Psychiatria Danubina, 2011; Vol. 23, No. 1, pp 76–78
© Medicinska naklada - Zagreb, Croatia
ZOLPIDEM DEPENDENCE AND WITHDRAWAL SEIZURE -
Report of two cases
Liang-Jen Wang1,2, Shao-Chun Ree1, Chin-Lin Chu3 & Yeong-Yuh Juang2,3
1Department of Psychiatry, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan
2Chang Gung University School of Medicine, Taoyuan, Taiwan
3Department of Psychiatry, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
received: 7.1.2011; revised: 15.2.2011; accepted: 25.2.2011
Zolpidem is a non-benzodiazepine property which binds selectively to the α1-GABAA receptors, and has been widely prescribed
to patients suffering from insomnia. We report two cases of zolpidem dependence with withdrawal seizure in the Asian population.
The first case is a 43-year-old woman who took zolpidem up to the dosage of 200 to 400 mg per night. The second case is a 35-year-
old woman who even began to take zolpidem every 15 to 30 minutes to get euphoric and relaxed, and she gradually increased the
dosage to 400 to 500mg per day. After abrupt discontinuation of zolpidem, both cases immediately developed anxiety, global
insomnia, restlessness, and tonic seizure. The purpose of this case report is to suggest that clinicians should pay close attention to
the potential of zolpidem tolerance, abuse and dependence. The possibility of withdrawal seizure cannot be excluded especially at
Key words: zolpidem - dependence - withdrawal - seizure
* * * * *
Zolpidem, an imidazopyridine derivative agent, has
been shown with rapid onset and ability to effectively
prolong sleep duration (Langtry & Benfield 1990).
Zolpidem displays a high affinity to α1-GABAA receptor
in in-vitro studies and minor anxiolytic, myo-relaxant
and anti-convulsant effects (Visser et al. 2003). It was
considered a safer hypnotic than benzodiazepines
because of a lesser liability for abuse and dependence
(Holm & Goa 2000).
Nevertheless, a growing body of cases reports of
zolpidem abuse or dependence (Sakkas et al. 1999,
Monti et al. 1996, Krueger et al. 2005), as well as epi-
leptic-seizure related to zolpidem withdrawal (Aragona
2000, Cubala & Landowski 2007, Tripodianakis et al.
2003) have been discussed in Western countries
(Victorri-Vigneau et al. 2007). For the Asian popu-
lation, a case of zolpidem dependence has also been
demonstrated (Huang et al. 2007); however, patients
with zolpidem withdrawal seizure have not been
reported yet. So far, there is no literature investigating
ethnic variation for the liability of zolpidem
dependence. Zolpidem has been widely prescribed in
recent years for patients with insomnia in Taiwan by
psychiatrists, other specialists and primary care
physicians. Therefore its safety and dependence
potential are of great concern.
Here we report two cases of seizure clearly related to
dependence and withdrawal of zolpidem after long-term
use in high dosage in Taiwan.
A 43-year-old woman suffering from dysthymic
disorder had been taking hypnotics for insomnia for
more than 20 years. Two years ago she began to take
zolpidem alone without mixing other kinds of
hypnotics, and 50 to 60 mg of zolpidem used to be
initially effective in treating her insomnia. Unfortu-
nately, as tolerance and psychological dependence
developed gradually, she had to go to several doctors to
get prescriptions for 200-400 mg that she needed per
night. At the end she had to discontinue zolpidem
abruptly because she could not afford it anymore.
Anxious mood, global insomnia and restlessness were
noted since that evening. She suddenly showed facial
spasm, mouth opening, tonic seizure, and loss of
consciousness for about 5 minutes early next morning.
Post-ictal confusion with clouded consciousness,
psycho-motor retardation, regressed attitude and
behavior, and disorientation to time persisted in the
subsequent 5 days. Then similar tonic seizure attacks
occurred twice on the seventh day after drug
discontinuation. She was therefore brought to hospital
and admitted to the neurology ward. EEG revealed
intermittent, generalized, diffuse theta wave and
diffused cortical dysfunction. After a series of
laboratory tests and other examinations, no other
etiologies than zolpidem withdrawal could be identified.
