Case Report: High doses of Zolpidem and QT interval lengthening: Is there a relationship? A case series

Abstract

Zolpidem is indicated in cases of severe insomnia in adults and, as for BDZs, its assumption should be limited to short periods under close medical supervision. Since several drugs cause corrected QT interval (QTc) elongation, the authors investigated whether high daily doses of Zolpidem could cause QTc elongation. The study was conducted in the Addiction Medicine Unit of the G.B. Rossi University Hospital in Verona. The data were collected from hospitalizations carried out between January 2015 and February 2020 and refer to a total of 74 patients, 38 males and 36 females, who were treated for detoxification from high doses of Zolpidem with the “Verona Detox Approach With Flumazenil.” One patient out of 74 had QTc elongation (479 ms). The patient was male and took a daily dose of 50 mg of Zolpidem; he did not take concomitant therapies that could cause QTc lengthening. He had no electrolyte alterations, no contemporary or previous intake of barbiturates, heroin, cocaine, THC, alcohol, NMDA or nicotine which could cause an elongation of the QTc interval. The present study highlights the low risk of QTc elongation due to high dosages of Zolpidem; however, if, on one hand, we can affirm that Zolpidem is a safe drug, on the other, the widespread use of high dosages of this drug for prolonged periods of time is problematic and worrying.

Full text

fpsyt-13-1033061 October 19, 2022 Time: 10:39 # 1
TYPE Case Report
PUBLISHED 20 October 2022
DOI 10.3389/fpsyt.2022.1033061
OPEN ACCESS
EDITED BY
James Rowlett,
University of Mississippi Medical
Center, United States
REVIEWED BY
Bradford Fischer,
Cooper Medical School of Rowan
University, United States
Roberta Tittarelli,
University of Rome Tor Vergata, Italy
*CORRESPONDENCE
Lorenzo Zamboni
lorenzo.zamboni88@gmail.com
SPECIALTY SECTION
This article was submitted to
Addictive Disorders,
a section of the journal
Frontiers in Psychiatry
RECEIVED 31 August 2022
ACCEPTED 04 October 2022
PUBLISHED 20 October 2022
CITATION
Campagnari S, Zamboni L, Fusina F,
Casari R and Lugoboni F (2022) Case
Report: High doses of Zolpidem
and QT interval lengthening: Is there
a relationship? A case series.
Front. Psychiatry 13:1033061.
doi: 10.3389/fpsyt.2022.1033061
COPYRIGHT
© 2022 Campagnari, Zamboni, Fusina,
Casari and Lugoboni. This is an
open-access article distributed under
the terms of the Creative Commons
Attribution License (CC BY). The use,
distribution or reproduction in other
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original publication in this journal is
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academic practice. No use, distribution
or reproduction is permitted which
does not comply with these terms.
Case Report: High doses of
Zolpidem and QT interval
lengthening: Is there a
relationship? A case series
Simone Campagnari 1, Lorenzo Zamboni1,2*,
Francesca Fusina 3,4, Rebecca Casari 1and
Fabio Lugoboni 1
1Unit of Addiction Medicine, Department of Internal Medicine, G.B. Rossi Hospital, Verona, Italy,
2Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy,
3Department of General Psychology, University of Padua, Padua, Italy, 4Padova Neuroscience
Center, University of Padua, Padua, Italy
Zolpidem is indicated in cases of severe insomnia in adults and, as for
BDZs, its assumption should be limited to short periods under close medical
supervision. Since several drugs cause corrected QT interval (QTc) elongation,
the authors investigated whether high daily doses of Zolpidem could cause
QTc elongation. The study was conducted in the Addiction Medicine Unit of
the G.B. Rossi University Hospital in Verona. The data were collected from
hospitalizations carried out between January 2015 and February 2020 and
refer to a total of 74 patients, 38 males and 36 females, who were treated for
detoxification from high doses of Zolpidem with the “Verona Detox Approach
With Flumazenil.” One patient out of 74 had QTc elongation (479 ms). The
patient was male and took a daily dose of 50 mg of Zolpidem; he did not
take concomitant therapies that could cause QTc lengthening. He had no
electrolyte alterations, no contemporary or previous intake of barbiturates,
heroin, cocaine, THC, alcohol, NMDA or nicotine which could cause an
elongation of the QTc interval. The present study highlights the low risk of
QTc elongation due to high dosages of Zolpidem; however, if, on one hand,
we can affirm that Zolpidem is a safe drug, on the other, the widespread use
of high dosages of this drug for prolonged periods of time is problematic
and worrying.
