Benzodiazepine Poisoning and Withdrawal

10/15/2019 Benzodiazepine poisoning and withdrawal - UpToDate
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Benzodiazepine poisoning and withdrawal

Authors: Howard Greller, MD, Amit Gupta, MD
Section Editor: Stephen J Traub, MD
Deputy Editor: Jonathan Grayzel, MD, FAAEM
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2019. | This topic last updated: Oct 12, 2018.
INTRODUCTION
Benzodiazepines (BZD) are sedative-hypnotic agents that have been in clinical use since the 1960s. The first benzodiazepine, chlordiazepoxide,
was discovered serendipitously in 1954 by the Austrian scientist Leo Sternbach. Three years later, it was marketed as a therapeutic medication
under the brand name Librium. Diazepam was released in 1963; multiple other compounds followed over subsequent years.
BZDs are used for sedation and to treat anxiety, seizures, withdrawal states, insomnia, and drug-associated agitation. They are frequently
combined with other medications for procedural sedation. Due to their many uses, BZDs are widely prescribed and nearly 50 different agents are
available worldwide. The high incidence of BZD overdose mirrors their widespread use and availability [1,2].
The diagnosis and management of acute benzodiazepine poisoning will be reviewed here. A general approach to the poisoned patient and the
management of poisonings involving other agents with sedative properties are discussed elsewhere. (See "General approach to drug poisoning
in adults" and "Ethanol intoxication in adults" and "Acute opioid intoxication in adults" and "Gamma hydroxybutyrate (GHB) intoxication".)
PHARMACOLOGY AND CELLULAR TOXICITY
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Benzodiazepines (BZD) are organic bases with a benzene ring and a seven member diazepine moiety; various side chains determine the
potency, duration of action, metabolite activity, and rate of elimination for specific agents [3]. BZDs exert their effect via modulation of the
gamma-aminobutyric acid A (GABA-A) receptor. Gamma-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the central nervous
system.
The GABA-A receptor is composed of five subunits (alpha, beta, and gamma) arranged in various combinations [4-9]. The composition of
subunits determines the affinity of the various xenobiotics that bind to the receptor. Benzodiazepines bind at the interface of the alpha and
gamma subunits and, once bound, lock the GABA-A receptor into a conformation that increases its affinity for GABA. BZDs do not alter the
synthesis, release, or metabolism of GABA but rather potentiate its inhibitory actions by augmenting receptor binding. This binding increases the
flow of chloride ions through the GABA ion channel, causing postsynaptic hyperpolarization and a decreased ability to initiate an action potential.
The low incidence of respiratory depression with orally ingested BZDs appears to be related to the low density of binding sites in the brainstem
respiratory center [8]
KINETICS
Benzodiazepines are commonly divided into three groups based upon half-life duration: short-acting (half-life of less than 12 hours),
intermediate-acting (half-life between 12 and 24 hours), and long-acting (half-life greater than 24 hours). A table describing the kinetics of
common BZDs is provided (table 1).
Short-acting benzodiazepines generally have few active metabolites, do not accumulate with repeated doses, and demonstrate clearance that is
largely unaffected by age and liver disease. Examples include triazolam and oxazepam. Although midazolam possesses a short half-life, it has
active metabolites that can accumulate with repeated dosing.
Intermediate-acting benzodiazepines include lorazepam and temazepam. Long-acting benzodiazepines generally have pharmacologically active
metabolites, accumulate in tissues after multiple doses, and demonstrate impaired clearance in older patients and those with liver disease.
Examples include diazepam and chlordiazepoxide [10-12].
BZDs are rapidly absorbed in the GI tract and most are highly lipophilic and highly protein bound. The metabolism of BZDs is primarily hepatic.
Within the liver, most BZDs are metabolized to a significant extent by the CYP2C19 and CYP3A4 enzymes. Alprazolam and midazolam are
metabolized by CYP3A4. Diazepam is metabolized by both CYP3A4 and CYP2C19.
Interactions with other drugs that are metabolized by CYP enzymes may prolong the half-lives of certain BZDs, leading to prolonged clinical
effects and therapeutic misadventures [10-12]. Examples of drugs that inhibit the CYP3A4 enzyme and reduce the metabolism of BZDs, thereby
prolonging their effects, include macrolide antibiotics, diltiazem, HIV protease inhibitors, and grapefruit juice (table 2). Inducers of CYP3A4, which
may enhance metabolism of BZDs, include phenobarbital, phenytoin, carbamazepine, rifampin, and St. John's wort (table 2).
Oxazepam, temazepam, and lorazepam are directly conjugated to an inactive, water-soluble glucuronide metabolite that is excreted by the
kidney [3,13]. Therefore, these agents are not susceptible to CYP interactions and are less likely to accumulate in patients with CYP inhibition.
Chlordiazepoxide, diazepam, and flurazepam are metabolized to active metabolites, which then are conjugated and excreted [3].
The main active metabolite of diazepam is desmethyldiazepam. Diazepam's other active metabolites include temazepam and oxazepam. Active
metabolites of chlordiazepoxide include desmethylchlordiazepoxide, demoxepam, desmethyldiazepam, and oxazepam. Triazolam, alprazolam,
and midazolam are converted to hydroxylated intermediates that are rapidly conjugated and do not contribute to the drug's overall effect.
Midazolam has a very rapid onset of clinical effect and a shorter duration of action than other benzodiazepines, which explains its preferential
use in procedural sedation [14]. However, successive doses of midazolam lead to bioaccumulation of its hydroxy-metabolites and may prolong
the drug's sedative effects [15]. (See "Procedural sedation in adults outside the operating room".)
CLINICAL FEATURES OF OVERDOSE
Benzodiazepine poisoning — Oral benzodiazepines (BZD), taken in overdose without a coingestant, rarely cause significant toxicity [16]. The
classic presentation of a patient with an isolated BZD overdose consists of CNS depression with normal vital signs. Many patients are arousable
and able to provide an adequate history. Of note, most intentional ingestions of BZDs involve a coingestant, the most common being ethanol.
Patients with a clinically apparent ingestion manifest slurred speech, ataxia, and altered (most commonly depressed) mental status. Respiratory
compromise is uncommon with isolated oral ingestions, but may be seen when patients ingest additional sedative hypnotic agents (such as
ethanol) or opioids, or when clinicians administer BZDs as one of several agents for procedural sedation. The latter scenario more often leads to
