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Original Contribution |

Sodium Oxybate for Excessive Daytime Sleepiness in Parkinson Disease:  An Open-Label Polysomnographic Study FREE

William G. Ondo, MD; Thomas Perkins, MD; Todd Swick, MD; Keith L. Hull Jr, MD; J. Ernesto Jimenez, MEd; Tippy S. Garris, RN; Daniel Pardi, MS
[+] Author Affiliations

Author Affiliations: Departments of Neurology, Baylor College of Medicine (Dr Ondo and Mr Jimenez), and Methodist Neurological Institute, The Houston Sleep Center (Dr Swick), Houston, Texas; Raleigh Neurology Associates, PA, Raleigh, North Carolina (Drs Perkins and Hull and Ms Garris); and Jazz Pharmaceuticals, Inc, Palo Alto, California (Mr Pardi).


Arch Neurol. 2008;65(10):1337-1340. doi:10.1001/archneur.65.10.1337.
Text Size: A A A
Published online

Background  Many patients with Parkinson disease (PD) have excessive daytime sleepiness and numerous nocturnal sleep abnormalities.

Objective  To determine the safety and efficacy of the controlled drug sodium oxybate in a multicenter, open-label, polysomnographic study in subjects with PD and sleep disorders.

Design, Setting, and Patients  Inclusion required an Epworth Sleepiness Scale (ESS) score greater than 10 and any subjective nocturnal sleep concern, usually insomnia. An acclimation and screening polysomnogram was performed to exclude subjects with sleep-disordered breathing. The following evening, subjects underwent another polysomnogram, followed by an evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) while practically defined off (“off”) PD medications, ESS (primary efficacy point), Pittsburgh Sleep Quality Inventory, and Fatigue Severity Scale. Subjects then started sodium oxybate therapy, which was titrated from 3 to 9 g per night in split doses (at bedtime and 4 hours later) across 6 weeks, and returned for subjective sleep assessments. They then returned at 12 weeks after initiating therapy for a third polysomnogram, an off-medication UPDRS evaluation, and subjective sleep assessments. Data are expressed as mean (SD).

Results  We enrolled 38 subjects. At screening, 8 had sleep apnea (n = 7) or depression (n = 1). Twenty-seven of 30 subjects completed the study. Three dropped out owing to dizziness (n = 3) and concurrent depression (n = 1). The mean dose of sodium oxybate was 7.8 (1.7) g per night. The ESS score improved from 15.6 (4.2) to 9.0 (5.0) (P < .001); the Pittsburgh Sleep Quality Inventory score, from 10.9 (4.0) to 6.6 (3.9) (P < .001); and the Fatigue Severity Scale score, from 42.9 (13.2) to 36.3 (14.3) (P < .001). Mean slow-wave sleep time increased from 41.3 (33.2) to 78.0 (61.2) minutes (P = .005). Changes in off-medication UPDRS scores were not significant, from 28.4 (10.3) to 26.2 (9.6).

Conclusion  Nocturnally administered sodium oxybate improved excessive daytime sleepiness and fatigue in PD.

Trial Registration  clinicaltrials.gov Identifier: NCT00641186

Parkinson disease (PD) is strongly associated with the following 2 broad categories of sleep abnormalities: excessive daytime sleepiness (EDS) and nocturnal sleep dysfunction. Excessive daytime sleepiness has been well demonstrated using the subjective Epworth Sleepiness Scale (ESS) and objective polysomnography (PSG), including multiple sleep latency testing. The consequences of EDS, however, are sometimes difficult to segregate clearly from fatigue, lethargy, and depression, all of which are also common in PD.

