HYPNOTICS AND SLEEP AT ALTITUDE
Zaleplon and Zolpidem Objectively Alleviate Sleep Disturbances in Mountaineers
at a 3,613 Meter Altitude
Maurice Beaumont, MD, PhD1; Denise Batéjat, Ing1; Christophe Piérard, PharmD, PhD1; Pascal Van Beers1; Matthieu Philippe1; Damien Léger, MD, PhD2; Gustave
Savourey, MD, PhD3; Jean-Claude Jouanin, MD, PhD1
Institut de Médecine Aérospatiale du Service de Santé des Armées (IMASSA), Brétigny-sur-Orge, France; 2Sleep Center, Hôtel-Dieu APHP, Paris,
France; 3Centre de Recherches du Service de Santé des Armées (CRSSA), La Tronche, France
1
Study Objectives: To assess the effects of zolpidem and zaleplon on
nocturnal sleep and breathing patterns at altitude, as well as on daytime
attention, fatigue, and sleepiness.
Design: Double-blind, randomized, placebo-controlled, cross-over trial.
Setting: 3 day and night alpine expedition at 3,613 m altitude.
Participants: 12 healthy male trekkers.
Procedure: One week spent at 1,000 m altitude (baseline control), followed by 3 periods of 3 consecutive treatment nights (N1-3) at altitude, to
test 10 mg zolpidem, 10 mg zaleplon, and placebo given at 21:45.
Measures: Sleep from EEG, actigraphy and sleep logs; overnight arterial saturation in oxygen (SpO2) from infrared oximetry; daytime attention,
fatigue and sleepiness from a Digit Symbol Substitution Test, questionnaires, and sleep logs; acute mountain sickness (AMS) from the Lake
Louise questionnaire.
Results: Compared to baseline control, sleep at altitude was significantly
impaired in placebo subjects as shown by an increase in the amount
of Wakefulness After Sleep Onset (WASO) from 17 ± 8 to 36 ± 13 min
(P<0.05) and in arousals from 5 ± 3 to 20 ± 8 (P<0.01). Slow wave sleep
(SWS) and stage 4 respectively decreased from 26.7% ± 5.8% to 20.6%
± 5.8% of total sleep time (TST) and from 18.2% ± 5.2% to 12.4% ± 3.1%
INTRODUCTION
MOUNTAIN CLIMBERS EXPOSED TO HIGH ALTITUDE
OFTEN SHOW POOR SLEEP QUALITY (I.E., SLEEP FRAGMENTATION, INCREASED LIGHT SLEEP, DECREASED
slow wave and REM sleep1,2). Concurrently, respiration is disturbed by periodic breathing with apneic episodes and subsequent
swings in arterial saturation in oxygen (SpO2). Periodic breathing
may also be the cause of frequent arousals.3 Conversely, arousal
from sleep may induce ventilation instability.4 Poor sleep quality may adversely affect daytime mental performance and motor
function,5 and sleepiness may enhance risk for potential hazards.
Hypnotic drugs are commonly used by climbers to relieve poor
sleep at high altitude levels. By reducing the frequency of arousals, the use of hypnotic drugs may further reduce the extent of peDisclosure Statement
This study was supported by a grant from Sanofi-Aventis Group, Paris, France.
The authors did not receive any income from this company and are all appointed by the French Government and work in governmental institutions.
Submitted for publication June, 2006
Accepted for publication August, 2007
Address correspondence to: Dr Maurice Beaumont, BioAnalytical Sciences
Dept, Nestlé Research Center, PO box 44, Vers-chez-les-blanc, 1000 Lausanne 26, Switzerland; Tel: + 41 21 785 8054; Fax: + 41 21 785 8556; E-mail:
[email protected]
SLEEP, Vol. 30, No. 11, 2007
TST (P<0.05 and P<0.001, respectively). Subjects also complained from
a feeling of poor sleep quality combined with numerous O2 desaturation
episodes. Subjective fatigue and AMS score were increased. Compared to
placebo control, WASO decreased by ~6 min (P<0.05) and the sleep efficiency index increased by 2% (P<0.01) under zaleplon and zolpidem, while
SWS and stage 4 respectively increased to 22.5% ± 5.4% TST (P<0.05)
and to 15.0% ± 3.4% TST (P<0.0001) with zolpidem only; both drugs further
improved sleep quality. No adverse effect on nighttime SpO2, daytime attention level, alertness, or mood was observed under either hypnotic. AMS
was also found to be reduced under both medications.