respiratory depression due to the intravenous administration of BZDs and the consequent rapid rise in central nervous system concentrations.
The doses required to produce respiratory compromise are difficult to quantify and depend upon many factors, including tolerance, weight, age,
coingestants, and genetics.
Patients with severe toxicity can present stuporous or comatose. One observational study found oxazepam to be the least and temazepam the
most sedating BZD in intentional overdose [17]. The authors speculate that this is because temazepam is more rapidly absorbed and oxazepam
more slowly absorbed than other BZDs. Another observational study found that alprazolam overdose resulted in significantly longer hospital
stays, higher ICU admission rates, and a greater need for mechanical ventilation and the use of reversal agents (ie, flumazenil) [18]. These
studies, while providing some information, are limited by their observational nature.
Propylene glycol poisoning — Propylene glycol (1,2 propanediol) is the diluent used in parenteral formulations of diazepam and lorazepam
and the cause of a unique complication related to the prolonged parenteral administration of these BZDs. The potential effects of PG toxicity
include skin and soft tissue necrosis (from extravasation), hemolysis, cardiac dysrhythmias, hypotension, lactic acidosis, seizure, coma, and
multisystem organ failure.
PG toxicity is rare but may be considered when patients receiving large or continuous infusions of parenteral BZDs (eg, mechanical ventilation,
severe sedative hypnotic or ethanol withdrawal syndromes, undifferentiated agitated delirium, management of chloroquine overdose) develop an
anion gap metabolic acidosis. The osmolal gap correlates with PG concentrations and can be used as a surrogate marker of PG toxicity [19]. PG
poisoning from IV BZD infusions is discussed in greater detail separately. (See "Sedative-analgesic medications in critically ill adults: Properties,
dosage regimens, and adverse effects", section on 'Propylene glycol toxicity'.)
Of note, PG is also used in food, cosmetics, and oral medicines, and rare cases of poisoning from intentional ingestion have been reported.
DIFFERENTIAL DIAGNOSIS
Altered mental status, a common finding in BZD overdose, is found in a wide range of medical and toxicologic conditions (table 3 and table 4).
(See "Diagnosis of delirium and confusional states" and "Evaluation of abnormal behavior in the emergency department".)
BZD overdose is usually suspected on the basis of history and the clinical scenario. Any number of sedative-hypnotic medications share clinical
features with BZDs in overdose, including ethanol, barbiturates, gamma hydroxybutyrate (GHB), and chloral hydrate. (See "Gamma
hydroxybutyrate (GHB) intoxication".)
The sedative hypnotic toxidrome is characterized by a depressed mental status, an unremarkable physical examination, and normal vital signs,
hence the common description "coma with normal vitals." Ethanol and phenobarbital intoxication can be ruled out by obtaining serum
concentrations. Patients with GHB intoxication often manifest abrupt alterations in mental status without intervention and severe respiratory
depression can occur. (See "Ethanol intoxication in adults" and "Gamma hydroxybutyrate (GHB) intoxication".)
Other life-threatening causes of depressed mental status must be considered in the differential diagnosis, including hypoglycemia and carbon
monoxide exposure. Stroke, meningitis and encephalitis, and head trauma can present with altered mental status and should be investigated as
clinically indicated. An isolated overdose with oral BZDs rarely causes profound respiratory depression requiring invasive airway management or
cardiopulmonary instability. In such cases, the presence of coingestants should be investigated. (See "Carbon monoxide poisoning" and
"Overview of the evaluation of stroke" and "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Viral encephalitis in
adults" and "Initial management of trauma in adults".)
LABORATORY EVALUATION
Testing for benzodiazepine toxicity — Benzodiazepines (BZDs) are themselves not detected in standard urine screening tests for drugs of
abuse. However, the most common BZD urine test identifies metabolites of 1,4-benzodiazepines, such as oxazepam. This test may not detect
clonazepam, lorazepam, midazolam, or alprazolam. Importantly, a positive urine drug screen only indicates recent exposure; it does not confirm
causality for acute symptoms, toxicity, or overdose. More specific screening tests that can detect agents not traditionally measured by standard
tests may be available at some laboratories.
A number of factors, such as the amount of drug ingested, the presence of coingestants, and patient age and weight, can alter pharmacokinetics
and affect urine drug tests. In general, BZD metabolites can be detected as early as three hours after ingestion and may remain detectable for up
to two weeks [20]. Of note, efavirenz, a non-nucleoside reverse transcriptase inhibitor used to manage HIV infection, is well known to cause a
false positive result for benzodiazepine [21].
Serum BZD concentrations are not routinely available in the emergency setting, correlate poorly with clinical findings, and do not aid
management.
General diagnostic testing — Routine laboratory evaluation of the poisoned patient should include the following:
● Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status
● Acetaminophen and salicylate levels, to rule out these common coingestions
● Electrocardiogram (ECG), to rule out conduction system poisoning by drugs that affect the QRS or QTc intervals
● Pregnancy test in women of childbearing age
It is reasonable to obtain a serum ethanol concentration in patients with suspected BZD overdose, given the difficulty of distinguishing between
the clinical effects of BZDs and ethanol.
Clinicians should obtain additional tests based upon clinical findings. As examples, altered mental status in association with fever raises concern
for meningitis or other infections and warrants a thorough evaluation, including assessment of the cerebral spinal fluid. A head computed
tomography scan should be obtained if there is evidence or concern for intracranial pathology or trauma.
MANAGEMENT
Initial treatment — As with any poisoning, the management of benzodiazepine (BZD) overdose begins with a rapid assessment of the patient's
airway, breathing, and circulation. Endotracheal intubation should not be delayed if needed. Oxygen is administered, intravenous access
established, and continuous cardiac monitoring employed. A fingerstick serum glucose is immediately obtained. End tidal CO2 (ie, capnography)
can be useful for monitoring patients at risk for hypoventilation, as can occur with severe benzodiazepine overdose. General discussions of the
basic facets of the management of poisonings are found elsewhere. (See "General approach to drug poisoning in adults".)
