Pharmacotherapy of Insomnia: Focus on Zolpidem Extended Release

REVIEW
Pharmacotherapy of Insomnia: Focus on Zolpidem
Extended Release
J.M. Monti1, D. Warren Spence2, S.R. Pandi-Perumal3, Salomon Z. Langer4
and R. Hardeland5
1Dept. of Pharmacology and Therapeutics, School of Medicine, Clinics Hospital, Montevideo 11300,
Uruguay. 2Sleep and Alertness Clinic, 750 Dundas Street West, Toronto, ON M6J-3S3, Canada.
3Somnogen Inc, 8790 112th Street, New York, NY 11418, U.S.A. 4Euthymia Ltd, 8 H. Rosenblum St.,
apt. 4650, Tel Aviv 69379, Israel. 5Johann Friedrich Blumenbach Institute of Zoology and Anthropology,
University of Göttingen, Göttingen, Germany.
Abstract: The imidazopyridine drug zolpidem (N,N,6-trimethyl-2[4-methyl-phenyl]imidazo[1,2-a]pyridine-3-acetamide)
is a sedative/hypnotic with relative selectivity for α1 subunits of the GABAA receptor/chloride channel complex. Because
of this selectivity and regional receptor distribution, zolpidem is less generalized in its CNS depressive actions than benzo-
diazepines and largely devoid of their major, undesired side- and after-effects, at recommended doses. Zolpidem is rapidly
taken up and distributed, binds extensively to plasma proteins, and is readily inactivated by hepatic cytochrome P450 mono-
oxygenases, especially CYP3A4. Zolpidem is thus a rapidly acting agent which provides effective facilitation of sleep onset.
However, plasma levels of the immediate release (IR) formulation frequently decline too quickly for effective sleep main-
tenance. To address this problem zolpidem extended release (ER) has been developed. At age-specifi c dosages, it increases,
in middle-aged and elderly patients, total sleep time and reduces the number of nocturnal awakenings. Both zolpidem IR
and ER have favorable toxicological profi les. Adverse effects are moderate, frequently in the incidence range of placebos,
and certainly less frequent and severe than those of benzodiazepines. Zolpidem IR and ER are practically devoid of next-day
hangover effects and only infrequently cause rebound insomnia of usually short duration. Both variants of zolpidem have
a limited potential for dependence and abuse.
Keywords: extended release, GABAA receptor, hypnotics, insomnia, sleep, zolpidem
Introduction
Most people experience insomnia at some time during their lives. Because of its high incidence, and
also because its symptoms are usually mild and transient, the importance of insomnia is frequently
underestimated. However, as a chronic disorder, which affects about 10% of the population, its treat-
ment is often challenging and, moreover, it is associated with a substantial number of comorbid
symptoms.1–3 Various conditions are associated with insomnia and can contribute to its development.
They can be related to neurological or psychiatric disorders, which in turn may be aggravated by a
defi ciency of restorative sleep and daytime fatigue. Insomnia can also result from a primary dysfunction
or an age-related decline in the circadian system.
Insomnia is characterized by one or more of the following: diffi culty falling asleep [e.g. sleep onset
latency (SOL) of more than 30 minutes], insuffi cient sleep [e.g. total sleep time (TST) of less that
5.5–6 hours], numerous nocturnal awakenings, early morning awakenings with inability to resume
sleep, or nonrestorative sleep. Common daytime complaints include somnolence, fatigue, irritability,
and diffi culty concentrating and performing everyday tasks. Because insomnia is associated with
reductions in attention span, affected individuals can often be impulsive and experience impaired
judgment, and thus are at an increased risk for having injuries at home or work, or involvement in
accidents while driving. Psychiatric and other medical illnesses, including cardiovascular diseases,
weight gain and glucose intolerance, are other conditions which include insomnia in their overall
symptom complex.4
Correspondence: Prof. Rüdiger Hardeland, Johann Friedrich Blumenbach Institute of Zoology and Anthropology,
University of Göttingen, Berliner Str. 28, D-37073 Göttingen, Germany. Tel: +49-551-395414; Email: rhardel@gwdg.de
Copyright in this article, its metadata, and any supplementary data is held by its author or authors. It is published under the
Creative Commons Attribution By licence. For further information go to: http://creativecommons.org/licenses/by/3.0/. The
authors grant exclusive rights to all commercial reproduction and distribution to Libertas Academica. Commercial reproduction
and distribution rights are reserved by Libertas Academica. No unauthorised commercial use permitted without express consent
of Libertas Academica. Contact tom.hill@la-press.com for further information.
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Monti et al
The International Classification of Sleep these side effects was an important factor leading
Disorders (ICSD-2)5 considers severity criteria to the development of structurally dissimilar non-
as a guide to be applied in conjunction with con-
BZD hypnotics. These included the sedating
sideration of the patient’s clinical status. Mild antihistamines, the melatonin receptor agonists
insomnia refers to complaints of an insuffi cient ramelteon and tasimelteon, certain antidepressants,
amount of sleep almost every night or of not feel-
and the so-called z-drugs, i.e. the cyclopyrrolones
ing rested the following day. There is little or no zopiclone and eszopiclone, the pyrazolopyrimi-
impairment in social and/or occupational func-
dine zaleplon, and the imidazopyridine derivative,
tioning. Moderate and severe insomnia refers to zolpidem (N,N,6-trimethyl-2[4-methyl-
complaints of experiencing an insuffi cient amount phenyl]imidazo[1,2-a]pyridine-3-acetamide)
of sleep every night or of not being rested after (Fig. 1).
