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The Effects of Sodium Oxybate on Clinical Symptoms and Sleep Patterns in Patients with Fibromyalgia

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Source: Journal of Rheumatology. 2003;30(5):1070-1074  Scharf MB, Baumann M, Berkowitz DV

Scharf and colleagues report a double-blind, randomized, placebo-controlled cross-over trial of sodium oxybate in patients with fibromyalgia (FM). They evaluated the effects of sodium oxybate, a commercial form of gamma-hydroxybutyrate (GHB), on the subjective symptoms of pain, fatigue, and sleep quality and the objective polysomnographic sleep variables of alpha intrusion, slow-wave (stage 3/4) sleep, and sleep efficiency in patients with FM. They studied 24 female patients of which 18 completed the trial. The patients who dropped out were in the active medication portion of the study, and none of the side effects were considered serious events (transient episodes of headache, anxiety attack, or paresthesia).

In the intention-to-treat analysis of all patients who entered the protocol, tender-point index was decreased from baseline by 8.5, compared with an increase of 0.4 for the placebo (P = .0079) portion of the cross-over trial. Sodium oxybate was associated with relief of 29% to 33% of 6 of the 7 pain/fatigue scores (overall pain, pain at rest, pain during movement, end-of-day fatigue, overall fatigue, and morning fatigue), compared with relief of 6% to 10% with placebo (P < .005). Slow-wave (stage 3/4) sleep was significantly increased while alpha intrusion, sleep latency, and rapid eye movement (REM) sleep were significantly decreased compared with placebo (P < .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 = .0033) and quality of sleep (improved by 33% and 10%, respectively; P = .0003).

The investigators conclude that sodium oxybate effectively reduced the symptoms of pain and fatigue in patients with FM, dramatically reduced the sleep abnormalities of alpha intrusion, and decreased slow-wave sleep associated with the characteristic nonrestorative sleep. This study is important for rheumatologists, because fatigue and fibromyalgia are common problems in our patients and a new effective class of drugs may improve functional outcome in FM patients.

FM is associated with alpha intrusion during sleep[1] and low growth hormone secretion.[2] Moldofsky and coworkers have demonstrated that alpha intrusion on the electroencephalogram (EEG) is a normal part of wakefulness; however, when it occurs too frequently in sleep, it is accompanied by daytime complaints of musculoskeletal pain, fatigue, and altered mood.[2,3]

Although the mechanisms of sleep induction maintenance in normal individuals are poorly understood,[4] they are even more complex and multifactorial in patients with FM[2] and in patients with inflammatory processes associated with proinflammatory cytokines such as tumor necrosis factor.[5] In normal subjects, patients with FM or inflammatory conditions, and animal models, evidence for an increasingly important role for GHB has been accumulating.[6,7]

GHB is a naturally occurring metabolite of the human nervous system, with the highest concentration in the hypothalamus and basal ganglia. A commercial form of GHB has been developed as sodium oxybate. In healthy human volunteers, sodium oxybate has been shown to promote a normal sequence of non-REM and REM sleep for 2 to 3 hours. However, it is also important to recognize that GHB has gained wide recognition in the popular press as a "recreational drug" used for date rape[8,9] as it is tasteless and creates a sense of amnesia when taken with alcohol.

Thus, GHB is both a therapeutic agent and a recreational drug. It has sedative, anxiolytic, and euphoric effects. These effects are believed to be due to GHB-induced potentiation of cerebral gamma-aminobutyric acid-ergic and dopaminergic activities, and recent studies suggest the serotonergic system might also be involved.[10] As the serotonergic system may be involved in the regulation of sleep, mood, and anxiety, the stimulation of this system may be involved in certain neuropharmacologic events induced by GHB administration.[10]

The biology of GHB may shed light on the important abnormality in sleep and the associated hypothalamic diurnal variations found in FM.[2,11] The potential importance of the study by Sharf and coworkers is that no medication has previously been shown to improve the EEG sleep arousal disorders that include phasic (alpha-delta), tonic alpha non-REM sleep disorders, or the periodic alpha cycling alternating pattern disorder.[12]

Traditional hypnotic agents, while helpful in initiating and maintaining sleep and reducing daytime tiredness, do not provide restorative sleep or reduce pain. Tricyclic drugs, such as amitriptyline and cyclobenzaprine, may provide long-term benefit for improving sleep but may not have a continuing benefit beyond 1 month for reducing pain.

