The_Clinical_and_Forensic_Toxi.pdf

REVIEW ARTICLE

The Clinical and Forensic Toxicology of Z-drugs

Naren Gunja

Published online: 13 February 2013
# American College of Medical Toxicology 2013

Abstract The Z-drugs zolpidem, zopiclone, and zaleplon
were hailed as the innovative hypnotics of the new millen-
nium, an improvement to traditional benzodiazepines in the
management of insomnia. Increasing reports of adverse
events including bizarre behavior and falls in the elderly
have prompted calls for caution and regulation. Z-drugs
have significant hypnotic effects by reducing sleep latency
and improving sleep quality, though duration of sleep may
not be significantly increased. Z-drugs exert their effects
through increased γ-aminobutyric acid (GABA) transmis-
sion at the same GABA-type A receptor as benzodiazepines.
Their pharmacokinetics approach those of the ideal hypnotic
with rapid onset within 30 min and short half-life (1–7 h).
Zopiclone with the longest duration of action has the great-
est residual effect, similar to short-acting benzodiazepines.
Neuropsychiatric adverse events have been reported with
zolpidem including hallucinations, amnesia, and parasom-
nia. Poisoning with Z-drugs involves predominantly seda-
tion and coma with supportive management being adequate
in the majority. Flumazenil has been reported to reverse
sedation from all three Z-drugs. Deaths from Z-drugs are
rare and more likely to occur with polydrug overdose. Z-
drugs can be detected in blood, urine, oral fluid, and post-
mortem specimens, predominantly with liquid chromatog-
raphy–mass spectrometry techniques. Zolpidem and
zaleplon exhibit significant postmortem redistribution.
Zaleplon with its ultra-short half-life has been detected in
few clinical or forensic cases possibly due to assay unavail-
ability, low frequency of use, and short window of detection.
Though Z-drugs have improved pharmacokinetic profiles,

their adverse effects, neuropsychiatric sequelae, and inci-
dence of poisoning and death may prove to be similar to
older hypnotics.

Keywords Zolpidem . Zopiclone . Zaleplon . Poisoning .

Analysis

Introduction

Zolpidem, zopiclone, and zaleplon are non-benzodiazepine
drugs used in the treatment of insomnia and commonly re-
ferred to as the “Z-drugs.” Insomnia is an underrecognized
and undertreated medical condition that leads to lifestyle
impairment, loss of occupational productivity, and potential
physical harm from accidents as well as exacerbation of other
medical conditions. The rate of diagnosed insomnia in the UK
and North America is estimated at 5–15 %, with up to 40 % of
the population experiencing symptoms of daytime sleepiness
[1, 2]. Some studies quote that up to a third of elderly North
Americans are prescribed either a Z-drug or benzodiazepine
for sleep disturbance, an alarming statistic given the risks
associated with hypnotics in the elderly [3].

Traditional therapy for insomnia has predominantly in-
volved the use of benzodiazepines for several decades. Since
the 1980s, development of non-benzodiazepine drugs for the
management of insomnia has been driven by the significant
adverse effect profile of the former group of drugs. The Z-
drugs have unique advantages over benzodiazepines both in
their pharmacodynamic and pharmacokinetic properties. Z-
drugs have significant hypnotic effects by reducing sleep
latency and improving sleep quality, though their ability to
prolong total sleep time is debatable [4]. Currently, there are
three Food and Drug Administration (FDA)-approved, com-
mercially available, non-benzodiazepine drugs in the USA for
the treatment of insomnia: zaleplon, zolpidem, and eszopi-
clone (the active enantiomer of zopiclone) [5].