Conclusions: Both zolpidem and zaleplon have positive effects on sleep
at altitude without adversely affecting respiration, attention, alertness, or
mood. Hence, they may be safely used by climbers.
Keywords: Polysomnography, sleep quality, control of breathing, hypobaric hypoxia, zolpidem, zaleplon, cognitive performance
Citation: Beaumont M; Batéjat D; Piérard C; Van Beers P; Philippe M;
Léger D; Savourey G; Jouanin JC. Zaleplon and zolpidem objectively
alleviate sleep disturbances in mountaineers at a 3,613 meter altitude.
SLEEP 2007;30(11):1527-1533.
riodic breathing. Benzodiazepines such as loprazolam (1 mg) and
temazepam (10 mg) have been studied in trekkers during highaltitude expeditions.2,6,7 In healthy subjects exposed one night at
a simulated altitude of 4,000 meters, non-benzodiazepines such
as zolpidem (10 mg) and zaleplon (10 mg) have also been found
to bear positive effects on sleep quality without adverse impact
on nighttime ventilation or cognitive performance the following
morning.8
The present study was designed to assess the safety and effectiveness on sleep of zolpidem and zaleplon in subjects exposed
to an altitude of 3,613 m over 3 nights of rest and 2 days of cognitive and physical activity in the Alps. Zaleplon and zolpidem
may prove even more beneficial than temazepam as hypnotic
agents for use among mountain climbers due to a shorter duration
of cognitive impairment; indeed, as opposed to temazepam, zaleplon, and zolpidem exhibit a faster elimination rate (half-life of
zaleplon and zolpidem 1 h and 2.4 h vs. 8.4 h for temazepam).9-11
METHODS
Study Design
A randomized, placebo-controlled, double-blind, cross-over
design was used. The protocol was approved by the ethical committee and registered at the French Ministry of Health. Written informed consent was obtained from each subject, in keeping with
legal requirements.
1527 Zolpidem, Zaleplon, and Sleep Disturbances at High Altitude—Beaumont et al
Subjects
A homogeneous group involving 12 healthy male trainees (age:
22.2 ± 0.6 years, body height: 177.5 ± 1.3 cm; body weight: 69.5
± 0.8 kg; body mass index 22.1 ± 0.6 kg/m2) volunteered for this
study. All underwent thorough medical and biological examination prior to the experiment. They completed the questionnaire
designed by Horne and Östberg12 to ensure that they were neither
“morning” nor “evening” types. The volunteers had no record history of sleep disorders, addiction, or neurological or psychiatric
disorders. They were all nonsmokers and reported caffeine consumption <3 cups of coffee/day. None of the subjects underwent
any medical treatment at the time of our experiment.
below baseline were also taken into account to reflect the high
altitude-related level of periodic breathing.16
Daytime Measurements
Measures
Attention capacity was measured with the digit symbol substitution test (DSST).17 It consisted in substituting figures by symbols on 10 sheets, at the rate of 20 figures per line, 6 lines per
sheet. The correspondence between figures and symbols was the
same for a given sheet but was different from sheet to sheet to
avoid any training effect. Subjects were given 1 min to fill in one
sheet. The number of right substitutions was assessed: the higher
the number of right answers, the higher the attention rate.