Excessive daytime sleepiness in PD has generally been associated with greater age, more advanced disease, and dopaminergic drug use.15 Therefore, both PD and its treatment can cause EDS. Nocturnal sleep in PD is also markedly abnormal. Documented problems include fragmented sleep with multiple arousals and/or full awakenings associated with rigidity, dystonia, tremor, pain, sialorrhea, and nocturia68; rapid eye movement sleep behavior disorder911; periodic limb movements12,13; restless legs syndrome14; and sleep apnea.15 Some of these may precede the motor symptoms of PD by many years. Intrinsic changes in sleep architecture are less marked but include reduced slow-wave sleep (SWS) and reduced sleep spindles.16,17 Although it seems intuitive, studies have not confirmed a correlation between nocturnal sleep dysfunction and EDS in PD.16,18

Relatively little therapeutic research has addressed these problems. Modafinil1921 has been demonstrated to have some benefit for EDS in patients with PD, although the improvement was modest. To our knowledge, no reported therapeutic studies have carefully evaluated a specific treatment for nocturnal sleep problems in the PD population.

Sodium oxybate (Xyrem; Jazz Pharmaceuticals, Inc) is a unique compound approved by the US Food and Drug Administration for the treatment of cataplexy and EDS in patients with narcolepsy.22,23 Owing to the potential for abuse, especially when mixed with alcohol (this is a salt of γ-hydroxybutyrate, the “date rape drug”), use of sodium oxybate is restricted through a central pharmacy registry. Sodium oxybate is a metabolite of γ-aminobutyric acid, although it may be an independent endogenous neurotransmitter, with a very short half-life and short clinical effect, usually 2.5 to 4.0 hours. Therefore, 2 doses are used to achieve a typical full night of sleep, one at initiation of sleep and the other 4 hours later. Polysomnographic studies show a consistent increase in SWS in subjects with normal sleep24 and in those with sleep abnormalities.25 We evaluated the use of sodium oxybate for EDS in subjects with PD in a multicenter, open-label, PSG study.

Subjects were recruited from the Baylor College of Medicine Parkinson Disease Center and Movement Disorder Clinic and Raleigh Neurology Associates. The protocol was approved by the Baylor College of Medicine Institutional Review Board and the Western Institutional Review Board. All subjects signed informed consent.

We enrolled subjects with PD, aged 30 to 75 years, with Hoehn and Yahr stages 1.5 to 4.0 during periods while practically defined off (“off”) medication, Mini-Mental State Examination scores of greater than 24, ESS scores of greater than 10, and a patient report of unsatisfactory sleep. This could include any sleep concern, but always resulted in some insomnia. The subjects could not be taking medications with known central nervous system–depressant properties and had been receiving stable PD medications for at least 30 days before and throughout the study. We excluded subjects with serious medical conditions, including renal insufficiency or congestive heart failure, depression (Beck Depression Inventory score, >16), or known sleep apnea or narcolepsy.

The subjects underwent a screening/acclimation PSG. They were subsequently excluded if they had more than mild sleep apnea (apnea/hypopnea index >15) and oxygen desaturation levels consistently below 90%. Obstructive apneas were scored as 10 seconds of more than 90% airflow reduction with continued respiratory effort. Obstructive hypopneas were scored as 10-second epochs of more than 30% airflow reduction associated with either a 3% oxygen desaturation or an electroencephalographic arousal.

Within 7 days, the subjects underwent the entry PSG. They returned to the clinic the following morning without taking their usual PD medications (off-medication state) and underwent assessment with the Unified Parkinson Disease Rating Scale (UPDRS). After taking their PD medications, they completed the Fatigue Severity Scale (FSS), Pittsburgh Sleep Quality Inventory (PSQI), the 36-Item Short Form Health Survey quality-of-life assessment, and the ESS (primary efficacy point). The subjects then started sodium oxybate therapy, 4.5 g per night, to be taken in 2 equally divided doses: 2.25 g (4.5 mL) at bedtime, and 2.25 g (4.5 mL) 2.5 to 4.0 hours later. They woke naturally or set an alarm for their second dose. A follow-up telephone call 1 week later reviewed medication adherence and any possible adverse effects. The subjects were examined after 2 weeks of therapy with reevaluations of the ESS score, vital signs, and adverse events. The dose was increased to 6 g per night, to be taken in 2 equally divided doses. After another follow-up telephone call and according to the clinical judgment of site investigators, the dose was increased weekly by 1.5-g increments to a maximum nightly dose of 9.0 g. In the event that adverse effects developed with the higher doses, the dose could be reduced to a tolerated level for the remainder of the trial. The final clinic visit (study day 56) included a final PSG, followed by an off-medication UPDRS evaluation, then a repeated battery of tests after PD medication therapy was restored. The subjects returned all unused drug.

