Accepted Manuscript

Title: Zolpidem’s use for insomnia

Author: Jaime M. Monti MD David Warren Spence Kenneth

Buttoo Seithikurippu R. Pandi-Perumal

PII: S1876-2018(15)30026-5
DOI: http://dx.doi.org/doi:10.1016/j.ajp.2016.10.006
Reference: AJP 968

To appear in:

Received date: 8-10-2015

Revised date: 11-9-2016
Accepted date: 9-10-2016

Please cite this article as: Monti, Jaime M., Spence, David Warren, Buttoo, Kenneth,
Pandi-Perumal, Seithikurippu R., Zolpidem’s use for insomnia.Asian Journal of
Psychiatry http://dx.doi.org/10.1016/j.ajp.2016.10.006

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 1

Zolpidem’s use for insomnia

Jaime M. Monti1,CA, David Warren Spence2, Kenneth Buttoo3,Seithikurippu R. Pandi-Perumal4

1
Department of Pharmacology and Therapeutics, University of the Republic School of Medicine,
Montevideo, URUGUAY.
2
652 Dufferin Street, Toronto, ON M6K 2B4, CANADA
3
Sleep Disorders Center, 601 Harwood Avenue South, Alax, ON L1S 2J5, CANADA
4
Somnogen Canada Inc, College Street, Toronto, ON, CANADA

Corresponding author

Jaime Monti, MD,

Department of Pharmacology and Therapeutics.
University of the Republic School of Medicine,
Montevideo, URUGUAY.
jmonti@mednet.org.uy

Highlights
 Both, zolpidem immediate-release (IR) and extended-release (ER) have considerable
advantages when compared to the benzodiazepine derivatives, the cyclopyrrolone
agents zopiclone and eszopiclone, and pyrazolopyrimidine derivative zaleplon.
 Among these a aredvantages include their more favorable side-effect profiles for next-
day hangover effects and potential for producing rebound insomnia, development of
tolerance, and potential for dependence and abuse.
 2

Abstract
Zolpidem is a short-acting non-benzodiazepine hypnotic drug that belongs to the
imidazopyridine class. In addition to immediate-release (IR) and extended-release (ER)
formulations, the new delivery forms including two sublingual tablets [standard dose (SD) and
low dose (LD)], and an oral spray form have been recently developed which bypass the
gastrointestinal tract. So far, Zolpidem has been studied in several clinical populations: cases
poor sleepers, transient insomnia, elderly and non-elderly patients with chronic primary
insomnia, and in comorbid insomnia.
Peak plasma concentration (Tmax) of zolpidem-IR occurs in 45 to 60 min, with the terminal
elimination half-life (t½) equating to 2.4 h. The extended-release formulation results in a higher
concentration over a period of more than 6 h. Peak plasma concentration is somewhat shorter
for the sublingual forms and the oral spray, while their t½ is comparable to that of zolpidem-IR.
Zolpidem-IR reduces sleep latency (SL) at recommended doses of 5 mg and 10 mg in elderly and
non-elderly patients, respectively. Zolpidem-ER at doses of 6.25 mg and 12.5 mg, improves
sleep maintenance in elderly and non-elderly patients, respectively, 4 h after its administration.
Sublingual zolpidem-LD (5 mg) and zolpidem oral spray are indicated for middle-of-the-night
(MOTN) wakefulness and difficulty returning to sleep, while sublingual zolpidem-SD (10 mg) is
marketed for difficulty falling asleep.
With their array of therapeutic uses and their popularity among physicians and patients; this
review describes the clinical pharmacology, indications and uses, identifying withdrawal
symptoms, abuse and dependence potentials, and adverse drug reactions are discussed.

Abbreviations
CAP cyclic alternating pattern
Cmax maximum plasma concentration
CNS central nervous system
ER extended-release
GABA γ-aminobutyric acid
GAD generalized anxiety disorder
IR immediate-release
LPS latency to persistent sleep
MDD major depressive disorder
 3

MOTN middle-of-the-night
NREMS non-rapid-eye-movement sleep
REMS rapid-eye-movement sleep
SE sleep efficiency
SOL sleep onset latency
SWS slow wave sleep
t½ terminal elimination half-life
Tmax peak plasma concentration
TST total sleep time
WASO wake time after sleep onset

Keywords
Hypnotic drugs; Insomnia disorder; Sleep; Non-rapid eye movement sleep; Rapid eye
movement sleep; Zolpidem.

Introduction
The identification in the nineteen seventies of high affinity stereospecific receptors for
benzodiazepines and the subsequent use of this class of drugs represented a significant
breakthrough in the clinical treatment of insomnia. Their effectiveness and safety compared to
the barbiturates, carbamates, and methaqualone focused considerable interest on the
benzodiazepines and led to their use as the preeminent pharmacological agents for treating
insomnia and allied sleep disorders (Harvey, 1980). In recent years however prescriptions for
benzodiazepines have progressively declined due to dissatisfaction with their adverse side
effect profile. These well documented effects have included their tendency to induce
somnolence, dizziness, mental confusion, fatigue, rebound insomnia, dependence and abuse.
These effects represented significant obstacles to patient acceptance and prevented the more
widespread use of benzodiazepines for disturbed sleep. These concerns thus stimulated
 4

research interest in other agents which had the beneficial sleep-promoting properties of
benzodiazepines but without their drawbacks. This interest led to the development of a
structurally dissimilar group of nonbenzodiazepine derivatives, including the cyclopyrrolone
agents zopiclone and eszopiclone, the imidazopyridine derivative zolpidem, and the
pyrazolopyrimidine compound zaleplon, all of which are now currently indicated for the
treatment of insomnia.

Chemistry

Zolpidem (N,N,6-trimethyl-2[4-methyl-phenyl]imidazo[1,2-a]pyridine-3-acetamide hemitartra-

te) is a hypnotic agent that belongs to the imidazopyridine class. It was synthesized by
Synthelábo Recherche in the early 1980s, and following its release into the market, its
therapeutic potential for the treatment of sleep disorders was quickly recognized.

Insomnia: diagnostic criteria

Insomnia is a complaint characterized by one or more of the following: difficulty falling asleep
[sleep onset latency (SOL) = > 30 min], insufficient sleep [total sleep time (TST) = < 5.5- 6 hours],
numerous nocturnal awakenings, increased wake time after sleep onset [WASO], early morning
awakenings with inability to resume sleep, or non-restorative sleep. Common daytime
complaints include somnolence, fatigue, irritability, and difficulty concentrating and performing
everyday tasks. In addition, subjects with a diagnosis of insomnia are at risk for injury,
drowsiness while driving, and illness (American Academy of Sleep Medicine, 2014).

The International Classification of Sleep Disorders (American Sleep Disorders Association, 1997)
advocates the application of severity criteria in addition to a consideration of the patient’s
clinical status as guides to be used for the diagnosis of the disorder. The criteria for mild
insomnia require that patients complain of not having a sufficient amount of sleep almost every
night or of not feeling rested the following day. Despite having these symptoms there must be
little or no impairment of social or occupational functioning. Moderate to severe insomnia
refers to nightly complaints of having insufficient sleep or of not feeling rested the following
 5

day, accompanied by a moderate to severe impairment of daytime activities, including social

and/or occupational functioning.

Insomnia has been classified into three major subtypes, including sleep-onset insomnia, sleep-
maintenance insomnia, and insomnia characterized by early morning awakenings. These
symptoms show considerable variation in individual patients however and the respective
patterns are not always stable over the course of time (Hohagen et al., 1994). The instability of
these symptoms therefore must be taken into consideration when determining the appropriate
drug for the treatment of the disorder. Short acting hypnotic for instance would cease to be
effective for many patients who received an initial diagnosis of sleep onset insomnia. An
effective treatment program for insomnia therefore requires that the clinician take into
consideration the dynamics of the sleep disorder over time and with attention to variations in
its presentation in particular patients.

