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NARCOLEPSY
A 12-month, Open-Label, Multicenter Extension Trial of Orally Administered Sodium Oxybate for the Treatment of Narcolepsy
U.S. Xyrem Multicenter Study Group
Objectives: To evaluate the long-term safety and efficacy of nightly sodium oxybate for the treatment of narcolepsy.
Design: A multicenter, 12-month, open-label trial.
Participants: 118 narcolepsy patients previously enrolled in a 4-week
double-blind sodium oxybate trial.
Interventions: Patients were administered 6 g sodium oxybate nightly,
taken in equally divided doses at bedtime and 2.5 to 4 hours later. The
study protocol permitted the dose to be increased or decreased in 1.5-g
increments at 2-week intervals based on efficacy response or adverse
experiences but staying within the range of 3 to 9 g nightly.
Measures: Narcolepsy symptoms and adverse events were recorded in
daily diaries. Safety measures included physical and laboratory examinations repeated at 6 and 12 months. The primary efficacy measure was
the change in weekly cataplexy attacks from baseline. Secondary measures included daytime sleepiness using the Epworth Sleepiness Scale
(ESS), inadvertent naps/sleep attacks, nighttime awakenings, and the
overall change in disease severity as rated by the investigators (Clinical
Global Impression of Change; CGI-c).
INTRODUCTION
NARCOLEPSY IS A CHRONIC, DEBILITATING CENTRAL NERVOUS SYSTEM ILLNESS. In its classic form it is characterized by
excessive daytime sleepiness, inadvertent naps or sleep attacks, fragmented or disturbed nighttime sleep, cataplexy, sleep paralysis, and hypnagogic hallucinations.1 These symptoms can be very disruptive for the
narcoleptic, often leading to an increased incidence of accidents, poor
interpersonal relationships, and a generally diminished quality of life.2,3
Narcolepsy is estimated to affect 140,000 people in the United States.4,5
The primary cause remains unknown; however, recent human and animal data have suggested that the pathophysiology of narcolepsy involves
the neuropeptide hypocretin (orexin).6 The cell bodies of hypocretincontaining neurons are found in the dorsal, lateral, and posterior
hypothalamus where they project to various parts of the brain, particularly nuclei involved in the regulation of sleep and wakefulness. In animals, disruption of hypocretin neurotransmission, at either the neurotransmitter7 or receptor level,8 results in the clinical presentation of narDisclosure Statement
None of the U.S. Xyrem Multicenter Study Group Members have any significant financial involvement in any organization with a direct commercial interest
in the subject discussed in the submitted manuscript.
The research involved in this manuscript involves the use of an Investigational
New Drug.
This study was sponsored by Orphan Medical, Inc., Minnetonka, MN.
Submitted for publication December 2001
Accepted for publication July 2002
Address correspondence to: H. Cook, Orphan Medical, Inc., 13911 Ridgedale
Drive, Suite 250, Minnetonka, MN 55305, Ph: 888-867-7426, Fax: 952-5419209, Email: [email protected]
SLEEP, Vol. 26, No. 1, 2003
Results: Sodium oxybate, in doses of 3 to 9 g nightly, produced overall
improvements in narcolepsy symptoms, which were significant at 4 weeks
and maximal after 8 weeks. Reported improvements included a significant decrease in frequency of cataplexy attacks (p < 0.001); diminished
daytime sleepiness (p < 0.001); and patient descriptions of nocturnal
sleep quality, level of alertness, and ability to concentrate (for each p <
0.001). Adverse events were generally mild and patients showed no evidence of tolerance.
Conclusion: Sodium oxybate is an effective and well-tolerated treatment
for narcolepsy.