the impaired sleep episode, accompanied by
Zolpidem has proved to be a suitable hypnotic,
moderate and severe impairment of social and/or especially with regard to effi cacy in sleep initia-
occupational functioning, respectively. The chal-
tion. As will be discussed below, it is relatively
lenge for clinical treatment is to select the therapy well tolerable and almost devoid of the side
which is most appropriate for these differing effects typically associated with BDZs. The low
degrees of severity.
incidence of side effects is, in part, a consequence
The last several decades have seen an evolution of a relatively short half-life in the circulation.
in thinking about the classes of medications which At usual doses of immediate-release (IR)
are to be preferred for treating insomnia. The zolpidem, the peak plasma concentrations are
benzodiazepines (BZDs) were introduced in attained between about 45 min and 2 h after
the 1970s, and rapidly increased in popularity intake [Ambien® (zolpidem tartrate) 10 mg:
because of their effi cacy and better safety com-
0.9 h],7 a kinetics profi le that corresponds well
pared to the barbiturates, carbamates, chloral with the time course of psychomotor tests,
derivatives and methaqualone.6 In recent years, in which the maximum efficacy was found
however, prescriptions for BZDs have progres-
around 1.5 h followed by a rapid decline.8 The
sively declined, especially because of their asso-
pharmacokinetics of such a short-acting drug,
ciated side effect profi le, including their tendency when given as an IR formulation, may be not
to promote dependence, the occurrence of rebound ideal in terms of promoting sleep maintenance.
insomnia following the withdrawal of short- and To respond to the clinical need for an agent
intermediate-acting derivatives, and the loss of which could reduce the number of noctur-
effi cacy after several weeks of treatment. The nal awakenings, zolpidem extended release
clinical need for medications which did not have (ER; = modified release: MR; = controlled
N
N
CH
CH OH
3
2
N
N
H C
H C
3
3
O
O
N CH
CH
3
N
3
H C
H C
3
3
Zolpidem
M-3
Figure 1. Chemical structures of zolpidem and its main, monohydroxylated metabolite, M-3, which accounts for 80% of the primary products.
Other, moderately abundant metabolites are hydroxylated at the other aliphatic methyl groups. In secondary, urinary metabolites, the aromate-
bound methyl residues can be further oxidized to carboxylic acids.
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Zolpidem extended release
release: CR; Ambien CRTM 12.5 or 6.25 mg; potential for dependence and abuse. Additionally,
Sanofi -Aventis) was developed, the characteris-
the distribution of BZ1 receptors within the CNS
tics of which will be in the focus of this article.
leads to a more specifi c action spectrum. This
receptor subtype is predominantly localized in
lamina IV of the sensorimotor and in the ventral
Mechanism of Action and Preclinical thalamic cortex, but also in olfactory bulb, pons,
Pharmacology
inferior colliculus, globus pallidus, pars reticulata
The imidazopyridine compound zolpidem was of the substantia nigra and the cerebellar molec-
synthesized by Synthélabo Recherche in the early ular layer.20,21 Taken together, the relative α1
1980s,9,10 and its therapeutic potential for the specifi city of zolpidem and the presence of bind-
treatment of sleep disorders was recognized soon ing sites in relevant structures could especially
after.11,12
explain the preservation of deep sleep stages 3
Zolpidem shares with the BDZs the property and 4 by this drug, contrary to the suppressive
of binding to α subunits (the “BDZ receptor”) of deep sleep actions observed with BZDs.22
the GABAA receptor/chloride channel complex,
Consistent with the findings of its binding
however, with a decisive difference in selectivity properties, preclinical studies have shown zolpidem
concerning the subtypes. BDZs are relatively to exhibit predominantly sedative-hypnotic effects,
non-selective in this regard and, therefore, cause although anticonvulsant and myorelaxant activities
antiexcitatory hyperpolarizations in many places have also been reported, however, with a different
in the CNS. These actions lead to more general-
dose dependence. In rats, zolpidem is more potent
ized neuronal inhibitions and numerous effects in suppressing locomotor activity (sedative effect)
exceeding sedation and sleep promotion, such as than pentylenetetrazol-induced convulsions (anti-
anxiolytic, anticonvulsant and myorelaxant convulsant activity) and rotarod performance
actions. The structurally unrelated compound (muscle relaxation). In contrast to zolpidem, the
zolpidem, however, displays a relative, but not BZD hypnotics produce a sedative effect with
absolute selectivity towards a specifi c BDZ bind-
doses which are similar to or greater than those
ing site, the so-called BZ1 receptor (ω1 receptor), producing anticonvulsant or myorelaxant
based on a particularly high affi nity to the α1 effects.23,24
subunit.13–15 Among the GABAA receptors, usu-
To what extent zolpidem interacts with the
ally consisting of α, β, and γ subunits (alternately hypothalamic25 and pontine26,27 sleep switches,
δ subunits), multiple isoforms such as α1–α6, which control sleep induction and sleep stages,
β1–β3, and γ1–γ3, lead to a spectrum of differen- respectively, is less clear, although GABAergic
tially regulated or pharmacologically accessible mechanisms are involved in both of them. In the
variants. The high α1/α5 affi nity ratio of zolpidem case of the hypothalamic sleep switch, which is
can be taken as a characteristic of this com-
strongly infl uenced by the circadian pacemaker,
pound.16 While both α1 and β2 knockout mice the suprachiasmatic nucleus, α4δ-containing
show decreases in sleep time, the α1 knockouts GABAA receptors seem to play a major role,25,28
are considerably more resistant to zolpidem.17 fi ndings that are in accordance with the sleep-
Similar conclusions were drawn from investiga-
promoting actions of gaboxadol and, perhaps, also