Mechanism of action of zolpidem

Due to its inhibitory actions γ-aminobutyric acid (GABA) is of particular interest for its
associated sleep promoting properties. Additionally it has been found that hypnotic drugs
which accomplish their sleep inducing actions by selectively affecting GABA receptors are the
most therapeutically useful (Möhler, 2010).

A number of sub classes of GABA receptors, including GABAA, GABAB, and GABAC, are receptors
which have now been characterized in the central nervous system (CNS) of several species
including man. Several hypnotic agents including the benzodiazepines, cyclopyrrolone
(zopiclone, eszopiclone), imidazopyridine (zolpidem), and pyrazolopyrimidine (zaleplon)
derivatives target the GABAA receptor as their site of action. These different classes of hypnotic
drugs modulate GABAergic function through different GABAA receptor subtypes, defined by the
subunits that participate in the receptor assembly. The majority of GABAA receptors consist of
α, β, and γ subunits which contain multiple isoforms or variants: α1-α6, β1-β3, and γ1-γ3 (Möhler,
2010).

Different experimental approaches including gene knockout strategies and knock-in point
mutations have been used to analyze GABAA receptors. The integrity of the α1 subunit has been
 6

shown to be critically important for the sedative/hypnotic activity of the benzodiazepines. The
α2- and α3-containing receptors on the other hand are mediators of anxiolytic, anticonvulsant,
myorelaxant, ataxic and withdrawal effects which are associated with the benzodiazepines
(Atack, 2005; Rudolph and Möhler, 2006). Zolpidem also binds to the GABAA receptor in a
manner similar to that of the benzodiazepine hypnotics, but unlike the benzodiazepines it
shows more selectivity for the α1 subunit (Ator and McCann, 2005; Niddam et al., 1987; Langer
et al., 1992). These two agents’ differential effects on sleep architecture could possibly be
explained by their respective modes of action as well as zolpidem’s lower incidence of adverse
events, including reduced amounts of rebound insomnia, tolerance, dependence and abuse.

Zolpidem has been shown to promote sedative, anticonvulsant, and myorelaxant states in
preclinical studies. In rats however zolpidem is relatively more powerful in reducing locomotor
activity (sedative effects) than in suppressing pentylenetetrazol-induced convulsions
(anticonvulsant effects) (Monti et al., 2008). Zolpidem also extends the duration of non-rapid-
eye-movement sleep (NREMS) and reduces wakefulness in freely moving animals. These effects
persist with subchronic administration of the drug, with no rebound effect occurring following
the drug’s abrupt withdrawal (Depoortere et al., 1988). Results of studies on zolpidem’s effects
on REM sleep (REMS) have been more varied. In a relevant study reductions of the behavioral
state have been shown to occur during the light period of the light/dark cycle (Renger et al.,
2004).

Pharmacokinetics and metabolism

The currently available formulations of zolpidem include an immediate-release (IR) and

extended-release (ER) preparations. Additionally, new delivery forms including two sublingual
tablets and an oral spray have now been developed which bypass the gastrointestinal tract.
Zolpidem-IR (Ambien - Sanofi) and zolpidem-ER (Ambien CR - Sanofi) are rapidly absorbed after
oral administration in healthy subjects. However an absolute bioavailability of 70% exists
following a substantial first pass metabolism in healthy subjects and this is not affected by the
dose nor the duration of administration. In laboratory animals which have undergone injections
of zolpidem the drug shows a generally homogenous distribution throughout the body. The
 7

highest concentrations of the drug occur in the glandular tissues and fat, whereas the lowest
concentrations are in the CNS. The clearance of the drug is primarily a metabolic one inasmuch
as approximately 92% of it is bound to plasma protein. In patients with liver cirrhosis and in
chronic uraemics the fraction of unbound zolpidem is augmented. Peak plasma concentration
(Tmax) of zolpidem-IR occurs in 45 to 60 min, and the terminal elimination half-life (t½) equates
to 2.4 h. The inactive metabolites of zolpidem are eliminated primarily through renal excretion
(Thenot et al., 1988; Durand et al., 1992; Fraisse et al., 1996; Drover, 2004).

The two-layer tablet formulation of zolpidem-ER 12.5 mg permits the biphasic release of the
drug. During the primary release phase 60% of the content is released as quickly as that which
is found in zolpidem-IR with a consequent elevation in plasma concentration occurring in the
first 30 min which does not differ from that of the IR values. Between 45 and 120 min after
administration of either formulation plasma levels are very similar in healthy subjects, although
the ER formulation results in a higher concentration over a period of more than 6 h.

The pharmacokinetic action of zolpidem-IR has been compared in healthy subjects who are
fasting or 20 min following a meal. It has been found that following food ingestion the mean
Tmax was extended by 60%. As a consequence it is not recommended that the hypnotic drug be
given with or immediately following a meal (Drover, 2004).

Presently, there are two sublingual forms of zolpidem, a low dose [LD - 3.5 and 1.75 mg
(Intermezzo - Transcept Pharmaceuticals)], and a standard dose [SD - 10 and 5 mg (Edluar -
Meda Pharmaceuticals)]. The duration of action of sublingual zolpidem-LD at the available
dosages of 3.5 mg and 1.75 mg is approximately 4 h for patients who experience middle-of-the-
night (MOTN) awakenings. A similar duration of action is observed following the administration
of sublingual zolpidem-SD at the available dosages of 10 and 5 mg for the treatment of sleep-
onset insomnia (Staner, 2015).

In the oral spray variant of zolpidem (Zolpimist-NovaDel Pharma), which is sprayed directly into
the mouth over the tongue, each metered actuation of the oral solution provides 5 mg of
zolpidem in 100 µL. This variant has a potential benefit in promoting a more rapid rise of drug
blood levels and consequently a faster onset of action (Neubauer, 2010).
 8

Studies of zolpidem-IR and zolpidem-ER in the elderly and in patients with severe hepatic
insufficiency or compromised renal function have concluded that the dose of the drugs should
be 5 and 6.25 mg, respectively (Greenblatt and Roth, 2012). Dosage adjustment applies also for
sublingual zolpidem. Thus, the 5 mg and the 1.75 mg dose should be indicated in elderly and
debilitated patients with an insomnia disorder, and patients with a major depressive disorder or
a hepatic impairment (Staner, 2015).

The finding of a gender effect on zolpidem metabolism characterized by 45% higher area under
the curve (AUC) and Tmax values in women than men led to the recommendation to reduce
zolpidem-IR and sublingual zolpidem-SD from 10 to 5 mg, and zolpidem-ER from 12.5 to 6.25
mg. No change was proposed with respect to sublingual zolpidem-LD (Greenblatt et al., 2013).

Clinical efficacy

The efficacy of zolpidem in clinical applications has been evaluated primarily by objective
measures based on polysomnography and on questionnaires (subjective self-evaluation). In
these measures the principal end points for evaluating efficacy have included SOL, latency to
persistent sleep (LPS), WASO, number of awakenings, TST, sleep efficiency (SE), quality of sleep,
fatigue, daytime sleepiness, cognitive impairment, mood disturbance, impaired work function
and impaired interpersonal function.

