C (n
= 11)
441 93.3 29.0* 73.3 12.9 45.9
437 96.3 13.9* 105.9 10.1 45.2
11.8 4.4 21.3
11.1 4.1 20.6
15*
healthy control patients; REM
=
rapid eye movement; NREM
=
nonrapid eye movement. June 1998 Volume 315 Number 6
Harding
50
In
Figure 5. Sleep parameters in fibromyalgia. The sleep variables for both groups are represented in percentages. The fibromyalgia group (FMS) had a higher value of wake time and a clear reduction in stages 3 NREM, 4 NREM, and REM sleep. (Adapted with permission from Branco J, Atalaia A, Paiva T. J RheumatoL 1994;21:1115.)
*
40
-
.% Wake
G,)
01
CIS (/)
Ili% 1NREM 11% 2NREM 1IIiil%3NREM O%4NREM IiiI%REM
30
C.
G,) G,)
20
u; 0~
10
0 NOR
FMS Diagnostic Groups
ative sleep in five patients with FM.46 Together, these findings suggest that low CNS levels of serotonin in patients with FM may be partially responsible for decreases in delta sleep and therefore may predispose these patients to the development of the alpha EEG rhythm. Elevated cerebral spinal fluid levels of substance P have also been found in patients with FMY Substance P, a neuroactive peptide, is widely distributed throughout the nervous system and may contribute to arousals; however, additional evidence is needed to verify its role in sleep regulation. 48 Levels of insulin growth hormone-I (somatomedin C) are related to the production of growth hormone
(*p < .05)
(GH), which is primarily secreted during stage 4 of slow wave sleep. Somatomedin C levels are low in approximately one third of FM patients. 49 Bennett et al showed that the administration ofGH improved sleep in patients with FM compared to those receiving a placebo. 50 In examining regional cerebral blood flow (rCBF) to specific brain structures, Mountz et al used neuroimaging of normal control subjects and of patients with FM and showed that rCBF to the thalamus and caudate nucleus was decreased compared to that of control subjects. 51 Although these brain structures are involved in encoding and inhibiting pain transmission, studies in the cat have shown that ablation
Table 1 (continued). Branco, 199431
Jennum, 19939
FM
C
(n = 11)
(n = 11)
15.7 26.6*
13.1 40.3*
4.8 10.4* 9.5*
6.6 20.4* 19.5*
32.5*
5.7*
FM (n = 20)
C (n = 10)
348
358
15 107 5.5 57.6 15.5
24 131 6.8 58.7 16.9
17.5 3.9* 10.2*
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
16.8 1.1* 2.7*
Leventhal, 1995 41
Shaver, 19978
FM (n = 8)
C (n = 7)
82.1 21.1
90.2 19.1
88
91
5.0* 57.5 17.5
15.6* 48.1 14.2
14.4* 46.7
10.4* 46.8
5.8 1.7
7.6 4.9
18.5
22.1
7.5
7.1
20.8
13.6
FM (n = 11)
C (n = 11)
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of the thalamus leads to persistent and severe insomnia. 52,53,54 Also, clinical observations by Culebras et al have linked lesions in the dorsal medial nucleus of the thalamus with loss of growth hormone secretion during slow wave sleep. 55 This suggests that altered thalamic rCBF may be involved in the GH secretion abnormalities observed in patients with FM. Approach to the Management of Sleep in Fibromyalgia
Before considering the pharmacologic and nonpharmacologic interventions available for modifying . the disordered sleep that commonly afflicts patients with FM, it is of utmost importance to obtain a complete history to uncover the patient's sleeping habits, environment, disruptions, and sleep disorders. AB important as it may be to determine the presence of sleep apnea (loud snoring, witnessed apneic events, nocturnal choking, and daytime hypersomnolence) or PLMS, it also is critical to determine the patient's sleep environment (snoring partner, baby in the room, outside traffic), sleep/wake time cycle over the 24-hour day (same or different during weekdays and weekends), and practice of unhealthy behaviors (caffeine intake, smoking, alcohol), as well as to obtain a complete (current and past) pharmacologic history. By properly obtaining these data, some simple but valuable recommendations can be made that may significantly improve the patient's quality of sleep without resorting to pharmacologic agents. Such recommendations may include adhering to a regular sleep/wake schedule that is the same every day, including weekends, ensuring sufficient potential sleep time (ie, at least 7 or 8 hours per night), performing daily exercise (but not before going to bed or late in the evening), avoiding heavy meals before bedtime, relaxing prior to turning the lights out (eg, reading [but not with a bright light]), and eliminating physical disturbances such as noise, light, and poor temperature control (with earplugs and eye shades if necessary). Finally, the patient's medications should be reviewed and those compounds which affect sleep should be avoided if at all possible. Table 2 reviews important sleep management issues in FM patients. Several of the pharmacologic agents evaluated in FM patients have been tested specifically for their potential for improving sleep. The following compounds have been examined: chlorpromazine, amitriptyline, zopiclone, fluoxetine, and trazodone. 30,39,56-59 Moldofsky et al showed that chlorpromazine, which decreases alpha-delta frequencies, reduced pain and trigger point tenderness. 3o Gronblad et al reported that zopiclone increases delta sleep, improves subjective sleep quality, and decreases awakenings during the night; it should be noted, however, that patients in their study reported a 90% improvement in the quality of their 374
Table 2. Basic Issues to be Addressed in the Management of Sleep in Patients With Fibromyalgia 1. Presence of primary sleep disorders including sleep apnea and PLMS 2. Adequate sleep hygiene Sleep time Sleep environment Regular sleep/wake cycle Life-style habits (caffeine, smoking, alcohol, physical activity) Relaxation 3. Adequate pain management 4. Judicious use of pharmacologic agents Avoidance of those which may disrupt sleep narcotics cocaine clonidine beta blockers (lipophilic-propranolol) nicotine Use of those which may facilitate sleep Tricyclic antidepressants (eg, amitriptyline) Selective serotonin reuptake inhibitor (eg, fluoxetine) Other antidepressants (eg, trazodone) Chlorpromazine Zopiclone
PLMS = periodic leg movements of sleep.
sleep and that similar improvement was reported by more than 60% of patients on placebo, suggesting that zopiclone had only marginal effects. 56 Goldenberg and colleagues recently showed that treatment with both amitriptyline and fluoxetine resulted in significant improvement among FM patients in general sleep scores and appeared to be superior to either drug alone. 57 Other trials (Carette et al,45 Goldenbert8 ) have also noted self-reported sleep improvement using amitriptyline. Finally, Branco et al examined the effects of trazodone, an antidepressant with an inhibitory effect on 5-HT reuptake, on sleep architecture in 13 patients in a double-blind crossover placebo controlled trial. 59 Polysomnography was performed with spectral analysis before and after 2 months of placebo or trazodone 150 mg/day.59 Interestingly, trazodone almost doubled the amount of stage 3 and 4 sleep over basal and placebo levels, but there was no difference in sleep latency, sleep efficiency, or percentage of wake time; alpha activity was also reduced with trazodone. 59 The long-term effects of this medication on sleep architecture are unknown. There is a lack of well-controlled, randomized trials evaluating sleep parameters with medications. Medications which show promise in improving sleep quality include amitriptyline, fluoxetine, trazodone, and chlorpromazine. However, it is essential for future clinical trials to include evaluations of sleep architecture as well as self-reports of sleep quality. The medications' June 1998 Volume 315 Number 6
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role in restoring sleep architecture may be a link to clinical benefits. In conclusion, screening for primary sleep disorders, improving sleep hygiene, and pharmacologic management may improve sleep quality and symptoms in FM patients. Treatment strategies should be individualized to improve the patient's quality of life.
16. 17.
18.
Acknowledgments
The author is supported by a NHLBI Sleep Academic Award (5K07HL03633), and thanks Len Shigley, RPSGT, for editing Figures 1, 2, and 4, and Martin Robbins and Felicia M. Fields for their editorial assistance.
19. 20. 21.
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