tions on H101R mice expressing zolpidem-
with a particular role of extrasynaptic GABAA
insensitive subunits.16 Via α1 binding, zolpidem receptors.28,29 With regard to the pontine REM/
acts as an allosteric modulator of the GABAA non-REM (REM/NREM) switch, the situation is
receptor/chloride channel complex. On the other complicated inasmuch as GABAergic inhibitions
hand, the anxiolytic, anticonvulsant, myorelax-
are present at both sides of the switch.26 Although
ant, ataxic and also several withdrawal effects of NREM sleep is favored by zolpidem, the infl uences
GABAergic sedatives are largely associated of zolpidem on the stage distribution within the
with the α2- and α3-containing receptor com- sleep pattern, apart from deepening sleep, are
plexes, which accounts for zolpidem’s relative moderate. It remains to be clarifi ed whether this
absence of anticonvulsant and myorelaxant switch system is less affected by the drug, or in a
effects.18,19 More importantly for a hypnotic drug, more balanced way. A spectral analysis of sleep
zolpidem’s relative selectivity reduces the EEGs in curarized rats has revealed that its power
probability of withdrawal effects, with their density in non-REM (NREM) sleep is predominantly
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Monti et al
increased in the low frequency band (1.0–4.0 Hz). latter amounting to approximately 2.9 hours.43
In freely moving animals, zolpidem has been found Thus, a reduction of the initial dose from 10 to
to augment the duration of NREM sleep and to 5 mg in the elderly is recommended. These changes
reduce wakefulness. The effect endured during may be partially related to hormonal declines,42
sub-chronic administration with no rebound occur-
but largely reflect an age-related decrease in
ring after abrupt withdrawal.30,31 On the other hand, hepatic metabolism. Accordingly, studies on
variable results have been reported in regard to populations at risk have shown that zolpidem clear-
REM sleep. Depoortere et al30 for instance, ance is impaired in patients with severe hepatic
described an increase of REM sleep in rats recorded insuffi ciency, thus requiring dose reduction, but
during the light period, whereas Renger et al32 not in patients with compromised renal function.
reported the opposite effect.
Therefore, dose adjustment is generally not
required in patients with renal failure.38,43
Zolpidem tartrate ER, in its formulation as
Metabolism and Pharmacokinetic
Ambien CRTM 12.5 mg, consists of a coated two-
Profi le in Healthy Adults
layer tablet. The primary release comprising
and Populations at Risk
about 60% of the content is as fast as that of
Zolpidem is rapidly absorbed and extensively zolpidem tartrate IR 10 mg and the rise in plasma
distributed to body tissues, including the brain. concentration within the fi rst 30 min does not
Bioavailability is reported to be in the range of differ from the IR values. Between 45 and
70%.33 A large fraction is bound to plasma protein 120 min, plasma levels are very similar in healthy
(92.5%), independently of concentrations between male adults, but the ER formulation leads to a
40 and 790 ng/mL. Because of the extensive protein subsequently higher concentration over more than
binding, its direct excretion is negligible and clear-
8 h.7,40,44 The maximum is considerably broad-
ance is predominantly a metabolic one. Zolpidem ened and values between 45 min and 3.5 h differ
is metabolized by several cytochrome P450 mono- only by about 12%.7,21 The mean peak concentra-
oxygenases, but predominantly by CYP3A4, to tion (Cmax) was reported to be 134 ng/mL (range
inactive metabolites.34,35 The principal primary 69–197 ng/mL), at a median Tmax of 1.5 h7,21
metabolite, M-3, which accounts for more than (higher value reported by ref. 40: Tmax = 2.4 h),
80% of the products, is a compound monohydrox-
while the mean AUC was 740 ng × h/mL (range:
ylated at the methyl group of the benzene moiety35 295–1359 ng × h/mL).7 The mean elimination
(Fig. 1). Differently hydroxylated and some further half-life, t½, was 2.8 h (range 1.62–4.05 h). The
oxidized metabolites are also produced, including substantial interindividual variation in Cmax and
compounds carrying carboxyl groups. After oral AUC is largely explained by differences in
administration, the more polar zolpidem metabo-
resorption, but not so much by metabolic clear-
lites, which poorly bind to plasma proteins, are ance. Correspondingly, studies on food effects
readily excreted.33,36–38 Zolpidem carboxylic acid (intake while fasting or 30 min after a meal)
is found as a major urinary product.39
showed that half-life was not changed, whereas
After a single therapeutic dose of 10 mg food intake reduced Cmax and AUC by 30 and
zolpidem IR to healthy adults, peak plasma con-
23%, respectively.7 In view of these fi ndings,
centrations (Tmax) are attained after 45–60 min, but administration of zolpidem ER (and also zolpi-
high levels in the maximum range may be found dem IR) with or directly after a meal should not
up to 2 h,40 and the mean terminal-phase elimina-
be recommended.
tion half-life (t½) amounts to about 2.4 hours.7,21
Concerning the low-dose formulation designed
Zolpidem clearance is reported to be lower in for the elderly (Ambien CRTM 6.25 mg), the fol-
women than in men.41 This is in agreement with a lowing pharmacokinetic parameters were deter-
positive correlation between testosterone levels mined for healthy subjects of 65 years and older:7
and clearance as observed in males.42
Cmax 70.6 ng/mL (range 35–161 ng/mL); Tmax 2.0 h;
The metabolic clearance of zolpidem is reduced AUC 413 ng × h/mL; (range 124–1190 ng × h/mL)
in elderly patients, aged 66 years and older, result-
elimination t½ 2.9 h (range 1.59–5.50 h). Not
ing in increases in maximum plasma concentration unexpectedly, the interindividual variation is larger
(Cmax), area under the concentration curve (AUC), in this group, and for some individuals the higher
and prolonged terminal-phase elimination (t½), the dosage may be more appropriate.