Studies of zolpidem immediate-release (IR) in subjects with transient insomnia

Transient symptoms of insomnia can be provoked in normal subjects by special circumstances

such as jet travel across multiple time zones (jet lag) or by sleeping in an unfamiliar
environment (American Sleep Disorders Association, 1997). Inasmuch as the first night of
polysomnographic testing, as compared to subsequent nights, is often associated with sleep
disruption (Webb and Campbell, 1979; Browman and Cartwright, 1980), this “first night effect”
has been taken as a model of transient insomnia, and has been used in a number of studies to
evaluate the effects of various sleep medications.

The effect of zolpidem-IR on insomnia in healthy adults who slept in a sleep laboratory for one
night was assessed by Koshorek et al. (1988). The study which included 224 subjects who were
 9

naïve to sleep laboratory testing, involved assigning the subjects to one of six treatment groups
(placebo, zolpidem-IR 5, 7.5, 10, 15 or 20 mg). Continuous polysomnographic recordings were
carried out during the 8 hours that they spent in bed. Upon arising in the morning the subjects
were interviewed to evaluate their sleep experience and the possible occurrence of any
residual psychomotor drug effects. Subjects who took zolpidem-IR showed superior sleep
profile effects when compared to other subjects who had taken placebo. Stage 2 sleep latency,
the number of awakenings, WASO, and REMS in min were significantly reduced by zolpidem-IR.
Additionally, SE, slow wave sleep (SWS) (stage 3 + 4), and REM latency were increased.
Performance testing did not reveal any adverse effects associated with zolpidem-IR.

A similar experimental design (first night effect) was used to evaluate the effects of zolpidem-IR
(5, 7.5, 10, 15 and/or 20 mg) on transient insomnia in 225 healthy noninsomniac adults (Vogel
et al., 1988). Both sleep induction and sleep continuity were improved by zolpidem-IR, and
additionally reductions in WASO and increases in SE were observed. Nevertheless zolpidem-IR
had an adverse effect on REMS which was dose related (it increased REM latency and
decreased the amount of REMS).

The first night effect was additionally used by Roth et al. (1995) to compare the efficacy of
zolpidem-IR with placebo in a large population of normal subjects. Zolpidem-IR (7.5 and 10
mg), when compared to placebo, was found to significantly reduce the LPS, the number of
awakenings, and WASO. Sleep efficiency was increased. These findings were paralleled by
subjective sleep evaluations concerning SL, the number of awakenings, and the quality of sleep.
In the zolpidem-IR 7.5 mg treatment group SWS was significantly increased whereas subjects in
both the 7.5 and 10 mg groups showed significantly less REMS than the placebo group. No
significant differences were found between placebo and zolpidem groups in terms of “morning
after” effects (reduced ability to concentrate, perception of sleepiness or drugged feelings).

A three hour phase shift in sleep time was used as a model of transient insomnia in a study by
Walsh et al. (1990). In this study slightly less than 50% of the subjects with normal sleep
showed some transient sleep disturbance following exposure to the experimental phase shift.
Among those whose sleep was disturbed zolpidem-IR (5, 10, 15 or 20 mg) was found to reduce
 10

LPS, WASO, stage 1 sleep, and the percentage of REMS, whereas TST and stage 2 sleep were
increased when compared to placebo values. Subjective evaluations of SL and TST were found
to correlate closely with the objective measures.

The effects of zolpidem in a true transient insomnia population was investigated by Morgan et
al. (1997). In this study zolpidem-IR (10mg) or placebo were given in a double blind design to
238 presurgical patients on the night prior to their scheduled surgical operation. Subjective
self-reports based on a questionnaire which was filled out the following morning revealed that
the speed of sleep induction, the number of nocturnal awakenings, and the duration and
quality of sleep were superior in the zolpidem-IR group when compared to the placebo group.
No differences were found between the groups with respect to their ability to concentrate,
their drowsiness, their anxiety about the operation, or their condition upon awakening.

Another study of the first night effect carried out by Erman et al. (1995) employed a 2 hour
phase advance manipulation in a single night laboratory-based study protocol. The
investigators compared the effects of zolpidem-IR 10 mg or placebo on sleep variables in 358
healthy young adults. The number of awakenings and WASO were significantly reduced in the
zolpidem-IR group and additionally SE was increased. Effects on subjective outcome measures,
which included SL, number of awakenings, WASO, TST, and quality of sleep, were significantly
superior in the zolpidem-IR group when compared to placebo.

Jamieson et al. (2001) studied the efficacy of zolpidem-IR on sleep initiation and sleep
maintenance as well as its effect on subjectively evaluated daytime alertness and performance
following jet travel across five to nine time zones. After an eastward bound transatlantic flight
the subjects received zolpidem-IR 10 mg or placebo in a double blind administration over three
consecutive nights. When compared to placebo zolpidem-IR was found to significantly increase
the TST (on night 1) and to improve sleep quality (on nights 1, 2, and 3) as well as reducing the
number of nocturnal awakenings (on nights 1 and 2). During the treatment period SL and WASO
did not differ significantly between the zolpidem-IR and placebo groups.

These studies which were carried out using several models of transient insomnia in normal
sleepers demonstrate that zolpidem-IR has the ability to improve disturbed sleep. Without
 11

taking into consideration the doses the most consistent findings of these studies show that
zolpidem-IR has the ability to reduce SL, the number of awakenings, and WASO and further has
the ability to increase the TST, SE, and quality of sleep.

Studies of zolpidem immediate-release (IR) in patients with chronic primary insomnia

During the period 1988 to 1997 at least 12 studies were carried out on zolpidem’s use in
patients suffering from chronic primary insomnia. These included a total of 1757 outpatients
and 1807 inpatients (Herrmann et al., 1988; Monti, 1989; Wheatley, 1989; Lorizio et al., 1990;
De Roeck and Cluydts, 1991; Kryger et al., 1991; Scharf et al., 1994a; 1994b; Biondi and Casadei,
1994; Monti et al., 1996; Dockhorn and Dockhorn, 1996; Lahmeyer et al., 1997). Six of the
studies used polysomnography and either a single blind or double blind experimental design to
evaluate zolpidem-IR 10 mg in terms of its effect on sleep quality in outpatients with chronic
primary insomnia. In the majority of studies the patients had been free of hypnotic medications
for periods of 4-30 nights prior to participating in the study. Zolpidem-IR was found to decrease
the latency to stage 2 sleep and WASO. There were very limited benefits with respect to
reducing the number of nocturnal awakenings and increasing TST and SE. More recent studies
have mainly focused on the comparison with other hypnotics (Allain et al., 2003; Uchimura et
al., 2006; Erman et., 2008) or were designed for testing EEG methodologies (Terzano et al.,
2003), but despite these differences in emphasis their findings were consistent with those of
the earlier data.

Spectral EEG analyses in patients with moderate-to-severe chronic primary insomnia under
treatment with daily doses of 10 mg zolpidem-IR for 15 nights showed that the drug provided
only moderate sleep enhancing effects (Monti et al., 2000). Power density of NREMS was
significantly increased in the delta (0.25–1.0 Hz) band only during the first two-hour interval,
both during short and intermediate-term treatments. In contrast to BZD hypnotics, zolpidem-IR
did not suppress low frequency EEG activity in patients with chronic primary insomnia.

Studies of zolpidem immediate-release (IR) in patients with comorbid insomnia

There are only a limited number of studies where zolpidem-IR was given to patients with
chronic comorbid insomnia. Quadri et al al. (2009) determined the effect of zolpidem-IR on
 12

excessive daytime sleepiness, overall apnea/hypopnea index and obstructive apnea index in a
group of patients with idiopathic central sleep apnea. A follow-up polysomnogram showed that
administration of zolpidem-IR 10 mg, 30 min before bedtime induced a significant decrease of
both the central apnea and hypopnea frequency and the number of awakenings. In addition,
excessive daytime sleepiness was reduced while oxygenation remained stable.