N. Gunja
NSW Poisons Information Centre,
The Children’s Hospital at Westmead, Sydney, Australia

N. Gunja (*)
Discipline of Emergency Medicine, Sydney Medical School,
University of Sydney, Sydney, NSW, Australia
e-mail: [email protected]

J. Med. Toxicol. (2013) 9:155–162
DOI 10.1007/s13181-013-0292-0

The ideal anti-insomnia drug is a potent sedative during
the night without causing the same residual sedation during
the daytime. Suboptimal clinical and adverse effects of
traditional benzodiazepines have driven the development
of alternative sedative–hypnotic drugs. While hypnosis and
sedation are adequately achieved from oral benzodiaze-
pines, they invariably alter sleep architecture, reduce deep
(stage 3 and 4) sleep, and lead to dependence, tolerance, and
withdrawal [6]. Furthermore, benzodiazepines carry the risk
of residual daytime effects such as impairment of cognitive
and psychomotor function. Like benzodiazepines, the newer
Z-drugs are agonists at the same γ-aminobutyric acid-type A
(GABAA) receptor. However, they possess shorter duration of
action and half-life, do not disturb overall sleep architecture,
and cause less residual effects during daytime hours, making
them more clinically attractive than benzodiazepines.

Initial trials and experience with the Z-drugs were prom-
ising with respect to lower incidence of adverse effects and
reduced potential for dependence and abuse. Over the last
15 years, increasing reports of bizarre and complex behav-
ioral effects from Z-drugs have prompted drug regulatory
agencies to issue warnings and restrictions on the prescrib-
ing, dispensing, and use of Z-drugs [7]. This review focuses
on the pharmacology and toxicology of Z-drugs with respect
to their adverse effect profile, toxicity, and forensic consid-
erations of detection and analysis. Ovid MEDLINE (1980–
Nov 2012), Embase (1980–Nov 2012), and Google Scholar
were searched using the terms: “zolpidem,” “zopiclone,”
“eszopiclone,” “zaleplon” in combination with “mecha-
nism,” “pharmacokinetics,” “detection,” “analysis,” “level,”
“interaction,” “poisoning,” “toxicity,” or “death”. Articles
relevant to human pharmacology, toxicology, and analysis
of Z-drugs were retrieved. Furthermore, the bibliographies
of the retrieved articles as well as textbooks, FDA, and other
drug agency reports were searched for additional relevant
publications. The hypnotic effects of Z-drugs and their
clinical efficacy in treating insomnia are not reviewed here.
Neither does this review examine the purported benefits of
Z-drugs over traditional benzodiazepines in the manage-
ment of insomnia.

Pharmacology

Benzodiazepines primarily cause their sedative–hypnotic
effect by binding non-selectively to the ω1 (BZ1) and ω2
(BZ2) receptor subtypes of the GABAA receptor complex.
This leads to increased binding of GABA, a major inhibitory
neurotransmitter in the central nervous system (CNS), to its
own separate binding site and thereby increases the frequen-
cy of chloride channel opening [8]. Type 1 (BZ1) benzodi-
azepine receptors contain α1β1-3γ2 subunits while BZ2
subtypes contain α2,3,5β1-3γ2 subunits [9]. Sedation and

amnesia are mediated through the α1 subunit, the most
commonly distributed subunit throughout the brain, while
those mediated via the α2 and α3 subunits appear to be
involved in sleep regulation and anxiolysis [10]. Z-drugs
bind to the same binding site as benzodiazepines, both of
which rely on the presence of GABA to exert their effects—
hence the term “GABAergic.” There appears to be differen-
tial binding of Z-drugs to the various GABAA receptor
isoforms.

Zolpidem, an imidazopyridine agent, mediates its effects
largely through activation of the α1-containing GABAA
(BZ1) receptor, though it has some agonist activity at α2
and α3 subunits, and very little at the α5 subunit. Hence,
zolpidem is considered a potent sedative and hypnotic with
minimal anxiolytic efficacy. The standard oral dose is 10 mg
taken at bedtime, though a lower 5 mg dose is recommended
in the elderly or in patients with hepatic impairment.
Zolpidem is also available as an extended-release prepara-
tion (12.5 and 6.25 mg) intended for better management of
sleep maintenance [11, 12]. Treatment duration is com-
monly for 1 to 6 months depending on patient age,
comorbidities, and type of pharmacokinetic preparation
(immediate- or extended-release). Clinical efficacy of
zolpidem for insomnia has been shown in multiple trials to
be comparable to both short-acting and long-acting benzodia-
zepines, with regard to time to sleep onset, duration, and
quality of sleep [13].

