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Benzodiazepine use disorder

AUTHOR: Tae Woo Park, MD, MSc
SECTION EDITOR: Murray B Stein, MD, MPH
DEPUTY EDITOR: Michael Friedman, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jun 2024.

This topic last updated: May 31, 2024.

INTRODUCTION

Benzodiazepines have anxiolytic, hypnotic, anticonvulsive, and muscle-relaxing properties,

which have made them a widely prescribed treatment, primarily for anxiety and insomnia. They
also are associated with physical dependence and addiction. Benzodiazepine use disorder can
involve misuse of prescribed benzodiazepines and use of diverted benzodiazepines.

Benzodiazepine use disorder can be a chronic, relapsing disorder and benzodiazepine use has
been associated with increased morbidity and mortality in some studies. Misuse of
benzodiazepines can be difficult to distinguish from undertreated anxiety or insomnia.

The epidemiology, pathogenesis, clinical manifestations, course, diagnosis, and treatment of

benzodiazepine use disorder are reviewed here. Clinical assessment of substance use disorders,
identification and management of prescription drug misuse, including misuse of
benzodiazepines, are reviewed separately. (See "Substance use disorders: Clinical assessment"
and "Prescription drug misuse: Epidemiology, prevention, identification, and management".)

TERMINOLOGY

● Controlled substances – Because of their potential for misuse, addiction, and illicit
diversion and sale, opioid analgesics, stimulants, and benzodiazepines and other
sedatives/hypnotics are regulated, restricting whether and how they can be prescribed. In
the United States, these medications are referred to as "controlled substances" and
subject to federal regulations ( table 1).
 ● Prescription drug (eg, benzodiazepine) misuse – Any use of a prescription medication
that is outside of the manner and intent for which it was prescribed; this includes overuse,
use to get high, diversion (sharing or selling to others), and having multiple prescribers or
nonprescribed sources of the medication, or nonprescribed controlled medications.
Misuse is a necessary but not sufficient criterion for a substance use disorder. (See
"Prescription drug misuse: Epidemiology, prevention, identification, and management".)

● Nonmedical use – A narrower definition of prescription drug misuse, defined as use of a

medication that was not prescribed to the individual or use “only for the feeling or
experience it caused” [1].

● Prescription drug (eg, benzodiazepine) use disorder – Misuse of a prescription drug

meeting the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition, Text Revision (DSM-5-TR) criteria as a substance use disorder [2].

EPIDEMIOLOGY

Prevalence — Precise data are not available, but estimates suggest a lifetime prevalence of
benzodiazepine use disorder of somewhat less than 1 percent. In epidemiologic surveys,
benzodiazepines are often categorized with other drugs to create therapeutic drug classes such
as sedatives, tranquilizers, and hypnotics; thus, the prevalence of benzodiazepine use disorder
specifically in the United States can be difficult to tease out. Nevertheless, the existing data
sources roughly describe the scope of the disorder from the late 1990s through the early 2020s:

● The lifetime prevalence of tranquilizer and sedative use disorders (including

benzodiazepines, barbiturates, and other older sedative medications) in the United States
was estimated to be 1.0 and 1.1 percent respectively [3].

● Past-year prevalence of tranquilizer or sedative use disorder in the United States was
estimated to be 0.8 percent, an increase of four times over prior estimate [4].

● In persons age 12 years or older in the United States, 1.3 percent reported past-year illicit
use of benzodiazepines. This represents nearly 5 percent of total illicit drug use in this age
range [4].

● Substance use disorder treatment admissions for benzodiazepines as the primary

substance used have consistently risen and have increase from 0.5 percent to 1.2 percent
over a 14-year interval (2007 to 2021) [5].
 ● Nationally representative surveys were largely limited to the United States, but as an
international point of comparison, in Australia, among Australian individuals 14 years or
older, 1.6 percent had past-year nonmedical tranquilizer use [6].

Risk factors — Several risk factors for benzodiazepine use disorder have been identified [7]:

● Longer duration of benzodiazepine use

● Higher benzodiazepine doses
● Lower level of education

Misuse of prescribed benzodiazepines, which can contribute to or result from benzodiazepine

use disorder, is associated with a [8]:

● Greater insomnia severity

● Current antidepressant use

High rates of misuse of benzodiazepines have also been found among people who use injection
drugs [9] and those receiving methadone maintenance treatment [10,11].