In a study by Joffe et al. (2010), breast cancer patients who had hot flashes in association with
nocturnal awakenings and who were receiving 75 mg venlafaxine, were randomized to double-
blind treatment with 10 mg zolpidem-IR of placebo for 5 weeks. Augmentation of venlafaxine
with zolpidem-IR significantly improved sleep and quality of life in the affected patients.

Dashti-Khavidaki et al. (2011) compared the effect of zolpidem-IR (10 mg for patients younger
than 60 years old and 5 mg for older participants) and clonazepan (1 mg), on the sleep quality
of hemodialysis patients. Sleep quality was assessed using the Pittsburgh Sleep Quality Index.
While both zolpidem-IR and clonazepam significantly improved sleep quality in the study
subjects, clonazepam was more effective in this respect. Zolpidem however was better
tolerated by the patients.

Zolpidem-IR has been shown to significantly reduce sleep SOL for stage 2 sleep or WASO during
the first part of the night. Nevertheless it has not been demonstrated to reduce the number of
nocturnal awakenings, a finding that is sometimes attributed to its less than ideal
pharmacokinetic efficacy, and more particularly to its short elimination half-life and a lack of
active metabolites. This would also explain the inconsistencies observed in supporting sleep
maintenance. However, subjective assessments of feeling more refreshed upon awakening,
which is reported by many patients, should not be underrated, even when not supported by
objective measures.

Therefore, the development of ER formulations of zolpidem have been pursued as a potentially

productive avenue of research for improving zolpidem’s therapeutic potential, or at least for
improving its pharmacokinetic profile.

Non-nightly administration of zolpidem immediate-release (IR)

 13

It has been proposed that zolpidem in its immediate-release formulation be used on a non-
nightly basis as an alternative to nightly drug intake. Perlis et al. (2004) studied the effects of
zolpidem-IR 10 mg and placebo which were administered to patients with chronic primary
insomnia for a period of twelve weeks. Patients were instructed to take no more than 5 and no
fewer than 3 tablets per week. The patients taking zolpidem showed improvements in sleep
induction and maintenance which persisted over time. Neither rebound insomnia nor dose
escalation occurred in the experimental group.

Long-term nightly versus non-nightly administration of zolpidem-IR in the treatment of

chronic primary insomnia

It is often noted that long term use of hypnotic drugs should be discouraged due to the risk of
rebound insomnia, withdrawal reactions, and/or the promotion of dependence. This
recommendation however is relevant only for the older benzodiazepines. The recommendation
has been extended to recently introduced non-benzodiazepine hypnotics despite the fact that
they have only a small risk of producing these potential adverse effects (Monti, 2004;
Zhdanova, 2004). In this regard evidence from a number of controlled and clinical practice
reports tend to support the generalization that long term pharmacological treatment of
insomnia with zolpidem-IR (and eszopiclone) is efficacious and safe (Sauvanet et al., 1988;
Krystal et al., 2003; Perlis et al., 2004). Nevertheless further studies are required with overnight
sleep testing to confirm objectively these potential associated risks.

It has been proposed that long term treatment with hypnotic medications can be used in
patients who have persistent insomnia but who do not suffer from underlying mental disorders,
neurological diseases, medical conditions, or who have a history of substance or medication
abuse. Advocacy of long term treatment with hypnotics is nevertheless restricted to patients
for whom all non-pharmacological therapies have failed. Circumstances in which hypnotic drugs
must be discontinued include those in which there is evidence that tolerance has developed,
dose escalation, the occurrence of severe adverse effects, and/or the diagnosis of newly
developed disabilities.
 14

An alternative to the nightly usage of hypnotic drugs has been the proposal that they be
prescribed for non-nightly use. At the present time information on the safety and efficacy of
such a regimen is only available for zolpidem-IR. Zolpidem-IR 10 mg has been administered for
five nights followed by placebo for two nights per week for two weeks and has been found to
induce an improvement of sleep that was comparable to nightly zolpidem treatment in patients
with chronic insomnia. In this particular study rebound insomnia did not occur on the nights in
which a placebo was substituted for zolpidem-IR use (Cluydts et al., 1998). In a similar study
the performance of nightly and non-nightly zolpidem-IR was compared using the same design
with the exception that the two placebo nights were randomly assigned. In this study
improvements in sleep quality were also found to be equivalent in both groups of patients
(Hajak et al., 2003). In another study zolpidem-IR 10 mg or placebo was administered for
twelve weeks to patients who had been diagnosed with chronic primary insomnia. The patients
did not take fewer than three nor more than five pills per week. Sleep quality was evaluated
with sleep diaries. The patients in the zolpidem-IR group showed an improvement in sleep
induction and sleep maintenance that persisted over time. Neither dose escalation nor
rebound insomnia were shown by the experimental zolpidem group (Perlis et al., 2004). The
available evidence thus supports the conclusion that long term non-nightly administration of
zolpidem-IR 10 mg is as effective as nightly use in patients with chronic primary insomnia.

Zolpidem extended-release (ER) in patients with chronic primary insomnia

Zolpidem-ER 12.5 mg has been investigated for its effectiveness in treating chronic primary
insomnia in several placebo controlled studies. These studies, which have used both
polysomnographic and subjective measures, have shown that zolpidem-ER 12.5 mg promotes
significant improvements in sleep quality by reducing LPS and WASO during the first six hours of
sleep. In addition benefits have been shown with respect to subjective reports of SOL, WASO,
the number of awakenings, and TST. Krystal et al. (2008) studied the effectiveness of zolpidem-
ER on outpatients with chronic insomnia for a period of six months. Subjective measures were
the principal dependent measure. Those who took the drug 3 to 7 times per week had
improvements in SOL, number of awakenings, WASO, TST, and sleep quality, and additionally
reported sustained improvements with respect to morning sleepiness and ability to
 15

concentrate. Walsh et al. (2008) determined the effectiveness of a lower dose of zolpidem
(zolpidem-ER 6.25 mg) in a sample of elderly patients with chronic primary insomnia. Using
polysomnography and subjective self-reports the formulation was shown to be as effective as
its full strength zolpidem counterpart. The reduced strength formulation is of particular interest
inasmuch as the potential risk of hangover effects from zolpidem-ER 12.5 mg, including drowsy
driving, has led to recommendations that only the 6.25 mg strength be used in older patients.

Zolpidem extended-release (ER) in patients with comorbid insomnia

Zolpidem-ER´s effectiveness has been shown in patients who were suffering from insomnia and
who had additionally been diagnosed with major depressive disorder (MDD) or generalized
anxiety disorder (GAD). In both instances patients were also taking escitalopram therapy. In
this multicenter study adult patients with MDD who were taking escitalopram (10 mg /day) also
received zolpidem-ER (12.5 mg /night) concomitantly or placebo for a period of eight weeks
(Phase I). Those who responded to the therapy continued in the study for an additional 16
weeks of double blind treatment (phase II). By the end of phase I significant improvements had
been shown in SOL, WASO, TST, sleep quality, and next-day functioning. The depressive
symptoms however did not change. At the end of phase II improvements in sleep quality
associated with the zolpidem-ER /escitalopram regimen were limited to an increase in TST (Fava
et al., 2011).

In another multicenter double blind study combination therapy with either zolpidem-
ER/escitalopram or placebo/escitalopram was investigated with GAD patients. Significant
improvements were observed in SOL, WASO, TST, SE, and next day functioning in patients
receiving the hypnotic medication. However, no substantial changes were observed in the
psychiatric symptoms (Fava et al., 2009b).

