CASE REPORT

A Fatal Case of Benzodiazepine Withdrawal

Meredith A. Lann, MD,* and D. Kimberley Molina, MD

Abstract: Medical examiners often receive cases with limited medical

history. Sometimes the medical history received is slightly skewed, or even
incorrect. Here we describe a case which was initially referred to the Bexar
County Medical Examiners Office from a large community hospital as a
case of zolpidem overdose. The deceased presented to the hospital with
hypertension, elevated temperature, worsening bizarre behavior, and movement irregularities. While in the hospital, the decedent developed seizure-like
activity and died approximately 15 hours after admission. A complete
autopsy was performed and yielded no significant gross or histologic abnormalities. A full toxicologic analysis revealed therapeutic levels of citalopram
and phenytoin. Zolpidem was not present. Further review of the decedents
medical history as well as information provided by the next of kin revealed
that the deceased had been taking diazepam for several years but had recently
been switched to alprazolam. The decedent had abruptly stopped taking the
alprazolam approximately 4 days before admission when she ran out of
the medication, after taking approximately 200 mg in a 6-day period. Given
the inconsistent clinical presentation and the findings at autopsy, we suspect that she suffered from benzodiazepine withdrawal and not an overdose as
initially reported. Although it is possible that the zolpidem, reportedly taken
in the 12 hours before admission, masked the initial symptoms of withdrawal, the constellation of symptoms and signs at presentation are more
consistent with benzodiazepine withdrawal than of zolpidem overdose. In
this report, we emphasize to the forensic community that one must maintain
a high index of suspicion for alternative explanations if the initial report does
not seem to fit the presentation or autopsy findings. This case illustrates that
although it may take some extra time and effort, further investigation into
clinical history can prove crucial to obtaining the correct cause of death and
manner of death. This is only the second case within the English literature of
death because of benzodiazepine withdrawal.
Key Words: benzodiazepine withdrawal, benzodiazepine overdose,
alprazolam, zolpidem
(Am J Forensic Med Pathol 2009;30: 177179)

ccording to the World Health Organization, benzodiazepines are

the most commonly prescribed drugs worldwide, after cardiac
and circulatory medications. They are used as anxiolytics, muscle
relaxants, and anticonvulsants, as well as to treat insomnia and
alcohol withdrawal. Benzodiazepines are also frequently encountered as illicit drugs.
Withdrawal from benzodiazepines was first described in the
1960s. The various symptoms of withdrawal include dissociative
disorders, depression, insomnia, palpitations, agitation, confusion,
gastrointestinal symptoms, muscle twitching, seizures, and elevated
blood pressure. Withdrawal symptoms are often mistaken for a return of
the illness for which the drug was being administered. For this reason,

Manuscript received April 24, 2007; accepted July 25, 2007.

From the *Department of Pathology, University of Colorado Denver, Aurora, CO;
and Bexar County Medical Examiners Office, San Antonio, TX.
Reprints: Meredith A. Lann, MD, Department of Pathology-AIP, University of
Colorado Denver, 12605 E. 16th Avenue, Rn 3026, Mailstop F768, Aurora,
CO 80045. E-mail: meredith.lann@ucdenver.edu.
Copyright 2009 by Lippincott Williams & Wilkins
ISSN: 0195-7910/09/3002-0177
DOI: 10.1097/PAF.0b013e3181875aa0

Am J Forensic Med Pathol Volume 30, Number 2, June 2009

long-term or high-dose users of benzodiazepines are usually weaned or

tapered off the drug to minimize withdrawal symptoms.
Alprazolam is an intermediate-acting triazolobenzodiazepine
used to treat anxiety and panic disorders. Both physiologic and
psychologic dependence are often problems with long-term use of
this medication. Alprazolam withdrawal syndrome is well described
in the literature; however, only 1 case report of a death because of
withdrawal from this medication could be found using both PubMed
and Ovid Medline search engines. Here we describe a second fatality
that can be attributed to complications of alprazolam withdrawal.