Keywords: Narcolepsy, cataplexy, sodium oxybate, gamma-hydroxybutyrate
Citation: U.S. Xyrem Multicenter Study Group. A 12-month, openlabel, multi-center extension trial of orally administered sodium oxybate
for the treatment of narcolepsy. SLEEP 2003;1:31-5.
colepsy. In addition, hypocretin was undetectable in the cerebrospinal
fluid in 37 of 42 (88%) of patients with narcolepsy,9 and an 85% to 95%
decrease in hypocretin-containing cells has been demonstrated in the
postmortem examination of brains from narcoleptic patients.10
The possible therapeutic properties of sodium oxybate (gammahydroxybutyrate; GHB) in humans were first suggested 40 years ago.11
Since then, numerous studies have explored the potential clinical uses of
sodium oxybate, including the treatment of narcolepsy.12-18 These studies demonstrated that sodium oxybate produces clinical improvement in
cataplexy and other symptoms related to narcolepsy. These results have
also established an acceptable safety profile with a lack of tolerance
when used long-term for the treatment of narcolepsy.19
Recently, a prospective, randomized, double-blind, parallel-group,
multicenter trial revealed that 6 g and 9 g of sodium oxybate, taken in
divided doses immediately before bedtime and repeated 2.5 to 4 hours
later, produced significant clinical improvement of narcolepsy symptoms. At nightly doses of 6 g and 9 g, statistically significant improvements were seen in the reported number of weekly cataplexy attacks and
inadvertent daytime naps. At the 9 g dose, there were also significant
improvements in nocturnal awakenings, daytime sleepiness, and the
overall investigator assessment of disease severitity. This 4-week study
found sodium oxybate to be generally well tolerated.20 The present
study is an open-label, long-term, multicenter extension of the above
trial.
Study Objectives
The objectives of this study were to evaluate the safety and efficacy
of sodium oxybate when administered in narcoleptic patients for 12
months at doses of 3, 4.5, 6, 7.5, or 9 g nightly. Protocol amendments
allowed patients to continue the study for up to 24 months. Measures of
safety included adverse experiences, clinical laboratory analyses, vitalsign measurements, and general physical examination. Measurements
of efficacy included reports of the change in the frequency of cataplexy
31 Orally Administered Sodium Oxybate—U.S. Xyrem Multicenter Study Group
attacks, daytime sleepiness, frequency and duration of inadvertent naps
or sleep attacks, the number of nocturnal sleep awakenings, total amount
of sleep, incidence of hypnagogic hallucinations, and sleep paralysis by
the study participants in daily diaries. It also included the assessment of
change in overall disease severity by the investigators. This assessment
was compared to disease severity at baseline following a washout of
anticataplectic medications but while remaining on stable doses of stimulants.
METHODS
Subjects
This study included patients who were 18 years of age or older and
expressed a willingness to complete the entire study. Diagnostic criteria included a valid polysomnogram within the previous 5 years and a
current diagnosis of narcolepsy for at least 6 months based on criteria
established by the American Academy of Sleep Medicine. This study
excluded patients who were receiving investigational therapy other than
sodium oxybate/placebo in the 30 days prior to the study; diagnosed with
sleep apnea or had any other cause of daytime sleepiness; taking hypnotics, anxiolytics, antidepressants, antihistamines, clonidine, or anticonvulsants; at risk of pregnancy; experiencing unstable disease states or
any history of seizure disorder; known to have a history of psychiatric
disorders that might prevent them from completing the study; at risk of
substance abuse; shown to have serum creatinine greater than 2.0
mg/dL, aminotransferase or serum bilirubin values more than twice or
1.5 times normal, respectively; shown to have an abnormal electrocardiogram or history of recent myocardial infarction; taking any medication for narcolepsy other than a stable dose of stimulant for treating
excessive daytime sleepiness; working in an occupation requiring variable or routine night shifts.
Treatments
Prior to receiving trial medication in the initial 4-week double-blind
study, patients discontinued any hypnotic medications and, over a 4-
week period, gradually withdrew from all anticataplectic medications.
This was followed by a washout period of 5 days or five times the halflife of the discontinued anticataplectic medication up to 28 days,
whichever was longer. During a subsequent 14 to 21-day baseline period, patients recorded the frequency of cataplexy episodes and other
symptoms of narcolepsy in daily patient diaries. A minimum of 3 cataplexy attacks per week during the last 2 weeks of the baseline period
were required to enter the double-blind treatment study.