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Zolpidem extended release
Although this has not been studied in detail for although subjects reported a subjective impression
zolpidem tartrate ER (Ambien CRTM), the experi-
of decreased SOL and improved quality of sleep.
ence with IR formulations would imply a caveat Lund et al58 using 10 or 20 mg in 10 subjects
for individuals with hepatic insuffi ciencies as well, reported decreases in NREM sleep latency and
but not so much for those with renal impairment.
stage 1 sleep, at 10 mg. Merlotti et al59 studied the
effects of 2.5 to 20 mg zolpidem in 12 volunteers
Clinical Studies
and found decreases in objectively evaluated SOL
and REM sleep percentage, reductions in the num-
ber of awakenings, while simultaneously total sleep
Basic fi ndings with zolpidem IR during time was increased. Brunner et al60 investigated
normal sleep and in induced, transient the effects of 10 mg zolpidem on subjective and
insomnia
polysomnographic (PSG) sleep measures in
Zolpidem’s suitability as a hypnotic drug in 8 healthy young men and did not detect signifi cant
humans has been investigated in several studies changes in PSG data, except for a reduction in
and results of the IR formulations have been REM sleep, but neither in sleep induction nor in
repeatedly reviewed, though not always in any sleep maintenance.
detail.45–55 With regard to the basic hypnotic prop-
Quantitative EEG spectral analyses in healthy
erties and for reasons of comparison, the main normal sleepers60 revealed that 10 mg zolpidem
fi ndings obtained with zolpidem IR, based on caused a signifi cant depression of power density
questionnaires (subjective self evaluation) and on in the low-frequency range of NREM sleep epi-
objective measures obtained by polysomnography sodes. By contrast, Patat et al61 observed a
(PSG), will be summarized fi rst. The effi cacy end-
signifi cant increase of delta wave power and a
points used in many studies have included sleep reduction of alpha activity after oral (20 mg) or
onset latency (SOL; or latency to persistent sleep: intravenous (10 mg) administration of zolpidem.
LPS), REM onset latency (REMOL), wake time On the other hand, Ferrillo et al62 did not observe
after sleep onset (WASO), number of awakenings, significant differences in slow-wave spectral
total sleep time (TST), sleep effi ciency (SE), qual-
power between placebo and zolpidem 10 mg.
ity of sleep, daytime ability to function, daytime Feinberg et al63 made use of the period-amplitude
alertness, and sense of physical well-being. Various analysis method to determine the effect of zolpi-
populations have been included in studies assess-
dem (10 mg) on delta, sigma, and beta bands of
ing zolpidem’s effi cacy and safety: healthy volun-
night sleep EEG. The amplitude of delta waves
teers, poor sleepers, non-elderly and elderly was signifi cantly reduced, whereas its incidence
patients with chronic primary insomnia, and was slightly but not significantly increased.
patients with secondary or comorbid insomnia.
Sigma and beta waves showed minor changes in
In healthy young and middle-aged adults not amplitude or incidence that did not attain sig-
affected by insomnia, earlier, usually placebo-
nifi cance. As noted by Okuma and Monti,64 dis-
controlled, trials with single-dose treatments in crepancies in the findings of these different
rather limited samples led to the following results. studies could have refl ected variations in experi-
Nicholson and Pascoe,56 double-blind study using mental design, drug dose, and methodology of
10, 20 and 30 mg zolpidem in 6 young and data analysis.
6 middle-aged adults: Decreased stage 2 sleep and
Scharf et al65 used polysomnography and
augmented stage 4 sleep in the young adults, reduc-
subjective reports to study 30 healthy elderly non-
tion in the number of awakenings, of WASO and insomniac subjects and found a significant
stage 1 sleep, and increased stage 3 sleep and reduction of LPS and WASO and increased SE.
REMOL in the middle-aged adults, who also Slow wave sleep (SWS; stages 3 and 4) was not
reported subjective reduction of SOL and improve-
modifi ed. Doses of 10 and 20 mg also caused slight
ment of sleep quality. A double-blind study of but signifi cant decreases in REM sleep.
8 subjects using 10 to 40 mg zolpidem by Blois
The value of studies involving asymptomatic
and Gaillard57 found increases in stage 2 (40 mg) volunteers has qualifi ed signifi cance inasmuch as
and stage 4 sleep (20 and 40 mg) and reductions their sleep variables are within normal limits.
in REM sleep (40 mg), whereas sleep induction However, these investigations, which are based on
and maintenance were not signifi cantly altered, relatively small samples, have a rather preliminary
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Monti et al
character and only a limited number of dependent Subjective effi cacy measures were obtained from
measures. Nevertheless, they show that 5 to 10 mg a questionnaire on the following morning. In terms
zolpidem can induce objectively demonstrable of sleep latency, number of nocturnal awakenings,
hypnotic effects that only slightly disrupt sleep duration and quality of sleep, zolpidem proved to
architecture in subjects with normal sleep.