Psychiatric comorbidity — Benzodiazepine use disorder has been associated with a broad
range of comorbid psychiatric disorders. In a survey of the United States general population,
sedative and tranquilizer use disorders were strongly associated with [3]:

● Other substance use disorders

● Other prescription drug misuse
● Panic disorder with agoraphobia
● Bipolar I disorder
● Antisocial personality disorder

PHARMACOLOGY

Mechanism of action — Benzodiazepines bind to gamma-aminobutyric acid type A (GABAA)

receptors, which are responsible for most of the inhibitory neurotransmission in the central
nervous system and a major target of alcohol, barbiturates, muscle relaxants, and other
medications with sedative effects. GABAA receptors are ligand-gated chloride ion channels.
When gamma-aminobutyric acid (GABA) binds to these receptors, it increases the amount of
chloride current generated by the receptor. Benzodiazepines augment GABA’s inhibitory effect
by increasing the frequency of channel openings [12]. This inhibitory effect leads to the
anxiolytic, hypnotic, anticonvulsive, and muscle-relaxing properties of benzodiazepines.
Pharmacokinetics — Benzodiazepines can be categorized into short (15 to 30 minutes),
intermediate (30 to 60 minutes), and long-acting agents (one hour or longer). There are at least
three determinants of the speed of action of benzodiazepines: half-life, rate of absorption, and
lipophilicity. Half-life is determined by how the drug is metabolized and whether it has any
active metabolites. A table ( table 2) provides data on the dosing and pharmacology of
individual benzodiazepines, including their comparative potency, time to onset, metabolism
type, and elimination half-life.

As an example, diazepam has a long half-life because it is oxidized by the liver (a relatively
slower process) and is metabolized into oxazepam, which is an active anxiolytic.

Most benzodiazepines are absorbed completely but have differing rates of absorption.
Clorazepate and diazepam are both rapidly absorbed, which leads to more rapid increases in
plasma levels of these drugs. The greater the lipophilicity of a benzodiazepine, the quicker it
enters the brain and therefore a more rapid anxiolytic effect. Lipophilicity varies by >50-fold
among benzodiazepines [13]. Diazepam is an example of a highly lipophilic benzodiazepine and
lorazepam of a less lipophilic drug.

Physical dependence — Chronic benzodiazepine use can cause physical dependence, as

evidenced by the benzodiazepine withdrawal syndrome observed in many people who use
benzodiazepines long-term upon cessation of the drug. The exact molecular mechanism for
physical dependence from benzodiazepine use is not clear [14].

Chronic exposure to benzodiazepines causes reduced GABAA receptor response, and there are
changes to GABAA receptor subtype expression with chronic benzodiazepine exposure, which
leads to a reduced inhibitory response. There is an increased expression of excitatory
glutamatergic receptors upon benzodiazepine withdrawal after chronic exposure, which could
underlie the symptoms observed in the benzodiazepine withdrawal syndrome.

Addiction liability — In a review of animal and human studies that incorporated both human
laboratory self-administration and epidemiological data, the liability to misuse benzodiazepines
varied by type [15,16]. Speed of onset appears to play a major role in the addiction liability of
different benzodiazepine types. Diazepam and flunitrazepam (widely available in Europe,
Mexico, and Colombia, but not in the United States), two benzodiazepines with rapid onset, and
lorazepam appear to have the greatest likelihood for misuse, although several commonly
prescribed benzodiazepines, such as alprazolam and clonazepam, were not included in these
studies.

In a study that used doctor shopping as a proxy for benzodiazepine misuse, flunitrazepam had
the highest potential for misuse, followed by diazepam, alprazolam, and clonazepam [17].
Flunitrazepam and diazepam are highly lipophilic and are rapidly absorbed. This causes a more
rapid onset of action and may lead to a higher liability for misuse.

PATHOGENESIS

The pathogenesis of addiction is not fully understood; however, use of all addictive drugs,
including benzodiazepines, involves increases in dopamine levels in the mesolimbic dopamine
system, the reward system of the brain. The ventral tegmental area, located at the origin of the
mesolimbic dopamine system, consists of gamma-aminobutyric acid (GABA) interneurons, and
dopamine and glutamate neurons. When benzodiazepines bind gamma-aminobutyric acid type
A (GABAA) receptors on GABA interneurons, they decrease the release of GABA onto dopamine
neurons. This lowers the inhibitory effect of GABA interneurons on dopamine neurons, leading
to increased dopamine transmission, a process called disinhibition. Benzodiazepines bind a
pocket between the alpha and gamma subunits on GABAA receptors, and the alpha-1 subunit
isoform is believed to be responsible for addictive behavior [18]. GABAA receptors with the
alpha-1 subunit are abundant in GABA interneurons in the ventral tegmental area of mice [19].