The primary efficacy point was change in the ESS score (daytime sleepiness). Other measures of daytime symptoms (the FSS score) and nocturnal symptoms (the polysomnogram and PSQI) were secondary measures. Statistics included descriptive calculations and paired, 2-tailed t tests. Significance was set at P < .05. Study design, data management, database design, statistical analysis, and manuscript drafting were all performed by the primary investigator (W.G.O.), who maintains ownership of the data. The primary investigator received an Investigational New Drug exemption from the US Food and Drug Administration for the study. Unless otherwise specified, data are expressed as mean (SD).

Thirty-eight subjects with PD were enrolled to achieve 30 successful screenings. We excluded 8 subjects at screening secondary to sleep apnea criteria (n = 7) and depression (n = 1). Three subjects dropped out after randomization for dizziness (n = 3) and concurrent depression (n = 1); 2 of these dropped out before any follow-up data were collected and were therefore excluded from the efficacy analysis. The 6-week subjective sleep data in the third subject were included as the last observation carried forward.

The mean age of the 30 subjects (of whom 24 were men) was 61.5 (8.7) years, and the duration of PD was 8.6 (5.5) years (range, 1-25 years). The Hoehn a nd Yahr stages were 2.0 (n = 14), 2.5 (n = 11), and 3.0 (n = 5). Twenty-seven subjects were white, 2 were Hispanic, and 1 was Asian. The mean entry Mini-Mental State Examination score was 29.1 (1.3) (range, 25-30). All subjects were treated with a dopamine agonist without levodopa (n = 8), levodopa without a dopamine agonist (n = 3), or levodopa and a dopamine agonist (n = 19). Six of the subjects taking levodopa and a dopamine agonist also took a monoamine oxidase type B inhibitor; 10 subjects took a catechol-O-methyl-transferase inhibitor; and 11 subjects took amantadine hydrochloride.

The mean final dose of sodium oxybate was 7.8 (1.7) g per night. The final nightly doses were 3.0 g (n = 2), 4.5 g (n = 1), 6.0 g (n = 6), 7.5 g (n = 4), and 9.0 g (n = 17).

The ESS, PSQI, and FSS scores improved significantly. Changes in the 36-Item Short Form Health Survey score were not significant (Table 1).

Slow-wave sleep time increased in 27 subjects, (P = .005) (Table 2), whereas rapid eye movement sleep time was modestly reduced. Total apneas mildly increased, but the mean and maximum oxygen desaturation values did not change. No other PSG features changed significantly. Increased SWS time (in minutes) did not correlate with reduced ESS scores (r = 0.10; P = .09).

Table Graphic Jump LocationTable 2. PSG Results in 27 Subjects With Parkinson Disease

Mean off-medication morning UPDRS motor scores were stable in 27 subjects, changing from 28.4 (10.3) to 26.2 (9.6) (NS). No subject subjectively reported that there was any meaningful change in his or her motor symptoms.

Adverse events probably or definitely related to the drug included dizziness (n = 3), nocturia/enuresis (n = 3), nausea (n = 1), daytime sleepiness (n = 1), reduced alertness (n = 1), and rebound morning tremor (n = 1). One subject reported increased morning tremor. Additional adverse events that were considered not related to the study drug included constipation (n = 1),1 delusions (n = 1),1 and, in a single subject, bradycardia, anxiety, depression, and edema. Twenty-two of 30 subjects (73%) reported no adverse events.

At the study's conclusion, 18 of 27 subjects (67%) completed application forms for the central distribution pharmacy to continue sodium oxybate therapy.

Overall, nocturnally administered sodium oxybate was well tolerated, increased SWS, and improved subjective nighttime and daytime sleep problems and daytime fatigue in subjects with PD. Improvements in ESS were similar to or better than those found when the drug is used as therapy for narcolepsy.22,23 The PD motor features were unchanged.