be superior to placebo. No signifi cant differences
The effects of zolpidem on transient insomnia between the placebo and zolpidem groups occurred
have been studied using the so-called ‘fi rst night with respect to the subjects’ ability to concentrate,
effect’ as a model. Such a disturbance can be drowsiness, anxiety concerning the operation nor
caused, apart from jet lag phenomena, by sleeping condition upon awakening.
in an unfamiliar environment.5 Thus, the sleep of
Walsh et al72 made use of a 3-hour phase-shift
normal subjects is disrupted on the fi rst night in in sleep time as a model of transient insomnia.
the sleep laboratory as compared to subsequent Slightly fewer than 50% of the subjects with nor-
nights.66,67 Using this model, Koshorek et al68 mal sleep did show transient sleep disturbance. In
investigated 224 subjects with no sleep laboratory the group whose sleep was signifi cantly altered,
experience who received placebo or 5, 7.5, 10, 15 zolpidem (5, 10, 15 or 20 mg) reduced LPS,
or 20 mg zolpidem. The study included 8 h of WASO, stage 1 sleep and the percentage of REM
continuous PSG recordings, next-morning inter-
sleep, whereas TST and stage 2 sleep were aug-
views about effi cacy of treatment, and residual mented relative to placebo. Subjective estimates
next-day psychomotor drug effects. Zolpidem of SOL and TST closely corresponded to objective
reduced stage 2 SOL, the number of awakenings, measures. Erman et al73 combined the fi rst night
WASO, and REM sleep, and increased SE, SWS, effect and a 2-hour phase advance in a single night
and REM onset latency. Subjective measures sup-
laboratory-based study protocol, to compare the
ported the reduction of SOL and of the number of effects of zolpidem 10 mg or placebo on sleep
awakenings while increasing total sleep time. No variables in 358 healthy young adults. Zolpidem
detrimental morning effects were detected on per-
signifi cantly reduced the number of awakenings
formance tests. Vogel et al69 conducted a similar and WASO and additionally increased SE, whereas
study on transient insomnia in 225 healthy other-
the percentage of time spent in different sleep
wise non-insomniac adults, using 5, 7.5, 10, 15 stages was not modifi ed. Subjective outcome mea-
and/or 20 mg zolpidem. Again, zolpidem improved sures, including SOL, number of awakenings,
both sleep induction and sleep continuity (reduc-
WASO, TST, and quality of sleep, were also sig-
tion of WASO and an increase in SE). On the other nifi cantly superior to placebo.
hand, it showed a dose-related detrimental effect
The effi cacy of zolpidem for facilitating sleep
on REM sleep (increases of REM onset latency initiation and sleep maintenance as well as for
and decreases in REM sleep). Later, Roth et al70 enhancing subjective daytime alertness and per-
used the fi rst night effect to further compare the formance following a rapid travel across 5–9 time
effi cacy of zolpidem with placebo in a large popu-
zones (jet lag) was evaluated in a double-blind
lation of subjects with normal sleep habits. study by Jamieson et al.74 Zolpidem 10 mg or
Compared to placebo, zolpidem (7.5 and 10 mg) placebo were administered for 3 consecutive nights
signifi cantly reduced LPS, the number of awaken-
following an eastward bound transatlantic fl ight.
ings and WASO, and increased SE. Subjective Compared to placebo, zolpidem significantly
SOL, number of awakenings and quality of sleep increased TST (night 1), improved sleep quality
paralleled the objective fi ndings. SWS was sig-
(nights 1, 2 and 3), and reduced the number of
nifi cantly increased in the 7.5 mg treatment group, nocturnal awakenings (nights 1 and 2), whereas
whereas both the 7.5 and 10 mg groups exhibited SOL and WASO did not differ signifi cantly.
reductions in REM sleep. No signifi cant differ-
In summary, zolpidem tended to improve
ences between zolpidem and placebo groups were disturbed sleep in several models of transient
detected in terms of “morning after” effects, includ-
insomnia in normal sleepers. Disregarding the
ing ability to concentrate, perception of sleepiness, doses used, the most consistent fi ndings included
or drugged feelings. Morgan et al71 studied the reductions in SOL, number of awakenings and
effect of 10 mg zolpidem vs. placebo in a transient WASO, and increases in TST, SE and quality of
insomnia population consisting of 238 pre-surgical sleep. However, in several instances, the subjects
patients on the night before a surgical operation. spent significantly less time in REM sleep.
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Zolpidem extended release
Zolpidem may, therefore, be useful in treating regard has been investigated in 13 studies
transient insomnia associated with acute stress, involving a total of 1757 outpatients and 1807
travel across time zones or sleeping in unfamiliar inpatients.11,12,82–92 Six of the studies used PSG
surroundings.
and either a single-blind or double-blind experi-
mental design to evaluate the effect of zolpidem
IR 10 mg on sleep quality in patients with chronic
Zolpidem IR in sleep pathology—poor primary insomnia. The drug was administered for
sleepers and chronic insomniacs
periods ranging from 7 to 35 nights. In most of the
According to Declerck,75 complaints of poor studies, the patients had not been taking hypnotic
quality sleep occur frequently in general medical medication prior to the study for periods ranging
practice, accounting for 4%–5% of all consulta-
from 4 to 30 nights. The outcome was, again,
tions. Poor sleepers generally do not consider heterogeneous: (1) stage 2 SOL was reduced in
themselves to be insomniacs, despite having dif-
three studies (range: 13.0–40.1 min); (2) WASO
fi culties in getting to sleep and staying asleep. They was decreased in two studies (1 missing value);
usually have no signifi cant psychological symp-
(3) the number of nocturnal awakenings was not
toms and seldom take hypnotic medication.75 Three significantly modified (2 missing values); (4)
studies have assessed the effi cacy of zolpidem on values corresponding to TST were found to be
disrupted sleep of poor sleepers.76–78 In all these increased in three studies (range: 32.0–62.5 min)
studies, investigators made use of a sleep labora-
(1 missing value); (5) SE was increased in three
tory to obtain objective evidence of zolpidem’s studies (range: 3.0%–8.3%) (1 missing value).