CASE REPORT
The death of a 43-year-old AfricanAmerican woman was
referred to the Bexar County Medical Examiners Office from a
large community hospital on suspicion of being a zolpidem
overdose case. The initial report received was that the decedent had
taken 60 mg of zolpidem within the 12-hour period before arrival at
the hospital. She died within 15 hours of admission.
The decedent had been brought to the emergency department
by her sister, who described that the decedent was acting strangely
and experiencing visual and auditory hallucinations, none of which
were typical for the decedent. Reportedly, the decedent had told her
sister that she had taken several zolpidem because she could not
sleep. In the emergency room, the patient was disoriented, alert to
person only; however, she was awake and conversant. She denied
taking the medications. The patient stated that she had a history of
bipolar disorder, but did not remember the medications she was
taking. She denied any drug allergies or illicit or intravenous drug
use. Screening laboratory tests were all within normal limits with the
exception of a urine drug screen, which was positive for benzodiazepines. Vital signs showed a markedly elevated blood pressure
(213/125 mm Hg) with 98% oxygen saturation on room air. Her
physical examination was otherwise unremarkable. A head computed tomography scan was negative for any acute abnormality, and
an electrocardiogram showed a rapid sinus rhythm, without ST or T
wave changes. Ultimately, she was diagnosed with acute altered
mental status, most likely secondary to zolpidem overdose and
admitted to the medicine unit.
Upon arrival to the medical floor, the patient continued to
behave bizarrely and presented with a progressive increase in
blood pressure up to 215/150 mm Hg and pulse up to 130 bpm.
Approximately 12 hours after admission, the patient began having
shaking episodes with posturing and an elevated temperature.
She was treated for pseudoseizures with haloperidol, dantrolene, and
phenytoin. She was also given enalapril and labetalol for her
elevated blood pressure; however, the medications had little effect.
In addition, citalopram, piperacillin/tazobactam, ceftriaxone, vancomycin, acyclovir, and vitamin K were administered, most likely in
an attempt to cover for the other causes of acute mental status
changes such as infection or psychosis.
Approximately 14 hours after admission, the patient was
found in her room cyanotic and without respirations. Cardiopulmonary resuscitative measures were performed, but she expired 45
minutes later.
At autopsy, the decedent was an overweight, normally developed woman, 62 inches in length, and weighing 175 lbs (body mass
index, 32.8). She had some minor contusions and abrasions of
www.amjforensicmedicine.com | 177

Am J Forensic Med Pathol Volume 30, Number 2, June 2009

Lann and Molina

differing stages of healing to her arms and legs, but no indications

of major trauma. An endotracheal tube as well as multiple intravascular catheters and a urethral catheter were present. Internal examination revealed a mildly enlarged heart (400 g) with mild, noncalcific, nonobstructing atherosclerosis. No other abnormalities were
noted. A full microscopic examination revealed no evidence of
natural disease, trauma, or toxicity to include polarization examination of the kidneys and lungs. Toxicologic analysis was performed
at the Bexar County Medical Examiners Office on the ante-mortem
blood, taken around the time of the seizures, and included screens
for benzodiazepines, narcotics, cocaine, alkaline drugs, alcohol, and
acid and neutral drugs. The alkaline and acid and neutral drug
screens were performed by gas chromatography/mass spectrophotometry; the alcohol screen by gas chromatography/flame ionization
detection; and the narcotic, cocaine, and benzodiazepine screens by
immunoassay. The toxicologic analysis of blood showed therapeutic
levels of medications administered to the decedent while hospitalized, including phenytoin (10 mg/L), citalopram (0.07 mg/L), and
the metabolite desmethylcitalopram (0.07 mg/L). Other medications such as mirtazepine, haloperidol, acetaminophen, diphenhydramine, and chlorpheniramine were detected, although the
levels were less than the limit of quantitation. Cocaine, narcotics,
benzodiazepines, zolpidem, and ziprasidone were not detected in
the ante-mortem blood.
The essentially negative toxicology results prompted further
investigation, to include a review of the deceaseds prior medical
records. Much of the information was obtained from her primary
psychiatrist. It was discovered that the decedent had actually been
taking benzodiazepines steadily for years, at 10 mg diazepam 4
times a day until 10 days before her death. At that time, the
diazepam was discontinued by the psychiatrist and 2 mg alprazolam
to be taken 3 times per day was prescribed in its place. The decedent
was prescribed 100 alprazolam pills along with her other medications,
including ziprasidone (20 mg), citalopram (2 mg), and zolpidem (10
mg). The decedent reportedly took all 200 mg of the alprazolam within
6 days of receiving her prescription. This dose is much higher than the
dose prescribed, and this degree of abuse of the drug can be effectively
considered an overdose. Of note, the decedent then stopped taking the
alprazolam abruptly when she ran out of pills. Approximately 4 days
after the last dose of alprazolam, she complained of intolerable insomnia and reportedly took 60 mg of zolpidem. During this period of time,
the sister noticed that the decedent began behaving bizarrely and
experiencing hallucinations, prompting her to bring the decedent to the
local emergency department.
Given the clinical presentation, the additional history acquired from the next of kin, and the contents of the various medical
records in combination with the findings at autopsy, the cause of
death is suspected to be acute withdrawal from benzodiazepines
rather than zolpidem overdose. The symptoms of acute mental status
changes, insomnia, and autonomic arousal approximately 4 days
after her last dose of alprazolam support a diagnosis of acute
withdrawal. Of note, the high dose of zolpidem taken in the 12 hours
before admission likely masked her withdrawal symptoms at the
time of her hospital admission. Officially, the cause of death was
ruled complications of chronic benzodiazepine use with cardiomyopathy listed as a contributing condition.