The level of subjective fatigue was assessed using the SamnPerelli questionnaire which was scored as follows: 2 points for a
“better than” answer, 1 point for a “same as” answer, and 0 points
for a “worse than” answer. Scores ranged from 0 (extremely fatigued) to 20 (extremely alert).18,19
Sleepiness was measured using the sleepiness scale of the Karolinska Institute,20 which produced a score on a scale from 1 (very
alert) to 9 (very sleepy). Mood (alertness, calmness, and contentedness) was assessed from the 16 items of the Bond and Lader visual analogue scale.21 The occurrence of acute mountain sickness
was assessed by way of the Lake Louise questionnaire.22
Nighttime Sleep and Ventilation Parameters
Experimental Protocol
Sleep architecture was assessed through polysomnographic
recordings, including electroencephalography (EEG), electrooculography of each eye and chin electromyography using Embla
numerical recorders (Resmed SA, Saint Priest, France). Sleep was
analyzed from the EEG signals, according to standard criteria13
by a member of our research team who had no knowledge of the
medication administered to the subjects. The following variables
were calculated: amount of wakefulness after sleep onset (WASO),
sleep period time (time from falling asleep to last awakening), total sleep time (TST: difference between sleep period and WASO),
sleep efficiency index (TST/time in bed) and sleep onset latency
(time from lights out to the 1st episode of stage 2 sleep). Besides
WASO, sleep fragmentation was assessed by scoring EEG arousals defined as wakefulness episodes of 3-15 sec.13
Objective evaluation of sleep was also carried out through continuous wrist actigraphy.14 Subjects wore a piezoelectric accelerometer (Actiwatch, Cambridge Neurotechnology Ltd, Cambridge,
England) on the nondominant wrist throughout the night. This device provided us with the opportunity to measure time spent in
bed, total sleep time, sleep efficiency, and sleep latency. There is a
solid correlation between sleep parameters estimated by actimetry
and those estimated by polysomnography.15 Actimetry is proposed
as a useful tool to measure the impact of insomnia treatments.15
Sleep was subjectively evaluated through sleep logs completed
after wake-up phase. Sleep log questions bore on such items as:
sleep latency (<15 min, 15-30 min, 30-45 min, > 45 min), awakenings, and sleep periods (noted on a 24-h scale with a precision of 15
min), sleep quality (light, intermediate, deep), dream quality (pleasant, unpleasant), wake up quality (very easy to very difficult), and
subjective appraisal of sleep duration (sufficient or not).
Ventilation was assessed on account of arterial saturation in
oxygen (SpO2) measured by continuous arterial pulse oximetry.
Oxygen desaturation events determined as drops in SpO2 > 4%
The subjects were housed and trained over 5 days at the Military School of High Mountain, Chamonix, France (altitude: 1,000
m, barometric pressure: 898 hPa), and their routines were identical. During this period, they were familiarized with the experimental tests and measurements. The Chamonix altitude of 1,000
m requires no physiological adjustment in young healthy subjects
and tests performed there were considered as baseline control.
To become accustomed to the EEG recording procedure, subjects
were fitted with EEG electrodes during the 5 consecutive nights:
only the data of the last baseline control night, however, were
recorded, to avoid the first-night effect.23 This reference week
was followed by 3 periods of 3 treatment nights and following
days spent at the altitude of 3,613 meters (barometric pressure:
649 hPa). Such altitude was reached by the subjects within a few
hours so that no process of adjustment to altitude could occur. The
nights were spent in a hut (“Cosmiques” hut) in the French Alps
and the days were dedicated to various mountain activities. The
3 treatment periods were separated by at least 7 days of wash-out
spent in the baseline control environmental conditions in Chamonix. Drugs under scrutiny were given orally in random order using
a double-blind, cross-over design. Within one treatment period, a
given subject received the same medication over the 3 nights.
During the experimental nights (between 19:00 and 21:00)
subjects were fitted with EEG electrodes that were stuck on the
skull using collodion. At 21:00, they completed the Lake Louise
questionnaire and they were equipped with the actigraph, the
SpO2 finger probe, and the oronasal thermosensor. They were
given the medication (zolpidem, zaleplon, or placebo) at 21:45.
