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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_41_библиотеки_им_акад_М_И_Перельмана
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J. H. Dailey and S. Chowdhuri
eters were reported. Other AEs attributed to dosage, dose timing, and drug-drug
interactions were seen.
Summary Providers and consumers often try melatonin rst-line in treating insomnia due to its availability. However, melatonin is not recommended for treating
chronic insomnia due to inadequate supporting data with low quality of evidence
and potential for mild AEs.
Melatonin Receptor Agonist: Ramelteon
Ramelteon is a synthetic analog of melatonin. It is a melatonin receptor agonist and
acts by binding selectivity to the MT1>MT2 receptors, two G-protein-coupled
receptors [16].
Efcacy A SR [17] determined the efcacy of short-term use of ramelteon
(n=5812) for treating insomnia in mostly female individuals (62%) between 18 and
93years old. The dose range of ramelteon was 4–32mg/day (although the FDAapproved dose is 8mg/day) and mean duration of therapy was 38days. Relative to
placebo, ramelteon signicantly improved sSL and SQ, but not sTST. Ramelteon
improved secondary outcomes SE, SOL, and TST.
Safety The incidence of AEs with ramelteon was low. Somnolence was the only
signicant AE. Angioedema and anaphylaxis, complex sleep-related behavior,
hyperprolactinemia, and lower testosterone levels have been reported in postmarketing reports [16]. Ramelteon does not produce dependence and has no abuse
potential unlike the GABAergic drugs. There was no tolerance, rebound insomnia
on discontinuation, psychomotor, cognitive, or balance impairment [16].
Summary
Ramelteon had a favorable safety prole and responses on many sleep
parameters. However, its clinical efcacy was small, therefore, is not an efcacious
agent for the treatment of chronic insomnia.
Orexin Antagonists: Suvorexant andLemborexant
Orexin A and B (also called hypocretin-1 and 2) are neuropeptides located in the
perifornical regions of the lateral hypothalamus and project to the brain stem and
forebrain areas, innervating monoaminergic and cholinergic cells. While these neuropeptides inuence numerous functions such as food intake, appetite, autonomic
regulation, and endocrine function, they also serve to promote wakefulness and
inhibit REM sleep [18]. Suvorexant and lemborexant are dual orexin receptor antagonist agents (DORAs) and bind selectively to the G-protein-coupled receptors,
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OX1R and OX2R thus, altering the action of orexin in the brain and suppressing the
sleep-wake drive. (See Table2.4 for comparisons) [19, 20].
Efcacy Suvorexant was evaluated using dose ranges exceeding the current
approved doses; 5mg– 20mg daily. A two-period cross-over efcacy study [21]
examining suvorexant 10 and 20 mg versus placebo for 1 month included 254
patients with primary insomnia. The primary endpoint was SE. Secondary endpoints were WASO and latency to persistent sleep (LPS). After 4weeks of therapy,
compared to placebo, the 10 and 20 mg doses improved SE (4.7% and 10.4%),
decreased WASO (−21.4 and −28.1minutes) and LPS (−2.3 and −22.3minutes),
and improved the exploratory endpoint TST (22.3 and 49.9minutes), respectively
[21, 22]. To date, no head-to-head trials comparing suvorexant to other sedative
hypnotics exist.
One SR [23] reported patients responding to suvorexant 15 or 20mg at 3months,
a number to treat (NNT) of 13 and 16 would be required to achieve a ≥15% improvement in mean sTST and mean sWASO versus placebo, respectively. Other authors
reported a NNT of eight to achieve a ≥6-point improvement in the patient-rated
insomnia severity index (ISI) at 3months with suvorexant 15/20mg doses versus
placebo [24].
The efcacy of lemborexant was shown in two Phase 3 RCTs [25, 26].
SUNRISE-1 trial [25] compared lemborexant 5 and 10mg to placebo and active
comparator, zolpidem ER 6.25mg for 1month in adults (n=1006) aged ≥55years
with insomnia. Patients had a mean ISI score of 19 upon randomization and 86%
Table 2.4 Characteristics of orexin antagonists in adultsa [19, 20]
Generic name Suvorexant Lemborexant
Trade name Belsomra Dayvigo
Onset of action (min) 30 <30
Tmax, hrs (range) 2 (0.5–6) 1–3
Elimination half-life; hrs.