Synaptic plasticity, or changes in synaptic strength determined by prior synaptic activity, is

thought to underlie learning and memory processes. Addictive drugs can cause long-lasting
changes to the reward system. Early in this process, alpha-amino-3-hydroxy-5-methyl-4-
isoxazole propionic acid (AMPA) receptors move from the interior to the surface of dopamine
neurons, which leads to greater susceptibility to be stimulated by the excitatory
neurotransmitter glutamate [20]. Because of the AMPA receptor migration, future use of
addictive drugs can lead to even greater dopamine transmission. Similar to other addictive
drugs, benzodiazepine use in mice also leads to the same AMPA receptor migration and the
synaptic plasticity found in other addictive drugs [19,21].

The majority of genetic risk factors for benzodiazepine misuse or use disorder is believed to be
nonsubstance specific and thus shared among different substances. In two twin studies,
genetic influences were shared across multiple substances including sedatives, cannabis, and
stimulants and not specific to substance [22,23]. Twin studies also suggest that the majority of
environmental risk factors for substance use disorders shared between twin pairs, such as
family environment, is not specific to substance [23,24].

CLINICAL MANIFESTATIONS
Benzodiazepine use disorder — Patients with a benzodiazepine use disorder may present with
a range of severity. Milder cases may have no signs of benzodiazepine use or aberrant
medication-taking behaviors only, while patients with greater severity may present with acute
intoxication or benzodiazepine withdrawal.

Patients with a benzodiazepine use disorder may have symptoms or behaviors related to
benzodiazepine use, including:

● Benzodiazepines taken in larger amounts or over a longer period than intended

● Persistent desire or unsuccessful efforts to control benzodiazepine use
● Great deal of time spent obtaining or using benzodiazepines
● Craving to use benzodiazepines
● Recurrent benzodiazepine use resulting in failure to fulfill major role obligations
● Continued benzodiazepine use despite persistent interpersonal problems
● Important activities given up or reduced because of benzodiazepine use
● Recurrent benzodiazepine use in hazardous situations
● Continued benzodiazepine use despite persistent resulting problems
● Evidence of tolerance or withdrawal from benzodiazepine use

Withdrawal

Timing and course — Abrupt or overly rapid discontinuation of benzodiazepines after regular
use at a recommended dose most commonly leads to a short period (two to three days) of
rebound anxiety and insomnia that can occur as soon as one day after discontinuation,
depending on the half-life of the benzodiazepine. Some individuals will experience a broader
range of symptoms (listed above) that can last up to two weeks.

Clinical manifestations — Typical signs and symptoms of benzodiazepine withdrawal include

[25]:

● Mild (2 to 3 days)

• Anxiety
• Insomnia

● Moderate (2 to 14 days)

• Sleep disturbance
• Irritability
• Anxiety, panic attacks
• Tremor
 • Diaphoresis
• Poor concentration
• Nausea, vomiting
• Weight loss
• Palpitations
• Headache
• Muscle pain and stiffness

● Severe (2 to 14 days)

• Seizure
• Psychosis

Risk factors — Withdrawal seizures may be more likely in patients with a history of [26]:

● Brain damage
● Alcohol addiction
● Electroencephalogram abnormalities

Factors associated with increased severity of benzodiazepine withdrawal include [27]:

● Abrupt discontinuation after regular use

● Longer duration of use prior to discontinuation
● Higher doses
● Shorter half-life

Benzodiazepine withdrawal is reviewed further separately. (See "Benzodiazepine withdrawal"

and "Benzodiazepine poisoning", section on 'Management'.)

Intoxication — Signs of benzodiazepine intoxication include slurred speech, incoordination,

unsteady gait, and cognitive impairment (in particular, anterograde amnesia or the inability to
create new memories). Benzodiazepine intoxication is reviewed separately. (See
"Benzodiazepine poisoning".)

Overdose — Signs of benzodiazepine overdose include nystagmus, stupor or coma, and

respiratory depression. Signs of benzodiazepine withdrawal include anxiety, autonomic
hyperactivity, tremor, insomnia, and nausea or vomiting [2]. More severe benzodiazepine
withdrawal may lead to transient hallucinations, generalized tonic-clonic seizures, and delirium.
Benzodiazepine overdose is reviewed separately. (See "Benzodiazepine poisoning".)
COURSE

Little is known about the natural history of benzodiazepine use disorder; the more severe form
is believed to be a chronic, relapsing disorder similar to other substance use disorders.