Zopiclone is a cyclopyrrolone drug with a chemical
structure unrelated to zolpidem, benzodiazepines, or other
CNS depressants; it has similar pharmacodynamic and phar-
macokinetic properties to zolpidem. It is available as a
racemic mixture of two enantiomers one of which is mar-
keted in the USA, the (S)-enantiomer, eszopiclone.
Zopiclone shows preferential agonist activity at the α1 sub-
unit of the GABAA receptor and its duration of action is the
longest of the Z-drugs, comparable with some short-acting
benzodiazepines. Hence, zopiclone is useful in both
induction and maintenance of sleep. Eszopiclone differs
from its racemic mixture in that it has greater efficacy
at the α2 and α3 subunits. The addition of the R-enantiomer
in racemic zopiclone may augment efficacy at the α1 sub-
unit and potentially lead to increased sedation and residual
effects [14].

Zaleplon, a pyrazolopyrimidine drug, has unique proper-
ties in its receptor affinity as well as pharmacokinetics,
potentially increasing its utility in select sleep dis s.
Zaleplon exerts its effects through selective binding at BZ1
receptors (α1 subunit); it has low affinity and potency at α2
and α3 subunits [10]. It is an ultra-short-acting Z-drug that
has the benefit of reducing sleep latency and can be taken
after trying but failing to fall asleep. Zaleplon, though not
appropriate for sleep maintenance therapy, may be taken for
middle-of-the-night awakening [15].

156 J. Med. Toxicol. (2013) 9:155–162

Pharmacokinetics

The pharmacokinetics of the three Z-drugs are similar in that
they are all rapidly absorbed and have short half-lives.
These characteristics emulate the ideal hypnotic agent, one
with rapid peak levels to reduce sleep latency and fast
clearance to minimize undesirable residual effects. This is
in comparison with short-acting benzodiazepines that have
elimination half-lives around 8–10 h. However, too short a
half-life may be a problem for patients that require sleep
maintenance therapy. Pharmacokinetic properties of Z-drugs
are shown in Table 1; major metabolic pathways are in
italics [10, 12, 15–19].

Zolpidem is approximately 90 % protein-bound and is
extensively metabolized to inactive metabolites by cyto-
chrome P450 enzymes in the liver, predominantly
CYP3A4. Elderly patients and those with hepatic impair-
ment are known to have higher area under curve (AUC),
time to maximal concentration (Tmax), and half-life, neces-
sitating dosage reduction in these patient groups. A newer
sublingual formulation appears to further reduce sleep la-
tency compared with the oral tablet in a subset of insom-
niacs [20]. In January 2013, The FDA released a safety
announcement advising lower than standard zolpidem
doses, particularly in women, due to delayed elimination
and residual daytime effects [21].

Zopiclone has the longest latency and half-life of all the
Z-drugs with potential for residual effects. Although the
pharmacokinetics of eszopiclone is less well characterized,
they appear to be more advantageous than the racemic
mixture. Eszopiclone’s onset is shorter and its offset more
rapid than when the racemic mixture is administered to
healthy volunteers [22, 23]. This may be explained by the
reduced AUC and half-life of the active metabolite, (S)-
desmethylzopiclone, following eszopiclone administration
as compared to racemic zopiclone [22]. Metabolism of
zopiclone involves oxidation, methylation, and decarboxyl-
ation with active metabolites that are renally excreted. It is
the only Z-drug where dosage reduction in patients with
renal impairment is recommended, though accumulation of

metabolites has not been shown in studies; no such reduc-
tion is recommended for eszopiclone.

Zaleplon has the shortest Tmax and half-life providing it
with a rapid onset and offset profile. Its low bioavailability
is due to significant first-pass effect and dosage should be
reduced in patients with hepatic impairment. Hepatic metab-
olism is primarily through the enzyme aldehyde oxidase, with
a minor pathway through CYP3A4, to inactive metabolites.