The mechanism by which sodium oxybate improves EDS is not known. It is known to increase SWS26; however, our study did not show a significant correlation between improved SWS and ESS scores. The SWS change in our study compared only 2 nights and is variable. In addition, our study was not powered in any way to specifically address this question, so we cannot entirely exclude the possibility of SWS variations. Sodium oxybate has also been postulated to improve EDS by decreasing sleep fragmentation in narcolepsy trials25; however, we found improved EDS without reduced awakenings in this PD study. Furthermore, deep brain stimulation of the subthalamic nucleus improves sleep fragmentation associated with nocturnal motor abnormalities in subjects with PD but has not improved EDS in a small number of studied subjects.27

As an alternative explanation, nocturnal sodium oxybate use may result in the rebound vigilant state observed during the day after nighttime administration. The short half-life of sodium oxybate allows for complete washout by the morning, when increased release of stored dopamine and norepinephrine may occur and contribute to the observed enhanced wakefulness.28,29 Dopamine release is actually inhibited while the drug is active, which may account for the nonsignificant increase in periodic limb movements.30 We did not believe that the slight increase in apnea was clinically meaningful, but this needs to be monitored. There was no evidence of abuse.

This study has all of the shortcomings of any open-label trial. We intentionally designed broad inclusion criteria and did not exclude subjects with restless legs syndrome or rapid eye movement sleep behavior disorder, neither of which appears to affect EDS in PD.14 Given the robust efficacy and good tolerability of the study drug and the lack of effective treatment for EDS in patients with PD, we believe that controlled trials using objective measures of daytime sleepiness are justified.

Correspondence: William G. Ondo, MD, Department of Neurology, Baylor College of Medicine, 6550 Fannin, Ste 1801, Houston, TX 77030 (wondo@bcm.tmc.edu).

Accepted for Publication: April 13, 2008.

Author Contributions:Study concept and design: Ondo. Acquisition of data: Ondo, Perkins, Swick, Hull, Jimenez, Garris, and Pardi. Analysis and interpretation of data: Ondo. Drafting of the manuscript: Ondo. Critical revision of the manuscript for important intellectual content: Ondo, Perkins, Swick, Hull, Jimenez, Garris, and Pardi. Statistical analysis: Ondo. Administrative, technical, and material support: Ondo, Perkins, Swick, Hull, Jimenez, Garris, and Pardi. Obtained funding: Ondo. Study supervision: Ondo.

Financial Disclosure: Dr Ondo has received research grant support from Jazz Pharmaceuticals, Inc; is a member of the speaker's bureau for Allergan, Boehringer Ingelheim, GlaxoSmithKline, TEVA, UCB Pharma, and Valeant; and has received research funding from Allergan, Boehringer Ingelheim, Forest, Schwartz Pharmaceuticals, and Valeant. Dr Perkins is a member of the speaker's bureau for Boehringer Ingelheim, Cephalon, GlaxoSmithKline, and Jazz Pharmaceuticals, Inc; and has received research support and has served on the professional advisory board for Jazz Pharmaceuticals, Inc. Dr Swick is a member of the speaker's bureau for Boehringer Ingelheim, Cephalon, GlaxoSmithKline, Jazz Pharmaceuticals, Inc, Sanofi-Aventis, Sepracor, and Takeda Pharmaceuticals; has received research support from Cephalon, GlaxoSmithKline, Jazz Pharmaceuticals, Inc, Merck, Pfizer, Sanofi-Aventis, Somazon, and Takeda; and has served on the professional advisory board for Jazz Pharmaceuticals, Inc. Mr Pardi is an employee of Jazz Pharmaceuticals, Inc, and provided assistance in the analysis of the data and the review of the manuscript.

Funding/Support: This study was supported by an unrestricted research grant and supply of the study drug from Jazz Pharmaceuticals, Inc.