Following a 3 to 5-day washout period of sodium oxybate at the end
of the previous double-blind trial, 118 patients elected to enroll in the
current 12-month study. Patients began treatment at 6 g of sodium oxybate nightly taken in two equally divided doses. The first dose was taken
at bedtime immediately upon retiring and the second dose 2.5 to 4 hours
later. Patients were encouraged to use an alarm clock to ensure waking
for the second nightly dose of sodium oxybate. Based on clinical efficacy or adverse experiences, the investigator could choose to decrease
the total nightly dose to 3 g or 4.5 g or increase it to 7.5 g or 9 g. Dose
adjustments were recommended at 2-week intervals in 1.5 g increments.
Sodium oxybate was initially dispensed in powder form to be dissolved
in water. However, the powder was replaced following the development
of a liquid sodium oxybate formulation. These two forms of study medication were determined to be bioequivalent, and no change in patient
response to the liquid formulation was noted.
Because of the long-term nature of the trial, it was deemed unethical
to withhold stimulant medications. Patients were permitted to continue
on stimulant medications but were required to remain on a stable dose
throughout the trial. Thus, any improvements in patients’ condition were
likely to be due to nightly sodium oxybate therapy. Of the 118 patients
initially enrolled in the study, 104 (88.1%) were taking concomitant
stimulant medications, consisting of methylphenidate (N=52),
amphetamines (N=44), pemoline (N=21), and mazindol (N=1)(some
patients were taking more than one type of stimulant drug).
The investigators evaluated patients every 2 weeks during the first
month of the study, then every 2 months until month 12. Patients’ vital
signs were measured at each clinic visit. The baseline physical and neurological examinations, clinical laboratory tests and ECG were repeated
at 6 and 12 months. Compliance with study medication was assessed by
comparing the amount of medication remaining at each visit with the
amount predicted to remain if the patient were compliant.
Daytime subjective somnolence was assessed using the Epworth
Sleepiness Scale (ESS). The overall severity of each patient’s disease
was estimated using the Clinical Global Impression of Severity (CGI-s)
at baseline and prior to sodium oxybate treatment in the previous blinded study. Subsequent change in disease severity was measured with the
Clinical Global Impression of Change (CGI-c) administered at each clinic visit. Possible CGI-c assessments were Very Much Improved, Much
Improved, Minimally Improved, No Change, Minimally Worse, or Much
Worse.
Figure 1—Mean percent change in total number of cataplexy attacks per week following
the double-blind trial for all doses. This change was significant for all doses at one month
(p < 0.001). This was also true for individual doses except 3 and 4.5 g where the change in
cataplexy became significant after 2 months. The variability seen during the first two
months of treatment was due to the change in patient doses while undergoing dose titration,
which diminished as the study proceeded.
Table 1—Number of patients in each sodium oxybate dose group after 12 months of therapy.
DOSE
N
%
3g
16
13.7
4.5 g
11
9.4
SLEEP, Vol. 26, No. 1, 2003
6g
42
35.9
7.5 g
13
11.1
9g
35
29.9
Figure 2—Combined median change from baseline Epworth Sleepiness Scale per month
for all doses following the double-blind trial. This change was significant after month 1 (*
denotes p < 0.001) compared to a median score of 18 prior to entry in the previous 4-week
double-blind study.
32 Orally Administered Sodium Oxybate—U.S. Xyrem Multicenter Study Group
During the 12 months of the study, patients recorded clinical response
information in personal diaries on a daily basis. The daily patient diaries
were the same as those used in the previous blinded study and included
detailed descriptions of the symptoms to be recorded should they occur.
Patients were instructed on the use of diaries by study coordinators and
investigators. Patient diary information collected during the trial included the frequency of cataplexy events, number and duration of nocturnal
awakenings, total amount of sleep each night, the number of hypnagogic hallucinations, and the incidence of sleep paralysis. In addition,
diaries were used to document the occurrence of all adverse events.
