The concept of nonrestorative sleep (NRS) is based on the restorative theory, which considers brain activity during sleep as essential for the restoration of body and mind functioning. Abnormal sleep restoration results in feelings of tiredness, sluggishness, or fatigue, which are often associated with NRS, particularly when such feelings cannot be explained by insufficient sleep duration. Thus, NRS has been linked to waking up feeling unrefreshed. NRS is common among many patients with organic sleep disorders, including apnea, and has been considered a primary symptom of insomnia. However, NRS is often not a primary, but rather a secondary, symptom of insomnia, and is associated with poor health or negative mood.[2-4] NRS is particularly common among patients with chronic fatigue syndrome (CFS) and fibromyalgia.Although many studies have focused on symptoms of insomnia associated with these chronic pain syndromes, much less research has been devoted to NRS. One reason for the small number of studies on NRS is lack of a uniform definition, known pathogenesis, validated assessment, and treatment strategies for the condition. Thus, more studies are warranted in order to better understand this unique disorder, which could provide important clues to the causes of CFS and fibromyalgia and to the overall function of sleep.
Criteria for NRS
Individuals with NRS often report daytime symptoms, including cognitive difficulties, daytime fatigue, and daytime sleepiness, especially if they have difficulty initiating sleep or difficulty maintaining sleep. However, persons with NRS reported impairment in daytime functioning significantly more often than did those with difficulty initiating or maintaining sleep (P <. 001). Daytime impairment from sleepiness and fatigue appears to be associated with NRS, and is also frequently reported by patients with sleep apnea, insomnia, fibromyalgia, and CFS.
Currently, no standard definition for NRS exists, but some investigators have suggested labeling unrefreshing sleep as NRS if it occurs in the presence of a normal sleep duration.[3,5,8] Polysomnography can be used to objectively measure sleep duration and alpha-wave intrusions into non-rapid eye movement (non-REM) sleep. Variable definitions used for NRS, however, have resulted in overlap with other well-defined sleep problems.
Sleep Architecture and NRS
The association of electroencephalography (EEG) alpha activity with NRS during non-REM sleep was discovered in 1973. Although not unique to NRS, EEG alpha activity during non-REM sleep appears to be more pronounced in individuals with NRS than healthy controls.[10,11] Such empirical results support the theory that NRS is a sleep disturbance characterized by some form of arousal. Increased arousals, which seem to be characteristic of individuals with CFS and fibromyalgia, were initially considered pathognomonic of NRS. Subsequent work, however, identified EEG alpha activity as a sleep-maintaining factor rather than a sleep-disrupting one. Numerous studies have identified alpha activity in stages II-IV non-REM sleep in adults and children with fibromyalgia, as well as in individuals with CFS.[12-16]
In addition to EEG alpha activity in non-REM sleep, a cyclic alternating pattern (CAP) on EEG has been shown to be associated with NRS. CAP represents a short period (20-40 seconds) of EEG activity in non-REM sleep that consists of arousal fluctuations. Studies have demonstrated that the duration of CAP is longer in patients with insomnia and that CAP is associated with poor sleep. Increased EEG alpha activity during non-REM sleep occurs in 80%-90% of individuals with fibromyalgia and CFS, with 55% of them demonstrating CAP or CAP-like activity.[13,16]
Epidemiology of NRS
Lack of a standard definition has resulted in wide fluctuations of NRS prevalence, with estimates between 1.4% and 35% of the US population.[8,18] In the absence of difficulty initiating or maintaining sleep it has been estimated that NRS occurs in 1.4% of the population, whereas any form of NRS has been reported in 4.1%-5.1% of the population. In addition, fragmented sleep by itself has been shown to result in feeling unrefreshed upon awakening. Thus, it is unclear at this time whether insomnia is associated with feeling unrefreshed upon awakening. In general, the use of varying definitions of NRS has resulted in unreliable prevalence estimates.
Affective Spectrum Disorders and NRS
NRS seems to be associated with affective spectrum disorders. In one study, 34.2% of patients with NRS had affective spectrum disorders, including anxiety disorders, bipolar disorders, and depressive disorders. In addition, individuals who had experienced a stressful event in the last 12 months were more likely to report NRS. Not surprisingly, NRS is closely related to both anxiety and depressive disorders, not unlike unspecific insomnia. The cause-and-effect relationship among insomnia, NRS, anxiety, and depression is unknown. Thus, NRS may be a condition that is influenced by affective spectrum disorders or that interferes with their successful treatment.
Prevalence of NRS in Chronic Pain Disorders
NRS has been considered a primary symptom of insomnia or has been categorized within the spectrum of insomnia related to known organic factors. However, NRS is often found in individuals with such primary sleep disorders as periodic limb movement disorder, sleep apnea, and narcolepsy. It is one of the most important symptoms of CFS and fibromyalgia but has also been described in patients with temporomandibular joint disorder and irritable bowel syndrome. Additionally, autoimmune disorders, such as rheumatoid arthritis and systemic lupus erythematosus, are often accompanied by NRS, suggesting a substantial overlap in disease mechanisms.
Sleep Disturbances and Hyperalgesia
Deep tissue pain stimuli applied to healthy volunteers during sleep seem to strongly affect sleep stages, as indicated by decreased delta and sigma EEG activities. Not only does pain appear to disrupt all stages of sleep, but it worsens sleep quality as well. However, sleep disturbances also seem to have negative effects on pain sensitivity (ie, increased soreness and fatigue). Evidence for this negative impact has been demonstrated in healthy persons after disruption of stage IV non-REM sleep.[22,23] Although similar effects have been reported following REM sleep deprivation in healthy persons, which resulted in short-lasting hyperalgesia, sleep deprivation does not seem to alter pain sensitivity in such individuals. Overall, it appears as if slow-wave sleep fragmentation affects central pain processing in healthy individuals, resulting not only in pain but also in hyperalgesia.