Lights were switched off at 22:00; a signal was recorded on the
tape recorders of the subjects to document the beginning of time
in bed. Sleep and ventilatory parameters were recorded at the
same time for all subjects until 05:00, wake-up time. Equipment
was then removed and the subjects were asked to complete sleep
Medication
Medication was conditioned by the Central Pharmacy of the
Armed Forces in hard gelatine capsules containing the test substances (zolpidem 10 mg, zaleplon 10 mg, or placebo). The dose
of each active treatment was that recommended by the manufacturers for adult patients, i.e., 10 mg of zaleplon (not marketed in
France) and 10 mg of zolpidem.
SLEEP, Vol. 30, No. 11, 2007
1528 Zolpidem, Zaleplon, and Sleep Disturbances at High Altitude—Beaumont et al
Table 1—Sleep Architecture and Ventilation Parameters (Means ± SEMs)
Parameters
Sleep onset latency, min
Sleep period time, min
WASO, min
TST, min
Sleep efficiency index, %
Stage 1, % TST
Stage 2, % TST
Stage 4, % TST
SWS, min
SWS (1st half), min
SWS (2nd half), min
Rapid Eye Movement (REM) sleep, % TST
SWS latency, min
REM sleep latency, min
Sleep quality (scored in arbitrary units)
Subjective SEI (%)
Mean SpO2, %
Lowest SpO2, %
4% O2 desaturation events per hour of sleep
Number of arousals
Baseline control
14 ± 1
406 ± 1
17 ± 8
381 ± 31
94 ± 8
7.4 ± 2.6
47.6 ± 6.1
18.2 ± 5.0
101 ± 20
76 ± 16
25 ± 7
18.3 ± 4.2
33 ± 11
99 ± 48
6.7 ± 0.3
96 ± 5
96 ± 1
90 ± 0
0±0
5±3
Altitude + placebo
2 ± 1***
418 ± 1***
36 ± 13***
381 ± 15
91 ± 4**
9.1 ± 3.3*
51.4 ± 8.1
12.4 ± 4.1**
77 ± 21**
58 ± 19**
20 ± 7
18.9 ± 4.1
20 ± 18***
86 ± 27
6.2 ± 0.9**
89 ± 13**
83 ± 3***
70 ± 6***
10 ± 12***
20 ± 10***
Altitude + zaleplon
3 ± 1***
417 ± 1***
30 ± 13 §
388 ± 11
93 ± 3 §§
7.7 ± 2.8 §§
52.4 ± 7.3
13.1 ± 4.2***
81 ± 23
65 ± 19§§
16 ± 6
19.0 ± 5.0
18 ± 13***
80 ± 15
6.6 ± 0.8 §§
94 ± 11 §
84 ± 2***
69 ± 6***
12 ± 11***
18 ± 12***
Altitude + zolpidem
3 ± 2***
416 ± 2***
29 ± 15 §
387 ± 10
93 ± 3 §§
7.8 ± 2.7 §§
53.2 ± 6.7
15.0 ± 3.9 §§§/$$
86 ± 22 §§
72 ± 17 §§§/$$
15 ± 9
16.6 ± 7.2
19 ± 15***
100 ± 13
6.5 ± 0.8 §§
93 ± 12 §
82 ± 4***
70 ± 7***
10 ± 6***
19 ± 11***
Abbreviations: see text. Statistics: significant difference from baseline control data: *, **, *** (P<0.05, P<0.01, P<0.0001, respectively); significant difference from altitude + placebo: §, §§, §§§ (P<0.05, P<0.01, P<0.0001, respectively); significant difference from altitude + zaleplon:
$$ (P<0.01). Primary outcomes are shown in bold font.
logs and the Lake Louise questionnaire before having breakfast.