In cases of isolated BZD overdose, a history, physical examination (with particular attention paid to signs of respiratory dysfunction, trauma, and
poisoning from coingestants), and regular monitoring are likely to be all that is necessary. The period of observation and disposition depend upon
clinical findings. (See 'Disposition' below.)
BZD overdose involving a coingestant, such as an opioid or ethanol, increases the risk for dangerous complications [22-24]. In patients with BZD
overdose complicated by respiratory depression or failure, a concomitant opioid overdose may be present and it is reasonable to administer
appropriate doses of parenteral naloxone. Naloxone is much safer than flumazenil, which can precipitate seizures. (See "Acute opioid
intoxication in adults", section on 'Basic measures and antidotal therapy' and 'Antidote (flumazenil)' below.)
Decontamination — Gastrointestinal decontamination with activated charcoal (AC) is usually of NO benefit in cases of isolated BZD ingestion
and increases the risk of aspiration. We suggest that patients with BZD overdose NOT be treated with AC, unless a life-threatening coingestant
amenable to treatment with charcoal is suspected and the patient’s airway is protected (naturally or with a tracheal tube).
Whole bowel irrigation is generally unnecessary because of the rarity of sustained release preparations and the difficulty of initiating treatment in
the obtunded patient. Neither multidose activated charcoal nor hemodialysis is effective as an enhanced elimination technique.
Antidote (flumazenil) — Flumazenil is a nonspecific competitive antagonist of the BZD receptor. It can be used to reverse BZD-induced
sedation following general anesthesia, procedural sedation, or overdose [25,26]. However, the use of flumazenil in the setting of overdose
remains highly controversial. Administration of flumazenil can precipitate withdrawal seizures in patients who have developed a tolerance to
BZDs through chronic use or abuse. Such risks may be further increased if the patient has taken coingestants with proconvulsant properties [25-
27].
Young children are more susceptible to respiratory depression from BZDs and less likely to be tolerant of these medications. Thus, the
contraindications for flumazenil reversal are of less concern in the pediatric population, and flumazenil may be used if deemed necessary.
However, it is uncommon for an isolated ingestion to lead to a need for reversal. The need for flumazenil is more common following iatrogenic
complications, such as oversedation during a procedure. Of note, flumazenil does not consistently reverse respiratory depression caused by
BZD overdose [28].
Because oral BZD overdose has a low rate of morbidity and mortality is rare, the risks of flumazenil treatment often outweigh its benefits. The
purported benefit of flumazenil is to avoid the need for procedures, such as endotracheal intubation, CT imaging, and lumbar puncture, should
the patient's mental status return to normal when the BZD's sedative effects are reversed. We suggest consultation with a medical toxicologist or
poison control center whenever the use of flumazenil is contemplated. (See 'Additional resources' below.)
Flumazenil appears to be safe and effective when used to reverse the sedating effects of a BZD given for procedural sedation in patients who do
not use BZDs chronically. In adults, the recommended initial dose is 0.2 mg given intravenously (IV) over 30 seconds. Repeated doses of 0.2
mg, to a maximum dose of 1 mg, can be given until the desired effect is achieved [29]. In the event of resedation, the dosing regimen described
here can be repeated, but no more than 3 mg of flumazenil should be given within any one hour.
In children, the initial dose is 0.01 mg/kg given IV over 15 seconds (maximum dose 0.2 mg). The initial dose may be followed at one or more
minute intervals with up to four repeat doses of 0.005 to 0.01 mg/kg (maximum 0.2 mg) per dose. The maximum dose should NOT exceed 1 mg
total or 0.05 mg/kg; the lower dose is preferable.
The peak effect of a single flumazenil dose occurs approximately 6 to 10 minutes after IV administration. For patients at greater risk of seizure or
agitation with BZD reversal, a longer wait of several minutes between subsequent doses may be warranted.
The duration of flumazenil is short (0.7 to 1.3 hours) and the duration of effect of a long-acting BZD or a large BZD dose can exceed that of
flumazenil. Resedation may be treated in adults by using 0.2 mg doses (maximum total dose 1 mg) until the desired effect is achieved. For
patients with exposures to BZDs with prolonged durations of action or those with hepatic insufficiency with prolonged exposure to BZDs, a
continuous flumazenil infusion (0.25 to 1 mg per hour) may be needed [30,31]. Again, we suggest consultation with a medical toxicologist or
poison control center whenever a flumazenil infusion is thought to be necessary.
Disposition — Patients who require mechanical ventilation or have been exposed to a dangerous coingestant are admitted to a critical care
setting.
Most patients with an isolated BZD ingestion can be safely discharged or transferred for psychiatric evaluation following an observation period of
four to six hours, provided that any concerning symptoms, such as CNS depression, have resolved. The patient should be able to ambulate
safely by the end of this period. Patients with persistent signs of intoxication beyond six hours should be admitted to a monitored setting until
symptoms resolve.
WITHDRAWAL
Mechanism, signs, and prevention — Any abrupt or overly rapid reduction in benzodiazepine (BZD) dose among chronic users can produce
withdrawal. Rapid recognition and treatment of BZD withdrawal is crucial because the syndrome can be life-threatening. The symptoms and
signs of BZD withdrawal can include any of the following [32]:
● Tremors
● Anxiety
● Perceptual disturbances
● Dysphoria
● Psychosis
● Seizures
The occurrence and time of BZD withdrawal symptoms are related in part to the pharmacologic properties of the drug, dose, duration of use, and
abruptness of discontinuation [33]. In general, heavier use of BZD over a longer period increases the risk for withdrawal. However, there is no
known set dose or duration of use that increases the risk of withdrawal in tolerant patients.
The onset of withdrawal can vary according to the half-life of the BZD involved. Symptoms may be delayed up to three weeks in BZDs with long
half-lives, but may appear as early as 24 to 48 hours after cessation of BZDs with short half-lives. The severity and duration of withdrawal is
determined by many factors, including the period of BZD use, how rapidly use was tapered (if at all), the pharmacokinetics of the particular drug,
as well as possible genetic factors [34,35]. Although the onset and duration of withdrawal symptoms can vary widely based on these variables,
