Saturday, February 28, 2004

Yet More on Sleep Problems
Bad News for the Midnight Blogger
Good News for Basic Science Research

[left brain stuff:] Following up on my recent articles regarding sleep problems, here are four pieces that illustrate some intriguing links between brain activity, hormones, metabolism, and inflammation.  The findings suggest that sleep deprivation can increase insulin resistance, reduce plasma leptin concentrations, and increase the concentration of pro-inflammatory chemicals (cytokines) in the bloodstream.  If you aren't up to date on physiology, take my word for it.  All of these things are bad.  The Science News article refers to studies that link sleep apnea to increased cytokines.  The Lentz 1999 article in the Journal of Rheumatology shows that sleep deprivation (without sleep apnea) can increase C-reative protein, a cytokine associated with cardiovascular disease.   The following information is pretty technical.  Some persons might prefer to skim down to the bottom to see what to make of all this.

Week of Sept. 7, 2002; Vol. 162, No. 10 , p. 152

Missed ZZZ's, More Disease?

Skimping on sleep may be bad for your health

Kristin Cobb

As bleary-eyed college students in exam week will attest, lack of sleep impairs mood, performance, and judgment. They might guess, however, that the fast food and candy gobbled down during an all-nighter are far worse for bodily health than are the lost hours of slumber. After all, scientists have long been preaching that too many Big Macs and too few workouts are bad for you, but they have yet to demonstrate any definitive health costs of chronic sleep loss.


Loughborough Sleep Research Centre, UK

Bolstered by new evidence, however, some scientists are suggesting that poor sleep habits are as important as poor nutrition and physical inactivity in the development of chronic illness. They say that this country's sleep debt may be contributing to its current epidemics of obesity, diabetes, and cardiovascular disease. People in the United States sleep an average of 7.0 hours on weeknights, 1.5 hour less than they did a century ago, according to the National Sleep Foundation in Washington, D.C. One-third of the population sleeps 6.5 or fewer hours, far less than the 8 hours that many sleep specialists recommend. Several recent studies report that reducing sleep to 6.5 or fewer hours for successive nights causes potentially harmful metabolic, hormonal, and immune changes, at least in test volunteers in the sleep lab. "All of the changes are what you find in normal aging," says sleep researcher Eve Van Cauter of the University of Chicago.
[...]Van Cauter and her colleagues helped launch the field with a surprising 1999 study that showed that sleep deficits of several hours a night can impair the body's processing of the sugar glucose. The study reported that 11 healthy, lean young men showed signs of insulin resistance after several nights of sleep restriction. Insulin resistance, a condition in which the body handles glucose poorly because cells respond inefficiently to insulin, is a precursor to type II diabetes.

[...]Men who were held to 4 hours a night had markedly reduced 24-hour leptin concentrations compared with when they were fully rested, Van Cauter's research team reported at the 2001 Association of Professional Sleep Societies meeting in Chicago. Leptin is a hormone that signals satiety and regulates energy balance; mice that lack leptin overeat and become morbidly obese.

[...] Inflammatory ideas: Modest sleep deprivation may also be associated with low-grade inflammation, which can lead to a host of cardiovascular problems, according to Alexandros N. Vgontzas of the Pennsylvania State University College of Medicine in Hershey. [...]After a week of sleeping 6 hours per night, the test volunteers had higher blood concentrations of the cytokine IL-6, than they did in their pre-deprivation state. [...]Unremitting low-grade inflammation can damage the inner walls of the arteries, which sometimes leads to vessel narrowing, high blood pressure, stroke, and heart disease. Also, cytokines have been associated with insulin resistance, diabetes, and obesity. Cytokines cause fatigue. By overproducing cytokines, a person's body is probably trying to say, "Go to sleep," Vgontzas says. [...] Several recent studies have linked sleep apnea to elevated blood concentrations of IL-6, TNF-a, and C-reactive protein and to high blood pressure, cardiovascular problems, and stroke.[...]

(The following abstracts can be found on Medscape Medline)

Effect of sleep loss on C-Reactive protein, an inflammatory marker of cardiovascular risk
J Am Coll Cardiol 2004 Feb 18;43(4):678-83     (ISSN: 0735-1097)
Meier-Ewert HK; Ridker PM; Rifai N; Regan MM; Price NJ; Dinges DF; Mullington JM
Department of Cardiology, Lahey Clinic Medical Center, Burlington, and Tufts University Medical School, Boston, Massachusetts, USA.

OBJECTIVES: We sought to investigate the effects of sleep loss on high-sensitivity C-reactive protein (CRP) levels. BACKGROUND: Concentrations of high-sensitivity CRP are predictive of future cardiovascular morbidity. In epidemiologic studies, short sleep duration and sleep complaints have also been associated with increased cardiovascular morbidity. Two studies were undertaken to examine the effect of acute total and short-term partial sleep deprivation on concentrations of high-sensitivity CRP in healthy human subjects.