Arnulf  I Excessive daytime sleepiness in parkinsonism. Sleep Med Rev 2005;9 (3) 185- 200
PubMed Link to Article
Hobson  DELang  AEMartin  WRRazmy  ARivest  JFleming  J Excessive daytime sleepiness and sudden-onset sleep in Parkinson disease: a survey by the Canadian Movement Disorders Group. JAMA 2002;287 (4) 455- 463
PubMed Link to Article
Ondo  WGDat Vuong  KKhan  HAtassi  FKwak  CJankovic  J Daytime sleepiness and other sleep disorders in Parkinson's disease. Neurology 2001;57 (8) 1392- 1396
PubMed Link to Article
Tandberg  ELarsen  JPKarlsen  K Excessive daytime sleepiness and sleep benefit in Parkinson's disease: a community-based study. Mov Disord 1999;14 (6) 922- 927
PubMed Link to Article
Rye  DB The two faces of Eve: dopamine's modulation of wakefulness and sleep. Neurology 2004;63 (8) ((suppl 3)) S2- S7
PubMed Link to Article
Askenasy  JJYahr  MD Parkinsonian tremor loses its alternating aspect during non-REM sleep and is inhibited by REM sleep. J Neurol Neurosurg Psychiatry 1990;53 (9) 749- 753
PubMed Link to Article
Lees  AJBlackburn  NACampbell  VL The nighttime problems of Parkinson's disease. Clin Neuropharmacol 1988;11 (6) 512- 519
PubMed Link to Article
van Hilten  BHoff  JIMiddelkoop  HA  et al.  Sleep disruption in Parkinson's disease: assessment by continuous activity monitoring. Arch Neurol 1994;51 (9) 922- 928
PubMed Link to Article
Boeve  BFSilber  MHParisi  JE  et al.  Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology 2003;61 (1) 40- 45
PubMed Link to Article
Comella  CLNardine  TMDiederich  NJStebbins  GT Sleep-related violence, injury, and REM sleep behavior disorder in Parkinson's disease. Neurology 1998;51 (2) 526- 529
PubMed Link to Article
Wetter  TCTrenkwalder  CGershanik  OHögl  B Polysomnographic measures in Parkinson's disease: a comparison between patients with and without REM sleep disturbances. Wien Klin Wochenschr 2001;113 (7-8) 249- 253
PubMed
Högl  BRothdach  AWetter  TCTrenkwalder  C The effect of cabergoline on sleep, periodic leg movements in sleep, and early morning motor function in patients with Parkinson's disease. Neuropsychopharmacology 2003;28 (10) 1866- 1870
PubMed Link to Article
Wetter  TCCollado-Seidel  VPollmacher  TYassouridis  ATrenkwalder  C Sleep and periodic leg movement patterns in drug-free patients with Parkinson's disease and multiple system atrophy. Sleep 2000;23 (3) 361- 367
PubMed
Ondo  WGVuong  KJankovic  J Exploring the relationship between Parkinson disease and restless legs syndrome. Arch Neurol 2002;59 (3) 421- 424
PubMed Link to Article
Diederich  NJVaillant  MLeischen  M  et al.  Sleep apnea syndrome in Parkinson's disease: a case-control study in 49 patients. Mov Disord 2005;20 (11) 1413- 1418
PubMed Link to Article