(range)
Duration Intermediate Intermediate
Metabolism CYP3A4 (major);
Recommended daily dose,
adults; initial; maximum (mg)
Exposure Higher in women versus men and in obesity
Use in pregnancy AEs observed in some animal reproduction studies. No
Controlled substance IV
N/A not applicable; AE adverse events
a
Both agents are dosed ≥7hours before planned time of awakening
12 17–19
CYP2C19 (minor)
10; 20 5; 10
a
(>30kg/m2) vs. non-obesity
adequate studies in women during the use in pregnancy for
either agents.
CYP3A4
(major);
CYP3A5
(minor)
N/A
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J. H. Dailey and S. Chowdhuri
were women. The primary endpoint was the mean change from baseline (CFB) in
LPS versus placebo on days 29/30. Pre-specied key secondary outcomes included
mean CFB in SE and WASO compared to placebo and WASO in the second half of
the night (WASO2H) compared to zolpidem ER 6.25mg on days 29/30. Lemborexant
5 and 10 mg improved LPS 11.6 and 13.6 minutes versus placebo at 1 month,
respectively. The treatment effect of lemborexant 5 and 10mg versus placebo at
6months for SE was 3.9% and 4.9%; and for WASO was −7.7 and −9.1minutes,
respectively.
SUNRISE-2 [26] trial compared lemborexant 5 and 10mg versus placebo for
6months (Period 1) (n=959) followed by 6months active-treatment only period
(Period 2-https://doi.org/10.1016/j.sleep.2021.01.048). The primary outcome of
Period 1 was a mean CFB in sSL and the pre- specied key secondary efcacy endpoints were CFB for sSE and sWASO using electronic sleep diaries. At 6months,
both lemborexant doses demonstrated statistically signicant superiority to placebo
for all primary and key secondary outcomes. Lemborexant 5 and 10mg improved
LPS 11.2 and 14.1minutes from placebo at 1month, respectively. The treatment
effect of lemborexant 5 and 10mg compared to placebo at 6months for sSE was
4.6% and 4.7% and for sWASO, −17.5 and −12.7minutes, respectively.
A SR and network meta-analysis [27] evaluated the efcacy and safety outcomes between lemborexant and suvorexant. It included 4 double-blind, RCTs
(n=3237, mean age 58years). Treatment arms included lemborexant 10mg/day
(n=592); lemborexant 5mg/day (n=589); suvorexant 20/15mg/day (n=493);
zolpidem ER 6.25mg/day (n=263); and placebo (n=1300). The quality of evidence was rated low or very low. The analysis suggests that at 1month, lemborexant 10mg performed better compared to other agents and doses including
placebo for subjective time to sleep onset (primary outcome), sTST and sWASO
(secondary outcomesfrom sleep diaries) but was associated with a higher discontinuation rate due to AEs and a higher incidence of somnolence compared to
zolpidem ER 6.25mg/day.
Both DORAs are contraindicated in patients with narcolepsy. The most
Safety
common AEs with suvorexant during 1year of treatment were somnolence, fatigue,
and dry mouth [28]. A dose-related increase of AEs is seen [24–26]. The incidence
of somnolence with suvorexant was 0.4%, 1.6%, and 4.9% for placebo, 10 and
20mg/day, respectively [21]. The number needed to harm (NNH) using suvorexant
15 or 20mg/day versus placebo was 28 [24]. Next-day somnolence, CNS depression, and sleep-related activities including sleepwalking, sleep-driving, and making
phone calls while asleep without patients remembering have been reported.
Suvorexant can impair next-day performance of activities that require mental alertness and motor coordination as did some patients taking lemborexant 10mg/day. Of
note, performance on some memory and attention tests was reduced with lemborexant 10mg dose compared to placebo; 5mg dose did not differ signicantly from
placebo in any of these measures.
No clinically signicant respiratory depression in mild-to-moderate obstructive
sleep apnea (OSA) and mild-to-moderate chronic obstructive pulmonary disease
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were noted with suvorexant. There were no cases of severe cataplexy, although
some reports of “weaknesses” were noted. In patients with mild OSA, lemborexant
did not increase the frequency of apneic events or cause oxygen desaturation.