METHODS: In Experiment 1, 10 healthy adult subjects stayed awake for 88 continuous hours. Samples of high-sensitivity CRP were collected every 90 min for 5 consecutive days, encompassing the vigil. In Experiment 2, 10 subjects were randomly assigned to either 8.2 h (control) or 4.2 h (partial sleep deprivation) of nighttime sleep for 10 consecutive days. Hourly samples of high-sensitivity CRP were taken during a baseline night and on day 10 of the study protocol.

RESULTS: The CRP concentrations increased during both total and partial sleep deprivation conditions, but remained stable in the control condition. Systolic blood pressure increased across deprivation in Experiment 1, and heart rate increased in Experiment 2.

CONCLUSIONS: Both acute total and short-term partial sleep deprivation resulted in elevated high-sensitivity CRP concentrations, a stable marker of inflammation that has been shown to be predictive of cardiovascular morbidity. We propose that sleep loss may be one of the ways that inflammatory processes are activated and contribute to the association of sleep complaints, short sleep duration, and cardiovascular morbidity observed in epidemiologic surveys.

Effects of selective slow wave sleep disruption on musculoskeletal pain and fatigue in middle aged women.
J Rheumatol 1999 Jul;26(7):1586-92    (ISSN: 0315-162X)
Lentz MJ; Landis CA; Rothermel J; Shaver JL
Department of Biobehavioral Nursing and Health Systems, University of Washington, Seattle 98195-7266, USA.

OBJECTIVE: To determine whether disrupted slow wave sleep (SWS) would evoke musculoskeletal pain, fatigue, and an alpha electroencephalograph (EEG) sleep pattern. We selectively deprived 12 healthy, middle aged, sedentary women without muscle discomfort of SWS for 3 consecutive nights. Effects were assessed for the following measures: polysomnographic sleep, musculoskeletal tender point pain threshold, skinfold tenderness, reactive hyperemia (inflammatory flare response), somatic symptoms, and mood state.

METHODS: Sleep was recorded and scored using standard methods. On selective SWS deprivation (SWSD) nights, when delta waves (indicative of SWS) were detected on EEG, a computer generated tone (maximum 85 decibels) was delivered until delta waves disappeared. Musculoskeletal tender points were measured by dolorimetry; skinfold tenderness was assessed by skin roll procedure; and reactive hyperemia was assessed with a cotton swab test. Subjects completed questionnaires on bodily feelings, symptoms, and mood.

RESULTS: On each SWSD night, SWS was decreased significantly with minimal alterations in total sleep time, sleep efficiency, and other sleep stages. Subjects showed a 24% decrease in musculoskeletal pain threshold after the third SWSD night. They also reported increased discomfort, tiredness, fatigue, and reduced vigor. The flare response (area of vasodilatation) in skin was greater than baseline after the first, and again, after the third SWSD night. However, the automated program for SWSD did not evoke an alpha EEG sleep pattern.

CONCLUSION: Disrupting SWS, without reducing total sleep or sleep efficiency, for several consecutive nights is associated with decreased pain threshold, increased discomfort, fatigue, and the inflammatory flare response in skin. These results suggest that disrupted sleep is probably an important factor in the pathophysiology of symptoms in fibromyalgia.

The effects of sodium oxybate on clinical symptoms and sleep patterns in patients with fibromyalgia.
J Rheumatol 2003 May;30(5):1070-4    (ISSN: 0315-162X)
Scharf MB; Baumann M; Berkowitz DV
Tri-State Sleep Disorders Center, Cincinnati, Ohio 45246, USA.
OBJECTIVE: Fibromyalgia (FM) is associated with the sleep phenomenon of alpha intrusion, and with low growth hormone secretion. Sodium oxybate has been shown to increase both slow-wave sleep and growth hormone levels. This double blind, randomized, placebo controlled crossover trial was conducted to evaluate the effects of sodium oxybate on the subjective symptoms of pain, fatigue, and sleep quality and the objective polysomnographic (PSG) sleep variables of alpha intrusion, slow-wave (stage 3/4) sleep, and sleep efficiency in patients with FM.

METHODS: Patients received either 6.0 g/day sodium oxybate or placebo for 1 month, with an intervening 2 week washout period. Efficacy measures included PSG evaluations, tender point index (TPI), and subjective measurements from daily diary entries. Safety measures included clinical laboratory values, vital signs, and adverse events.

RESULTS: Twenty-four female patients were included in the study; 18 completed the trial. TPI was decreased from baseline by 8.5, compared with an increase of 0.4 for placebo (p = 0.0079). Six of the 7 pain/fatigue scores (overall pain, pain at rest, pain during movement, end of day fatigue, overall fatigue, and morning fatigue) were relieved by 29% to 33% with sodium oxybate, compared with 6% to 10% relief with placebo (p < 0.005). Alpha intrusion, sleep latency, and rapid-eye-movement sleep were significantly decreased, while slow-wave (stage 3/4) sleep was significantly increased, compared with placebo (p < 0.005). Two of the 5 subjective sleep related variables were significantly different from placebo: morning alertness (improved by 18% with sodium oxybate, compared with 2% for placebo; p = 0.0033) and quality of sleep (improved by 33% and 10%, respectively; p = 0.0003).