The basic balance between sleep and wakefulness has been an area of active interest in neurochemistry in recent years. There have been significant advances in understanding the molecular biology involved, largely based on studies of patients with narcolepsy and cataplexy.

One emerging area of importance is the neuro-hormone hypocretin (orexin), whose deficiency (< 40 pg/mL) is highly associated with narcolepsy and cataplexy (89.5%).[13] In animal models of narcolepsy, the absence of hypothalamic orexin (hypocretin) neuropeptides leads to inability to maintain wakefulness and intrusion of REM sleep into wakefulness.[14] Absence of oxyrexen-2 receptor eliminates orexin-evoked excitation of histaminergic neurons in the hypothalamus, which gate non-REM sleep onset.

In summary, the article by Scharf and colleagues demonstrates that sodium oxybate improves functional status in fibromyalgia patients. This benefit may result from a significant reduction in the sleep abnormalities (alpha intrusion and diminished slow wave sleep) associated with the nonrestorative sleep that is a critical feature of FM. According to the authors, no other compound has been reported to reduce the alpha sleep abnormality. Although this abnormality is not specific to FM and its presence has not been distinguished as a cause or effect in FM, reducing alpha intrusion appears to correlate with clinical improvement.

References

1. Roizenblatt S, Moldofsky H, Benedito-Silva AA, Tufik S. Alpha sleep characteristics in fibromyalgia. Arthritis Rheum. 2001;44:222-230.

2. Moldofsky HK. Disordered sleep in fibromyalgia and related myofascial facial pain conditions. Dent Clin North Am. 2001;45:701-713.

3. Moldofsky H, Lue FA, Shahal B, Jiang CG, Gorczynski RM. Diurnal sleep/wake-related immune functions during the menstrual cycle of healthy young women. J Sleep Res. 1995;4:150-159.

4. Willie JT, Chemelli RM, Sinton CM, Yanagisawa M. To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci. 2001;24:429-458.

5. Dickstein JB, Moldofsky H, Hay JB. Brain-blood permeability: TNF-alpha promotes escape of protein tracer from CSF to blood. Am J Physiol Regul Integr Comp Physiol. 2000;279:R148-R151.

6. Gamma hydroxybutyrate (Xyrem) for narcolepsy. Med Lett Drugs Ther. 2002;44:103-105.

7. Xyrem approved for muscle problems in narcolepsy. FDA Consum. 2002;36:7.

8. Tellier PP. Club drugs: is it all ecstasy? Pediatr Ann. 2002;31:550-556.

9. Smalley S. The perfect crime. Newsweek. February 3, 2003:141:52.

10. Gobaille S, Schleef C, Hechler V, Viry S, Aunis D, Maitre M. Gamma-hydroxybutyrate increases tryptophan availability and potentiates serotonin turnover in rat brain. Life Sci. 2002;70:2101-2112.

11. Scharf MB, Hauck M, Stover R, McDannold M, Berkowitz D. Effect of gamma-hydroxybutyrate on pain, fatigue, and the alpha sleep anomaly in patients with fibromyalgia. Preliminary report. J Rheumatol. 1998;25:1986-1990.

12. Brooks S, Black J. Novel therapies for narcolepsy. Expert Opin Investig Drugs. 2002;11:1821-1827.

13. Krahn LE, Pankratz VS, Oliver L, Boeve BF, Silber MH. Hypocretin (orexin) levels in cerebrospinal fluid of patients with narcolepsy: relationship to cataplexy and HLA DQB1*0602 status. Sleep. 2002;25:733-736.

14. Willie JT, Chemelli RM, Sinton CM, et al. Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron. 2003;38:715-730.

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