KEYWORDS
Zolpidem, abuse, high dose, addiction, QTc, Z-drug
Introduction
Benzodiazepines (BDZs) and Z-drugs (Zolpidem, Zaleplon, Zopiclone) are among
the most prescribed drugs in Western countries and, while there has been a downward
trend in annual BDZ prescriptions, Z-drug prescriptions have instead increased
exponentially. This is probably due to a widespread opinion among doctors that the
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latter don’t involve the problems associated with chronic use
of BDZs, while, in fact, Z-Drug (ZD) use requires the same
safeguards that apply to BDZs (1–4).
The use of ZDs is indicated in cases of severe insomnia
in adults and, as for BDZs, it should be limited to short
periods under close medical supervision. The pharmacokinetic
differences between the molecules allow for some important
considerations with respect to the selection criteria of these
drugs. Zolpidem and Zopiclone, being eliminated more slowly,
are more suitable for the treatment of insomnia with central
awakenings, unlike Zaleplon, which has a rapid elimination
and is thus best suited for the management of initial insomnia
(5). The main contraindications to the use of Z-drugs are
the following: drug hypersensitivity, myasthenia gravis, severe
respiratory insufficiency, Obstructive Sleep Apnea Syndrome
(OSAS) and advanced hepatic insufficiency. The use of ZDs is
contraindicated in children.
ZDs, like BDZs, are characterized by high manageability,
and starting from their introduction on the market it was
initially thought that they could offer advantages in terms
of efficacy and safety compared to classic BDZs. However,
over time it was shown that even this class of drugs can
lead to important side effects, such as cognitive impairment,
worsening of psychomotor performance, and increasing the risk
of falls and fractures, especially if taken at higher doses or in
association with other psychoactive substances such as alcohol.
(6–9).
Zolpidem and Zopiclone abuse are primarily described
in patients with a history of drug addiction, alcoholism or
psychiatric disorders and, minimally, also in patients not
belonging to these categories. Their use should, therefore, reflect
careful indications concerning posology (10,11).
Zolpidem is an imidazopyrimidine and, although it is not
structurally connected to BDZs, it has a similar mechanism
of action: it enhances the inhibitory effect of GABA on nerve
transmission, binding the related receptor with consequent
increases in permeability to chlorine ions.
Although early reports highlighted a profile of low abuse risk
for Zolpidem, in recent years an important increase in Zolpidem
dependence has been detected; for this reason, Zolpidem was
transferred to Schedule IV of the 1971 Convention (i.e., for
drugs inducing dependence such as BDZs) in 2001 (12–14).
High-dose Zolpidem use (600-2000 mg/die) has
been associated with psychostimulant effects, such as
feelings of well-being, euphoria (“high”), energy, alertness,
sociability, talkativeness, delusions and psychotic experiences,
sleepwalking, falling asleep while driving, sleep-related eating
disorders or engaging in other activities while not fully awake
(15–17).
It is also interesting to note that, in a large number of
hypnotic drug abusers, a selective preference for Zolpidem was
reported by subjects that were positive at screening tests for
adult Attention Deficit/Hyperactivity Disorder (18,19).
Finally, intense craving, inability to stop use and
withdrawal were associated with long-term high dose Zolpidem
consumption. Through the analysis of adverse reaction data
provided by the European Medicines Agency and after assessing
the potential for abuse and dependence of ZDs, it has been
shown that Zolpidem is more frequently involved in both abuse
and withdrawal problems.