Symptoms similar to mild cataplexy can occur with lemborexant. No evidence of
rebound insomnia, physical dependence, or withdrawal symptoms were seen with
either agents. The incidence of somnolence or fatigue in a combined analysis pool
(rst 30days) for SUNRISE-1 and SUNRISE-2 trials [22] for placebo, lemborexant
5 and 10 mg, was 1.3%, 6.9% (NNH=18), 9.6% (NNH=12), respectively. In
SUNRISE-2 trial [23], the incidence of somnolence was higher in patients ≥65years
of age (19%) vs. subjects <65 years (10.9%) with lemborexant 10mg (data on le,
Eisai Inc.).
Summary The DORAs are indicated for sleep onset and maintenance insomnia.
No comparative trials between these two agents exist. Long-term outcomes are not
known. Lemborexant 10mg compared to zolpidem 6.25 ER had better outcomes in
many of the subjective sleep parameters, however with more somnolence. The incidence of AEs is dose-dependent for both agents.
Antidepressants
Several antidepressants are used off-label to treat insomnia although few controlled,
short- or long-term studies to validate their efcacy and safety in patients with primary insomnia exists. The tolerability and safety of these agents used in highquality trials long term is lacking. Patients with depression or anxiety disorders
treated with SSRI (serotonin reuptake inhibitor) and SNRI (serotonin and norepinephrine reuptake inhibitor) antidepressants often complain of insomnia or daytime
somnolence occurring with long-term treatment [29].
Low-dose doxepin
Low-dose doxepin due to its antihistamine effects is FDA-
approved for the treatment of sleep maintenance insomnia. One SR [30] comprised
of 6 RCTs of low-quality evidence compared the efcacy of low-dose doxepin
versus placebo in individuals with insomnia disorder diagnosis with treatment
duration varying from 1day to 12weeks. The outcome, ISI, signicantly improved
at week four in 2 RCTs in older adults, favoring doxepin 3 or 6mg dose over
placebo.
None of the RCTs found signicant differences in AE rates between low-dose
doxepin and placebo treatment, although the SR did not combine AEs from different RCTs. Headache and somnolence were the most common AEs reported with
low-dose doxepin with no signicant next-day residual effects or withdrawal effects.
Doxepin may potentially be an inappropriate medication in geriatric patients [31],
and should be avoided when used in doses >6mg/day due to the possible orthostatic
hypotension, anticholinergic effects, or toxicity [32].
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Antidepressants Used Off-Label
Trazodone Trazodone produces sedation by blocking the 5HT-2a/2c receptor.
Trazodone continues to be a highly prescribed drug for insomnia even though the
efcacy for treating insomnia has been studied in only small populations in
depressed individuals, usually with limited subjective sleep evaluations and without
objective PSG data.
In an SR, [33] three of 7 trazodone trials (n=379) used doses between 25 and
150 mg. Moderate improvement in subjective sleep outcomes over placebo was
seen. Two PSG trazodone studies resulted in little or no difference in SE (lowquality evidence). Two studies with low-quality evidence had more AEs with trazodone than placebo. Another SR [34] included seven trazadone trials of which only
one trial included patients with primary insomnia (n=306). The trial of 2weeks in
duration included three arms: trazodone 50 mg, zolpidem 10 mg, and placebo.
Patients self-reported that both trazodone and zolpidem had shorter sleep latency
than placebo, but similar in sleep duration.
Rates of AE were low in two of the trials; the other ve studies did not present
this data [34]. Trazodone has an FDA blackbox warning for the possibility of
increasing suicidal thoughts and behaviors in pediatric and young adult patients
[35]. Due to numerous other AEs and drug-drug interactions, trazodone is not considered a treatment of choice for chronic insomnia.
J. H. Dailey and S. Chowdhuri
Summary Only low-dose doxepin is FDA-approved for treatment of sleep maintenance insomnia. There is limited clinical evidence for using other antidepressants
for managing insomnia.
Antipsychotic Agents
Traditional and atypical antipsychotics are sedating due to their antagonism of
dopaminergic, histaminergic, serotonergic, α(alpha)1-adrenergic systems.
Anticholinergic effects, including sedating and hypotensive effects, occur with all
antipsychotics in varying frequency and severity.
A SR [36] evaluated the benets and AEs of atypical antipsychotics used to
treat insomnia. Only one low-quality study using quetiapine met the inclusion criteria, and reported no statistically signicant differences from baseline between
quetiapine and placebo for TST, SL reduction, or sleep satisfaction improvement.
