Non-restorative sleep

Non-restorative sleep (NRS), also known as unrefreshing sleep,^[1] is a subjective symptom in which sleep is experienced as insufficiently refreshing and hence subjective sleep quality as poor.^[2][3][4] This can be despite the appearance of otherwise normal sleep, like adequate sleep duration and lack of nighttime awakenings.^[2][3] NRS is associated with daytime cognitive dysfunction, affective symptoms, fatigue, sleepiness, and increased pain sensitivity.^[2][3][5][4] It is diagnosed exclusively via self-report or sleep questionnaires.^[2][6]

Conditions

NRS is often a symptom of sleep disorders such as insomnia and shift work sleep disorder.^[2][3] It can also occur in hypersomnia and narcolepsy.^[2][3] In addition, NRS is frequently a symptom of conditions like fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), long COVID, autoimmune disorders like rheumatoid arthritis and systemic lupus erythematosus (SLE), and infections.^{[2][3][7][5][8][4]} NRS has been especially associated with fibromyalgia and ME/CFS, with approximately 65 to 95% of people with fibromyalgia and 85 to 95% of people with ME/CFS reporting unrefreshing sleep.^[2][3][5] NRS may in fact be causally related to cognitive impairment, fatigue, and myalgia (muscle pain) in people with fibromyalgia and ME/CFS.^[3][5][4] Other conditions associated with NRS include sleep apnea, periodic limb movement disorder (PLMD), and chronic pain.^[2][3][5] Psychiatric disorders such as depression or anxiety have been associated with NRS as well.^[2][3] On the other hand, NRS can occur without any comorbidity.^[2][3]

Correlates

Older age is strongly correlated with NRS, although conflicting findings exist.^[3] In addition, women experience NRS more often than men, though this is likewise not always observed.^[3] Relatedly, in the case of fibromyalgia, which is characterized by very high rates of NRS, more than 90% of people with this condition are women.^[2][5] People who are unemployed or retired have been found to experience more NRS than employed people.^[3] Shift workers have a relatively high level of NRS.^[3] Moderate to high stress has been associated with NRS.^[3]

Causes

Research on the mechanisms underlying NRS are controversial and inconclusive.^[2][3] NRS is correlated with sleep onset latency and to a lesser extent with sleep duration.^[3] The symptom might be due to disturbance of slow wave sleep (SWS; non-REM sleep or "deep sleep") and due to insufficiently deep sleep.^[3][2][5][4] Alternatively or additionally, it might be related to REM sleep deprivation.^[5] Pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor α (TNFα) may have negative effects on sleep and increase the likelihood of NRS.^[2] These findings provide a possible mechanism by which immune disorders and related conditions may affect sleep and cause NRS.^[2]

Treatment

See also: Hypnotic

There is little information available on treatment of NRS as of 2008.^[3][5] Treatments that might be helpful in some cases of NRS include behavioral measures like cognitive–behavioral therapy (CBT) and hypnotherapy, exercise, hypnotics, and certain antidepressants.^[5] Some hypnotics have been found to improve SWS, such as sodium oxybate (γ-hydroxybutyrate (GHB); Xyrem)^[9][10] and gaboxadol,^[11][12] and hypnotics of this sort might be more useful than other hypnotics in the treatment of NRS, though more research is needed to substantiate such notions.^[5][13][4]

Sodium oxybate is used as a hypnotic in the treatment of narcolepsy and uniquely improves sleep quality as well as symptoms like daytime sleepiness and cataplexy in people with this condition.^[14][15] The drug also underwent and completed formal clinical development for treatment of fibromyalgia.^[9][10] This condition is characterized by very high rates of NRS,^[2][3][5] and sodium oxybate was shown to increase SWS in people with the condition.^[9][10] Relatedly, the drug not only improved sleep and insomnia in people with fibromyalgia, but also moderately improved general symptoms such as pain and fatigue as well as multiple quality of life measures.^[9][10] However, sodium oxybate was ultimately not granted regulatory approval for treatment of fibromyalgia, owing mostly to concerns about potential misuse.^[9][10] In addition, the drug has garnered a reputation as a date-rape drug, with diversion concerns, although the actual prevalence of this use appears to be much lower than popular perception.^[16] Besides fibromyalgia, sodium oxybate might also be useful for treatment of NRS in other conditions like ME/CFS and long COVID.^{[15][7][2][17]} Due to its very short elimination half-life, sodium oxybate must be administered twice per night, with the second dose being taken 4 hours after the first.^[9][18] However, in 2023, an extended-release once-nightly formulation was introduced.^[19] In addition, a once-nightly prodrug known as valiloxybate (XW-10172) is being developed.^[20][21]