Can enhancing SWS improve daytime function in patients with CFS?

Sleep disturbance is a core symptom of chronic fatigue syndrome (CFS) and has a huge negative impact on daytime function and quality of life. Studies of sleep in the past 10 years have provided evidence that brain mechanisms of sleep regulation, and in particular homeostasis, are disrupted in CFS. Impaired homeostatic mechanisms of sleep result in poor sleep at night and sleepiness and fatigue during the day, contributing to the subjective and objective cognitive impairment seen in these patients. This study will bring together experts in CFS, sleep and psychopharmacology, to study the nature of homeostatic impairment in CFS and its impact on daytime function. We propose to use a pharmacological agent which increases deep restorative sleep (slow wave sleep) which is a marker for homeostatic drive to sleep at night. We will perform a single-dose challenge test in patient with CFS, to ascertain the extent to which this brief and safe pharmacological enhancement of slow wave sleep (and thus of homeostatic mechanisms) will have a significant beneficial impact on daytime impairment. We will include measures of sleepiness, vigilance, memory and subjective well-being. If our results are positive, this will clearly have several potential benefits to CFS sufferers. First, it will underscore the extent to which a major biological function, namely the homeostatic component of the sleep-wake cycle, is impaired in CFS. Second, it will enable us to focus on a specific important brain pathway. Third, it will allow us to evaluate the extent to which patients' daily functions and quality of life are likely to improve following a good night's refreshing sleep. Fourth, our results would direct future major programmes of research into understanding better the underlying sleep disorder in CFS. Finally, the proposed work may suggest potential therapeutic interventions.

"Alterations in slow wave sleep (SWS) and slow wave activity (SWA), the most reliable markers of sleep homeostasis, suggest there may be homeostatic dysregulation in CFS. SWS enhancement improves daytime sleepiness and performance on a number of tasks and the detrimental effects of sleep deprivation on performance can be rescued by administering SWS enhancing drugs. We hypothesised that pharmacological enhancement of SWS may lead to improvements in sleep main-tenance and daytime function in CFS patients suffering from non-restorative sleep. This may represent a new avenue for future treatment.

The objective of the research is to compare aspects of daytime performance, notably sleepiness, memory, subjective well-being and fatigue after a night's sleep in which SWS has been enhanced with sodium oxybate in comparison with placebo. This is a randomised, double-blind, placebo-controlled crossover study in patients with CFS. 24 patients will spend two 20-hr periods in the research centre, separated by at least a week, where they will have their sleep recorded overnight. They will be given oral liquid sodium oxybate (3g) or matching placebo in divided doses; 15 minutes prior to usual bedtime and again after 3 hours. Sleep will be recorded continuously until subjects' usual rise time or after a maximum of 10 hours. The following day, assessments of sleep propensity (MSLT) will be made, by the standard method of creating sleep opportunities every 2 hours and measuring time to fall asleep. Tests of vigilance, memory, visual processing, executive function and subjective experience will be made at intervals during the day. Sleep will be scored using standard methods and spectral analysis will be used to obtain measures of microarchitecture. Subject's daily routines will be measured with actigraphy for the entire study duration.

The results will be published in peer-reviewed journals and more widely in the non-academic community, and will be used to plan future research."

"The primary potential beneficiaries are patients with CFS, of whom there are a great number who are unresponsive to currently available therapies. If improving sleep can improve the performance of patients, then this would represent a significant step forward. While there will be no direct benefit for those who take part in the research itself, future interventions that improve sleep drive and its dissipation would have a more secure evidence base and the results of this research would direct future research. Treatment could thus be directed towards sleep as a target in the treatment of CFS, and indeed oxybate itself could then be tested as a potential treatment. Patients often consider that there is nothing that can be done about their poor sleep patterns and poor sleep maintenance. The proposed research may demonstrate that this is not necessarily the case. It is also likely to appeal to patients who feel that their social, functional and employment impairment is hopeless, and provide a fresh focus for future treatment.

If the pharmacological enhancement of slow wave sleep provides an effective way to improve both sleep maintenance and daytime symptoms in CFS, this enhancement could be a target for future pharmacological treatments for CFS, which would prove interesting to pharmaceutical companies. This could be tested with future clinical trials following longer-term treatment.

In addition to the self-evident social cost incurred by sufferers, CFS has been shown to be associated with a large economic cost to the country at large, in terms of lost income tax, the cost to the NHS, and social, sickness and disability costs. A positive finding from our research may impact positively on both these social and financial costs. Furthermore, if our research gives rise to the potential for novel therapeutic intervention, then if future research trials were to be conducted by a British-based pharmaceutical company, this could lead to benefits to the British economy from future export-led earnings; there are, for example, estimated to be approximately eight million CFS patients in the United States of America alone.
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