No AEs were reported in the placebo group, but dry mouth and daytime drowsiness
were found in the quetiapine with undetermined frequency. Quetiapine has a
blackbox warning indicating a 1.6 to 1.7-fold increase in mortality in elderly populations with dementia-related psychosis and increased suicidal tendencies in children, adolescents, and young adults [37]. In addition, all atypical antipsychotics
carry a strong recommendation to avoid their use in the elderly except in schizophrenia or bipolar disorders due to an increased risk of cerebrovascular accident
and a greater rate of cognitive decline and mortality in persons with dementia [31].
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Summary The atypical antipsychotic used off-label most commonly to treat insomnia
is quetiapine. There are limited number of studies with small sizes regarding efcacy
of antipsychotics for treating insomnia and the drugs have risk for AEs in the elderly.
OTC Drugs
Off-label use of antihistamines such as diphenhydramine and doxylamine produces
subjective drowsiness and reduced SL but tolerance develops within 2weeks of use
[11]. The use of these agents and other antihistamines is not supported by rigorous
data for treating chronic insomnia [11]. Valerian available as OTC is a plant extract
with GABA activity and shortens SL and improves SE; however, evidence for its
efcacy for treatment of insomnia is limited [11].
Wake-promoting Drugs
Drugs that are agonistic to the wake-promoting nuclei can potentially increase alertness. Thus, wake-promoting agents used to treat excessive daytime sleepiness
(EDS) act via the activation of the noradrenergic, dopaminergic, serotonergic systems, and/or histamine [1] (Fig.2.2). Agents treat narcolepsy symptoms, primarily
EDS, but also REM sleep dysregulation symptoms (i.e., cataplexy, hypnagogic/
Wake-promoting drugs
Fig. 2.2 Demonstrates the potential sites of action of wake-promoting drugs. DA dopamine, NE
norepinephrine, MAO monoamineoxidase, DNRI dopamine and norepinephrine reuptake inhibitor, H3 histamine 3, VMAT-2vesicular monoamine transporter, GABAgamma aminobutyric acid
Mechanism of action Drugs/Drug categories
DA and NE transporter inhibition,
VMAT-2 inhibition, and
MOA activity inhibition
DA and NE transporter inhibition,
serotonin 1A receptor agonist
Probably DA reuptake inhibition
Probably GABA
thalamocortical neurons
Antagonist/inverse agonist
at H3 receptors; modulates
release of NE and DA
, NE, DA,
o
Probably DNRI
Amphetamine
Methylphenidate
Modafinil
Armodafinil
Sodium oxybate
Solriamafetol
Pitolisant
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Table 2.5 Pharmacology of wake-promoting agents [67, 78]
Usual daily
Generic/
(trade name) Half-life (h)
CNS stimulants
(e.g., amphetamines;
detroamphetamine)
Desoxyn®;
Dexedrine®)
Methylphenidates
(Concerta®; Ritalin®)
Modanil
(Provigil®)
Armodanil
(Nuvigil®)
Sodium oxybate
(Xyrem®)
Calcium, magnesium,
potassium, and
sodium oxybates
(Xywav™)
Pitolisant
(Wakix®)
Solriamefetol
(Sunosi®)
CNS central nervous system; N/A not applicable; OSA obstructive sleep apnea
a
Low-dose sodium oxybate
Varies,
depending on
the
formulation
1.5–3 20–30
15 200–400
15 150–250
0.5–1 4.5–9g/night
0.5–1 Same as
a
~20 8.9–35.6 Pre-clinical studies have
2–3 75–150
dose range
(mg) Use in pregnancy
5–60
(divided
doses)
(narcolepsy;
divided doses)
200 (OSA)
divided into 2
doses
Xyrem
(narcolepsy)
37.5–150
(OSA)
The safety of CNS
stimulants during human
pregnancy has not been
established. There may be
risks to the fetus
associated with the use of
CNS stimulants.
Registry data suggest
potentially a higher rate of
major congenital
malformations than in the
general population
exposed within 6weeks
prior to conception or
pregnancy.
Insufcient data to
determine developmental
risk.
Insufcient data to
determine developmental
risk.
shown reproductive
toxicity. Insufcient
human data to establish
toxicity.
Insufcient data to
determine drug-associated
risk of major birth defects,
miscarriage, or adverse
maternal or fetal
outcomes.