A study of 221 Swedish individuals (average age of 43 years old when first hospitalized)
interviewed approximately 40 years after hospitalization for primary sedative-hypnotic
dependence found that approximately [28]:

● Half were misusing sedative-hypnotics at follow-up

● One-fourth died of an unnatural death
● Eighteen percent died of suicide

Longitudinal studies of patients who successfully discontinued benzodiazepine use after long-
term use and/or developing physically dependence (not assessed for benzodiazepine use
disorder) found:

● After 3 years, 73 percent continued to be abstinent from benzodiazepines [29]

● After 10 years, 59 percent continued to be abstinent [30]

Few studies have examined the medical consequences of benzodiazepine use disorder. A study
of 384 persons with benzodiazepine use disorder found that their mortality was increased
compared with the general population but not compared with those without benzodiazepine
use disorder who had similar psychiatric illnesses [31]. Numerous studies of benzodiazepine
use have found an increased risk of:

● Falls in older adults [32]

● Fractures in older adults [33]
● Cognitive dysfunction [34]
● Overdose death when combined with opioids [35,36]

Benzodiazepine use has also been associated with an increased risk of all-cause mortality
[37,38]; however, a large, population-based cohort did not find an increased risk of all-cause
mortality with benzodiazepine initiation [39].

Benzodiazepine discontinuation has also been associated with increase mortality and other
harms, including nonfatal overdose, suicidal behaviors, and emergency department visits [40].

ASSESSMENT
● Substance use history – When assessing a patient for benzodiazepine use disorder, it is
important to take a complete substance use history including details of benzodiazepine
use, past treatment, and use of other addictive substances.

Patients may obtain benzodiazepines by prescription or by illicit means. Those that are
receiving benzodiazepines by prescription may be nonadherent to the prescriber’s
instructions. It is important to ask patients, regardless of the source of medication, about
the amount of benzodiazepines being consumed. Shorter half-life benzodiazepines have
been associated with greater benzodiazepine withdrawal severity [25], and longer
duration of benzodiazepine use and higher benzodiazepine dose have been associated
with greater benzodiazepine use disorder severity and benzodiazepine withdrawal severity
[7].

Online prescription monitoring programs in the United States and other countries allow
clinicians to identify all prescriptions for a patient of a controlled substance, including
benzodiazepines, by all prescribers in a given state or region. When possible, prescribers
should (and, in some cases, are required to) query these online databases before further
prescription to verify a patient’s reported medication history and to detect undisclosed
prescriptions from other clinicians. Prescription monitoring programs are reviewed further
separately. (See "Prescription drug misuse: Epidemiology, prevention, identification, and
management".)

Patients should be asked specifically about:

• Benzodiazepine type
• Dose
• Average number of tablets consumed daily
• Duration of use
• Date of last use

Date of last use and half-life provide information on when withdrawal symptoms may
begin.

● Other substance use – Patients should be assessed for use and disorders associated with
alcohol and other drugs, in particular opioids and alcohol [41,42]. Combined use of
benzodiazepines with other sedating drugs may increase risk of over-sedation and
overdose death. Addiction to benzodiazepines may predispose patients to other substance
use disorders. (See 'Risk factors' above.)
● Current or past substance use disorder treatment – Treatment for benzodiazepine use
disorder and other substances includes medically supervised withdrawal (detoxification),
residential rehabilitation treatment, mutual help groups, or outpatient substance use
disorder services (eg, counseling or medication for addiction). (See "Substance use
disorders: Determining appropriate level of care for treatment", section on 'Levels of
care'.)

● Comorbidities – Patients should be assessed for psychiatric comorbidities including

depression, anxiety disorders, and insomnia. Antidepressant use and greater insomnia
severity have been found to be risk factors for benzodiazepine use disorder among
outpatients using benzodiazepines [7]. Treating depression can reduce anxiety and
insomnia [43], which may reduce reliance on benzodiazepines [44]. (See 'Risk factors'
above.)

Because benzodiazepine use has been associated with an increased risk of cognitive
dysfunction and Alzheimer disease, it is important to assess for cognitive functioning
[35,45].

Assessing for medical comorbidities, particularly chronic obstructive pulmonary disease

(COPD) and chronic noncancer pain, is important in determining the risks of further
benzodiazepine use. Benzodiazepine use in patients with COPD has been associated with
an increased risk of mortality in a dose-response fashion [46]. Benzodiazepine use is
common among patients who take opioids for chronic pain [47]. Benzodiazepines have a
dose-response relationship with an increased risk of overdose death in patients receiving
opioid analgesics [34]. While assessing for COPD and chronic pain, patients with these
conditions who use benzodiazepines can be educated about the mortality risks.