Patients were encouraged to utilize the daily diary every morning and
evening. Thus, daily diary recordings were made in a manner consistent
with the previous double-blind trial.20
Statistical Analysis
Each patient was assigned to a treatment group by calculating the
average dose used over the course of the study and rounding to the nearest dose category, i.e., 3, 4.5, 6, 7.5 or 9 g. Treatment group comparisons
were made for the frequency of cataplexy attacks, the primary efficacy
measure. These comparisons were based on the analysis of covariance
and the use of log transformation of the data prior to analysis when the
criteria for normal data distribution were not met. Within-group and allpatient analyses were performed using Wilcoxon Sign Rank Test. For
secondary efficacy variables that were continuous measures, ANCOVA
was used to examine overall treatment effects. Within-group comparisons were performed using paired t-tests. For dichotomous efficacy
measures, Fisher’s Exact Test was used to examine overall treatment
effects. Missing data were excluded from calculations. Patients who
discontinued the study were included in all analyses up to the time of
their withdrawal. Although patients were permitted to continue the
study beyond the originally planned 12 months, only data from the first
12 months of the study were analyzed.
accordance with the ethical principles delineated in the Helsinki Declaration of 1975, as revised in 1997.
RESULTS
One hundred eighteen patients were initially enrolled in this study.
One patient failed to return diary information and was excluded from the
analysis. Of the remaining patients, the mean age was 43.4 years (range
18 – 79); 51 were male and 66 were female; 95 (81.2%) patients completed 3 months of therapy, 87 (74.4%) patients completed 6 months,
and 80 (68.4%) patients completed the 12-month protocol. Reasons for
failing to complete the study included adverse events (11), withdrawn
consent (7), noncompliance (5), lost to follow-up (5), and other reasons
not directly related to the study, such as geographic relocation (9).
Of the 117 patients included in this open-label extension trial, 86
(73.5%) reached a stabilized dose defined as no change in dose for at
least 3 consecutive visits. The mean time to stabilization for these
patients was 3.38 weeks. The last reported dose for each patient entered
into the study is shown in Table 1.
EFFICACY
Cataplexy
The number of cataplexy events recorded in patient diaries was compared to that recorded at baseline from the 4-week double-blind trial.
There was a positive effect across all treatment groups. This effect was
significant at one month, decreasing by an average of 23.65 cataplexy
attacks per week (p < 0.001), and further declining by an average of
35.48 attacks at the end of the study period. These data are presented in
Figure 1 and are expressed as dose groups. No attempts were made to
assess the severity of cataplexy attacks during the trial.
Daytime Sleepiness
Ethics statement
During the baseline phase of the previous 4-week double-blind trial,
the mean score of the ESS was 18. In the present study, there was a significant improvement in daytime sleepiness, adjunctive to that achieved
by stimulants alone. This was significant for all treatment groups at 1
month except for the 4.5 g dose group, due to the small
number of patients (N = 6). The overall improvement
Table 2—Adverse events occurring in during the initial 12 months of the study. Incidence of most frequently
was maximal after 2 months (p < 0.001) and significant
reported (=10%) adverse events through 12 months by body system, COSTART term, and average treatment
across all doses, representing an approximately 30%
group. Each adverse event is counted only once per patient. Only dizziness, dream abnormality, cough, pharyndecrease in mean score. This response was maintained
gitis occurred at a significant level across treatment groups (p < 0.05).
for the remainder of the study period. Data for 12
Body System
TOTAL
3g
4.5 g
6g
7.5 g
9g
p-value
months, showing the combined median change from
COSTART Term
(N = 117) (N = 15)
(N = 20)
(N = 37)
(N = 25)
(N = 20)
baseline ESS scores, are displayed in Figure 2.