From 06:00 to 06:30, the volunteers underwent DSST and completed Karolinska, Samn-Perelli, and Bond and Lader scales
(morning session). Subsequently, the subjects underwent trekking throughout the day and came back to the hut at 17:00. One
hour later, all scales and DSST were completed again (evening
session).
Outcome Measures
The primary outcome for our study was sleep quality determined by the amount of slow wave sleep (known for its positive
impact on recovery) and by the amount of sleep fragmentation
(number of arousals and amount of wakefulness after sleep onset).
Indeed, the high altitude-related decreased SWS and increased
sleep fragmentation as factors of daytime sleepiness and impaired
cognitive performance are well documented. The secondary outcomes were the parameters reflecting high altitude related periodic breathing (number of decreased SpO2 events, averaged SpO2),
scores of daytime fatigue, sleepiness, mood and attention, as well
as the score of acute mountain sickness.
Statistical Analysis
Statistical analysis of different variables was carried out from
means of successive nights or days for each drug period spent at
altitude, except for scores of acute mountain sickness.
The normality of all variables was checked using Skewness
and Kurtosis tests. If the distribution of variables was non-Gaussian, a logarithmic transformation was applied. Subsequently a linear mixed model with treatment as fixed effect, baseline control
as covariate and subject as random effect was performed. TukeyKramer multiple comparison adjustment was used for treatment
SLEEP, Vol. 30, No. 11, 2007
comparisons at high altitude. In case of non-Gaussian distribution, comparisons between treatments were done with Wilcoxon
signed-rank test.
The comparison between baseline control and high altitude
levels was carried out with paired t-Test or Wilcoxon signed-rank
test in keeping with the distribution of variables.
The rejection level in statistical tests was equal to 5%.
All statistical analyses were made with SAS software (version
9.1; SAS Institute, Cary, NC).
RESULTS
Sleep and Ventilatory Data (Polysomnography and Actigraphy)
Effect of Altitude on Sleep and Ventilatory Parameters
Sleep architecture was significantly influenced at altitude level.
Main sleep and respiratory parameters are presented in Table 1. In
comparison with EEG recordings from the baseline control night,
sleep under placebo at high altitude was fragmented, as demonstrated by a significant increase in the number of 3-sec to 15-sec
arousals from 5 ± 3 to 20 ± 10 (P <0.0001) and in WASO from 17
± 8 to 36 ± 13 min (P <0.0001), while the sleep efficiency index
significantly decreased from 94% ± 8% to 91% ± 4% (P <0.01).
A substantial decrease in sleep onset latency was also found (P
< 0.0001). Looking at sleep architecture, SWS occurred 13 min
earlier (P <0.0001) and decreased from 26.7% ± 5.8% to 20.6% ±
5.8% TST (P <0.0001).
Sleep fragmentation at altitude level was associated with numerous episodes of O2 desaturation events (about 10/h sleep) reflecting the occurrence of periodic breathing episodes. The mean
and lowest SpO2 values at altitude were significantly lower than
baseline control throughout the altitude period.
1529 Zolpidem, Zaleplon, and Sleep Disturbances at High Altitude—Beaumont et al
100
£ $
90
*
80
SWS (min)
70
£
£
*
£
*
Control (800 m)
60
Placebo (3,613 m)
50
40
Zaleplon (3,613 m)
30
20
Zolpidem (3,613 m)
10
0
Ni gh t 3
Night 2
C ont ro l
Ni g h t 1
Figure 1—SWS duration (mean values ± SEMs) in baseline control (1,000 m) and altitude conditions (placebo control, zaleplon and zolpidem)
along the first half (22:00-01:30) for each night. *: significant difference from baseline control condition, P<0.05; £ and $: significant difference
from altitude + placebo and from altitude + zaleplon conditions respectively, P<0.05.
Sleep logs confirmed the detrimental impact of altitude over
sleep (Table 1). Subjects felt that their sleep was of poor quality (P <0.01) and the sleep efficiency index was also subjectively
decreased (P <0.01).