Sublingual zolpidem in healthy subjects and patients with chronic primary insomnia

Staner et al. (2009) compared the effects of 5 or 10 mg sublingual zolpidem-SD with 10 mg of

zolpidem-IR in a post-nap insomnia model in healthy subjects aged 26.7±5.3 years. Sublingual
zolpidem-SD 10 mg significantly reduced SOL and LPS compared to zolpidem-IR. No significant
difference in SOL and LPS was observed between sublingual zolpidem-SD 5 mg and zolpidem-IR
 16

10 mg. Sleep maintenance, sleep architecture and subjective sleep ratings were not affected by
the treatments.

In a study by Valente et al. (2013) where a two hour phase shift in sleep time was used as a
model of transient insomnia, the effects of sublingual zolpidem-SD 5 and 10 mg were compared
to those of zolpidem-IR 10 mg in healthy subjects. Both doses of sublingual zolpidem-SD
significantly decreased SOL and LPS as compared to zolpidem-IR 10 mg. In addition, subjects
given sublingual zolpidem-SD 10 mg reported a subjective perception of earlier sleep onset.

In another study Staner et al. (2010) compared the effects of sublingual zolpidem-SD 10 mg
with those of zolpidem-IR 10 mg in patients with a diagnosis of chronic primary insomnia (37
males aged 35.7±11 years and 42 females aged 45.5±9.5 years). Sublingual zolpidem-SD
significantly reduced SOL, LPS and improved SE. Other sleep maintenance parameters including
WASO and TST, and subjective sleep were comparable between zolpidem-IR and sublingual
zolpidem-SD.

Roth et al. (2008) determined the efficacy and safety of sublingual zolpidem-LD 3.5 and 1.75 mg
in patients with insomnia characterized by MOTN awakenings. The patients were awakened 4 h
after lights out, given sublingual-zolpidem-LD or placebo, and then kept awake for 30 min, and
allowed to sleep for an additional 4 h. Compared with placebo both doses of sublingual
zolpidem-LD significantly reduced LPS and augmented TST after the scheduled MOTN
awakening. Subjective SOL and TST were also improved by both doses of the hypnotic drug.

Roth et al. (2013) performed an additional study in patients with a diagnosis of chronic primary
insomnia, and a history of at least 3 months of MOTN awakenings occurring 3 or more times a
week. The patients were administered sublingual zolpidem-LD 3.5 mg or placebo for 28 nights.
The hypnotic agent induced a significant reduction of SOL. There was also an increase of TST
that persisted for the first two weeks of treatment only. Neither rebound insomnia nor an
increase in drug utilization was reported during the study.

Zolpidem oral spray in patients with sleep-onset insomnia

 17

Studies of the effects of zolpidem oral spray in patients with insomnia have yet to be carried
out or published. This formulation of zolpidem essentially reflects that of zolpidem-IR tablets
and includes the treatment of insomnia with sleep-onset difficulty as one of its indications
(Neubauer, 2010).

Safety and tolerability

Zolpidem-IR and zolpidem-ER have very similar safety profiles. Several commonly observed
adverse effects do occur however, with use of either variant of zolpidem. These include
headaches, drowsiness, dizziness, nausea, diarrhea, and myalgia. The complaints however
occur only with moderate frequency. Rebound insomnia as well as next day hangover effects
have been observed with zolpidem, but these symptoms are usually of short duration. Several
categories of patients with certain conditions should be monitored closely when they are taking
zolpidem. These include patients with hepatic or renal impairment, those with respiratory
ailments (especially those with obstructive sleep apnea syndrome, and chronic obstructive
pulmonary disease), pregnancy, or concomitant use of CNS depressants (Monti and Monti,
2006). In non-elderly primary insomniacs usage of zolpidem-IR for 12 months has not been
found to promote dose escalation (Roehrs et al., 2011). On the other hand, zolpidem has the
potential for abuse and dependence in patients with a history of drug abuse. There have been
some case reports in which certain behavioral changes have been observed in patients taking
zolpidem-IR. These have included the occurrence of bizarre behaviors, agitation, and sleep-
related complex behaviors, such as sleep eating, sleep walking, sleep conversations, sleep
driving, and sleep shopping, often times with amnesia for the episode (Dolder and Nelson,
2008). It has been shown that zolpidem-IR 10 mg when taken immediately before bedtime, and
allowing 8 h of uninterrupted sleep, did not affect driving performance (Vermeeren et al.,
1995). However, when zolpidem-IR 10 mg was taken in the MOTN, or at higher dosages than
recommended (20 mg, 4h before driving), performance on the driving test was significantly
impaired (Verster et al., 2002). In this respect, an increasing number of traffic accidents have
been related to the misuse of zolpidem-IR (Verster et al., 2007).
 18

Vermeeren et al. (2014) investigated the effect of a single dose of sublingual zolpidem-LD 3.5
mg administered in the MOTN before driving in healthy subjects. A minimal risk of impairing
driving performance was observed when the agent was administered 4 h before driving.

Comparison of zolpidem with other hypnotic drugs

1. Studies comparing zolpidem-IR to benzodiazepines

In a number of clinical trials zolpidem-IR has been compared to benzodiazepine hypnotics.

These have included the long-acting (flurazepam), intermediate-acting (flunitrazepam,
temazepam), and short-acting (triazolam) benzodiazepine hypnotics. Compared to flurazepam
30 mg zolpidem-IR 10 mg or 20 mg has been found to be more effective for sleep outcomes in
patients with chronic insomnia. However, more adverse events have been found to be linked to
zolpidem-IR 20 mg (Fleming et al., 1995).

Zolpidem-IR 20 mg and flunitrazepam 2 mg, and placebo have been compared in healthy young
subjects. In terms of subjective assessments both drugs were found capable of helping the
subjects to get to sleep. In contrast to zolpidem-IR however flunitrazepam increased subjective
ratings of sleepiness and impaired memory performance and psychomotor skills as these were
tested in subjects (Bensimon et al., 1990). Both zolpidem-IR 10 mg and flunitrazepam 2 mg
were found to reduce stage 2 latency in subjects with mild insomnia. Additionally WASO and
REMS percentage were reduced and SWS was improved during the first 2 hours of overnight
sleep testing with zolpidem-IR. Flunitrazepam however, reduced stage 1 sleep during the first 2
hours, increased stage 2 sleep during the second 2-hour period and decreased REMS for the
three 2-hour recording periods. The drug also decreased maximum delta activity.

In patients with chronic primary insomnia the effects of zolpidem-IR 10 mg, flunitrazepam 1 mg
and placebo have been compared. In this study zolpidem-IR did not significantly improve sleep
parameters. In contrast, flunitrazepam did improve sleep maintenance as judged by the
increase in TST and SE. Flunitrazepam had an augmenting effect on stage 2 sleep but decreased
SWS and REMS. Additionally flunitrazepam was associated with reductions in attention span
and memory when compared with zolpidem-IR and placebo, although zolpidem-IR did not
differ from placebo in this regard (Dujardin et al., 1998).
 19

Zolpidem-IR 20 mg has been compared to flunitrazepam 2 mg for severe comorbid insomnia

which is symptomatic of neuropsychiatric disorders. In one study both hypnotic drugs were
shown to promote significant improvements in SL and sleep duration, the number of
awakenings, and WASO when compared to placebo. The two drugs did not differ significantly
with each other in terms of the tested sleep variables. Further, neither zolpidem-IR nor
flunitrazepam had any effect on anterograde memory or psychomotor performance (Frattola et
al., 1990).