The Institutional Review Board for each of the 15 trial centers
approved the protocol, and written informed consent was obtained from
each patient prior to initiation of the study. This study was conducted in
Body as a Whole
Asthenia
Flu syndrome
Headache
Infection, viral
Injury, accidental
Pain
Digestive
Diarrhea
Dyspepsia
Nausea
Nervous
Confusion
Depression
Dizziness
Dream abnormality
Nervousness
Sleep disturbance
Somnolence
Respiratory
Cough
Pharyngitis
Sinusitis
Urogenital
Incontinence, urine
19 (16.2%)
17 (14.5%)
39 (33.3%)
32 (27.4%)
20 (17.1%)
30 (25.6%)
3 (20.0%)
3 (20.0%)
9 (60.0%)
2 (13.3%)
1 (6.7%)
6 (40.0%)
4 (20.0%) 6 (16.2%) 4 (16.0%)
3 (15.0%) 5 (13.5%) 3 (12.0%)
5 (25.0%) 10 (27.0%) 11 (44.0%)
6 (30.0%) 12 (32.4%) 7 (28.0%)
5 (25.0%) 8 (21.6%) 4 (16.0%)
5 (25.0%) 8 (21.6%) 8 (32.0%)
2 (10.0%)
3 (15.0%)
4 (20.0%)
5 (25.0%)
2 (10.0%)
3 (15.0%)
p=0.950
p=0.971
p=0.059
p=0.732
p=0.608
p=0.474
14 (12.0%) 3 (20.0%)
12 (10.3%) 4 (26.7%)
33 (28.2%) 7 (47.7%)
3 (15.0%) 2 (5.4%) 3 (12.0%)
2 (10.0%) 3 (8.1%)
2 (8.0%)
7 (35.5%) 10 (27.0%) 5 (20.0%)
3 (15.0%)
1 (5.0%)
4 (20.0%)
p=0.524
p=0.355
p=0.412
13 (11.1%)
12 (10.3%)
31 (26.5%)
12 (10.3%)
17 (14.5%)
11 (9.4%)
23 (19.7%)
2 (13.3%) 3 (15.0%)
0 (0.0%) 2 (10.0%)
6 (40.0%) 11 (55.0%)
0 (0.0%) 6 (30.0%)
4 (26.7%) 5 (25.0%)
2 (13.3%) 3 (15.0%)
5 (33.3%) 7 (35.0%)
5 (13.5%)
3 (8.1%)
8 (21.6%)
2 (5.4%)
4 (10.8%)
3 (8.1%)
6 (16.2%)
2 (8.0%)
5 (20.0%)
4 (16.0%)
3 (12.0%)
2 (8.0%)
1 (4.0%)
4(16.0%)
1 (5.0%)
2 (10.0%)
2 (10.0%)
1 (5.0%)
2 (10.0%)
2 (10.0%)
1 (5.0%)
p=0.859
p=0.388
p=0.015
p=0.047
p=0.348
p=0.750
p=0.126
10 (8.5%) 4 (26.7%)
14 (12.0%) 5 (33.3%)
13 (11.1%) 4 (26.7%)
3 (15.0%)
4 (20.0%)
2 (10.0%)
3 (8.1%)
3 (8.1%)
3 (8.1%)
0 (0.0%)
1 (4.0%)
3 (12.0%)
0 (0.0%)
1 (5.0%)
1 (5.0%)
p=0.018
p=0.048
p=0.382
10 (8.5%)
0 (0.0%)
1 (2.7%)
4 (16.0%)
3 (15.0%)
p=0.077
SLEEP, Vol. 26, No. 1, 2003
2 (13.3%)
Clinical Global Impressions of Change
The CGI-c is a clinical measure based on the clinical
investigator’s overall impression of the change in the
patient’s condition compared to the Clinical Global
Impression of Severity established at baseline. Approximately 80% of patients were determined to have a positive response to treatment after 2 months, being categorized as Much Improved or Very Much Improved by the
investigators. This positive response was maintained
during the course of the study and is graphically presented in Figure 3.
Other Parameters
Other improvements reported by patients in daily
diaries included patient descriptions of nocturnal sleep
quality, level of alertness, and ability to concentrate
adjunctive to that achieved by stimulants alone (for each
33 Orally Administered Sodium Oxybate—U.S. Xyrem Multicenter Study Group
p<0.001).
While not reaching statistical significance, there was also a substantial decrease in the number and duration of inadvertent naps or sleep
attacks over the course of the study. Compared to baseline values, the
change in the total number of daily sleep attacks (SD) was -0.77 (1.28)
after 1 month of treatment and -1.03 (1.29) after 12 months; the change
in the mean duration of sleep attacks (SD) was -20.27 min (39.0) at 1
month and -29.64 min (47.74) at 12 months. There were similar decreases in the number and duration of planned naps and nighttime awakenings
over the course of the study although the total duration of nightly sleep
remained unchanged (data not shown).