most patients experience symptoms that last from one to two weeks, although there is a small subset that can experience prolonged symptoms
[36,37].
Chronic ingestion of BZDs leads to conformational changes in the GABA receptor, which ultimately reduce the receptor's affinity for the agent
and result in decreased GABA activity [32]. This decreased activity manifests as tolerance to the agent. When BZDs are no longer present or
present at lower concentrations, this decreased GABA receptor activity has less inhibition of excitatory neurotransmitters, and thus, there is a
pro-excitatory state.
Withdrawal can usually be avoided or minimized through the use of BZDs with a long half-life, such as diazepam or chlordiazepoxide, and a
gradual tapering of the patient's BZD dose over several months, depending upon the dosage and degree of dependency.
Treatment — BZD withdrawal is treated with a BZD that has a prolonged clinical effect, such as diazepam, given intravenously and titrated to
effect. The goal is to eliminate withdrawal symptoms without causing excessive sedation or respiratory depression. Once symptoms are
controlled, the BZD dose should then be tapered gradually over a period of months [38-41]. BZD therapy should be avoided or used cautiously in
patients with obstructive sleep apnea. (See "Management of obstructive sleep apnea in adults", section on 'Concomitant medications'.)
For patients in mild BZD withdrawal, a long-acting oral BZD may be given; it is also reasonable to give such a patient the BZD that they had been
using chronically.
A number of medications have been used to treat BZD withdrawal, but none has been found to be as effective as BZDs. Beta blockers,
antipsychotics, selective serotonin reuptake inhibitors, and antihistamines have all been shown to be inferior to standard treatment [38,41].
Although no controlled trials have assessed valproic acid in the treatment of BZD withdrawal, a systematic review of valproic acid for the
management of alcohol withdrawal found no benefit [42]. Another systematic review identified one trial in which carbamazepine showed a trend
toward benefit in BZD withdrawal, but this was in patients already receiving BZD therapy [43,44]. A 2018 systematic review of 38 trials noted a
high risk of bias in all but one study and concluded that it is not possible to draw firm conclusions regarding pharmacologic interventions to
facilitate BZD discontinuation in chronic BZD users [45]. Pending further study, treatments other than BZDs cannot be recommended for the
management of BZD withdrawal.
ADDITIONAL RESOURCES
Regional poison control centers in the United States are available at all times for consultation on patients who are critically ill, require admission,
or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have clinical and/or medical toxicologists available for
bedside consultation and/or inpatient care. Whenever available, these are invaluable resources to help in the diagnosis and management of
ingestions or overdoses. The World Health Organization provides a listing of international poison centers at its website:
www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See
"Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Benzodiazepine use disorder and
withdrawal" and "Society guideline links: Treatment of acute poisoning caused by recreational drug or alcohol use".)
SUMMARY AND RECOMMENDATIONS
● Benzodiazepines (BZD) are widely prescribed and commonly involved in cases of drug overdose and substance abuse. They are commonly
categorized by half-life duration (table 1). (See 'Pharmacology and cellular toxicity' above and 'Kinetics' above.)
● Oral BZDs taken in overdose without a coingestant rarely cause significant toxicity. The classic presentation of a patient with an isolated
BZD overdose consists of CNS depression with normal vital signs. Severe overdose can cause respiratory depression and stupor or coma.
Coingestants are common in cases of overdose. (See 'Clinical features of overdose' above.)
● Propylene glycol (1,2 propanediol), the diluent used in parenteral formulations of diazepam and lorazepam, is the cause of a unique and rare
complication related to prolonged parenteral administration of BZDs. Potential adverse effects include hemolysis, cardiac dysrhythmias,
hypotension, lactic acidosis, seizure, coma, and multisystem organ failure.
● Altered mental status, a common finding in BZD overdose, is found in a wide range of medical and toxicologic conditions (table 3 and table
4). Life-threatening causes of depressed mental status include hypoglycemia, carbon monoxide poisoning, stroke, meningitis and
encephalitis, and head trauma. (See 'Differential diagnosis' above.)
● Many BZDs are not detected in standard urine screening tests for drugs of abuse. However, the most common BZD urine test identifies
metabolites of 1,4-benzodiazepines, such as oxazepam. This test may not detect clonazepam, lorazepam, midazolam, or alprazolam. The
need for further testing is discussed in the text. (See 'Laboratory evaluation' above and "Testing for drugs of abuse (DOA)".)
● Most cases of isolated BZD ingestion are managed successfully with supportive care alone. Gastrointestinal decontamination with activated
charcoal (AC) is usually of NO benefit and increases the risk of aspiration. (See 'Management' above.)
● Flumazenil is a nonspecific competitive antagonist of the BZD receptor. It can be used to reverse BZD-induced sedation following general
anesthesia, procedural sedation, or overdose. Administration of flumazenil can precipitate withdrawal seizures in patients who have
developed a tolerance to BZDs. Therefore, the use of flumazenil in the setting of overdose remains highly controversial. We suggest
consultation with a medical toxicologist or poison control center whenever the use of flumazenil is contemplated. (See 'Antidote (flumazenil)'
above.)
● Any abrupt or overly rapid reduction in BZD dose among chronic users can produce withdrawal. Rapid recognition and treatment of BZD
withdrawal is crucial because the syndrome can be life-threatening. Symptoms and signs can include tremors, anxiety, perceptual
disturbances, dysphoria, psychosis, and seizures. BZD withdrawal is treated with a BZD that has a prolonged clinical effect (eg, diazepam)
given intravenously and titrated to effect. (See 'Withdrawal' above.)
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REFERENCES
1. Drug Abuse Warning Network: The DAWN Report. April 2004. Benzodiazepine in Drug-Abuse Related Emergency Department Visits: 1995
-2002. www.oas.samhsa.gov/2k4benzodiazepinesTrends.pdf (Accessed on May 04, 2009).
2. Lader M. Benzodiazepines revisited--will we ever learn? Addiction 2011; 106:2086.
3. Chouinard G, Lefko-Singh K, Teboul E. Metabolism of anxiolytics and hypnotics: benzodiazepines, buspirone, zoplicone, and zolpidem.
Cell Mol Neurobiol 1999; 19:533.
4. Hevers W, Lüddens H. The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel
subtypes. Mol Neurobiol 1998; 18:35.
5. Smith TA. Type A gamma-aminobutyric acid (GABAA) receptor subunits and benzodiazepine binding: significance to clinical syndromes
and their treatment. Br J Biomed Sci 2001; 58:111.
6. Ali NJ, Olsen RW. Chronic benzodiazepine treatment of cells expressing recombinant GABA(A) receptors uncouples allosteric binding:
studies on possible mechanisms. J Neurochem 2001; 79:1100.
7. Olsen RW. GABA-benzodiazepine-barbiturate receptor interactions. J Neurochem 1981; 37:1.
8. Potokar J, Coupland N, Wilson S, et al. Assessment of GABA(A)benzodiazepine receptor (GBzR) sensitivity in patients on
benzodiazepines. Psychopharmacology (Berl) 1999; 146:180.
9. Snead OC 3rd, Nichols AC, Liu CC. gamma-Hydroxybutyric acid binding sites: interaction with the GABA-benzodiazepine-picrotoxin
receptor complex. Neurochem Res 1992; 17:201.
10. Fukasawa T, Suzuki A, Otani K. Effects of genetic polymorphism of cytochrome P450 enzymes on the pharmacokinetics of
benzodiazepines. J Clin Pharm Ther 2007; 32:333.
11. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4
inhibition. Clin Pharmacokinet 2000; 38:41.
12. Greenblatt DJ, Shader RI, Divoll M, Harmatz JS. Benzodiazepines: a summary of pharmacokinetic properties. Br J Clin Pharmacol 1981;
11 Suppl 1:11S.
13. Wynn G, Oesterheld J, Cozza K, Armstong G. Clinical manual of drug interaction principles for medical practice. Chapters 2, 3, 19. America
n psychiatric publishing Inc, Washington, DC 2009.
14. Nordt SP, Clark RF. Midazolam: a review of therapeutic uses and toxicity. J Emerg Med 1997; 15:357.
15. Bauer TM, Ritz R, Haberthür C, et al. Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet 1995;
346:145.
16. Höjer J, Baehrendtz S, Gustafsson L. Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year
period. J Intern Med 1989; 226:117.
17. Buckley NA, Dawson AH, Whyte IM, O'Connell DL. Relative toxicity of benzodiazepines in overdose. BMJ 1995; 310:219.
18. Isbister GK, O'Regan L, Sibbritt D, Whyte IM. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin
Pharmacol 2004; 58:88.
19. Riker RR, Fraser GL. Adverse events associated with sedatives, analgesics, and other drugs that provide patient comfort in the intensive
care unit. Pharmacotherapy 2005; 25:8S.
20. Garzone PD, Kroboth PD. Pharmacokinetics of the newer benzodiazepines. Clin Pharmacokinet 1989; 16:337.
21. Blank A, Hellstern V, Schuster D, et al. Efavirenz treatment and false-positive results in benzodiazepine screening tests. Clin Infect Dis
2009; 48:1787.
22. Park TW, Saitz R, Ganoczy D, et al. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving
opioid analgesics: case-cohort study. BMJ 2015; 350:h2698.
23. Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths From Combined Use of Opioids and Benzodiazepines. Am J
Prev Med 2015; 49:493.
24. Jones CM, Paulozzi LJ, Mack KA, Centers for Disease Control and Prevention (CDC). Alcohol involvement in opioid pain reliever and
benzodiazepine drug abuse-related emergency department visits and drug-related deaths - United States, 2010. MMWR Morb Mortal Wkly
Rep 2014; 63:881.
25. Weinbroum AA, Flaishon R, Sorkine P, et al. A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose. Drug
Saf 1997; 17:181.
26. Seger DL. Flumazenil--treatment or toxin. J Toxicol Clin Toxicol 2004; 42:209.
27. Kreshak AA, Cantrell FL, Clark RF, Tomaszewski CA. A poison center's ten-year experience with flumazenil administration to acutely
poisoned adults. J Emerg Med 2012; 43:677.
28. Shalansky SJ, Naumann TL, Englander FA. Effect of flumazenil on benzodiazepine-induced respiratory depression. Clin Pharm 1993;
12:483.
29. Romazicon package insert. Roche Pharmaceuticals. www.dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=6844 (Accessed on May 05, 200
9).
30. Maxa JL, Ogu CC, Adeeko MA, Swaner TG. Continuous-infusion flumazenil in the management of chlordiazepoxide toxicity.
Pharmacotherapy 2003; 23:1513.
31. Höjer J, Baehrendtz S, Magnusson A, Gustafsson LL. A placebo-controlled trial of flumazenil given by continuous infusion in severe
benzodiazepine overdosage. Acta Anaesthesiol Scand 1991; 35:584.
32. Marriott S, Tyrer P. Benzodiazepine dependence. Avoidance and withdrawal. Drug Saf 1993; 9:93.
33. Busto UE, Sellers EM. Anxiolytics and sedative/hypnotics dependence. Br J Addict 1991; 86:1647.
34. Hood HM, Metten P, Crabbe JC, Buck KJ. Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11. Genes
Brain Behav 2006; 5:1.
35. Authier N, Balayssac D, Sautereau M, et al. Benzodiazepine dependence: focus on withdrawal syndrome. Ann Pharm Fr 2009; 67:408.
36. Pétursson H. The benzodiazepine withdrawal syndrome. Addiction 1994; 89:1455.
37. Higgitt A, Fonagy P, Toone B, Shine P. The prolonged benzodiazepine withdrawal syndrome: anxiety or hysteria? Acta Psychiatr Scand
1990; 82:165.
38. Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs 2009; 23:19.
39. Voshaar RC, Couvée JE, van Balkom AJ, et al. Strategies for discontinuing long-term benzodiazepine use: meta-analysis. Br J Psychiatry
2006; 189:213.
40. Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution--a treatment alternative for high-dose benzodiazepine-dependent
patients? Addiction 2010; 105:1870.
41. Parr JM, Kavanagh DJ, Cahill L, et al. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis.
Addiction 2009; 104:13.
42. Lum E, Gorman SK, Slavik RS. Valproic acid management of acute alcohol withdrawal. Ann Pharmacother 2006; 40:441.
43. Denis C, Fatséas M, Lavie E, Auriacombe M. Pharmacological interventions for benzodiazepine mono-dependence management in
outpatient settings. Cochrane Database Syst Rev 2006; :CD005194.
44. Schweizer E, Rickels K, Case WG, Greenblatt DJ. Carbamazepine treatment in patients discontinuing long-term benzodiazepine therapy.
Effects on withdrawal severity and outcome. Arch Gen Psychiatry 1991; 48:448.
45. Baandrup L, Ebdrup BH, Rasmussen JØ, et al. Pharmacological interventions for benzodiazepine discontinuation in chronic
benzodiazepine users. Cochrane Database Syst Rev 2018; 3:CD011481.
Topic 314 Version 25.0
GRAPHICS
Benzodiazepine and nonbenzodiazepine hypnotic pharmacokinetics
Usual
Oral peak Half-life (hours) Metabolite CYP3A4
Generic name Trade name single adult
(hours) parent activity* interactions
dose (oral)
Benzodiazepines
Alprazolam Xanax 0.25-0.5 mg 1-2 6-27 Inactive Yes
Bromazepam ¶ Lectopam 2-6 mg 1-2 8-20 Inactive Limited
Chlordiazepoxide Librium 5-25 mg 0.5-4 5-30 Active Yes
Clobazam Onfi 10-20 mg 0.5-4 36-42 Active (half-life 71-82 Limited (interacts via
hours) CYP2C19)
Clonazepam Klonopin 0.25-0.5 mg 1-2 18-50 Inactive Limited
Clorazepate Tranxene 7.5-15 mg 1-2 Prodrug Active No
Diazepam Valium 2-10 mg 0.5-1 20-50 Active Limited
Estazolam Prosom 0.5-2 mg 0.5-6 10-24 Inactive Limited
Flunitrazepam ¶ Rohypnol 0.5-2 mg 1-2 16-35 Active Limited
Flurazepam Dalmane 15-30 mg 0.5-1 2-4 Active Limited
Lorazepam Ativan 0.5-3 mg 2-4 10-20 Inactive No
Midazolam Versed 0.25 to 1 mg/kg 1-2 1.5-3 Active Yes