Zolpidem-IR 10 mg has been compared to temazepam for the treatment of chronic insomnia in
non-elderly patients. Both zolpidem-IR and temazepam were effective in reducing the time to
sleep onset and the number of nocturnal awakenings and increased TST. Both drugs had similar
efficacy in terms of the studied sleep variables and also in rebound insomnia (Vashaar et al.,
2004). The two drugs were also compared in elderly patients with chronic insomnia. Zolpidem-
IR 5 mg was compared to temazepam 15 mg in this treatment group. The two drugs were
found to be similar in terms of their efficacy and safety profiles and were better than placebo in
the 28 day test period. The effectiveness of both active drugs did not diminish over time
(Leppik et al., 1997).

Zolpidem-IR 10 mg has been compared to triazolam 0.25 mg. Zolpidem-IR was found to
increase SWS and to reduce total wake time and stage 1 sleep. By comparison triazolam
increased stage 2 sleep in subjects with normal sleep. REMS was increased by triazolam during
the withdrawal period, thus suggesting that the drug was associated with the occurrence of
rebound insomnia (Kanno et al., 2000).

Zolpidem-IR 10 mg and triazolam 0.25 mg were also compared in subjects undergoing both
conventional and cyclic alternating pattern (CAP) parameters under conditions of basal and
perturbed environmental conditions (acoustic perturbation produced by a continuous 55 dB
white noise sound). Situational insomnia was produced by acoustic perturbation in the placebo
condition. Zolpidem-IR was found to induce a significant decrease in WASO during the
disturbed nights. Additionally, CAP time and rate were significantly reduced during both
zolpidem-IR and triazolam administration (Parrino et al., 1997).
 20

Zolpidem-IR 10 mg was also compared to triazolam 0.25 mg or 0.5 mg. Both drugs showed
significant efficacy compared to placebo in both poor sleepers and in patients with chronic
primary insomnia. In poor sleepers SOL, TST, SE, WASO, and number of awakenings showed
improvement. Zolpidem-IR was found to increase SWS but reductions in SWS were observed
after triazolam administration (Silvestri et al., 1996).

In patients with chronic primary insomnia both zolpidem-IR 10 mg and triazolam 0.5 mg were
found to increase TST. In the zolpidem-IR group however the increase in TST was associated
with a greater number of sleep cycles. Additionally, zolpidem-IR was found to increase total
wake time whereas REM latency was augmented with triazolam (Monti et al., 1994).
Pronounced symptoms of rebound insomnia were observed in the triazolam group when the
active treatment was discontinued.

In patients with comorbid insomnia zolpidem-IR 20 mg and triazolam 0.5 mg were compared
and both were found to have similar efficacy levels and adverse effects during an
administration period of three months (Pagot et al., 1993).

The effects of zolpidem-IR 5 mg and triazolam 0.125 mg were tested in elderly patients with
chronic insomnia and sleep outcomes were found to be similar for both drugs (Scharf et al,
1991). In contrast to these findings were those of Ochs et al. (1992) who found that zolpidem-
IR 5 mg was more effective than triazolam 0.125 mg in elderly patients with long term
insomnia.

Taken together these findings support the conclusion that in poor sleepers and in patients with
primary and comorbid insomnia zolpidem-IR was similar to benzodiazepines in efficacy.
Compared to zolpidem-IR, more adverse events were associated with benzodiazepine
administration.

2. Studies comparing zolpidem-IR to zopiclone and eszopiclone

Zolpidem-IR 10 mg and zopiclone 7.5 mg were found to significantly increase SWS in a

crossover of three nights of treatment in healthy young subjects. Zopiclone was additionally
found to augment stage 2 sleep and to reduce total wake time and stage 1 sleep. Compared to
 21

baseline, scores on subjective evaluations showed that patients taking zolpidem-IR and
zopiclone were not significantly different in terms of mood nor physical status in the following
morning (Nakajima et al., 2000). Zolpidem-IR 10 mg and zopiclone 7.5 mg were compared in
terms of both conventional and CAP parameters under normal and perturbed (noisy
environment) conditions in middle aged subjects with normal sleep. Acoustic perturbation
produced a situational insomnia in subjects taking placebo. As indicated by the significant
decrease in WASO zolpidem-IR and zopiclone were found to reduce sleep fragmentation.
Further, zolpidem-IR was found to induce significantly lower values in CAP time and rate, thus
indicating its value for diminishing sleep instability (Parrino et al., 1997).

Zolpidem-IR 10 mg and zopiclone 7.5 mg were tested in 479 patients suffering from chronic
primary insomnia. The investigation was performed as a double blind clinical trial over a two
week period. Both zolpidem-IR and zopiclone were essentially identical in terms of improving
sleep outcomes when compared to placebo. However, zopiclone produced more rebound
insomnia and drug related adverse events in a larger number of patients than zolpidem-IR
(Tsutsui, 2001).

Eszopiclone, the S-isomer of racemic zopiclone, and zolpidem-IR were compared against
placebo in terms of their hypnotic efficacy in patients suffering from primary insomnia.
Zolpidem-IR 10 mg and eszopiclone 2.5 and 3 mg were found to be more effective than placebo
for objective measures of SL and TST. Additionally, eszopiclone was found to significantly
reduce WASO. The experimental test groups’ various sleep parameters did not significantly
differ from one another. These included subjective measures next day effects, including
morning sleepiness, daytime alertness, and daytime ability to function (Erman, 2005).

Taken together these findings support the conclusion that zolpidem-IR and zopiclone show no
significant differences in terms of sleep induction. Nevertheless the cyclopyrrolone groups
produced longer TST which could possibly be related to differences in the mean elimination
half-life between the drugs.

3. Studies comparing zolpidem-IR to zaleplon

 22

In two studies the effects of zaleplon and zolpidem-IR were compared with placebo treatment
in adults under the age of 65 who were suffering from chronic insomnia. Zaleplon (5, 10, or 20
mg) was compared with placebo, and zolpidem-IR 10 mg was used as an active comparator.
Several sleep parameters were compared using postsleep questionnaires. These included the
patients’ perceptions of sleep quality, the occurrence of rebound insomnia, and withdrawal
effects. Patients taking zaleplon 10 and 20 mg reported significantly lower levels of SL
compared to placebo at most time points during the four weeks of treatment. Sleep latency
among patients taking zolpidem-IR 10 mg was similarly less than that of placebo during the
same time period. The effectiveness of zaleplon 5 and 10 mg was not significantly different
from that of placebo in terms of the number of awakenings, sleep duration, and sleep quality.
Conversely, zolpidem-IR 10 mg and zaleplon 20 mg were associated with significant
improvements in sleep duration, and sleep quality when compared to placebo. After
discontinuation of zolpidem-IR treatment patients showed evidence of rebound insomnia and
withdrawal symptoms (Elie et al., 1999; Fry et al., 2000).

In elderly patients aged 65 years and older who were suffering from chronic primary insomnia
the efficacy and safety of zaleplon 5 and 10 mg was compared to zolpidem-IR 5 mg. Morning
questionnaires were used to assess sleep quality. Reductions in SL during the fourteen nights
of the double-blind treatment period were shown following administration of zaleplon 10 mg
and zolpidem-IR 5 mg, while zaleplon 5 mg was shown to be effective only during week two.
Zolpidem-IR 5 mg and zaleplon 10 mg were shown to improve subjective TST and sleep quality
although these improvements were shown by zaleplon 10 mg only during week one.
Discontinuation of treatment with zolpidem-IR was associated with evidence of rebound effects
(Ancoli-Israel et al., 1999).

In summary, these findings show that in adult and elderly patients with chronic insomnia the
starting doses of zaleplon and zolpidem-IR were significantly different from placebo but
zolpidem-IR showed more favorable effects than zaleplon on a number of parameters.