DISCUSSION
Alprazolam is an intermediate-acting triazolobenzodiazepine
that is FDA-approved for treatment of anxiety and panic disorder. It
has been promoted for its anxiolytic and sedative properties as well
as antidepressant effects. The recommended maximum daily dosage
is 4 mg in divided doses; however, it should be noted that higher
doses ranging 6 to 10 mg/d are often required for effective manage178 | www.amjforensicmedicine.com

ment of panic disorder. The half-life for alprazolam is 6 to 20 hours

for the standard formulation and approximately 11 to 16 hours for
extended release tablets. Elimination is primarily by metabolism via
cytochrome P450 3A. Alprazolam has many drug interactions, as
plasma concentrations of alprazolam have been shown to increase
with co-administration of some selective serotonin reuptake inhibitors (fluoxetine, fluvoxamine), some tricyclic antidepressants (imipramine, desipramine), oral contraceptives, and cimetidine.1
Zolpidem is a nonbenzodiazepine imidazopyridine sedative/
hypnotic agent. Although the chemical structure differs from benzodiazepines, they share some pharmacological properties because
of their shared interaction with the gamma-aminobutyric acid
(GABAA) receptor complex. Benzodiazepines such as alprazolam
bind nonspecifically and activate the GABAA receptor subtypes,
while zolpidem preferentially binds and activates the sedative receptor ( subunit) of the GABAA receptor complex. In contrast to
alprazolam, zolpidem has a much shorter half-life (approximately
2.5 hours) and is eliminated primarily by renal excretion.1 Alprazolam is detected by screening for benzodiazepines, whereas zolpidem
is detected by screening for alkaline drugs.
Alprazolam is thought to have approximately 10 times the
anxiolytic effect of diazepam on a milligram-for-milligram basis, as
it has a higher affinity for the benzodiazepine GABAA receptor.
Binding of the receptor by the drug enhances the receptors ability to
open a chloride channel and therefore inhibits development of
neuropotentials, resulting in an inhibitory or slowing effect within
the involved pathways. With long-term use of benzodiazepines there
is a compensatory decrease in GABA at the level of the synaptic
cleft. Sudden removal of stimulation of this receptor pathway, as
seen in states of withdrawal, results in a generalized disinhibition of
all the neuropathways modulated by GABA. Various monoaminergic systems can be affected to include emotional, cognitive, perceptual, and autonomic pathways. Involvement of each of these areas is
suggested in the current case, given the constellation of symptoms at
presentation.
Both alprazolam and zolpidem show similar symptoms when
taken in excess including: somnolence, decreased respiratory rate,
heart rate and blood pressure, coma, and even death. The constellation of symptoms at presentation in the current case was not
consistent with benzodiazepine or zolpidem overdose. The early
stage of benzodiazepine withdrawal can show increased irritability,
rebound anxiety, apprehension, headache, anorexia, insomnia, perceptual disturbances, and autonomic dysregulation, whereas psychosis, delirium, myoclonus, and seizure appear later.211 Symptoms of
alprazolam withdrawal usually begin within 72 hours of the last
dose; however, some symptoms have been described as early as 14
hours after discontinuation.2 Others report symptoms beginning as
late as 4 days after the last dose,12 similar to the current case.
The withdrawal symptoms are often not tolerated well, and
contribute largely to psychologic and physiologic dependence. The
manifestations of withdrawal are related to the rate of elimination and
dose and duration of use of the drug. Symptoms are more pronounced
in patients taking larger amounts of alprazolam. Short-acting benzodiazepines such as lorazepam and oxazepam may cause an earlier, more
abrupt, and more severe withdrawal syndrome. On the other hand,
longer-acting benzodiazepines such as diazepam, chlordiazepoxide, and
clorazepate leave the system gradually and withdrawal is usually
milder. The most recent manufacturer guidelines recommend a gradual
decrease in dosage of no more than 0.5 mg every 3 days to avoid
withdrawal effects.1 However, many patients still experience withdrawal symptoms despite this gradual tapering schedule.3,8,10,12,13
The withdrawal syndrome for benzodiazepines is comparable
with that of ethanol withdrawal. Withdrawal from ethanol causes
autonomic dysregulation commonly known as delirium tremens, and
2009 Lippincott Williams & Wilkins