Drug interactions are predictable for Z-drugs metabolized
by CYP3A4, especially zolpidem and zopiclone. Flumazenil
has been reported to antagonize the sedative effects of all
three Z-drugs [24–27]. Zaleplon has few significant inter-
actions due to its main metabolic pathway being aldehyde
oxidase. Smoking and oral contraceptive use have been
studied in young women, with little effect on zolpidem
kinetics [28]. The combination of zolpidem and benzodia-
zepines has been shown to significantly increase the risk of
hospitalization and hip fractures in the elderly [29].
Clinically significant drug interactions of Z-drugs are shown
in Table 2 [8, 18, 30–34].

Adverse Effects

In general, Z-drugs are well tolerated and the most common
adverse effects include headache, gastrointestinal upset, and
dizziness [4, 6]. For a given dose, adverse reactions appear
to be worse in elderly patients; hence, lower doses are
recommended in this group [4, 16]. A bitter or unpleasant
taste has been reported in a dose-dependent fashion in 10–
35 % of patients taking zopiclone or eszopiclone, enough to
cause cessation of the drug; less common adverse effects
include pruritus, visual disturbance, and xerostomia [19].
The daytime residual effects of hypnotic drugs on cognitive
and psychomotor performance are a major concern in
patients regularly taking these medications.

In March 2007, the US FDA released a list of 13 drugs,
including all three Z-drugs, for which stronger labeling was
required regarding potential risk from complex sleep-related
behaviors, such as sleep-eating and sleep-driving [35]. Of the

Table 1 Pharmacokinetic properties of Z-drugs

Z-drug Tmax (h) Oral bioavailability Elimination t½ (h) Dose range Metabolism

Zolpidem IR 1–2 65–70 % 2.5–3 5–10 mg CYP 3A4, 2C9, 1A2
Zolpidem ER 1.5–2.5 65–70 % 2.5–3 6.25–12.5 mg

Zopiclone 1.5–2 75–80 % 5–6 3.75–7.5 mg CYP 3A4, 2C8

Eszopiclone 1–1.5 75–80 % 6–7 1–3 mg CYP 3A4, 2E1

Zaleplon 0.7–1.4 30 % ∼1 5–20 mg Aldehyde oxidase, CYP 3A4

Major metabolic pathways are in italics. References include [10, 12, 15–19]

IR immediate-release preparation, ER extended/controlled-release preparation, Tmax time to maximal concentration (hours), t½ half-life (hours),
CYP cytochrome P450 enzyme

J. Med. Toxicol. (2013) 9:155–162 157

Z-drugs, the majority of these events appear to relate to
zolpidem though this may merely reflect its higher usage rates
or higher doses [7]. Z-drugs have the potential to cause resid-
ual effects post-awakening that relate to cognition, memory,
parasomnia, and bizarre behavior. They have a profound effect
on nocturnal and next-day psychomotor performance includ-
ing body balance, reaction times, and the ability to multi-task.
Z-drug-induced neuropsychiatric adverse effects such as hal-
lucinations and psychosis have been described for over
15 years, particularly with zolpidem [36–38]. The mechanism
does not appear to be entirely dose-related or due to elevated
plasma concentrations of zolpidem. Drug interactions be-
tween zolpidem and various serotonergic and noradrenergic
agents including SSRIs, venlafaxine, and tricyclic antidepres-
sants have been reported to induce hallucinations [39].

Tolerance, dependence, and withdrawal are all reported
with Z-drugs, though this appears to be less severe and with
lower incidence than for traditional benzodiazepines in the
treatment of insomnia [5, 13, 40, 41]. Withdrawal symptom-
atology resembles that from benzodiazepines, including in-
somnia, delirium, craving, anxiety, tremor, palpitations, and
rarely, seizures and psychosis [42]. Rebound insomnia, upon
immediate cessation of the hypnotic drug, has been reported
with higher doses of zolpidem [43]. This phenomenon has not
been reported with therapeutic doses of zopiclone and zale-
plon [1, 8]. The potential for zolpidem abuse and dependence
in insomniacs is being increasingly recognized with warnings
on product labels appearing since 2004 [44]. Though abuse
potential exists for all Z-drugs, it is more commonly reported
for zolpidem and zopiclone [43, 45].