effects on sleep induction, continuity measures, NREM sleep architecture fi ndings were: stage 2
and sleep architecture. Taken together, these fi nd-
sleep was increased in three studies; stage 3 and
ings indicate that zolpidem 10 mg can signifi cantly stage 4 sleep were not significantly modi-
reduce stage 2 SOL and WASO (two studies), and fied (3 missing values), whereas total SWS
increase TST (three studies) in poor sleepers. In (stage 3 + stage 4) was increased in two studies
two of the investigations, however, the increase in (2 missing values). In relation to REM sleep vari-
TST only occurred on a limited number of nights. ables, REM latency was increased in one study
Concerning sleep architecture, stage 1 sleep was whereas REM sleep, in min or as percentage of
not signifi cantly modifi ed (two studies), whereas TST, was not signifi cantly modifi ed (1 missing
stage 2 sleep and SWS were increased (two stud-
value). More recent studies have mainly focussed
ies). Zolpidem’s effects on REM sleep duration, on the comparison with other hypnotics93–95 or were
however, were not entirely consistent. Although designed for testing EEG methodologies,96 but
this parameter was increased after 10 mg zolpidem despite these differences in emphasis their fi ndings
in one study, a 20 mg dose of zolpidem was found were consistent with those of the earlier data.
to reduce REM sleep time and to lengthen REMOL
Spectral EEG analyses in patients with moderate-
in another one. Rebound insomnia was reported to-severe chronic primary insomnia under treat-
for the fi rst withdrawal night (one report). Rebound ment with daily doses of 10 mg zolpidem for
effects upon discontinuation were also observed 15 nights showed only moderate effects.97 Power
in another study.79
density of NREM sleep was signifi cantly increased
Among women with subjective complaints of in the delta (0.25–1.0 Hz) band only during the
insomnia quantitative EEG analysis did not reveal fi rst two-hour interval, both during short- and
significant differences between zolpidem and intermediate-term treatments. In contrast to BZD
placebo concerning nocturnal delta activity, which hypnotics, zolpidem did not suppress low fre-
progressively declined in amplitude and duration quency EEG activity in poor sleepers nor in
in either case.80 Benoit et al81 also found that zol-
patients with chronic primary insomnia.
pidem had almost no infl uence on nocturnal delta
In chronic primary insomnia, both the polysom-
activity, even in young individuals with long-
nographic and EEG spectral studies demonstrated
standing histories of poor sleep.
predominantly early nocturnal effects, fi ndings that
Considerable research attention has been given are consistent with the known pharmacokinetics
to the suitability of zolpidem IR for chronic insom-
of zolpidem. Results with zolpidem IR 10 mg
nia, representing the most challenging sleep dis-
indicate that the compound is capable of reducing
order. The effectiveness of zolpidem IR in this stage 2 SOL and WASO, and, with certain
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Monti et al
qualifi cations, can augment TST and SE. With a low potential of causing rebound insomnia,
respect to sleep architecture, zolpidem tended to dependence, or other adverse effects on health.102,103
increase stage 2 sleep and SWS while REM sleep In this respect, evidence from accumulated clinical
was not signifi cantly modifi ed. In summary, these practice and controlled studies tends to indicate
results demonstrate limited suitability of zolpidem that long-term pharmacological treatment of
IR for treating chronic insomnia, especially in insomnia with zolpidem is efficacious and
improving sleep induction. With regard to other safe.104–106 More recent studies on zolpidem ER
objective measures, benefi cial effects were largely over 6 months support this conclusion, as will be
restricted to statistical tendencies or not confi rmed discussed below.
in all studies. However, the subjective rating by
Sateia and Pigeon107 have proposed that
patients or caregivers was sometimes better than long-term treatment with hypnotic medications
the outcome of the objective parameters (details could be used in patients with persistent insomnia,
not included). However, some of the studies are given the qualifi cation that it is not secondary to
affected by methodological shortcomings such as mental disorders, neurological diseases, medical
inadequate sample sizes as well as confounding conditions, nor the effect of a substance of abuse
variables such as age, gender, diagnostic criteria or medication. In addition, advocacy of this
and the simultaneous administration of other psy-
approach is restricted to patients for whom all non-
chotropic drugs.
pharmacological therapies have proven to be
The predominant reduction of stage 2 SOL or ineffective. Circumstances in which the long-term
WASO during the fi rst part of the night, in conjunc-
administration of hypnotic drugs must be discon-
tion with few or no reductions in the number of tinued include the development of tolerance and
nocturnal awakenings, is most easily interpreted dose escalation, the occurrence of severe adverse
to be the result of zolpidem’s less than ideal phar-
events, and the diagnosis of newly developed dis-
macokinetics, i.e. its short elimination half-life and abilities.