Am J Forensic Med Pathol Volume 30, Number 2, June 2009

can result in death if not treated appropriately. Their management is

similar, as the focus is to control symptoms of confusion, anxiety,
and vital sign abnormalities.14 This is best achieved by administering long-acting sedative-hypnotic agents (ie, diazepam or chlordiazepoxide). Incomplete cross-tolerance between alprazolam and
other benzodiazepines has been described, and therefore, in some
cases this type of treatment may not be effective.3,4,8,11 Once the
patient is stabilized, the dose of benzodiazepine should be carefully
reduced as symptoms allow.
The shaking episodes and posturing that occurred during the
decedents hospitalization were diagnosed as pseudoseizure. These
aberrant movements, however, likely represented episodes of myoclonus attributable to alprazolam withdrawal and not pseudoseizure. Myoclonus in alprazolam withdrawal has been described.3,5,6 The current
case echoes 2 cases previously reported by Rapport and Covington6
in which a similar movement disorder was initially considered to be
psychogenic; however, the muscle spasms were found to resolve
with the administration of benzodiazepines and therefore determined
to be part of the withdrawal syndrome. The myoclonic fits are
thought to be due to disinhibition of subcortical GABA-dependent
pathways.6
Seizures secondary to alprazolam withdrawal are well described despite being one of the less common symptoms of alprazolam withdrawal.2,3,6,7,9,12,15 Patients usually suffer grand mal
tonic-clonic seizures; however, 1 case of atypical-absence nonconvulsive seizure reported by Olnes et al15 presented with a waxing
and waning state of confusion and bizarre behavior. In a recent
review of FDA phase II and III clinical trials by Alper et al,16
alprazolam was associated with increased incidence of seizure when
compared with placebo. The seizures were attributed to withdrawal
effects of the drug. It is unknown whether the decedent of the current
case experienced true seizures or myoclonus, as an electroencephalogram was not obtained.
An extensive literature review yielded only one other case
report describing a fatality associated with abrupt discontinuation of
alprazolam.12 The clinical presentation of the case reported by
Haque et al12 is very similar to the current case, as insomnia, bizarre
behavior, and new-onset psychosis and elevated blood pressure and
pulse were seen. However, the 2 cases differ in several aspects. In
the case reported by Haque et al, the patient suffered well-documented seizures and progressive cardiac arrhythmias in the terminal
stages. Moreover, severe coronary atherosclerotic disease and myocardial scarring were identified at autopsy. Therefore, the cause of
death was determined to be cardiac arrhythmia instigated by seizure
activity during alprazolam withdrawal, in the setting of severe
cardiac disease. In contrast, in the current case the presence or
absence of true seizure activity was not confirmed. Only mild
cardiomegaly and obesity were identified at autopsy, without any
further contributing factors for cardiac disease. Cardiomegaly was
included in part II of the death certificate, as it was contributing
factor but did not cause death. The exact mechanism of immediate