Effect of Zolpidem and Zaleplon on Sleep and Ventilatory Patterns
at Altitude Level
Both zolpidem and zaleplon had significant positive effects on
sleep at altitude (Table 1). Sleep fragmentation was significantly
reduced: with respect to placebo controls, WASO decreased by 6
min with zaleplon (df: 2, F: 3.46, P <0.05) and zolpidem (df: 2, F:
3.46, P <0.05), while the sleep efficiency index increased by 2.5%
under both agents (df: 2, F: 5.20, P <0.01). Furthermore, actigraphy showed a significant decrease in the number of wrist movements with zaleplon and zolpidem (P <0.01, P <0.05, respectively), providing further evidence for reduced sleep fragmentation.
However, neither zaleplon nor zolpidem reduced the number of
arousals. Sleep onset latency under either drug was as low as the
value obtained under placebo.
Looking at sleep architecture with respect to placebo control,
SWS duration was significantly lengthened by zolpidem (+9.2%,
df: 2, F: 4.09, P <0.01). To take into account the pharmacokinetics
of either drug, statistics were also conducted on the basis of halfnight periods (1st half: 22:00-01:30; 2nd half: 01:30-05:00). SWS
was increased with zolpidem by 24% compared with placebo (df:
2, F: 17.32, P <0.0001) and by 12% compared to zaleplon (df: 2,
F: 3.76, P <0.01) during the 1st half-night only (Figure 1, Table
1).
Subjects expressed a significant positive effect of zaleplon
and zolpidem on subjective sleep quality and sleep efficiency (P
<0.01, Table 1).
Neither zolpidem nor zaleplon influenced respiratory parameters at altitude. Compared to placebo control, the O2 desaturation
events per hour of sleep and the mean or lowest SpO2 were not
significantly affected by either drug (n.s.; table 1).
SLEEP, Vol. 30, No. 11, 2007
Subjective Fatigue, Attention, Sleepiness and Mood (Table 2)
Comparisons between altitude and baseline control conditions
exhibited the negative impact of altitude on subjective fatigue
(P <0.0001) in the morning and on alertness (P <0.05) in the evening, under all treatment conditions. Considering the attention capacity, the digit symbol substitution test showed an increased level
in all altitude conditions compared to baseline control (P <0.01)
with a more marked effect under both hypnotics compared with
placebo control in the evening (df: 129, F: 3.68, P <0.05).
Tolerance to Altitude
The Lake Louise questionnaire—filled out at 05:00 just after
wake-up and at 21:00 before going to bed—revealed headaches
and tiredness in the three drug groups during the first day (D1)
spent at 3,613 m (Figure 2), providing evidence of the occurrence
of an acute mountain sickness at its first degree. This may be accounted for by the fast ascent to the hut of subjects not yet adjusted to the environment.
Scores significantly decreased the following days in subjects
who were given either hypnotic drug as opposed to placebo.
DISCUSSION
To our knowledge, the present study is the first to objectively
evaluate the efficacy of zaleplon and zolpidem on sleep using
polysomnography, and to assess the potential unwanted effects
of these medications on cognitive functions in healthy trekkers
exposed to real high mountain conditions throughout three days
and nights.
The main findings of our current experiment stand as follows:
•
The hypnotics, particularly zolpidem, do improve sleep
quality (less amount of WASO, better sleep efficiency, greater
amount of slow wave sleep, i.e. of recovery sleep) at high
altitude without any additional impairment in respiration.
1530 Zolpidem, Zaleplon, and Sleep Disturbances at High Altitude—Beaumont et al
Figure 2
Placebo (3,613 m)
Zaleplon (3,613 m)
Score
5
*
4
*
3
*
*
Zolpidem (3,613 m)
*
*
2
£
$
£
£ $
$
D2, 21:00
D3, 5:00
£
$
1
0
D0, 21:00
D1, 5:00
D1, 21:00
D2, 5:00
Time
Figure 2—Score obtained with the Lake Louise questionnaire used to assess the occurrence of acute mountain sickness at 3,613 m of altitude.