maximum 20 mg (oral
syrup for pediatric
sedation)
Oxazepam Serax 10-30 mg 2-4 5-20 Inactive No
Temazepam Restoril 7.5-30 mg 1-2 3-19 Inactive No
Triazolam Halcion 0.125-0.25 mg 0.7-2 2-3 Inactive Yes
Nonbenzodiazepine hypnotics
Eszopiclone Lunesta 1-3 mg 1 6-9 Active (less than Yes

parent)
Zaleplon Sonata 5-15 mg 1 1 Inactive Limited
Zolpidem Ambien, Edluar, 5-10 mg 1-2 1.5-8.4 Inactive Limited

Zolpimist
¶
¶
Zopiclone Imovane, Rhovane 3.75-7.5 mg 5-7 <2 Active (less than Yes
parent)
Other US FDA approved hypnotics
Doxepin Δ Silenor 3-6 mg 3.5 15 Active (half-life 31 Limited (interacts via

hours) CYP2D6)
Ramelteon Rozerem 8 mg 0.5-1.5 1-2.6 Active (half-life 2-5 No

hours)
Suvorexant Belsomra 10-20 mg 2 12 Inactive Yes
Duration of action of compounds having active metabolite(s) is significantly greater than predicted by half-life of parent.
* Half-life of active metabolite(s) may exceed 50-100 hours.