lack of active metabolites. This would also explain
Non-nightly hypnotic administration has been
the inconsistencies observed in supporting sleep proposed as an alternative option to nightly drug
maintenance. However, the subjective feeling of intake. To date, information on the effi cacy and
being more refreshed on awakening, as reported safety of non-nightly intake of hypnotic medication
by many patients, should not be underrated, even is available only for zolpidem. Administration of
when not supported by objective measures. There-
10 mg zolpidem tartrate IR for fi ve nights followed
fore, the development of ER formulations of zol-
by two nights of placebo per week for two weeks
pidem appeared to have therapeutic potential, or induced an improvement of sleep that was compa-
was at least justifi ed for improving its pharmaco-
rable to nightly zolpidem treatment in patients with
kinetic profi le.
chronic insomnia. Rebound insomnia did not occur
on the nights during which zolpidem was substi-
tuted by a placebo.108 Nightly and non-nightly
Long-term nightly versus non-nightly
zolpidem treatment were compared using the same
administration
design except that the two placebo nights per week
Despite the proliferation of numerous sleeping were randomly assigned. Again, improvements in
aids, the development of a new sleep promoting sleep quality were equivalent in the two groups of
agent is justifi ed in view of the disruptiveness of patients.109,110 More recently, zolpidem IR 10 mg
primary chronic insomnia to overall health, as well or placebo were administered for 12 weeks to
as by the resistance of the condition to long-term patients with a diagnosis of chronic primary insom-
treatment with classic hypnotics, which, addition-
nia. The patients were instructed to take no fewer
ally, are often linked to undesirable side effects. than three and no more that fi ve pills per week.
The long-term use of hypnotic drugs has been Sleep was evaluated daily with sleep diaries.
generally discouraged on the grounds of risk of Patients receiving zolpidem exhibited an improve-
rebound insomnia, withdrawal reactions and/or ment of sleep induction and maintenance that
dependence.98–101 In fact, this recommendation is persisted over time. There was no evidence of
mainly relevant to the BZDs. The recommendation either rebound insomnia or dose escalation.106
has nevertheless been extended to the recently Although a thorough comparison between the
introduced non-BZD hypnotics, which have only single-dose studies and those with long-term
130
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Zolpidem extended release
treatment would be required to convincingly judge ER was confi rmed in a 6-months randomized,
the progress, the currently available data suggest double-blind Phase IIIb trial on 1018 outpatients
that long-term non-nightly administration of diagnosed with primary chronic insomnia,115,116 on
zolpidem (10 mg) for patients with chronic primary the basis of subjective measures (Patients Global
insomnia is an effective and more conservative Impression and Clinical Global Impression-
alternative to its continued nightly use or infrequent Improvement). Patients taking the drug 3–7 times
repetitions of zolpidem for recurrent symptoms of per week showed consistent improvements in SOL,
insomnia.
TST, number of awakenings, WASO and sleep
quality, and also reported sustained improvements
concerning morning sleepiness and ability to con-
Zolpidem extended release
centrate. In view of the usual diffi culties in long-
While early research had demonstrated the term management of chronic insomnia, these
zolpidem IR’s potential for sleep induction, as well fi ndings are signifi cant, especially because of the
as its effectiveness during the initial hours follow-
effi cacy over a relatively long period of time. In
ing sleep onset,102 the assumption that an ER for-
elderly patients with primary chronic insomnia,
mulation might improve sleep maintenance the low-dose formulation of zolpidem ER 6.25 mg
throughout the night had to be thoroughly tested. proved to be similarly effective, in 3-week studies
In particular, the superiority of zolpidem ER over using both PSG and subjective measures,117–119 in
zolpidem IR should have been of interest, but most accordance with earlier data of the Ambien-CR
clinical studies of the ER formulation were limited Prescribing Information.120
to comparisons with placebo. The relative effi cacy
In addition to subjective sleep parameters, a
of zolpidem ER vs. IR vs. placebo has been par-
study in 752 otherwise healthy employees with
ticularly studied in healthy subjects. In 54 subjects chronic insomnia121 investigated the effect of
who had been awakened 3, 4 or 5 h after adminstra-
zolpidem ER 12.5 mg on work effi ciency, using a
tion of the tablet and exposed to a noise interfering standardized Work Limitations Questionnaire
with resumption of sleep, PSG measurements taken (WLQ). Throughout 24 weeks, highly signifi cant
among the 4- or 5-h post-dose groups showed improvements were reported for the WLQ
greater improvements of LPS associated with parameters of “Time Management” and “Work
zolpidem ER compared to IR.111 Findings were Output.”
consistent with sedation and cognitive impairment
The effi cacy of zolpidem ER was also demon-
data during awakenings. Another double-blind strated in patients with comorbid insomnia and
ER/IR comparison was conducted by Greenblatt major depressive disorder (MDD)122,123 or general-
et al40 in 70 healthy young subjects. Apart from the ized anxiety disorder (GAD),124 in either case with
pharmacokinetic differences, EEG data on the concurrent escitalopram therapy. In a multicenter,
β amplitude demonstrated a signifi cantly stronger double-blind, randomized and placebo-controlled
effect of ER compared to IR, for both 0–8 h and Phase I and II study,122 adult MDD patients
3–6 h after sleep onset.