*: significant difference from the data obtained before taking the medications after the arrival at 3,613 m of altitude (D0, 21:00); £: significant difference from the maximal score obtained on D1 at 21:00; $: significant difference vs. placebo control at the same time; P<0.05. Scores are mean
values ± SEMs.
Table 2—Subjective Fatigue, Attention Level, Sleepiness and Mood (Means ± SEMs) Assessed by the Samn-Perelli Questionnaire, the Digit
Symbol Substitution Test (DSST), the Karolinska Institute Sleepiness Scale and the Bond and Lader Visual Analogue Scale
Parameters
Subjective fatigue
Attention level
Sleepiness
Mood
Alertness
Contentedness
Calmness
M
E
M
E
M
E
Baseline control
11 ± 3
10 ± 2
130 ± 25
151 ± 32
3±1
5±2
M
E
M
E
M
E
61 ± 12
85 ± 13
73 ± 14
83 ± 17
76 ± 14
63 ± 12
Altitude + placebo
7 ± 3***
11 ± 3
147 ± 30**
162 ± 31**
5±1
3±1
54 ± 13
76 ± 14*
68 ± 14
77 ± 17
74 ± 14
64 ± 22
Altitude + zaleplon
8 ± 3**
11 ± 4
153 ± 31**
169 ± 33** / §
5±2
3±1
58 ± 16
71 ± 20*
70 ± 16
79 ± 14
77 ± 13
65 ± 20
Altitude + zolpidem
8 ± 3**
10 ± 4
155 ± 33**
170 ± 32** / §
5±1
3±1
58 ± 12
72 ± 16*
66 ± 15
74 ± 18
69 ± 13
64 ± 20
For each item, morning (06:00-06:30) and evening (17:30-18:00) values are shown on upper (M) and lower (E) lines.
Statistics: significant difference from baseline control data: *, **, *** (P<0.05, P<0.01, P<0.0001, respectively); significant difference from
altitude + placebo: §, (P<0.05).
•
•
Despite positive effects on sleep, cognitive functions were
not found to be improved by either drug, except attention
level in the evening. Nevertheless, no single unwanted side
effect of either medication was observed on daytime alertness,
wakefulness, or mood.
Acute mountain sickness was further relieved under zaleplon
and zolpidem intake after the first night spent at altitude.
SLEEP, Vol. 30, No. 11, 2007
Our placebo control subjects presented the sleep disturbances
that are classically observed at high altitude2,6: increased light sleep
and poor deep sleep with frequent arousals and intra-sleep wakefulness episodes associated with numerous O2 arterial desaturation
events, providing evidence of an instability of breathing control.4
A major finding rests with the fact that sleep fragmentation
(WASO) observed at altitude proved significantly reduced; further, sleep efficiency (total sleep time/time in bed) significantly
1531 Zolpidem, Zaleplon, and Sleep Disturbances at High Altitude—Beaumont et al
increased with either hypnotic compared to placebo, while latency
to sleep was shortened in all altitude conditions. The same effects
of 10 mg zaleplon and 10 mg zolpidem on sleep have already
been demonstrated in previous studies performed in conditions
not conducive to sleep, such as noise.24,25 At a simulated altitude
of 4,000 meters, we also demonstrated a significantly decreased
latency to sleep with zolpidem or zaleplon as well as a trend towards a decreased amount of WASO. Nicholson et al. also reported shortened latency and increased sleep efficiency with low-dose
temazepam in the Himalayas providing evidence for a better sleep
stability at altitude under hypnotics2.