Among the 102 (87.2%) patients reporting hypnagogic hallucinations
and 103 (88.0%) reporting sleep paralysis at baseline, there was a nonsignificant decrease in the frequency of episodes of both phenomena that
became evident after 1 month and continued over the duration of the
study. The change from baseline (SD) for weekly number of hypnagogic hallucinations was -0.48 (1.83) to -0.78 (2.38) and for weekly number
of sleep paralysis episodes -0.38 (0.95) to -0.51 (1.29).
SAFETY
Adverse event terms used in this report are based on the Coding Symbols for the Thesaurus of Adverse Reactions Terms (COSTART). Event
descriptions supplied by the investigators were categorized by body system and by preferred COSTART terms. Adverse events of any kind were
reported by 109 patients (93.2%) during the 12-month study.
Adverse Events
The most commonly reported adverse events were headache, nausea,
viral infection, dizziness, pain, enuresis and somnolence. Of these seven
events, only dizziness occurred at a significant level (p < 0.05) for overall treatment group comparisons. Adverse events occurring in at least
10% of patients for any one of the five average doses during the initial
12 months of the study are summarized in Table 2. There were no deaths
occurring during the study.
Three patients experienced a serious adverse event during the course
of the study. One patient was a 41-year-old male who developed recurrent chest pain. Although his electrocardiogram was normal, the investigator chose to discontinue treatment with sodium oxybate. Subsequently, 26 days after his last dose of sodium oxybate, the patient suffered a mild myocardial infarction and chose not to continue the study.
Another patient, a 56-year-old male with a history of breast tumor
removal, developed a ductal carcinoma in his left breast requiring surgical removal. This patient continued treatment and completed the 12month study. Neither of these serious adverse events was considered to
be related to sodium oxybate therapy. The third case occurred in a 76year-old woman who experienced agitation. This occurred on her first
Figure 3—Investigator’s Clinical Global Impressions of Change for all treatment groups
following the double-blind trial. These data depict the percent of patients categorized as
Much Improved or Very Much Improved by study investigators. This change was significant at month 2 (* denotes p < 0.05).
SLEEP, Vol. 26, No. 1, 2003
night following an upward titration of her sodium oxybate dosage and
after her second nightly dose. She was treated in a local hospital where
her physical and laboratory examination were found to be normal and
she was discharged to home. Although this event was considered to be
possibly related to the medication, she completed the 12-month study
without recurrence.
Laboratory Abnormalities
The majority of endpoint laboratory values remained unchanged at the
end of the study. There was a significant change in serum phosphorus
(hypophosphatemia; p = 0.023) across dose groups. This change was
believed to be due to natural variability as there was no significant
change within dose groups. Similarly, there was a significant change in
serum calcium (hypocalcemia; p = 0.034). Although these values
dropped below the normal range, they were not considered clinically significant and, as these changes were observed only within the 6 g dose
group, this effect was believed to be spurious. Only a mild increase in
SGPT was determined to be possibly related to the study medication.
However, it was considered to be of no clinical significance. No patients
discontinued drug therapy because of an adverse laboratory event.
Vital signs
The only significant change in vitals signs was a mild decrease in
diastolic blood pressure observed across treatment groups. The maximum decrease observed was 7 mm Hg and was determined to be clinically insignificant.
Adverse Events Resulting in Withdrawal from Study
Eleven patients chose to discontinue participation in the study due to
an adverse event during the first 12 months of the trial, representing
9.4% of all patients who began the study. The COSTART terms for these
events were abnormal coordination, amnesia, apathy, asthenia,
decreased libido, depression, dyspnea, hypesthesia, headache, metallic
taste, nervousness, pregnancy (protocol violation), psychosis, somnolence, stomach upset, and weight loss (4 patients experienced more than
one adverse event). The adverse event “psychosis” represents a single
patient who had a previous history of mental illness.
DISCUSSION
Efficacy
The data from this open-label study demonstrate that 3 g to 9 g doses
of sodium oxybate, taken nightly in equally divided doses at bedtime and
again 2.5 to 4 hours later, produced significant and long-term clinical
improvement in the frequency of cataplexy attacks and diminished daytime sleepiness. Clinical improvement was maintained throughout the
study. Of the 118 patients who entered the trial, 103 (87%) were taking
concomitant stimulant mediations, making the adjunctive improvement
in daytime sleepiness especially noteworthy.