(21–64 years) were investigated (Phase I: 8 weeks,
Several placebo-controlled studies have been completed by 119 subjects treated with zolpidem
conducted in patients with primary chronic insom-
ER/escitalopram and 125 with placebo/escitalopram;
nia. In 212 middle-aged subjects (completed by Phase II: additional 16 weeks, completed by 67 and
192 patients) treated nightly for 3 weeks,112 PSG 60 patients, respectively). Signifi cant improve-
(on nights 1/2 and 15/16) and subjective measures ments were observed in most relevant subjective
(several nights) revealed often highly signifi cant sleep measures (TST, WASO, nocturnal awakenings;
improvements in sleep quality, in particular with sleep quality, SOL in Phase I, but not Phase II), and
respect to LPS, WASO during fi rst 6 h of sleep, also in parameters of next-day functioning (morn-
PSG sleep effi ciency, as well as self-reported SOL, ing energy, sleep impact on daily activities; and, in
WASO, number of awakenings and TST. In another Phase I, morning concentration). No rebound
study comprising 1025 insomnia patients, based insomnia occurred after discontinuation. Depres-
on self-ratings,113,114 subjective SOL, WASO, sive symptoms remained unchanged. Another
number of awakenings and sleep quality were randomized Phase I and II trial in 379 MDD
improved at a high signifi cance level, as possible patients, using the Sleep Impact Scale (SIS),
with the large samples. The effi cacy of zolpidem showed likewise improvements of sleep impact.123
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Monti et al
In GAD patients (21–64 years), a multicenter, category C, concomitant use of CNS depressants,
double-blind, placebo-controlled study of 8 weeks worsening of psychiatric disorders (in particular,
duration (completed by 116 subjects treated with depression), and, individually possible but never-
zolpidem ER/escitalopram and 126 with placebo/
theless rare, withdrawal effects. Drug interactions
escitalopram), also demonstrated significant are known or can be expected for substances inter-
improvements in TST, WASO, SOL, sleep effi -
fering with CYP3A4, such as the inhibitors
ciency, and also next-day morning energy, morning ciprofloxacin, clarithromycin, erythromycin,
concentration, and sleep impact on daily activities.124 doxycycline, fl uoxetine, fl uvoxamine, isoniazid,
Again, no rebound insomnia was observed, and no or verapamil, which lead to reduced metabolic
substantial change in the psychiatric symptoms.
clearance, whereas CYP3A4 inducers such as
carbamazepine, phenobarbital, phenytoin or rifam-
picin (rifampin) can substantially decrease plasma
Safety and Adverse Effects
levels and effi cacy of zolpidem.7,21,128 Rifampicin
With regard to the relatively similar phamacokinetic given 17 h before zolpidem caused reductions of
time courses of zolpidem IR and ER, adverse AUC by up to 73%. The relevance of interactions
effects should be expected to be mainly the same, mentioned can be individually variable, especially
except for the possibility of differences seen on the when the main effects of the drugs are CNS
next day. In fact, the safety profi les of the two targeted. This is the case with, e.g. fl uoxetine,
formulations were very similar.125,126 The most which only moderately enhances blood levels of
commonly observed adverse events associated with zolpidem,129,130 but, in its capacity as a serotonin
the use of zolpidem IR had been headache, drows-
uptake inhibitor, can lead, when coadministered
iness, dizziness, nausea, diarrhea, and myalgia, but with zolpidem, to hallucinations in individual
these complaints occurred only with moderate cases.131,132 This combination may also favor
frequency. Headaches and dizziness were some-
dependence,133 which is otherwise rare with zol-
times even less than in placebo groups.114 The pidem. Concomitant use of zolpidem and ethanol
nature of adverse events reported in adult patients has shown additive effects,128 fi ndings which are
receiving zolpidem IR 10 mg was similar to that in accordance with the actions of these compounds
described in studies that included elderly patients at the GABAA receptor level in animal studies.134
being given zolpidem IR 5 mg.53,127 The most
No indications exist for mutagenic, carcinogenic
commonly observed adverse events observed in or reproductive effects of zolpidem, and no tera-
adults and elderly patients treated with zolpidem togenic potential was demonstrable during prena-
ER (at daily doses of 12.5 and 6.25 mg, respec-
tal development, but some effects of reduced
tively) were next-day somnolence, headaches, and ossifi cation were detected at high doses in rats,
dizziness.7,99,120
which gave rise to the recommended precaution in
As in most medications, strict contraindications pregnancy category C.21 In rats, the no-effect dose
for zolpidem ER exist only for hypersensitivity to of embryo/fetal toxicity was 4 mg zolpidem
the drug itself or to other ingredients of the base/(kg × d).
tablets.21 Rare cases of presumably anaphylactic
Zolpidem contrasts with BDZs regarding after-
responses with angioedema, dyspnea, nausea, effects, behavioral and cognitive impairments. At
eventually throat closing have been observed,21 but recommended doses, zolpidem IR usually causes
these should be regarded as exceptional and are only minimal rebound insomnia.49,98 On the other
found with numerous medications. It should be hand, there is objective evidence of impaired sleep
noted that the experience with zolpidem and con-
in the elderly on the fi rst post-treatment night at
comitant systemic illnesses is still rather limited. levels above the 5 mg dose, which is recommended
Nevertheless, several reasons for precaution have for this clinical group.135,136 Rebound insomnia has
to be considered and require surveillance of the been described during the fi rst night after abrupt
patient.7,21 These include hepatic impairment discontinuation of zolpidem ER 12.5 mg in adult
(including reduced hepatic metabolism in the patients with chronic primary insomnia.112
elderly), concomitant use of CYP3A4 inhibitors,
Impairment of short-term memory, which is a
respiratory diseases, as with sedative/hypnotics in particularly undesirable effect of BZD hypnotics,
general, (especially sleep apnea and chronic has been also investigated in the case of zolpidem.
obstructive pulmonary disease), pregnancy Controlled studies in adults utilizing objective
132
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