Analysis and Detection of Z-drugs

The Z-drugs can be analyzed and detected in all common
biological matrices, both clinical and forensic samples. The

principal mode of analysis remains gas or liquid chromatog-
raphy with the detection method of choice being mass
spectrometry, due to its rapid turnaround time and low limits
of quantification [46]. These techniques are also useful in
screening for CNS depressants, including benzodiazepines
and Z-drugs, such as in cases of unknown drug exposure.
With increasing frequency of Z-drug prescriptions and
abuse in Europe and North America, benzodiazepine screen-
ing tests that employ highly sensitive mass spectrometers
are recommended to routinely include Z-drugs. Techniques
used in the analysis and detection of Z-drugs in various
biological matrices are shown in Table 3 [46–52].

Blood and urine are the commonest matrices for detection
of Z-drugs. Urine is most likely to be useful in cases of drug-
facilitated crimes where the detection window is longer than
in blood or plasma. The detection window in plasma for
therapeutic doses of Z-drugs is projected to be around 6–
20 h, in urine, roughly 24–48 h [16, 53]. This window is
likely to be increased with supratherapeutic ingestions and
Z-drug poisoning, though more definitive data are lacking. In
drug-facilitated crimes, where higher doses may have been
administered, maximum recommended time intervals for Z-
drug detection is 48 h in blood and 72 h in urine [54].
Therapeutic maximal concentrations (Cmax) and those found
in fatalities are shown in Table 4 [47, 51, 53, 55–62].

Oral fluid testing provides a simple and noninvasive
method for roadside and workplace-based testing. Risk of
transmissible infection is much less than blood testing and
there is evidence that oral fluid is more likely to show recent
drug exposure [63]. With increasing incidence of driving
under the influence of drugs, there is an incentive for im-
proving oral fluid testing technique and methodology.
Disadvantages of oral fluid as a reliable matrix include
significant operator variability, inadequate saliva volumes,
interference from food and beverages including deliberate
adulteration, and lower drug concentrations than in urine.

Table 2 Z-drug interactions

References include
[8, 18, 30–34]

Z-drug Pharmacodynamic Pharmacokinetic

Increased Z-drug effect Decreased Z-drug effect

Zolpidem CNS depressants
(including benzodiazepines
and ethanol)

Azole antifungals Rifampicin

Cimetidine St. John’s wort

Ciprofloxacin Carbamazepine
Chlorpromazine Fluvoxamine

Flumazenil Protease inhibitors
SSRIs

Zopiclone CNS depressants Azole antifungals Rifampicin
Chlorpromazine Erythromycin
Flumazenil

Zaleplon CNS depressants Cimetidine Rifampicin
Flumazenil

Thioridazine

158 J. Med. Toxicol. (2013) 9:155–162

Oral fluid samples are usually tested for benzodiazepines
and Z-drugs using gas chromatography–mass spectrometry
or liquid chromatography–mass spectrometry techniques.

Hair analysis may be useful in confirming prior exposure to
Z-drugs, such as in cases of chronic use or drug-facilitated
sexual assault. It can potentially complement tests done on
blood and urine, though in some scenarios hair may be the
only matrix available. Hair as a biological matrix has several
advantages including ease of sampling, storage, and transpor-
tation [64]. In general, detection of Z-drugs in hair is difficult
due to the low level of uptake into hair. The most developed
and sensitive method to detect Z-drugs in hair is liquid chro-
matography coupled with tandem mass spectroscopy [52].
Depending upon the dose and frequency of Z-drug use, length
of hair sampling, and analytical technique utilized, exposure
may be confirmed by hair testing weeks, if not months, later.
Hair testing must be interpreted appropriately based on limits

of detection, inability to determine dose ingested, and poten-
tial for poor drug uptake into hair at very low doses [65].