● Physical examination – The physical examination of patients with benzodiazepine use

disorder may reveal signs of benzodiazepine intoxication or withdrawal. Signs of
benzodiazepine intoxication include slurred speech, incoordination, unsteady gait, and
cognitive impairment. Signs of benzodiazepine withdrawal include anxiety, autonomic
hyperactivity, tremor, insomnia, and nausea or vomiting. (See 'Intoxication' above and
'Withdrawal' above.)

● Laboratory evaluation – Patients assessed for a possible benzodiazepine use disorder

can usefully be tested for benzodiazepines using a standard urine drug screen, typically
performed by immunoassay. Certain benzodiazepines can be more difficult to detect, due
to differences in their metabolic pathways. Screening assays are typically able to detect
diazepam, chlordiazepoxide, temazepam, oxazepam, and nordazepam (a metabolite).
 Newer benzodiazepines such as alprazolam, clonazepam, and lorazepam are often more
difficult to detect, producing false negative results [48,49].

A standard urine drug screen that tests for other substances, including opioids, cocaine,
barbiturates, and amphetamine is also suggested, along with testing for alcohol use with
a breathalyzer (alcohol detectable up to six hours after use) and/or a biomarker such as
ethyl glucuronide (alcohol detectable up to 80 hours after use).

DIAGNOSIS

Benzodiazepine use disorder — Benzodiazepine abuse and dependence were replaced by

benzodiazepine use disorder. Although the crosswalk between these disorders is imprecise,
benzodiazepine dependence is approximately comparable to benzodiazepine use disorder,
moderate to severe subtype, while benzodiazepine abuse is similar to the mild subtype [50].

DSM-5-TR diagnostic criteria for benzodiazepine use disorder are [2]:

“A problematic pattern of sedative, hypnotic, or anxiolytic use leading to clinically significant

impairment or distress, as manifested by at least two of the following, occurring within a 12-
month period:

● 1. Sedatives, hypnotics, or anxiolytics are often taken in larger amounts or over a longer
period than was intended.

● 2. A persistent desire or unsuccessful efforts to cut down or control sedative, hypnotic, or

anxiolytic use.

● 3. A great deal of time is spent in activities necessary to obtain the sedative, hypnotic, or
anxiolytic; use the sedative, hypnotic, or anxiolytic; or recover from its effects.

● 4. Craving, or a strong desire or urge to use the sedative, hypnotic, or anxiolytic.

● 5. Recurrent sedative, hypnotic, or anxiolytic use resulting in a failure to fulfill major role
obligations at work, school, or home.

● 6. Continued sedative, hypnotic, or anxiolytic use despite having persistent or recurrent

social or interpersonal problems caused or exacerbated by the effects of sedatives,
hypnotics, or anxiolytics.

● 7. Important social, occupational, or recreational activities are given up or reduced

because of sedative, hypnotic, or anxiolytic use.
 ● 8. Recurrent sedative, hypnotic, or anxiolytic use in situations in which it is physically
hazardous.

● 9. Continued sedative, hypnotic, or anxiolytic use despite knowledge of having a persistent

or recurrent physical or psychological problem that is likely to have been caused or
exacerbated by the sedative, hypnotic, or anxiolytic.

● 10. Tolerance.*

● 11. Withdrawal.*

*These criteria are not considered to be met for individuals taking sedatives, hypnotics, or
anxiolytics under medical supervision.

Specifiers for the diagnosis include:

● In early remission – After full criteria for sedative, hypnotic, or anxiolytic use disorder were
previously met, none of the criteria for sedative, hypnotic, or anxiolytic use disorder have
been met for at least three months but for less than 12 months.

● In sustained remission – After full criteria for sedative, hypnotic, or anxiolytic use disorder
were previously met, none of the criteria for sedative, hypnotic, or anxiolytic use disorder
have been met at any time during a period of 12 months or longer.

● In a controlled environment – If the individual is in an environment where access to

sedatives, hypnotics, or anxiolytics is restricted.

Specifiers for disorder severity are based on the number of criteria met:

● Mild – Presence of two to three criteria.

● Moderate – Presence of four to five criteria.

● Severe – Presence of six or more criteria.”