The QT interval begins with the beginning of the QRS
complex and ends with the end of the T wave and has an inverse
relationship with heart rate (HR). A rate-related (or corrected)
QT interval (QTc) according to Bazett’s formula (20) can be
calculated as:
QTc =QT interval
cardiac cycle insecond
The upper limit of a normal QTc interval is 470 ms in males
and 480 ms in females. As for the lower limits of the QTc, they
have not been well established, but sometimes values between
330 and 360 ms are mentioned. (21).
Long QT syndrome (LQTS) is a myocardial repolarization
disorder characterized by a prolonged QT interval on the
electrocardiogram (ECG). The main symptoms in patients
presenting LQTS include palpitations, syncope, seizures and
sudden cardiac death. This syndrome can be congenital or
acquired. The acquired form is related to drug therapy and the
presence of hypokalemia and hypomagnesaemia may accentuate
the risk of drug-induced LQTS development. One of the main
risks of LQTS is that it generates polymorphic ventricular
tachycardia, i.e., a ventricular rhythm greater than 100 bpm
with frequent changes in the QRS axis, its morphology, or both
(22,23).
Torsades de pointes (TdP) is a form of polymorphic
ventricular tachycardia which derives from either acquired or
congenital QT interval prolongation, and manifests with a
heart rate between 160 and 250 bpm. These variations take the
form of a progressive, sinusoidal and cyclical evolution of the
QRS axis; the peaks of the QRS complexes appear to “twist”
around the isoelectric line of the recording. This condition
tends to spontaneously regress; however, multiple episodes can
occur in rapid succession and may degenerate into ventricular
fibrillation and sudden cardiac death. Determining the absolute
and comparative risk of many drugs associated with QT interval
prolongation is difficult, as most of the available data comes
from case reports or small series of observations. Furthermore,
the incidence of QT prolongation without torsades de pointes
(Tdp) is much higher than the incidence of TdP itself.
The pathophysiological mechanism underlying drug-
induced TdP is the development of abnormal depolarizations
of the cell membrane in the final part of the action potential,
defined as early post-depolarization (EAD), or during diastolic
repolarization, termed late post-depolarization (DAD).
Almost all drugs that cause LQTS cause blockage of the
potassium channel, thereby inhibiting the rapid outward flow
of potassium ions and, therefore, cellular repolarization (24,25).
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Furthermore, lower heart rates result in a smaller potassium
output from the cell during repolarization, as there are
fewer repolarization events; also, the reduction of extracellular
potassium increases the degree of inhibition induced by the drug
on the rapid potassium current, consequently increasing the QT
interval. (25).
Most patients with drug-induced LQT have one or more risk
factors for the condition.
In a review of the literature that included 249 patients with
non-cardiac drug-associated QT prolongation, 97% had at least
one risk factor and 71% had at least two. These included: female
sex in 71%, history of heart disease in 41%, concomitant use of
another QT prolonging drug in 39%, hypokalemia in 28%, a high
dose of the drug in 19%, and a previous history of LQTS in 18%.
The most common risk factor for drug-induced LQTS is
being female. In a review of the literature of 332 patients
with cardiovascular drug-associated Torsades de pointes (Tdp),
70% were women. Compared to males, females have a longer
QTc and a greater response to drugs that block the rapid
potassium channel, favoring Tdp, possibly due to the effect of
sex steroids on ion channel expression. Estrogen potentiates the
prolongation of the QT interval induced by bradycardia and the
development of arrhythmia. Conversely, androgens reduce the
QT interval and make it less sensitive to drugs. (26–28).
In scientific literature, benzodiazepines and Z-Drugs are
considered safe concerning LQTS (29); to date, however, there
are no studies which address the abuse of high dosage of Z-drugs
and QTc elongation risk.