Unlike zaleplon, zolpidem resulted in a significant increase in
SWS at altitude. However, zaleplon is characterized by its very
short half-life time (1.1 h) so that positive effects on sleep may
be observed early after the intake and may be masked within the
whole night. To check this hypothesis, statistical analysis was also
run by half-night. The effect of zaleplon on SWS was found significantly positive on the first half of the night but remained less
marked than with zolpidem. It is difficult to discuss the beneficial effect of zaleplon and zolpidem on sleep in healthy subjects
exposed to high altitude in relation to those of other hypnotics
such as benzodiazepines: to our knowledge, no previous study has
been performed in real environmental conditions using objective
tools for sleep measurement such as polysomnography. However,
Dubowitz found a subjective improvement of sleep quality under
temazepam at a 5,300-m altitude.7
The issue remains to establish whether the positive effects of
either drug on sleep involve alterations in respiratory control or
not. Hypnotics drugs such as benzodiazepines may affect ventilation control at moderate altitude26 and depress motor nerve input
to upper airway muscles, and therefore cause worsening of sleep
related breathing disorders.27 These potentially detrimental effects
on respiration require specific attention, because SpO2 is already
much reduced at altitude (lowest SpO2 at 3,613 m is between
67%-72%). The number of O2 desaturation events was not decreased under zolpidem or zaleplon, but on the other hand, none
of the respiratory parameters were significantly impaired by either
drug, confirming that the use of such medication at high altitude is
safe, in keeping with previous findings.8,28
Despite positive effects on sleep, cognitive functions were not
found to be improved by either hypnotic compared with placebo,
except for the attention level in the evening, when the subjects returned from their field assignment. In fact, no cognitive improvement was expected under hypnotic drugs at altitude because most
of these cognitive functions were at the same level as in baseline
control, which implies that they were not impaired by altitude
hypoxia. Indeed, our young, healthy, and well-trained subjects
were committed to a classic military assignment and exhibited
an increased attention capacity even under placebo. On the other
hand, considering the short half-life time of the hypnotics used, no
negative residual effect of these medications was expected since
they were administered at 21:45 and performance assessment was
launched the following morning at 06:00.
AMS was observed in all subjects from the first night of each
stay at altitude level because our subjects climbed to an intermediate altitude of 2,400 m using the cable car; subsequently, they
trekked easily to the final altitude of 3,600 m given their good
training level. A slower ascent might have been accompanied by
less AMS. Nevertheless, the fast ascent profile of our protocol
magnified the beneficial effects of either hypnotic that was found
SLEEP, Vol. 30, No. 11, 2007
to alleviate AMS. Because AMS was not decreased with time
spent in placebo control conditions, the positive effects of hypnotics on AMS can be attributed to their pharmacological properties and not to a hypothetical process of adjustment to altitude.
In conclusion, zolpidem and zaleplon induced beneficial effects
on abnormal sleep architecture observed in trekkers during three
nights spent at an altitude of 3,613 meters. Such positive effects
on sleep were obtained without any impairment on ventilation.
Furthermore, acute mountain sickness was found to be alleviated
under either drug. These results suggest that climbers may safely
use both drugs. There was no evidence for an improvement of
cognitive functions or mood in our young and well-trained militaries at altitude level, despite an improved sleep efficiency index
under zaleplon or zolpidem. It would be interesting to perform
further studies in less-trained subjects, such as tourists.
Therefore, the important finding of our study resulted in the
subsequent claim: zolpidem or zaleplon might alleviate altituderelated sleep disturbances without any detrimental effects on ventilation throughout a period of three days spent at high altitude in
real environmental conditions. So, either hypnotic might safely
reduce the main complain from climbers at high altitude.
ACKNOWLEDGMENTS
We are grateful to the Staff and the trainees of the Military
School of High Mountain (EMHM), Chamonix, France, for their
helpful assistance. We wish to extend our thanks to Marc Enslen,
NESTEC SA, for performing the statistical analysis of the study,
and to Frances Ash-Béracochéa for her helpful assistance in reviewing the English writing of the manuscript.
This study was supported by a grant from Sanofi-Aventis
Group, Paris, France.
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