¶ Not available in United States.
Δ Approach to diagnosis and management of overdose is reviewed separately. Refer to topic review of tricyclic antidepressant poisoning available in UpToDate.
Graphic 69184 Version 7.0
Cytochrome P450 3A (including 3A4) inhibitors and inducers
Strong inhibitors Moderate inhibitors Strong inducers Moderate inducers

Atazanavir Amiodarone* Apalutamide Bexarotene
Clarithromycin Aprepitant Carbamazepine Bosentan
Cobicistat and cobicistat-containing Ceritinib Enzalutamide Dabrafenib

coformulations
Cimetidine* Fosphenytoin Dexamethasone ¶
Darunavir
Conivaptan Lumacaftor Efavirenz
Idelalisib
Crizotinib Mitotane Eslicarbazepine
Indinavir
Cyclosporine* Phenobarbital Etravirine
Itraconazole
Diltiazem Phenytoin Lorlatinib
Ketoconazole
Duvelisib Primidone Modafinil
Lopinavir
Dronedarone Rifampin (rifampicin) Nafcillin
Mifepristone
Erythromycin Rifabutin
Nefazodone
Fedratinib Rifapentine
Nelfinavir
Fluconazole St. John's wort
Ombitasvir-paritaprevir-ritonavir
Fosamprenavir
Ombitasvir-paritaprevir-ritonavir plus
Fosaprepitant*
dasabuvir
Grapefruit juice
Posaconazole
Imatinib
Ritonavir and ritonavir-containing
coformulations Isavuconazole (isavuconazonium
sulfate)
Saquinavir
Lefamulin
Telithromycin
Letermovir
Voriconazole
Netupitant
Nilotinib
Ribociclib
Schisandra
Verapamil
For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the
CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation.
These classifications are based upon US Food and Drug Administration (FDA) guidance. [1,2] Other sources may use a different classification system resulting in some
agents being classified differently.
Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration.
Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors
and inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked
using a drug interaction program such as Lexicomp interactions included within UpToDate.
Refer to UpToDate topics on specific agents and indications for further details.
* Classified as a weak inhibitor of CYP3A4 according to FDA system. [1]

¶ Classified as a weak inducer of CYP3A4 according to FDA system. [1]
Data from: Lexicomp Online (Lexi-Interact). Copyright © 1978-2019 Lexicomp, Inc. All Rights Reserved.
References:
1. US Food & Drug Administration. Clinical drug interaction studies - Study design, data analysis and clinical implications; Guidance for industry (October 24, 2017) available at:
https://www.fda.gov/media/82734/download.
2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website.
Common causes of delirium and confusional states
Drugs and toxins

Prescription medications (eg, opioids, sedative-hypnotics, antipsychotics, lithium, skeletal muscle relaxers, polypharmacy)
Nonprescription medications (eg, antihistamines)
Drugs of abuse (eg, ethanol, heroin, hallucinogens, nonmedicinal use of prescription medications)
Withdrawal states (eg, ethanol, benzodiazepines)
Medication side effects (eg, hyperammonemia from valproic acid, confusion from quinolones, serotonin syndrome)
Poisons:
Atypical alcohols (ethylene glycol, methanol)
Inhaled toxins (carbon monoxide, cyanide, hydrogen sulfide)
Plant-derived (eg, Jimson weed, Salvia)
Infections
Sepsis
Systemic infections; fever-related delirium
Metabolic derangements
Electrolyte disturbance (elevated or depressed): sodium, calcium, magnesium, phosphate
Endocrine disturbance (depressed or increased): thyroid, parathyroid, pancreas, pituitary, adrenal
Hypercarbia
Hyperglycemia and hypoglycemia
Hyperosmolar and hypoosmolar states
Hypoxemia
Inborn errors of metabolism: porphyria, Wilson disease, etc
Nutritional: Wernicke encephalopathy, vitamin B12 deficiency, possibly folate and niacin deficiencies
Brain disorders
CNS infections: encephalitis, meningitis, brain or epidural abscess
Epileptic seizures, especially nonconvulsive status epilepticus*
Head injury*
Hypertensive encephalopathy
Psychiatric disorders*
Systemic organ failure

Cardiac failure
Hematologic: thrombocytosis, hypereosinophilia, leukemic blast cell crisis, polycythemia
Liver failure: acute, chronic
Pulmonary disease, including hypercarbia and hypoxemia
Renal failure: acute, chronic
Physical disorders
Burns
Electrocution
Hyperthermia
Hypothermia
Trauma: with systemic inflammatory response syndrome, head injury*, fat embolism
CNS: central nervous system.