Controlled
substance
II
IV
III
III
N/A
IV
hypnopompic hallucinations, sleep paralysis) and disrupted nighttime sleep. The
pharmacology and dosing of the wake agents are described in Table2.5.
Amphetamines andMethylphenidate
Amphetamines and methylphenidate are controlled substances that act by blocking
the reuptake and enhancing the release of norepinephrine, dopamine, and serotonin
[38]. Amphetamines reduce REM (rapid eye-movement) sleep, prolong REM
latency, increase SL, and reduce TST [39].
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Efcacy Efcacy data for the wake-promoting drugs are limited. Methylphenidate,
methamphetamine, and dextroamphetamine are FDA-approved for EDS, but are not
considered rst-line therapy due to lack of evidence on benet-to-risk ratios [40].
Safety Adverse events include headaches, irritability, nervousness or tremors, psy-
chosis, anorexia, insomnia, gastrointestinal complaints, dyskinesias, and palpitations. The drugs are contraindicated in patients with advanced arteriosclerosis,
symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, history of drug abuse, or with administration of MAO inhibitors. Labeling
for amphetamines includes a “black box” warning due to the high potential for abuse.
Summary Amphetamines and related medications have been used to improve
alertness in patients with narcolepsy for decades but are not rst-line therapy for
EDS.The drugs have signicant AEs and potential for abuse in specic situations.
Modanil andArmodanil
Modanil is a nonamphetamine indicated for treatment of EDS for patients with narcolepsy and shift-work disorder, and with obstructive sleep apnea (OSA) with residual daytime sleepiness on adequate positive airway pressure therapy (PAP).
Modanil’s mechanism of action (MOA) is not well understood but may be dopamine reuptake inhibition [41, 42].
Modanil is comprised of two enantiomers, the S-isomer with a half-life of
3–4 hours and the R-isomer with a half-life of ~15 hours. Armodanil is the
R-enantiomer of modanil. Modanil’s elimination half-life is almost 13hours for
single dosing and up to 15hours after multiple dosing; the maximum concentration
is achieved in 2–4hours.
Modanil Efcacy
Narcolepsy
A meta-analysis pooled data from nine double-blind RCTs [43] in
patients with narcolepsy (n=1054) with or without cataplexy and with 2–9weeks
follow-up at daily doses of 200-, 300-, and 400mg. Modanil versus placebo signicantly decreased EDS assessed by Epworth Sleepiness Scale (ESS) with WMD
of −2.73 points, improved multiple sleep latency test (MSLT) and maintenance of
wakefulness test (MWT) results, WMD of 1.11 and 2.82minutes, respectively.
Daytime sleepiness and the number of sleep attacks and naps per day decreased.
There were no changes in sleep architecture. Following 9weeks of treatment with
200 or 400mg/day, modanil improved quality of life on the SF-36 questionnaire
and on a validated narcolepsy-specic questionnaire. Performance and clinical
global impression (CGI) scores also improved. The likelihood of falling asleep
increased after withdrawing modanil [44]. Modanil had a similar effect on EDS
as sodium oxybate [45] with no difference in the change in ESS scores and mean
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J. H. Dailey and S. Chowdhuri
sleep latency (MSL) on MWT. There are no RCTs comparing modanil with
methylphenidate or other amphetamine-like stimulants. Withdrawal symptoms
such as those noted with amphetamines were absent, suggesting that modanil is
not “addictive” and has a lower potential for abuse. Modanil 400mg once daily
or as a split dose in the morning and at midday improved wakefulness than
modanil 200mg taken once daily in the morning [46]. Modanil had no effect on
cataplexy.
Obstructive Sleep Apnea
In one SR of 10 RCTs [47], modanil/armodanil used for the treatment of residual
daytime sleepiness in OSA after adequate PAP therapy improved ESS score by 2.2
points over placebo (effect size 0.55), MWT by 3minutes (effect size 0·41), and
MSLT by 1.3minutes (effect size 0.33).
Shift work disorder In shift work studies [48], the objective MSL increase was
small (approximately, 2minutes at both 200- and 400 mg); however, patients’
subjective assessment of sleepiness was much improved, with an ESS score
reduction by approximately 4 points and 6 points at 200 and 400 mg dosage,
respectively.