Since several drugs cause QTc elongation, with this case
series we want to analyze if QTc lengthening occurs on a total of
74 patients admitted to the Addiction Medicine Unit in Verona,
Italy for daily use of high doses of Zolpidem.
Patients and methods
The study was conducted in the Addiction Medicine
Unit of the G.B. Rossi University Hospital in Verona. The
data were collected from hospitalizations carried out between
January 2015 and February 2020 and refer to a total of
74 patients, of which 38 were males and 36 were females,
that were being treated for detoxification from high doses of
Zolpidem with “Verona Detox Approach With Flumazenil”
(30,31).
The criterion of dependence on high doses of ZDs
was defined on the criteria established by the DSM IV-
TR, which provide for the presence of continuous use
for a period greater than 6 months, a daily intake of
Zolpidem greater than at least five times the maximum
recommended daily dose and problematic use of ZDs, such
as mixing various molecules, increasing dosages, using for
pleasure, obtaining them through illegal means or deriving
negative social consequences. The dosage assumed was obtained
from a drug use history assessment performed by the
staff doctors.
The variables examined were demographic ones, that
considered age and sex, and clinical ones, that considered the
following: type of BDZ used; DDDE (mg); heart rate (HR;
bpm); QY (ms); QTc (ms); Na+; K +; Cl-; additional therapy
other than the BDZ.
Upon admission, blood samples were taken to assess
electrolyte concentration and an electrocardiogram was
performed in order to obtain HR and the QT interval. QT was
corrected with HR using Bazett’s formula : QTc =QT/Vrr.
Results
A total of 74 patients including 38 males and 36 females
(Table 1) that were hospitalized, between January 2015 and
February 2020, to the Addiction Medicine Unit of the G.B. Rossi
University Hospital in Verona, Italy.
The average age of these patients was 44 years (SD 11,77)
with a minimum of 23 and a maximum of 74 years; 38 were
workers, 25 were unemployed and 11 were students (Table 2).
The mean daily dose of Zolpidem was 402.36 mg/day
(SD ±368.88) (Table 3), with a minimum of 20 mg/day
and a maximum of 2,250 mg/day, while the mean DDD is
50.21 mg/day.
Assuming that the threshold value of QTc is 470 ms in
males and 480 in females, we recorded a single case exceeding
these threshold values (32). The patient was a male presenting
a QTc of 479 ms and taking 50 mg/day of Zolpidem (25 mg
of Diazepam equivalents daily dose); he also did not have
concomitant therapies that could have caused QTc lengthening,
no electrolyte alterations (Na 140 mmol/L, K + 3.75 mmol/L,
Cl- 105 mmol / L), no contemporary or previous intake of
barbiturates, heroin, cocaine, THC, alcohol, NMDA or nicotine.
It should also be noted that the QTc value of one of the 74
patients was not recorded.
TABLE 1 Gender.
Gender Frequency Percentage
Male 38 51.35
Female 36 48.65
Total 74 100
TABLE 2 Status.
Status Frequency Percentage
Worker 38 51.35
Unemployed 25 33.78
Other (student, retired) 11 14.86
Total 74 100
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TABLE 3 Drug dosage.
N Minimum Maximum Mean SD
Dosage mg
(mean)
74 20 2,250 402.36 368.88
DDD 74 2 300 50.21 58.61
Discussion
Zolpidem is a non-benzodiazepine receptor modulator used
in short-term treatment of insomnia aimed at patients with
difficulty starting sleep; it improves measures of sleep latency,
sleep duration, and reduces the number of awakenings in
patients with transient insomnia. It also improves sleep quality
in patients with chronic insomnia and can act as a minor muscle
relaxant. (33–35).
The main thing to consider when starting patients on
Zolpidem is the possibility of addiction and the development
of withdrawal symptoms following drug dismission if the
drug has been taken for a long time. An interprofessional
team approach comprising healthcare professionals such as a
pharmacist, a therapist, a nurse, and a clinician is critical;
patients should also be educated on possible withdrawal effects
resulting from the medication. Because Zolpidem has the
potential to cause dependence, it should not be prescribed for
long periods of time.