Z-drugs are becoming increasingly part of forensic toxi-
cology testing in postmortem cases. Z-drugs can be quanti-
fied in a variety of postmortem specimens including blood,
urine, bile, liver, kidney, spleen, vitreous humor, and gastric
contents. Central and peripheral postmortem blood speci-
mens show differential concentration for some Z-drugs.
This postmortem redistribution (PMR) is observed for many
drugs, including benzodiazepines [50]. With PMR, drugs
diffuse rapidly across membranes and tissues after death
causing differential concentrations between central and pe-
ripheral blood compartments. Both zolpidem and zaleplon
exhibit significant PMR, though this seems to be low or
negligible for zopiclone [48, 66–68]. Zolpidem has been
reported to have a central to peripheral blood concen-
tration ratio of 3.74 in postmortem specimens, though
previous studies have had lower values [48]. The extent
of PMR for zaleplon has yet to be quantified as it is
detected in few postmortem cases; this may be related
to its lower frequency of use or its very short half-life and
antemortem elimination.

Clinical Toxicology of Z-drugs

Overdose, chronic abuse, poisoning, and death have been
reported from all Z-drugs. The relative frequency of toxicity
appears to be related more to availability and prescription
numbers rather than the inherent toxicity of the agents
themselves. Comparative toxicity between the Z-drugs has
been difficult to quantify due to the fact that the denomina-
tor is unknown. However, for zaleplon, the improved

Table 3 Detection of Z-drugs

Z-drug Clinical specimens Analytical techniques Postmortem considerations

Zolpidem Plasma HPLC, LC-MS/MS Exhibits postmortem redistribution (PMR)
Urine LC-MS/MS with electrospray ionization (ESI)

Hair LC-MS/MS (ESI), GC-MS

Oral fluid LC-MS/MS (ESI), GC-MS

PM specimens GC-MS

Zopiclone Plasma LC-fluorescence or UV detection Low PMR. Unstable in vitro, in methanol
and alkaline solventsUrine Non-chiral: LC-MS/MS, GC-MS

Chiral: capillary electrophoresis (LIF detection)
and LC-fluorescence detection

Zaleplon Plasma LC-MS (ESI or chemical ionization) Exhibits PMR

Urine Capillary electrophoresis (LIF detection) and LC-MS Positive in very few postmortem cases
PM specimens GC-electron capture detection (LLE and SPE)

References include [46–52]

ESI electrospray ionization, GC gas chromatography, HPLC high-performance liquid chromatography, LC liquid chromatography, LIF laser-
induced fluorescence, LLE liquid–liquid extraction, MS mass spectroscopy, SPE solid-phase extraction, UV ultraviolet, PM postmortem, PMR
postmortem redistribution

Table 4 Z-drug blood concentrations (in nanogram per milliliter)

Z-drug Therapeutic
Cmax (dose)

Postmortem levels in
poisoning fatalities

Zolpidem 100–200 (10 mg) >4,000 (zolpidem only)

1,100–4,500 (co-ingestants)

Zopiclone 60–90 (7.5 mg) >600 (zopiclone only)

250–4,000 (co-ingestants)

Zaleplon 20–30 (10 mg) >1,000 (none solely
attributed to zaleplon)

Therapeutic maximal concentrations are in plasma and shown with
corresponding administered doses (in parentheses). Postmortem levels
are in whole blood; blood/plasma ratio for zopiclone and zaleplon is 1.
References include [47, 51, 53, 55–62]

Cmax maximal concentration

J. Med. Toxicol. (2013) 9:155–162 159

pharmacokinetic profile may contribute to its apparent lower
rate of toxicity and fatalities; a confounder to this postulate
is that the detection window is more limited and zaleplon
ingestion may be missed. In an American Poison Control
Center study, zolpidem overdose was more likely to lead to
intensive care admission when co-ingested with over-the-
counter cold and flu preparations, other psychotropic med-
ication, or ethanol [69].

Garnier et al. reported the first large series of zolpidem
poisoning cases in 1994, where the toxicity predominantly
involved sedation with ingestions up to 1.4 g [56]. Rarely
did zolpidem cause coma, respiratory depression, cardiovas-
cular toxicity, or death. Since then, reports of agitation,
hallucinations, psychosis, and coma from Z-drug overdose
have been published [70–73]. Other unusual reports include
hemolytic anemia and methemoglobinemia from zopiclone,
suggesting oxidative stress from either the parent drug or its
metabolites, one of which is an N-oxide derivative [74–76].