Rye  DBBliwise  DDihenia  BGurecki  P Daytime sleepiness in Parkinson's disease. J Sleep Res 2000;9 (1) 63- 69
PubMed Link to Article
Rye  DBJankovic  J Emerging views of dopamine in modulating sleep/wake state from an unlikely source: PD. Neurology 2002;58 (3) 341- 346
PubMed Link to Article
Arnulf  IKonofal  EMerino-Andreu  M  et al.  Parkinson's disease and sleepiness: an integral part of PD. Neurology 2002;58 (7) 1019- 1024
PubMed Link to Article
Adler  CHCaviness  JNHentz  JGLind  MTiede  J Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease. Mov Disord 2003;18 (3) 287- 293
PubMed Link to Article
Högl  BSaletu  MBrandauer  E  et al.  Modafinil for the treatment of daytime sleepiness in Parkinson's disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial. Sleep 2002;25 (8) 905- 909
PubMed
Ondo  WGFayle  RAtassi  FJankovic  J Modafinil for daytime somnolence in Parkinson's disease: double blind, placebo controlled parallel trial. J Neurol Neurosurg Psychiatry 2005;76 (12) 1636- 1639
PubMed Link to Article
U.S. Xyrem Multicenter Study Group, A 12-month, open-label, multicenter extension trial of orally administered sodium oxybate for the treatment of narcolepsy. Sleep 2003;26 (1) 31- 35
PubMed
Black  JHoughton  WC Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep 2006;29 (7) 939- 946
PubMed
Lapierre  OMontplaisir  JLamarre  MBedard  MA The effect of gamma-hydroxybutyrate on nocturnal and diurnal sleep of normal subjects: further considerations on REM sleep-triggering mechanisms. Sleep 1990;13 (1) 24- 30
PubMed
Mamelak  MBlack  JMontplaisir  JRistanovic  R A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy. Sleep 2004;27 (7) 1327- 1334
PubMed
Boero  JADuntley  SPJennifer  M Sodium oxybate improves slow wave sleep and daytime sleepiness in narcolepsy [abstract]. Sleep 2006;29 ((suppl)) A229
Lyons  KEPahwa  R Effects of bilateral subthalamic nucleus stimulation on sleep, daytime sleepiness, and early morning dystonia in patients with Parkinson disease. J Neurosurg 2006;104 (4) 502- 505
PubMed Link to Article
Hechler  VGobaille  SBourguignon  JJMaitre  M Extracellular events induced by gamma-hydroxybutyrate in striatum: a microdialysis study. J Neurochem 1991;56 (3) 938- 944
PubMed Link to Article
Szabo  STGold  MSGoldberger  BABlier  P Effects of sustained gamma-hydroxybutyrate treatments on spontaneous and evoked firing activity of locus coeruleus norepinephrine neurons. Biol Psychiatry 2004;55 (9) 934- 939
PubMed Link to Article
Abril  BCarlander  BTouchon  JDauvilliers  Y Restless legs syndrome in narcolepsy: a side effect of sodium oxybate? Sleep Med 2007;8 (2) 181- 183
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 2. PSG Results in 27 Subjects With Parkinson Disease