Moreover, long term use of Z-drugs causes cognitive
impairments: several case control studies report that
benzodiazepine or Z-drug use approximately doubles the
risk of being involved in a motor vehicle accident (7,36). Other
effects may include dependence (37), and next-day cognitive,
memory, psychomotor and balance impairments (38).
There is a mistaken belief that Z-drugs have advantages
both in terms of efficacy and safety compared to BDZs, and,
for this reason, many countries have seen a lower prescription
of BDZs in favor of an increase in prescriptions of Z-drugs,
especially Zolpidem. However, even this class of drugs can have
important side effects, such as reduced functionality of cognitive
abilities and worsening of psychomotor performances (1–4,
6,8,9).
Inadequate prescribing (non-therapeutic high-dosage
administration, long duration of the treatment, association
with different drugs, absence of monitoring) and poor overall
assessment of the risks associated with their prescribing
carries many potential risks to patients, including the risk of
developing addiction.
Several drugs have been proven or suspected to cause QT
prolongation; many of these medications are frequently used
in the intensive care unit (ICU), such as different types of
anesthetics, sedatives, antibiotics, antimycotics, antidepressants
and antipsychotics. The mechanism behind drug-induced
QT prolongation is primarily the blockade of potassium
ion channels (Ikr) in myocytes, causing prolonged cardiac
repolarization. A secondary mechanism is the blockade
of hepatic drug degradation because of inhibition of the
cytochrome P450 enzyme CYP3A4. Awareness on the many
medications known to cause drug-induced LQTS is imperative,
especially when the drugs are combined in the same patient
(39,40).
In literature there is no study that correlates the use of high
doses of Z-drugs, in particular Zolpidem, with the analysis of
QTc on the ECG. With this study we analyzed whether there was
a correlation between the intake of high doses of Zolpidem and
QTc prolongation.
The data collected showed that 1.35% of Zolpidem abusers
developed QTc elongation, which corresponds to only one
subject of the 74 total (with the exception of the single patients
for whom we didn’t record QTc data). We could deduce that
Zolpidem does not represent a significant cause of this side
effect, but this is the only study in literature that treats this
problem with very selective criteria. Regarding the population
that was taken into consideration, we can affirm that QTc
lengthening can be explained by the simultaneous intake of
other drugs that present this problem among their side effects
(41,42).
With the information we have, we are unable to formulate
a hypothesis that explains this phenomenon. Perhaps other
studies focusing on gender differences of patients taking high
doses of BDZs or Z-drugs might be more insightful.
Limitation
This study presents several limitations: it’s a retrospective
study, Zolpidem dosage was reported by subjects, no follow-up
was included and the sample size is small.
Conclusion
The present study shows a low risk of QTc elongation
caused by high daily doses of Zolpidem; however, it must
be considered that this is the only study currently present
in literature and it could be useful to expand the data by
analyzing a larger sample. Z-drugs and Zolpidem, proved to
be safe drugs considering the risk of QTc lengthening, however
the problem of abuse and dependence of this drug represents
a growing phenomenon which is often underestimated by
healthcare professionals.
Data availability statement
The raw data supporting the conclusions of this article will
be made available by the authors, without undue reservation.
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Ethics statement
The studies involving human participants were reviewed
and approved by the ethics committee of the Verona University
Hospital (approval code 683CESC). The patients/participants
provided their written informed consent to participate
in this study.
Author contributions
SC, LZ, RC, and FL were responsible for the study concept
and design. SC, FF, and LZ drafted the manuscript. LZ was
responsible for the study methodology. All authors critically
reviewed the content and approved the final version of the
manuscript for publication.
Conflict of interest
The authors declare that the research was conducted
in the absence of any commercial or financial relationships
that could be construed as a potential conflict
of interest.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed
or endorsed by the publisher.
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