Benzodiazepine withdrawal — Patients with benzodiazepine use disorder may present in

benzodiazepine withdrawal. Because symptoms of benzodiazepine withdrawal are similar to
those of alcohol withdrawal or withdrawal from other sedative-hypnotics such as barbiturates, it
is important to rule out other substance use disorders.

DSM-5-TR diagnostic criteria for benzodiazepine withdrawal are [2]:

● A. Cessation of (or reduction in) benzodiazepine use that has been prolonged.
 ● B. Two (or more) of the following, developing within several hours to a few days after the
cessation of (or reduction in) benzodiazepine use described in criterion A:

• 1. Autonomic hyperactivity (eg, sweating or pulse rate >100)

• 2. Hand tremor
• 3. Insomnia
• 4. Nausea or vomiting
• 5. Transient visual, tactile, or auditory hallucinations or illusions
• 6. Psychomotor agitation
• 7. Anxiety
• 8. Grand mal seizures

● C. The signs or symptoms in criterion B cause clinically significant distress or impairment

in social, occupational, or other important areas of functioning.

● D. The signs or symptoms are not attributable to another medical condition and are not
better explained by another mental disorder, including intoxication or withdrawal from
another substance.

Specify if:

● With perceptual disturbances – This specifier may be noted when hallucinations with
intact reality testing or auditory, visual, or tactile illusions occur in the absence of a
delirium.

Differential diagnosis — Assessing a patient for benzodiazepine use disorder can differ
depending on whether a patient is receiving a prescribed benzodiazepine or through illicit
means. In patients prescribed benzodiazepines, it is often difficult to distinguish between
treatment-seeking behavior in patients with undertreated anxiety or insomnia and behaviors to
obtain benzodiazepines for nonmedical use. Assessing for aberrant medication taking
behaviors can help with assessing for medication misuse. These behaviors include requests for
dose increases, running out of medications early, resisting a change in therapy despite adverse
effects of the medication, nonadherence with monitoring (eg, pill counts), and “lost” or “stolen”
prescriptions [51]. (See "Prescription drug misuse: Epidemiology, prevention, identification, and
management".)

Patients with benzodiazepine use disorder may present with symptoms of anxiety and
depression; anxiety and mood disorders should be ruled out as possible comorbid diagnoses.
TREATMENT

Treatment of benzodiazepine use disorder consists of safely tapering patients off of

benzodiazepines and preventing return to use once the medications are fully discontinued [52].

Medically supervised taper

Inpatient versus outpatient treatment — Most patients, even those on relatively high doses
of benzodiazepines (eg, 100 mg diazepam equivalent), can undergo successful benzodiazepine
taper in the outpatient setting [30]. Inpatient treatment may occasionally be warranted if the
patient has been unable to successfully taper in the outpatient setting despite several attempts
or has complicated medical comorbidities, such as a history of seizures, that should be
monitored during the taper.

Taper rate — In the outpatient setting, we recommend gradual reduction of the

benzodiazepine by 25 to 50 percent every 1 to 2 weeks over a period of 6 to 10 weeks. Within
this range, individualization of the taper rate depends on patient capacity to tolerate withdrawal
symptoms, as well as the dose and duration of benzodiazepine use. Some patients may require
longer tapers but prescribers should set clear and realistic goals for decreases in dose.

Longer durations of use are associated with a higher likelihood of symptoms during the taper.
Subjective benzodiazepine withdrawal symptoms during taper can worsen as the reduced dose
reaches 25 percent of the initial dose prior to improving as the dose reaches zero [53,54].

There are limited data on the rate of inpatient benzodiazepine taper. In one small prospective
study, 16 out of 23 patients on a mean dose of 150 mg of diazepam equivalent were
successfully tapered off benzodiazepines in the inpatient setting [53]. A loading dose of
diazepam equal to approximately 40 percent of their reported daily dose was followed by a
taper of 10 percent per day. While this is a reasonable rate to taper, it should be noted that
these patients were not followed up after discharge. For inpatient taper, we suggest that the
taper be completed prior to discharge to prevent return to use related to withdrawal symptoms.
(See 'Benzodiazepine withdrawal' above and 'Monitoring and symptom management' below.)

Clinicians should clearly convey the plan and schedule for tapering to the patient. (See
"Benzodiazepine withdrawal" and "Benzodiazepine poisoning", section on 'Management'.)