Lorazepam 2mg and alprazolam 0.5 mg were prescribed
to her. She had no further seizure attacks and her post-
ictal confusion resolved gradually seven days after
Liang-Jen Wang, Shao-Chun Ree, Chin-Lin Chu & Yeong-Yuh Juang: ZOLPIDEM DEPENDENCE AND WITHDRAWAL SEIZURE -
Report of two cases Psychiatria Danubina, 2011; Vol. 23, No. 1, pp 76–78
A 35-year-old woman suffering from major
depressive disorder had been abusing hypnotics and oral
analgesics prescribed by different doctors for more than
10 years. She began to take zolpidem one year ago with
an initial dose of 10 to 20mg. She increased the dosage
gradually up to 400 to 500mg per day and even began to
take it every 15 to 30 minutes to get euphoric and
relaxed. During the same period of time, no other
substance use was reported except for some over-the-
counter cold syrup for headache. One day she decided to
discontinue zolpidem and rapidly developed withdrawal
symptoms including insomnia, anxiety, palpitation, and
dyspnea hours later. On the next day, she showed
disturbance of consciousness, facial spasm, mouth
opening, tongue protrusion and limb convulsions for
about 3 minutes. She was brought to hospital for help.
At the emergency department, EEG performed revealed
spikes of epileptic discharge and grand mal seizure was
diagnosed. She was hospitalized and clonazepam was
prescribed to her. She then showed no further seizures
attacks during admission.
A number of double-blind randomized studies
demonstrated that sudden discontinuation of zolpidem
treatment after 2 to 4 weeks was not associated with
withdrawal symptoms, but the dosage in these
controlled studies were within the normal recommended
range (Holm & Goa 2000, Vartzopoulos et al. 2000)
Literature review and our cases suggest that the
withdrawal symptoms including insomnia, anxiety and
epileptic attack were noted soon after abrupt discon-
tinuation of zolpidem in the real world.
Benzodiazepines show non-selective affinity to all
the GABA-A receptors, which include α1, α2, α3, α4,
and α5 subunits receptors. The α1 receptors were
considered selectively involved in sleeping mecha-
nisms; α2 receptors contribute to anxiolytic action; and
α5 receptors are associated with cognition and memory
(McKernan et al. 2000). In the traditional view of
pharmacological mechanism, zolpidem displays high
affinity to α1-GABAA receptors, and it was considered
the key mechanism of zolpidem's pure hypnotic effect
(Visser et al. 2003). Nevertheless, zolpidem shows
physiologic and psychological reinforcing effects and
abuse potential similar to those of benzodiazepines
(Toner et al. 2000). Our report also suggests that
zolpidem might exhibit similar pharmacologic effects to
benzodiazepines and lose its selectivity on α1-GABAA
receptors, particularly at high doses and long-term use.
There are some assumptions about the variables
associated with the adverse effects of zolpidem use.
Gender is one of the susceptibility factors associated
with adverse effects of zolpidem. Women had been
found to have a significantly higher serum zolpidem
concentration than men at equivalent dosage (Cubala et
al. 2008). In addition, zolpidem is metabolized by the
hepatic enzyme cytochrome P450 3A4, and the degree
to which its isoenzyme could be inhibited by
concomitant psychotropic agents (Holm & Goa 2000).
Hence, the protein binding affinity of zolpidem makes it
higher in free form among patients with concomitant
medication use and hepatic impairment (Cubala &
Landowski 2007). This might have contributed to
toxicity and increase the risk of withdrawal seizure
attack. Ethnic differences have been demonstrated with
the drug metabolizing enzymes, CYP2C9, 2C19, and
2D6 (Anthony & Berg 2002). However, it is still
uncertain whether the ethic differences exist in the
properties of pharmacokinetics and pharmacodynamics,
and pharmacogenetics for zolpidem.
Our cases suggested that the potential of zolpidem
dependence and withdrawal seizure are also present in
the Asian population. The female-gender, high dosage
and long-term use of zolpidem might be risk factors for
development of adverse effects. It warrants further
investigation whether there is ethnic variation for the
liability of zolpidem dependence. Nevertheless,
worldwide clinicians should pay attention to the risk of
withdrawal seizure related to this agent, especially at
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Liang-Jen Wang, Shao-Chun Ree, Chin-Lin Chu & Yeong-Yuh Juang: ZOLPIDEM DEPENDENCE AND WITHDRAWAL SEIZURE - Download full-text
Report of two cases Psychiatria Danubina, 2011; Vol. 23, No. 1, pp 76–78
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Dr. Liang-Jen Wang
Department of Psychiatry, Chang Gung Memorial Hospital
Keelung. No.200, Lane 208, Ji-Jin 1st Rd., Anle District, Keelung City 204, Taiwan, R.O.C.