NRS in Patients With Fibromyalgia and CFS
Insomnia and feeling unrefreshed upon awakening are common concerns among patents with fibromyalgia. Compared with healthy controls, most patients with fibromyalgia perceive their sleep to be of poor quality, almost always reporting it as nonrestorative. More specifically, NRS is one of the major complaints among patients with fibromyalgia and CFS. Some patients may also have involuntary leg movements or sleep-related breathing disorders, such as obstructive sleep apnea. Whenever sleep is perceived as restful, patients with fibromyalgia report substantial improvement in their daytime symptoms. Poor sleep quality has been shown to be associated with pain and tender points in patients with fibromyalgia. In some studies, up to 65.7% of patients with fibromyalgia and up to 100% of patients with CFS reported NRS. Even after adjustment for depression, anxiety, or sleep disorders, NRS remained prevalent among patients with CFS. Although epidemiologic research strongly supports the association of NRS with both fibromyalgia and CFS, the lack of longitudinal data makes it difficult to determine a cause-and-effect relationship. There is, however, evidence for the important contributions of depression and sleep quality to fatigue. Depression appears to be the dominant factor, explaining 18% of the variability in fatigue; lower sleep quality is independently correlated with higher fatigue as well. Of note, when sleep quality and depression are taken into account, pain does not seem to contribute independently to fatigue. Cross-sectional data on pain and depression shared considerable variance, and the role of pain in fatigue was explained by its convergence with depression.
Primary sleep disorders, such as apnea, occur frequently in patients with fibromyalgia (up to 44%), with polysomnography typically demonstrating disordered sleep physiology. Most patients with fibromyalgia have arousal disturbances on their sleep EEG, known as alpha EEG (~10 Hz) sleep disorder,[4,36] which can occur in 3 distinct patterns: (1) phasic alpha sleep activity (50% of patients with fibromyalgia vs 7% of healthy controls); (2) tonic alpha sleep activity (20% of patients with fibromyalgia vs 9% of healthy controls); and (3) low alpha sleep activity (30% of patients with fibromyalgia vs 84% of healthy controls). Alpha intrusions into the sleep of individuals with fibromyalgia have been associated with pain, fatigue, and depressed mood. Overall, periodic central nervous system arousal disturbances on a sleep EEG are associated with insomnia and unrefreshing sleep and reflect the severity of clinical symptoms in patients with fibromyalgia. Population-based studies with twins suggest genetic and environmental influence on sleep and may play a role in the pathogenesis of NRS in fibromyalgia.
Pharmacologic Therapy for Fibromyalgia-Related Sleep Abnormalities
Although improving the quality of sleep is often associated with improvement in fibromyalgia symptoms, no specific treatments have been approved by the US Food and Drug Administration (FDA) for NRS. The pharmacologic agents FDA approved for fibromyalgia symptoms, including pregabalin, duloxetine, and milnacipran, may also improve sleep.[39-43] The efficacy of the alpha-2-delta ligand pregabalin in enhancing slow-wave sleep in healthy volunteers appears to be particularly promising for patients with fibromyalgia, who often have profound abnormalities of deep sleep stages. Gamma-hydroxybutyrate is a naturally occurring neurotransmitter, with the highest concentrations found in the hypothalamus and basal ganglia. A commercial form of gamma-hydroxybutyrate has been developed as sodium oxybate, which can cause dose-related increases in both slow-wave sleep and growth hormone levels. Sodium oxybate has been shown to promote normalization of non-REM and REM sleep by reducing alpha EEG sleep and increasing slow-wave sleep, thus improving the quality of sleep. In a proof-of-concept, 8-week, randomized, double-blind, placebo-controlled, multicenter study of patients with fibromyalgia, treatment with sodium oxybate significantly reduced the severity of pain, insomnia, and fatigue, while improving quality of life. Tricyclic antidepressants — that is, cyclobenzaprine and amitriptyline — do not seem to alter alpha non-REM sleep.
NRS is prevalent in the general population. NRS is poorly understood, however, and variably defined. A widely used definition of NRS includes feeling persistently unrefreshed upon awakening, despite normal sleep duration, and occurrence in the absence of distinct sleep disorders. Although NRS is strongly associated with daytime impairment, pain, fatigue, and EEG arousals in non-REM sleep, causal links have not yet been established. NRS should not be conceptualized as a symptom of insomnia, such as difficulty initiating and maintaining sleep. Because of the lack of standardization, however, only limited conclusions can be drawn about NRS. The condition has the potential to contribute to our understanding of sleep, which is an important goal with considerable health implications. Finally, NRS is an important symptom among patients with FMS and CFS, who often report widespread pain, fatigue, and cognitive and emotional difficulties. Overall, common symptoms of FMS and CFS, such as fatigue, psychological distress, and poor quality of sleep, seem to indicate disease mechanisms intrinsic to disturbances of the sleep-wake brain.
NRS is a hallmark of fibromyalgia and many other chronic pain syndromes. Only a few studies have been devoted to NRS in patients with fibromyalgia, mostly because of the lack of a widely accepted definition, an unknown pathogenesis, and no validated assessment and treatment strategies. Improved understanding of this important, unique symptom not only may enhance our understanding of fibromyalgia but could also result in improved treatment outcomes.
Supported by an independent educational grant from Forest Laboratories and Pfizer.
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