* Disorders that, while not truly systemic or "medical," may produce the clinical picture of delirium or confusional state in all other aspects.
Drugs believed to cause or prolong delirium or confusional states*
Analgesics Corticosteroids
NSAIDs Dopamine agonists
Opioids (especially meperidine) Amantadine
Antibiotics and antivirals Bromocriptine
Acyclovir Levodopa
Aminoglycosides Pergolide
Amphotericin B Pramipexole
Antimalarials Ropinirole
Cephalosporins Gastrointestinal agents

Cycloserine Antiemetics
Fluoroquinolones Antispasmodics
Isoniazid Histamine-2 receptor blockers
Interferon Loperamide
Linezolid
Herbal preparations
Macrolides
Atropa belladonna extract
Metronidazole
Henbane
Nalidixic acid
Mandrake
Penicillins
Jimson weed
Rifampin
St. John's wort
Sulfonamides
Valerian
Anticholinergics
Hypoglycemics
Atropine
Hypnotics and sedatives
Benztropine
Barbiturates
Diphenhydramine
Benzodiazepines
Scopolamine
Trihexyphenidyl Muscle relaxants

Baclofen
Anticonvulsants
Cyclobenzaprine
Carbamazepine
Levetiracetam Other CNS-active agents

Phenytoin Disulfiram
Valproate Cholinesterase inhibitors (eg, donepezil)
Vigabatrin Interleukin-2
Antidepressants Lithium
Mirtazapine Phenothiazines
Selective serotonin reuptake inhibitors
Tricyclic antidepressants
Cardiovascular and hypertension drugs

Antiarrhythmics
Beta blockers
Clonidine
Digoxin
Diuretics
Methyldopa
NSAIDs: nonsteroidal antiinflammatory drugs; CNS: central nervous system.

* Not exhaustive, all medications should be considered.
Contributor Disclosures
Howard Greller, MD Nothing to disclose Amit Gupta, MD Nothing to disclose Stephen J Traub, MD Nothing to disclose Jonathan Grayzel, MD,
FAAEM Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review
process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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PHARMACOLOGY AND CELLULAR TOXICITY

CLINICAL FEATURES OF OVERDOSE

● Acetaminophen and salicylate levels, to rule out these common coingestions

● Pregnancy test in women of childbearing age

clinical findings. (See 'Disposition' below.)

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

Use of UpToDate is subject to the Subscription and License Agreement.

2. Lader M. Benzodiazepines revisited--will we ever learn? Addiction 2011; 106:2086.

7. Olsen RW. GABA-benzodiazepine-barbiturate receptor interactions. J Neurochem 1981; 37:1.

36. Pétursson H. The benzodiazepine withdrawal syndrome. Addiction 1994; 89:1455.

Topic 314 Version 25.0

Benzodiazepine and nonbenzodiazepine hypnotic pharmacokinetics

Alprazolam Xanax 0.25-0.5 mg 1-2 6-27 Inactive Yes

Bromazepam ¶ Lectopam 2-6 mg 1-2 8-20 Inactive Limited

Chlordiazepoxide Librium 5-25 mg 0.5-4 5-30 Active Yes

Clonazepam Klonopin 0.25-0.5 mg 1-2 18-50 Inactive Limited

Clorazepate Tranxene 7.5-15 mg 1-2 Prodrug Active No

Diazepam Valium 2-10 mg 0.5-1 20-50 Active Limited

Estazolam Prosom 0.5-2 mg 0.5-6 10-24 Inactive Limited

Flunitrazepam ¶ Rohypnol 0.5-2 mg 1-2 16-35 Active Limited

Flurazepam Dalmane 15-30 mg 0.5-1 2-4 Active Limited

Lorazepam Ativan 0.5-3 mg 2-4 10-20 Inactive No

Midazolam Versed 0.25 to 1 mg/kg 1-2 1.5-3 Active Yes

Oxazepam Serax 10-30 mg 2-4 5-20 Inactive No

Temazepam Restoril 7.5-30 mg 1-2 3-19 Inactive No

Triazolam Halcion 0.125-0.25 mg 0.7-2 2-3 Inactive Yes

Eszopiclone Lunesta 1-3 mg 1 6-9 Active (less than Yes

Zaleplon Sonata 5-15 mg 1 1 Inactive Limited

Zolpidem Ambien, Edluar, 5-10 mg 1-2 1.5-8.4 Inactive Limited

Other US FDA approved hypnotics

Doxepin Δ Silenor 3-6 mg 3.5 15 Active (half-life 31 Limited (interacts via

Ramelteon Rozerem 8 mg 0.5-1.5 1-2.6 Active (half-life 2-5 No

Suvorexant Belsomra 10-20 mg 2 12 Inactive Yes

* Half-life of active metabolite(s) may exceed 50-100 hours.

Graphic 69184 Version 7.0

Cytochrome P450 3A (including 3A4) inhibitors and inducers

Strong inhibitors Moderate inhibitors Strong inducers Moderate inducers

Clarithromycin Aprepitant Carbamazepine Bosentan

Cobicistat and cobicistat-containing Ceritinib Enzalutamide Dabrafenib

* Classified as a weak inhibitor of CYP3A4 according to FDA system. [1]

Graphic 76992 Version 63.0

Common causes of delirium and confusional states

Drugs and toxins

Nonprescription medications (eg, antihistamines)

Withdrawal states (eg, ethanol, benzodiazepines)

Systemic infections; fever-related delirium

Endocrine disturbance (depressed or increased): thyroid, parathyroid, pancreas, pituitary, adrenal

Hyperglycemia and hypoglycemia

Hyperosmolar and hypoosmolar states

Inborn errors of metabolism: porphyria, Wilson disease, etc

Epileptic seizures, especially nonconvulsive status epilepticus*

Systemic organ failure

Hematologic: thrombocytosis, hypereosinophilia, leukemic blast cell crisis, polycythemia

Liver failure: acute, chronic

Pulmonary disease, including hypercarbia and hypoxemia

Renal failure: acute, chronic

CNS: central nervous system.

Graphic 59893 Version 5.0

Drugs believed to cause or prolong delirium or confusional states*

Antibiotics and antivirals Bromocriptine