Dosage and Administration

 23

For non-elderly patients the recommended starting dose of zolpidem-IR is 10 mg. Elderly
patients and women should be started out with 5 mg of zolpidem-IR immediately before
bedtime. Inasmuch as the metabolic clearance of zolpidem-IR in patients with hepatic
insufficiency is impaired the administration of this specific formulation is to be avoided;
alternatively, with close monitoring a dosage of not greater than 5 mg can be administered
(Monti and Monti, 2006). Zolpidem-ER 12.5 mg is the approved dose for adults, while for
women, elderly or debilitated patients the recommended dose of zolpidem-ER is 6.25 mg
immediately before bedtime.

The initial dose of sublingual zolpidem-SD and LD should be adjusted to 5 mg and 1.75 mg,
respectively, in the elderly, and debilitated patients. A similar approach should be followed with
respect to sublingual zolpidem-SD in women.

In the oral spray variant of zolpidem only one metered actuation of the oral solution (which
provides 5 mg of zolpidem in 100 µL), should be administered to women, elderly and
debilitated patients.

Adverse Events

Several commonly observed adverse events have been associated with zolpidem-IR. These have
included headache, drowsiness, dizziness, nausea, diarrhea, and myalgia. The adverse events
reported in association with zolpidem-IR 10 mg in adult patients has been shown to be similar
to those described in studies that included elderly patients being given zolpidem-IR 5 mg (Monti
and Monti, 2006; Harrison and Keating, 2005).

In adult and elderly patients treated with zolpidem-ER at daily doses of 12.5 and 6.25 mg
respectively, several adverse events have been shown to occur. These have included
somnolence, headache, dizziness and bizarre behaviors (Ambien-CR, prescribing information
from the Sanofi website; http://products.sanofi.us/ambien cr/ambien.CR.html - accessed on
06-09-2016).

The most common adverse events reported for sublingual zolpidem-SD are somnolence,
fatigue, headache, and dysgeusia, while those related to sublingual-zolpidem-LD administration
 24

include headache, nausea and fatigue (Staner, 2015; Roth et al., 2008, 2013). For sublingual
zolpidem-SD 5 and 10 mg, next-day residual effects in terms of vigilance, psychomotor
performance, attention and concentration did not differ from those observed in healthy
subjects and patients with chronic primary insomnia given zolpidem-IR 10 mg ( Staner et al.,
2009, 2010). Long-term safety profile for sublingual zolpidem is currently not available.

Safety and Tolerability

Rebound Insomnia

The accumulated evidence supports the conclusion that zolpidem-IR, when given at
recommended doses, produces minimal rebound insomnia (Holm and Goa, 2000; Lader, 2006).
Some objective evidence has been presented however, that in elderly patients impaired sleep
may occur on the first post-treatment night at levels above the 5 mg dose which is
recommended for this clinical group. Abrupt discontinuation of zolpidem-ER 12.5 mg in adult
patients with chronic primary insomnia has been reported to produce rebound insomnia (Roth
et al., 2006).

Tolerance

Zolpidem-IR 10 mg, when used on either a short term or long term basis, has not been shown
to produce tolerance (Schlich et al., 1991; Maarek et al., 1992; Scharf et al., 1994). Further, the
potential for tolerance with zolpidem-IR 10 mg per day, when used as needed, is very low
(Perlis et al., 2004; Walsh et al., 2000).

Memory Impairment

One of the undesirable side effects of benzodiazepine hypnotics is their tendency to impair
short-term memory. Zolpidem-IR has been investigated with respect to its memory impairment
potential when compared to placebo. Objective measures of memory in controlled studies of
adults have shown no consistent evidence of memory impairment in patients using zolpidem-IR
10 mg (Monti and Monti, 2006).

Withdrawal symptoms, abuse and dependence

 25

There is only limited evidence at this time that abrupt discontinuation of zolpidem promotes
withdrawal symptoms. Some evidence has shown however that discontinuation produces
symptoms of fatigue, nausea, flushing, light headedness, emesis, stomach cramps, panic attack,
nervousness, and abdominal discomfort (Monti et al., 2008).

In patients with a history of drug abuse, studies of abuse potential have shown that abuse of
zolpidem-IR 40 mg was similar to that of diazepam 20 mg. In spite of this zolpidem-IR
dependence and abuse are rare and have been described mainly in drug abusers with or
without an associated psychiatric disorder (Hajak et al., 2003).

Place in Therapy

Both zolpidem-IR and ER have considerable advantages when compared to other sedative
hypnotics in the benzodiazepine group. These include their more favorable side effect profiles
for next-day hangover effects and potential for producing rebound insomnia (which is
considerably milder and less frequent), development of tolerance, and potential for
dependence and abuse.

Although some variations exist, these advantages are also shared with other members of the
z-drug group. The variations that exist within the z-drug group are due partially to
bioavailability and the longer acting ER formulation does have some disadvantages relative to
the IR formulation. In particular these disadvantages may include next day effects, although
these are moderate. Additionally, some behavioral changes have been observed, but these are
uncommon. They nevertheless do occur among certain subgroups of patients. The actual or
assumed disadvantages are nevertheless balanced out in patients for whom discontinuous
sleep is a prominent clinical symptom, and for whom improvements in supporting sleep
maintenance may justify the potential side effects. As part of an overall treatment strategy it is
thus important to distinguish between the different causes and clinical phenomenology of the
different forms of insomnia when considering the various recommendations that have been
made for its treatment.

Perhaps first and foremost a distinction should be made between insomnia that is the result of
other potential etiologies. In the case of forms of insomnia that are induced by circadian phase
 26

shifts such as jet lag or shift work, or by a weak coupling between endogenous circadian
oscillators and various Zeitgebers (time cues; the environmental signals that effect
entrainment), the use of melatonergic agents such as ramelteon or melatonin extended-release
which act as chronobiotics (a chronobiotic can be defined as a substance that is capable of
shifting the phase of the circadian timing system) may be more advisable (Hardeland et al.,
2008; Pandi-Perumal et al., 2006; 2007). On the other hand, if the disturbances are associated
with psychiatric disorders, in particular depression, the course of symptomatology and the
applicability of hypnotics needs to be closely monitored, and any program of co-therapy with
antidepressants and potential interference with their action must be taken into consideration.

Zolpidem-ER has been successfully tested in MDD and therefore may be used for insomnia in
this context (Fava et al., 2011; Lasch et al., 2008) and GAD (Sheehan et al., 2008), but caution is
still advised for long-term treatment using this strategy (Mican and Bird, 2008; FDA Drug Info
website, 2008). In these circumstances an alternate medication of choice would be a drug such
as agomelatine inasmuch as it possesses sleep inducing melatonergic properties with the action
of an antidepressant (Hardeland et al., 2008; Pandi-Perumal et al., 2006; 2009).

For other forms of insomnia zolpidem is an effective treatment option with a very limited risk
for producing dependence and/or rebound insomnia. It does not require dose escalation during
prolonged treatment and is almost free of hangover effects. These potential side-effects
however should be distinguished between the IR and ER formulations.