2009 Lippincott Williams & Wilkins

Benzodiazepine Withdrawal

cause of death is very difficult to define in our case. We speculate

that the mechanism of death is arrhythmia induced by autonomic
dysregulation during the state of alprazolam withdrawal.
In summary, we report a unique case of death because of
complications of alprazolam withdrawal, which was initially reported to us as a zolpidem overdose. The clinical presentation was
incongruous with overdose, and the toxicology results showed that
the deceased did not have elevated levels of drugs in her blood at the
time of death. These findings prompted further review of prior
medical records and discussion with the next of kin yielded valuable
information regarding her use of alprazolam and introduced a
timeline of a possible withdrawal syndrome. Without this additional
clinical history, we may not have reached the appropriate conclusion
and cause of death. Unfortunately, in this case, the cause of the
patients symptoms went unrecognized and untreated. We emphasize to the forensic community the importance of further investigation to get the full story when things do not seem to fit, as it may give
clues to the appropriate cause and manner of death.
REFERENCES
1. In: Physicians Desk Reference. 61st ed. Montvale, NJ: Thomson Healthcare;
2007:28512855, 30923098.
2. Uhlenhuth EH, Starcevic V, Qualls C, et al. Abrupt discontinuation of
alprazolam and cognitive style in patients with panic disorder. J Clin
Psychopharmacol. 2006;26:519 523.
3. Browne JL, Hauge KJ. A review of alprazolam withdrawal. Drug Intell Clin
Pharm. 1986;20:837 841.
4. Noyes R Jr, Clancy J, Coryell WH, et al. A withdrawal syndrome after abrupt
discontinuation of alprazolam. Am J Psychiatry. 1985;142:114 116.
5. Kantor SJ. A difficult alprazolam withdrawal. J Clin Psychopharmacol.
1986;6:124 125.
6. Rapport DJ, Covington EC. Motor phenomena in benzodiazepine withdrawal.
Hosp Community Psychiatry. 1989;40:12771279.
7. Noyes R Jr, Perry PJ, Crow RR, et al. Seizures following the withdrawal of
alprazolam. J Nerv Ment Dis. 1986;174:50 52.
8. Zipursky RB, Baker RW, Zimmer B. Alprazolam withdrawal delirium unresponsive to diazepam: case report. J Clin Psychiatry. 1985;46:344 345.
9. Brier A, Charney DS, Nelson JC. Seizures induced by abrupt discontinuation
of alprazolam. Am J Psychiatry. 1984;141:1606 1607.
10. Fyer AJ, Liebowitz MR, Gorman JM, et al. Discontinuation of alprazolam
treatment in panic patients. Am J Psychiatry. 1987;144:303308.
11. Albeck JH. Withdrawal and detoxification from benzodiazepine dependence:
a potential role for clonazepam. J Clin Psychiatry. 1987;48(suppl):43 48.
12. Haque W, Watson DJ, Bryant SG. Death following suspected alprazolam
withdrawal seizures: a case report. Tex Med. 1990;86:44 47.
13. Mellman TA, Uhde TW. Withdrawal syndrome with gradual tapering of
alprazolam. Am J Psychiatry. 1986;143:1464 1466.
14. Olmedo R, Hoffman RS. Withdrawal syndromes. Emerg Med Clin North Am.
2000;18:273288.
15. Olnes MJ, Golding A, Kalpan PW. Nonconvulsive status epilepticus resulting
from benzodiazepine withdrawal. Ann Intern Med. 2003;139:956 958.
16. Alper K, Schwartz KA, Kolts RL, et al. Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA)
summary basis of approval reports. Biol Psychiatry. 2007;62:345354.

www.amjforensicmedicine.com | 179