CONCLUSION: Sodium oxybate effectively reduced the symptoms of pain and fatigue in patients with FM, and dramatically reduced the sleep abnormalities (alpha intrusion and decreased slow-wave sleep) associated with the nonrestorative sleep characteristic of this disorder.

[right brain stuff] The information summarized above shows that sleep deprivation, regardless of cause, has multiple adverse effects on the human body.  There is plenty of animal evidence also, but I thought I would spare you from the rat facts.  Aside from the obvious -- that people need their sleep -- what can we learn from this?  One thing is illustrated nicely by the last abstract.  This shows how observations from basic science (preclinical studies) can lead to the formulation of an hypothesis regarding a potential treatment.  Since there was evidence that decreased slow-wave sleep can contribute to some of the chemical changes observed in patients with fibromyalgia, it seemed reasonable to speculate that increasing slow-wave sleep might be therapeutic.  There are not very many drugs that do this.  Most sleeping pills, as well as alcohol, increase stage 1 and 2 sleep, but decrease stages 3 and 4 (slow wave) sleep.  Sodium oxybate  (Xyrem) is the most efficacious drug that increases SWS.  Don't rush out to get this; Xyrem is the pharmaceutical form of GHB, also known as the date rape drug.  Doctors and patients have to enter a special registry to prescribe and use it.  It can be given only to persons with cataplexy caused by narcolepsy.  (Note that it was produced under the orphan drug program, which was the subject of my 2/23/2004  post)

It is common for scientists to face criticism for doing basic science research, when it is not obvious at the front end how there will be any practical use for it.  But fibromyalgia is a common problem.  Finding a good treatment would create significant economic benefit for everyone.  Xyrem probably will not become a standard treatment, because of the serious problems that would result from drug diversion.  But there are some other drugs that could be helpful as well.  Both olanzapine (Zyprexa) and tiagabine (Gabitril) have been shown to increase SWS.  There was one study that showed improvement in fibromyalgia with olanzapine (Kiser et. al., J Pain Symptom Manage 2001 Aug;22(2):704-8); although they did not assess sleep architecture in that study, I would bet that if they had, it would have shown a correlation between increased SWS and pain relief.  Other studies have shown that tiagabine can be useful in treatment of pain, but I could not find one that studied fibromyalgia pain specifically. 

Getting back to the economic benefit from basic research, look at the following abstract:

Economic cost and epidemiological characteristics of patients with fibromyalgia claims.
J Rheumatol 2003 Jun;30(6):1318-25    (ISSN: 0315-162X)
Robinson RL; Birnbaum HG; Morley MA; Sisitsky T; Greenberg PE; Claxton AJ
Eli Lilly and Company, Indianapolis, Indiana 46285, USA. rlrobinson@lilly.com.

OBJECTIVE: Fibromyalgia (FM) is characterized by widespread pain that can lead to significant patient disability, complex management decisions for physicians, and economic burden on society. We investigated the total costs of FM in an employer population.

METHODS: Administrative claims data of a Fortune 100 manufacturer were used to quantify direct (i.e., medical and pharmaceutical claims) and indirect (i.e., disability claims and imputed absenteeism) costs associated with FM. A total of 4699 patients with at least one FM claim between 1996 and 1998 were contrasted with a 10% random sample of the overall beneficiary population. Employee-only subsets of both samples also were drawn.

RESULTS: Medical utilization, receipt of prescription drugs, and annual total costs were proportionately similar yet significantly greater among FM claimants than the overall sample (all p < 0.0001). Total annual costs for FM claimants were $5945 versus $2486 for the typical beneficiary (p < 0.0001). Six percent of these costs were attributable to FM-specific claims. The prevalence of disability was twice as high among FM employees than overall employees (p < 0.0001). For every dollar spent on FM-specific claims, the employer spent another $57 to $143 on additional direct and indirect costs.

CONCLUSION: Hidden costs of disability and comorbidities greatly increase the true burden of FM. Regardless of the clinical understanding of FM, when a claim for FM is present, considerable costs are involved. Findings suggest that within the management of FM there may be large cost-offset opportunities for reductions in patient, physician, and employer burdens.

I couldn't find an article that shows what I really want, which is the total cost to society imposed by the decreased productivity and the treatment costs associated with fibromyalgia.  But the study noted above indicates that the cost is large, and that treatment might be worthwhile from a pure economic standpoint (not to mention the humanitarian standpoint).  I can't advance this claim too strongly, on the basis of the one study; it was funded by Eli Lily, the makers of olanzapine; Zyprexa costs $307.99 for thirty 10mg tablets, at CVS online.   Still, the point that there are potentially huge economic benefits from basic science research, is  valid.