Onset of drowsiness from Z-drug overdose is early, and
recovery is often complete within several hours. Pediatric
cases of Z-drug ingestion have similarly demonstrated min-
imal toxicity in accidental poisoning [77]. Onset of drows-
iness was invariably within the first hour of ingestion and
few cases required any intervention. Manufacturers have
altered some zaleplon products by adding a blue colorant,
in to minimize covert drug administration into liquids
and drinks. The blue colorant, indigo carmine, has been
observed in overdose patients’ gastric contents and urine
(chromaturia) [27].

Treatment of Z-drug overdose is largely supportive, as
for benzodiazepine poisoning, with complete recovery
expected within 6 h. Attention to airway patency and sup-
portive management of ventilation and hemodynamics are
usually sufficient. With rapid absorption, potential for early
sedation and short duration of effect, decontamination meth-
ods are rarely warranted. The administration of activated
charcoal is likely to be more harmful than beneficial in pure
Z-drug overdose. Flumazenil, a competitive benzodiazepine
antagonist, has been shown to reverse the sedative effects of
all three Z-drugs [24–27]. Flumazenil has also been reported
to reverse sedation within minutes in pediatric ingestions of
zolpidem [78]. In pure Z-drug poisoning, where sedation is
of short duration and flumazenil may be indicated, bolus
doses are likely to be sufficient, with infusions being un-
necessary. Caution is advised when administering flumaze-
nil in unknown or polydrug overdose, as unmasking of
ingested pro-convulsant drugs may lead to seizure activity.

Z-drug Deaths

Early clinical trials failed to show major morbidity or mor-
tality from Z-drugs either used therapeutically or in

overdose. Over the past 15 years, increasing red flags from
forensic cases, drug-facilitated crimes, and motor vehicle
crash statistics indicate that mortality from Z-drugs may be
similar to benzodiazepines. Bizarre behavior, falls, acci-
dents, and other injuries may also lead to death.

In the study by Garnier et al., 6 % of zolpidem overdose
cases died; however, none were directly attributable to zol-
pidem [56]. A 10-year audit of coronial deaths in New South
Wales, Australia identified over 90 cases where zolpidem
was detected in postmortem blood or liver [79]. A quarter of
these cases had femoral blood zolpidem levels above
1,000 ng/mL (therapeutic Cmax 100–200 ng/mL). Of note,
the majority of cases in which zolpidem was thought to
contribute to death were mixed drug overdoses, with the
most common co-ingestants being alcohol, antidepressants,
benzodiazepines, and opioids.

Z-drugs had a significantly lower fatal toxicity index
(FTI) than benzodiazepines and barbiturates in a UK review
of deaths from 1983 to 1999 [80]. Zolpidem and zopiclone
caused ∼2 deaths per million prescriptions in England and
Scotland, compared with ∼7 for benzodiazepines and ∼150
for barbiturates. In this study, cumulative data on zopiclone-
related deaths suggest that it may have the lowest FTI of
anti-insomnia drugs. However, a New Zealand study contra-
dicted these findings showing that zopiclone had a similar
FTI to commonly prescribed benzodiazepines [81]. Caution
should be used in interpreting FTI as a reliable marker of
inherent drug toxicity, as it may merely represent frequency
of drug abuse or prescribing patterns in patients with higher
suicidality.

Z-drug concentrations in forensic cases are shown in
Table 4 with comparison plasma levels from therapeutic
dosing. Their short half-lives make them seldom found
substances in forensic cases, both in drug-related deaths as
well as in drug-facilitated crimes. Interpretation is compli-
cated by considerable individual variation, small sample
sizes, and the presence of co-ingestants. Polydrug overdose
is a major confounder in deciding whether the fatalities are
attributable to detected Z-drugs. Although there have been
several reported fatalities where zaleplon has been ingested
along with other drugs, none have been solely attributable to
zaleplon [66, 82]. This may represent lower zaleplon use or
difficulties in measuring zaleplon levels due to its ultra-short
half-life and rapid antemortem metabolism.

Summary

Z-drugs have few distinct advantages over their predeces-
sors, the benzodiazepines, and in many ways …