References

Arnulf  I Excessive daytime sleepiness in parkinsonism. Sleep Med Rev 2005;9 (3) 185- 200
PubMed Link to Article
Hobson  DELang  AEMartin  WRRazmy  ARivest  JFleming  J Excessive daytime sleepiness and sudden-onset sleep in Parkinson disease: a survey by the Canadian Movement Disorders Group. JAMA 2002;287 (4) 455- 463
PubMed Link to Article
Ondo  WGDat Vuong  KKhan  HAtassi  FKwak  CJankovic  J Daytime sleepiness and other sleep disorders in Parkinson's disease. Neurology 2001;57 (8) 1392- 1396
PubMed Link to Article
Tandberg  ELarsen  JPKarlsen  K Excessive daytime sleepiness and sleep benefit in Parkinson's disease: a community-based study. Mov Disord 1999;14 (6) 922- 927
PubMed Link to Article
Rye  DB The two faces of Eve: dopamine's modulation of wakefulness and sleep. Neurology 2004;63 (8) ((suppl 3)) S2- S7
PubMed Link to Article
Askenasy  JJYahr  MD Parkinsonian tremor loses its alternating aspect during non-REM sleep and is inhibited by REM sleep. J Neurol Neurosurg Psychiatry 1990;53 (9) 749- 753
PubMed Link to Article
Lees  AJBlackburn  NACampbell  VL The nighttime problems of Parkinson's disease. Clin Neuropharmacol 1988;11 (6) 512- 519
PubMed Link to Article
van Hilten  BHoff  JIMiddelkoop  HA  et al.  Sleep disruption in Parkinson's disease: assessment by continuous activity monitoring. Arch Neurol 1994;51 (9) 922- 928
PubMed Link to Article
Boeve  BFSilber  MHParisi  JE  et al.  Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology 2003;61 (1) 40- 45
PubMed Link to Article
Comella  CLNardine  TMDiederich  NJStebbins  GT Sleep-related violence, injury, and REM sleep behavior disorder in Parkinson's disease. Neurology 1998;51 (2) 526- 529
PubMed Link to Article
Wetter  TCTrenkwalder  CGershanik  OHögl  B Polysomnographic measures in Parkinson's disease: a comparison between patients with and without REM sleep disturbances. Wien Klin Wochenschr 2001;113 (7-8) 249- 253
PubMed
Högl  BRothdach  AWetter  TCTrenkwalder  C The effect of cabergoline on sleep, periodic leg movements in sleep, and early morning motor function in patients with Parkinson's disease. Neuropsychopharmacology 2003;28 (10) 1866- 1870
PubMed Link to Article
Wetter  TCCollado-Seidel  VPollmacher  TYassouridis  ATrenkwalder  C Sleep and periodic leg movement patterns in drug-free patients with Parkinson's disease and multiple system atrophy. Sleep 2000;23 (3) 361- 367
PubMed
Ondo  WGVuong  KJankovic  J Exploring the relationship between Parkinson disease and restless legs syndrome. Arch Neurol 2002;59 (3) 421- 424
PubMed Link to Article
Diederich  NJVaillant  MLeischen  M  et al.  Sleep apnea syndrome in Parkinson's disease: a case-control study in 49 patients. Mov Disord 2005;20 (11) 1413- 1418
PubMed Link to Article
Rye  DBBliwise  DDihenia  BGurecki  P Daytime sleepiness in Parkinson's disease. J Sleep Res 2000;9 (1) 63- 69
PubMed Link to Article
Rye  DBJankovic  J Emerging views of dopamine in modulating sleep/wake state from an unlikely source: PD. Neurology 2002;58 (3) 341- 346
PubMed Link to Article
Arnulf  IKonofal  EMerino-Andreu  M  et al.  Parkinson's disease and sleepiness: an integral part of PD. Neurology 2002;58 (7) 1019- 1024
PubMed Link to Article
Adler  CHCaviness  JNHentz  JGLind  MTiede  J Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease. Mov Disord 2003;18 (3) 287- 293
PubMed Link to Article
Högl  BSaletu  MBrandauer  E  et al.  Modafinil for the treatment of daytime sleepiness in Parkinson's disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial. Sleep 2002;25 (8) 905- 909
PubMed
Ondo  WGFayle  RAtassi  FJankovic  J Modafinil for daytime somnolence in Parkinson's disease: double blind, placebo controlled parallel trial. J Neurol Neurosurg Psychiatry 2005;76 (12) 1636- 1639
PubMed Link to Article
U.S. Xyrem Multicenter Study Group, A 12-month, open-label, multicenter extension trial of orally administered sodium oxybate for the treatment of narcolepsy. Sleep 2003;26 (1) 31- 35
PubMed
Black  JHoughton  WC Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep 2006;29 (7) 939- 946
PubMed
Lapierre  OMontplaisir  JLamarre  MBedard  MA The effect of gamma-hydroxybutyrate on nocturnal and diurnal sleep of normal subjects: further considerations on REM sleep-triggering mechanisms. Sleep 1990;13 (1) 24- 30
PubMed
Mamelak  MBlack  JMontplaisir  JRistanovic  R A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy. Sleep 2004;27 (7) 1327- 1334
PubMed
Boero  JADuntley  SPJennifer  M Sodium oxybate improves slow wave sleep and daytime sleepiness in narcolepsy [abstract]. Sleep 2006;29 ((suppl)) A229
Lyons  KEPahwa  R Effects of bilateral subthalamic nucleus stimulation on sleep, daytime sleepiness, and early morning dystonia in patients with Parkinson disease. J Neurosurg 2006;104 (4) 502- 505
PubMed Link to Article
Hechler  VGobaille  SBourguignon  JJMaitre  M Extracellular events induced by gamma-hydroxybutyrate in striatum: a microdialysis study. J Neurochem 1991;56 (3) 938- 944
PubMed Link to Article
Szabo  STGold  MSGoldberger  BABlier  P Effects of sustained gamma-hydroxybutyrate treatments on spontaneous and evoked firing activity of locus coeruleus norepinephrine neurons. Biol Psychiatry 2004;55 (9) 934- 939
PubMed Link to Article
Abril  BCarlander  BTouchon  JDauvilliers  Y Restless legs syndrome in narcolepsy: a side effect of sodium oxybate? Sleep Med 2007;8 (2) 181- 183
PubMed Link to Article

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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
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