Clinical improvement trends included decreased frequency and duration of inadvertent naps or sleep attacks and diminished frequency of
planned naps, hypnagogic hallucinations, and episodes of sleep paralysis. These improvements did not reach statistical significance, although
they did demonstrate a continuous improvement trend for the duration of
the 12-month trial.
There was no evidence that tolerance developed to the effects of sodium oxybate. Once a stable dose was achieved, there were few subsequent changes in dose, and substantial clinical efficacy was maintained
without dose escalation.
Together, these results confirm and extend the observations of other
investigators,13,15,16,17,18 and further support the therapeutic role of sodium oxybate for the treatment of cataplexy in patients with narcolepsy.
34 Orally Administered Sodium Oxybate—U.S. Xyrem Multicenter Study Group
Safety
Sodium oxybate was generally well tolerated. Adverse events
encountered in this study affected primarily the central nervous and
digestive systems. There was no dose relationship for the most common
adverse events, and the majority were mild to moderate in severity. Only
nausea, dizziness, somnolence, headache, and enuresis were considered
related to sodium oxybate therapy.
Although several patients who dropped from the study abruptly
stopped taking sodium oxybate, there were no reports of adverse events
suggestive of either dependence or withdrawal from the study medication. In addition, there was no evidence of dose-escalation, which might
suggest tolerance to the therapeutic benefits of sodium oxybate, or any
tendency for abuse. Both of these findings are consistent with other
long-term human trials with sodium oxybate for the treatment of narcolepsy.19 They are also consistent with recent reports that sodium oxybate has only very weak reinforcing properties.21
In summary, sodium oxybate was reported to produce clinical
improvement in narcolepsy symptoms, with a maximal effect seen after
2 months of treatment when administered at doses of 3 g to 9 g nightly.
These improvements included decreased frequency of cataplexy attacks,
diminished daytime sleepiness, and decreasing trends in the frequency
and duration of inadvertent naps, daytime sleep attacks, and decreased
frequency of hypnagogic hallucinations and sleep paralysis. Sodium
oxybate appears to be well tolerated when used over long periods. These
data indicate that sodium oxybate may safely be used in conjunction
with central nervous system stimulants and provide further evidence that
sodium oxybate is an effective therapy for narcolepsy.
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ACKNOWLEDGEMENTS
The members of the U. S. Xyrem Multicenter Study Group were Jed
Black and Christian Guilleminault, Stanford Sleep Disorders Clinic,
Stanford, CA; Richard Bogan, Baptist Medical Center Sleep Disorders
Center, Columbia, SC; Neil Feldman, St. Petersburg Sleep Disorders
Center, St. Petersburg, FL; Martha Hagaman, Sleep Medicine Associates, Nashville, TN; Gila Hertz, Center for Sleep and Insomnia Disorders, Huntington, NY; Vasudeva Iyer, Sleep Disorders Center University of Louisville Hospital, Louisville, KY; Salim Kathawalla, Pulmonary
Department Park Nicollet Clinic, Minneapolis, MN; D. Alan Lankford,
Sleep Disorders Center of Georgia, Atlanta, GA; Merrill Mitler and
Roza Hayduk, Pacific Sleep Medicine Services, La Jolla, CA; Pradeep
Sahota, University of Missouri Division of Neurology, Columbia, MO;
Thomas Roth, Sleep Center Henry Ford Hospital, Detroit, MI; Martin
Scharf, Center for Research in Sleep Disorders, Cincinnati, OH;
Lawrence Scrima, Sleep-Alertness Disorders Center, Inc., Aurora, CO;
Jonathan Schwartz, Southwest Medical Center, Oklahoma City, OK;
Gary Zammit, Sleep Disorders Institute St. Luke’s – Roosevelt Hospital
Center, New York, NY.
The authors extend their deep appreciation to Dr. Merrill Mitler for his
thoughtful review of this manuscript.
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SLEEP, Vol. 26, No. 1, 2003
35 Orally Administered Sodium Oxybate—U.S. Xyrem Multicenter Study Group