Choice of benzodiazepine for taper — Options include directly tapering the benzodiazepine
that the patient is already taking or switching the patient to a long-acting agent to complete the
taper. Our approach is to switch patients who are using a single short-acting benzodiazepine to
a long-acting benzodiazepine, typically diazepam or chlordiazepoxide, at an equivalent dose.
For those who are on several benzodiazepines, we add up the total daily dose and switch to a
single long-acting agent at that equivalent dose. Dosing equivalencies are listed in the table
( table 2).

There is no direct evidence that long-acting benzodiazepines perform better than short-acting
benzodiazepines in a taper. However, short-acting benzodiazepines are associated with higher
dropout rates from benzodiazepine discontinuation studies, worse “rebound” anxiety (eg,
return of underlying anxiety symptoms after benzodiazepine discontinuation), and more severe
withdrawal symptoms compared with long-acting benzodiazepines [27].

Other medication options — Several other agents have been evaluated to taper patients
off benzodiazepines, but we do not routinely use them.

● Flumazenil, a benzodiazepine receptor antagonist/partial agonist, has shown early

promise in limiting acute withdrawal symptoms and long-term sequelae of
benzodiazepine withdrawal in benzodiazepine use disorder; however, further studies on
dose, duration of infusion, and safety are needed [55-57]. As an intravenous medication,
its use is also limited to the inpatient setting.

● Phenobarbital taper has historically been used for medically supervised benzodiazepine
taper. While it appears to be effective, we do not recommend its use due to safety
concerns, such as a narrow therapeutic index, and limited supporting data [58,59].

Adjunctive therapies (eg, antidepressants and mood stabilizers) have also been evaluated in
combination with benzodiazepines during the taper but have a limited role in the absence of
specific comorbidities. Meta-analyses are inconclusive regarding the effect of such adjunctive
pharmacologic interventions on the success of medically supervised taper or on the frequency
of withdrawal symptoms; overall, the quality of evidence for these interventions is low [60,61].
Populations studied in trials were heterogenous, and very few included only patients with
benzodiazepine use disorder diagnosis.

Monitoring and symptom management — We recommend weekly sessions to monitor

patients who are being tapered off of benzodiazepines in the outpatient setting. If patients
cannot meet that frequently, we still limit prescriptions for the taper to a week supply to
minimize potential overuse.

If physical symptoms such as anxiety, concentration difficulties, appetite changes, palpitations,

restlessness, headache, tremor, or sweat on palms are noted (see 'Withdrawal' above), we favor
returning to the dose prior to the most recent reduction and slowing down the rate of taper. As
an example, if reducing diazepam from 20 mg daily to 10 mg daily precipitates tachycardia and
diaphoresis, we suggest increasing back to 20 mg daily and lowering to 15 mg instead of 10 mg
the next week.

In inpatient settings, monitoring symptoms using a standardized scale such as the Clinical
Institute Withdrawal Assessment-Benzodiazepines is recommended. In this case, a tapering
dose can be adjusted or augmented according to a scheduled assessments of score.

Managing comorbidities — There is limited evidence that treating comorbidities can improve
outcomes of benzodiazepine taper. Use of antidepressants and mood stabilizers has been
described for commonly occurring symptoms such as mood instability, anxiety, and insomnia,
though further studies are needed [62-64]. Further, evaluation and treatment of symptoms that
the patient may have been self-treating with benzodiazepines is prudent to help prevent return
to benzodiazepine use.

Depression or anxiety — For patients with pre-existing depression or anxiety, we

recommend ongoing treatment and close monitoring of comorbid symptoms during medically
supervised taper of benzodiazepines. Worsening depression or anxiety may affect the patient’s
ability to tolerate symptoms of withdrawal and may lead to early termination of planned taper
and escalation of use of benzodiazepines. Management of depression and anxiety are
discussed elsewhere. (See "Major depressive disorder in adults: Approach to initial
management" and "Unipolar depression in adults: Treatment with antidepressant
combinations" and "Generalized anxiety disorder in adults: Management" and "Comorbid
anxiety and depression in adults: Epidemiology, clinical manifestations, and diagnosis".)

Insomnia — We suggest melatonin for treatment of subjective insomnia during

benzodiazepine withdrawal. Melatonin has been shown in one small study to facilitate
discontinuation of benzodiazepines while maintaining sleep quality during taper of
benzodiazepines [65]. Limited evidence has supported the use of pregabalin on subjective sleep
disturbance during withdrawal from long-term benzodiazepine use; however, this must be
weighed against misuse potential [61,63,65-68]. (See "Overview of the treatment of insomnia in
adults".)