Zolpidem-IR 10 mg (or 5 mg for elderly patients) should be fully sufficient for insomnia
symptoms which are related to sleep initiation, since the rise in plasma concentration is almost
the same with zolpidem-IR and zolpidem-ER (cf. previous section). Cost considerations could
also be relevant for the ER formulation and other undesired behavioral changes may also be
more frequent. Zolpidem-IR is available as Ambien® 10 or 5 mg, and now also in generic form
(Ivedal®, Nytamel®, Stilnoct®, Stilnox®, Zoldem®, Zolnod®, Zolpihexal®), with these preparations
being less expensive in Africa, Asia, Australia, Europe, Latin America and North America than
the newly developed and patented Ambien CRTM.
 27

If the therapeutic objective however is to improve sleep maintenance the treatment strategy is
entirely different. In this particular situation the ER formulation is clearly indicated. While more
studies which comparatively evaluate zolpidem-IR versus ER would be desirable, the trials
comparing these two formulations that have been carried out thus far (see previous section)
indicate that sleep maintenance is more effectively treated by zolpidem-ER including primary
chronic insomnia. Only if zolpidem-ER fails to achieve its therapeutic objectives should
benzodiazepines be prescribed. The adverse effects of all formulations of zolpidem are certainly
less frequent and less severe than with benzodiazepines. Abuse and dependence following
zolpidem use has mainly been described in drug abusers, with or without a concomitant
psychiatric disorder. Some behavioral changes occurring in a small subpopulation may be a
possible matter of concern which has recently received some attention. However, zolpidem-ER
can be recommended as being both an efficacious and reasonably safe medication, and, where
the goal of sleep initiation is required, zolpidem-IR is an appropriate alternative.

Conclusions

Physicians often face a significant challenge when they need to evaluate and to manage
insomnia. This extremely common problem is a multidimensional disorder and therefore any
approach to its management should consider multimodal therapies relying on pharmacological
and non-pharmacological strategies. In practice the pharmacological approach is used more
commonly than other treatment methods. An alternative for treating the underlying disorder
needs to be considered for patients who experience chronic insomnia in the context of a
psychiatric, neurological, or medical condition. Zolpidem-IR, which has been available in
Europe, North America and Latin America since the 1990’s has been shown to exhibit sedative
effects in doses that are smaller than those that produce anticonvulsant or myorelaxant effects.
Inasmuch as zolpidem acts at the GABAA receptor it is somewhat similar to benzodiazepines but
unlike these hypnotics zolpidem has more selectivity for the a1 subunit, and this could
tentatively explain the difference in its effects on sleep architecture and the lower incidence of
adverse events.
 28

Zolpidem-IR has been studied in a number of different populations for the purpose of assessing
its efficacy and safety. These have included subjects with transient insomnia, poor sleepers,
elderly and nonelderly with chronic primary insomnia, and patients with comorbid insomnia. It
has shown effectiveness in increasing the speed of sleep induction (reduction of SL) at
recommended doses of 5 mg and 10 mg in elderly, women, and nonelderly patients,
respectively. Clinical studies involving subjective evaluations and objective polysomnographic
measures have shown that additionally zolpidem improves sleep maintenance (reduction of
WASO and of the number of awakenings, and an increase of TST). Some studies however
showed that improvement of sleep maintenance was restricted to the first part of the night.
This finding stimulated the development of a modified release formulation which extended the
plasma concentrations beyond four hours after administration. The available evidence suggests
that modified release zolpidem with 12.5 mg is effective in cases of insomnia characterized by
difficulties with sleep onset and/or sleep maintenance in adults with chronic primary insomnia.

The dosage level of zolpidem-ER should be reduced with elderly patients and women however,
in whom it has been demonstrated that a dose of 6.25 mg has the same benefit as the higher
dose with significantly reduced hangover effects. Under certain circumstances the use of
zolpidem-ER is to be preferred over zolpidem-IR. It has been observed for instance that
zolpidem-ER at doses of 6.25 mg and 12.5 mg improves sleep maintenance more effectively
than zolpidem-IR in women, elderly, and non-elderly patients, respectively, 4 h after its
administration.

Sublingual zolpidem-LD (5 mg) and zolpidem oral spray are indicated for MOTN wakefulness
and difficulty returning to sleep, while sublingual zolpidem-SD (10 mg) is administered for
difficulty falling asleep. The initial dose of sublingual zolpidem-SD and LD should be always
adjusted to 5 mg and 1.75 mg, respectively, in women, elderly and debilitated patients, or in
patients with a hepatic disorder.

Zolpidem at the recommended doses is associated with minimal rebound insomnia, according
to most of the evidence that is available. Unlike benzodiazepine hypnotics zolpidem does not
significantly alter values related to SWS and REMS. Some patients do however have difficulties
 29

in tolerating zolpidem therapy. As reviewed above, in direct comparisons with various

benzodiazepines, zolpidem-IR has been shown to be superior in terms of having fewer side
effects. A balanced assessment however requires acknowledgement that zolpidem is also not
completely free of the side effects associated with benzodiazepine therapy. Moreover, in at
least one study a greater number of adverse events were linked to zolpidem-IR 20 mg when
compared to flurazepam 30 mg. Some of the adverse events that have been reported following
zolpidem use, have included headache, drowsiness, dizziness, nausea, diarrhea and bizarre
behaviors. This review has found only limited evidence for the occurrence of a withdrawal
syndrome following zolpidem’s abrupt discontinuation. Generally the complaints occur with
only moderate frequency. Next day hangover effects have been observed with zolpidem, but
these symptoms are usually of short duration. There has been no evidence of development of
tolerance with zolpidem-IR 10 mg when used on either a short term or long term basis.
Clinicians should nevertheless be aware of and monitor signs of potential difficulties some
patients may have in tolerating therapy using zolpidem-IR. In view of the somewhat limited
amount of evidence that has been presented regarding the comparative benefits of zolpidem-IR
and zolpidem-ER, more independently funded studies are warranted to elucidate the tolerance
and withdrawal effects of these two variants of zolpidem.

As more evidence becomes available it may be possible to develop a general stepwise

prescribing heuristic for the appropriate use of zolpidem therapy. Such an undertaking would
require a comprehensive survey of numerous alternative treatment options, which is beyond
the scope of the present article. Nevertheless, the limited evidence that has been considered
here suggests that while zolpidem may be used safely for treating insomnia in MDD in
combination with antidepressants such as escitalopram, and, in at least one study, such
combined therapy treatment has been shown to improve SOL, WASO, TST, SE, and next day
functioning. Its long term use has not been studied however, and a preferred alternative would
be agomelatine. For treating problems of sleep maintenance zolpidem-ER is to be preferred,
but if it fails to demonstrate efficacy, benzodiazepines should be considered. Zolpidem-ER is a
safe and efficacious choice for many types of sleep disorders, but if the goal of sleep initiation is
required, zolpidem-IR is an appropriate alternative. Cautions should be used in prescribing
 30

zolpidem to patients with a history of drug abuse, in whom, dependency symptoms have been
described, irrespective of co-existing psychiatric disturbance. Further independent studies
comparing the effects of zolpidem-IR and zolpidem-ER with alternative agents may extend and
clarify these issues.

Funding Source

This study was partly supported by Programa de Desarrollo de las Ciencias Básicas (Pedeciba-
721419), Uruguay. However, the funders had no role in study design, data collection and
analysis, decision to publish, or preparation of the manuscript.
Conflicts of interest and disclosure Statement

The authors have read the journal’s policy and have the following potential conflicts: This study
was not an industry-supported study. S.R. Pandi-Perumal is a stockholder and the President
and Chief Executive Officer of Somnogen Canada Inc., a Canadian Corporation. This does not
alter his adherence to all the journal policies. He declares that he has no competing interests
that might be perceived to influence the content of this article. All remaining authors declare
that they have no proprietary, financial, professional, nor any other personal interest of any
nature or kind in any product or services and/or company that could be construed or
considered to be a potential conflict of interest that might have influenced the views expressed
in this manuscript.

Acknowledgments

The authors are indebted to the anonymous reviewers for their tremendous feedback and
insightful comments on the earlier draft of the manuscript, which have substantially improved
the content and presentation of this paper. They would also like to thank the Editors for their
generous comments and support during the review process.
 31

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