Armodanil Efcacy Armodanil resulted in a small (2.3 minutes) but statistically signicant increase from baseline MSL versus placebo on the rst four
30minutes MWT sessions in OSA patients with residual EDS [49, 50]. Armodanil
signicantly increased the MSL on MWT in narcoleptic patients [51]. In patients
with EDS associated with chronic shift-work disorder, armodanil signicantly
improved wakefulness during scheduled night work, raising mean nighttime SL
from 2.3minutes at baseline, to 5.3 minutes over a period of 12weeks [52]. The
effectiveness of armodanil lasted after long-term use (≥12month) and was well
tolerated in open- label trials in patients with EDS associated with treated OSA,
shift work disorder, or narcolepsy [52–54]. Armodanil was also effective in reducing sleepiness due to jet lag following eastward travel through 6 time zones [55].
Data compiled from six double-blind, RCTs demonstrated that modanil
Safety
has a good safety prole with low potential for abuse [42, 56]. The most common
side effect is headache and anxiety. It does not affect the sleep architecture by PSG
or any cardiovascular parameters (blood pressure or heart rate). A serious but rare
side effect is drug rash. Psychiatric alterations have been noted in patients under
combined treatment with sodium oxybate and modanil [57] and should be monitored accordingly. These drugs induce cytochrome P450 enzyme, leading to reduced
levels of oral contraceptives. Hence, female patients should use another form of
contraception while on these medications. Neither modanil nor armodanil is
FDA-approved for use in pediatric patients for any indication.
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Summary Modanil and armodanil are effective and safe agents in treating EDS
associated with narcolepsy, shift work disorder, andin OSAtreated with PAP.
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Sodium Oxybate
Sodium oxybate (Xyrem®) (SXB) and lower-sodium version (Xywav®) are oxybate salts of the recreational drug, gamma-hydroxybutyric acid (GHB). Both agents
are FDA-approved for the treatment of cataplexy and EDS in patients with narcolepsy ≥7years of age. While the MOA is unknown, both agents probably act by
binding to GABAB receptors. Given the abuse potential and CNS depressant effects,
the drugs are scheduled III controlled substances and available only through a
restricted distribution program. Both agents are rapidly absorbed with a high rstpass metabolism; absorption is slowed by fatty meals, so should be taken a few hours
after a meal. The agents aremetabolized to water and carbon dioxide and eliminated
rapidly from the circulation in 20–53minutes, necessitating twice- nightly administration, taken at bedtime while in bed and again 2.5–4hours later [58]
Efcacy In one meta-analysis, 2 RCTs measured the improvement of EDS with
SXB using different MWT protocols (n=192). At SXB doses, usually at 9g/night
for 4–8 weeks, SXB was signicantly superior to placebo for increasing MSL
(MD(mean difference): 5.18), and reducing mean sleep attacks (MD: −9.65) and
increased CGI scores. When compared with placebo, cataplexy attacks were statistically signicantly decreased with 4.5 g/night dose (pooled results: MD: −8.5,
https://doi.org/10.5664/jcsm.2048)
In another meta-analysis of 9 RCTs (n=1154), SXB also signicantly reduced
subjective daytime sleepiness (WMD −2.81) and sleep stage shifts (WMD −9.69,
[59]). In one of the RCTs, there was a signicant reduction of 20% and 27% in the
ESS scores in the SXB monotherapy and SXB + modanil combined therapy
groups, respectively [45]. After 8weeks, signicant changes in sleep architecture
among patients receiving SXB and SXB+modanil included a median increase in
Stage 3 and 4 sleep (43.5 and 24.25minutes, respectively) and delta power and a
median decrease in nocturnal awakenings (6.0 and 9.5, respectively) [60]. It did not
signicantly increase REM sleep versus placebo.
The efcacy of lower-sodium oxybate was established in Phase 3trial, 16weeks
in duration with 2weeks of data comparing it to placebo (n=201, [61]). The sodium
content in a 6–9 g dose SXB and lower-sodium oxybate is 1100–1640 mg vs.
87–131mg, respectively. The primary outcome was the change in weekly number
of cataplexy attacks from during the stable dose period (2weeks) to withdrawal
period (2weeks). The key secondary outcome was a change in EES score. Weekly
cataplexy scores and EES scores were signicantly reduced compared to placebo.
Most patients randomized to lower-sodium oxybate reported better PGIc(Patient
Global Impression of Change) ratings, Short Form (SF)-36 physical component
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