Opioid use disorder — Benzodiazepine use is widely reported in individuals with opioid
use disorder, including those on opioid agonist therapy. In patients with benzodiazepine use
disorder who are receiving opioid agonist therapy, we suggest maintaining a stable dose of
opioids throughout the benzodiazepine reduction period in order to prevent opioid withdrawal
[69,70]. The partial opioid agonist buprenorphine may carry a lower risk of respiratory
suppression in combination with benzodiazepine than the full agonist methadone [71]. (See
"Opioid use disorder: Pharmacologic management".)

Psychosocial augmentation — We suggest cognitive-behavioral therapy (CBT) for patients

undergoing medically supervised taper of benzodiazepines. In a meta-analysis that included
nine trials, adding CBT to a benzodiazepine taper resulted in higher rates of benzodiazepine
discontinuation compared with taper alone at three-month follow-up (relative rate of effect
1.51, 95% CI 1.15-1.98) [72]. However, the effects were less certain at six months and longer.

CBT is the best studied psychosocial intervention in this context. Other options include
relaxation training and education material, such as self-help books or tailored clinician letters,
which have also been shown to improve benzodiazepine discontinuation rates compared with
usual care [61,62,68,72-78]. These methods are discussed in detail elsewhere. (See "Substance
use disorders: Psychosocial management".)

Prevention of recurrence — For patients who have successfully tapered off benzodiazepines,
we continue counseling regarding the risks of benzodiazepine use disorder. We recommend
avoiding therapeutic use of benzodiazepines in such patients. For those who do need
benzodiazepine treatment for a different indication, we suggest careful evaluation of the
indication for treatment, adherence to dosing suggestions, and timely discontinuation of
treatment after four to six weeks [66]. Additionally, we favor referral to a mental health
professional for those patients with psychiatric comorbidity. (See 'Risk factors' above.)

As above, prevention of recurrent benzodiazepine use disorder mainly consists of avoidance of

benzodiazepines and psychosocial support. There are no randomized controlled trials that have
specifically tested an intervention aimed at preventing return to use after successful
benzodiazepine discontinuation.

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: Benzodiazepine use
disorder and withdrawal".)

SUMMARY AND RECOMMENDATIONS

● Prevalence – The lifetime prevalence of benzodiazepine use disorder is less than 1

percent. Substance use disorder treatment admissions for benzodiazepines as the primary
 substance used have consistently risen over the past decade. Benzodiazepine-related
treatment admissions, emergency department visits, and overdose deaths have also
increased over that time. (See 'Epidemiology' above.)

● Benzodiazepine use disorder – Patients with a benzodiazepine use disorder may present
with a range of severity. Milder cases may have no signs of benzodiazepine use or
aberrant medication-taking behaviors only, while patients with greater severity may
present with acute intoxication or benzodiazepine withdrawal. (See 'Clinical
manifestations' above.)

• Symptoms – Predominant signs or behaviors of benzodiazepine use disorder include

taking larger amounts over a longer period than intended, unsuccessful efforts to
control benzodiazepine use, use of benzodiazepines despite persistent resulting
problems, and evidence of tolerance or withdrawal from benzodiazepine use. (See
'Benzodiazepine use disorder' above.)

• Intoxication – Signs of benzodiazepine intoxication include slurred speech,

incoordination, unsteady gait, and cognitive impairment (in particular, anterograde
amnesia or the inability to create new memories). (See 'Intoxication' above.)

• Overdose – Signs of benzodiazepine overdose include nystagmus, stupor or coma, and

respiratory depression. (See 'Overdose' above.)

• Withdrawal – Signs of benzodiazepine withdrawal include anxiety, autonomic

hyperactivity, tremor, insomnia, and nausea or vomiting. More severe benzodiazepine
withdrawal may lead to transient hallucinations, generalized tonic-clonic seizures, and
delirium. (See 'Withdrawal' above.)

• Course – Little is known about the natural history of benzodiazepine use disorder; the
more severe form is believed to be a chronic, relapsing disorder similar to other
substance use disorders. (See 'Course' above.)

● Assessment – When assessing a patient for benzodiazepine use disorder, we ask about a
history of past substance use or treatment, benzodiazepine type being used, dose,
average number of daily tablets consumed, duration of use, date of last use, and use of
other substances with potential for misuse or dependence. (See 'Assessment' above.)

● Treatment – Treatment of benzodiazepine use disorder consists of safely tapering

patients off of benzodiazepines and preventing return to use once the medications are
fully discontinued. Tapering can occur in outpatient or inpatient settings. We suggest
 using a long-acting benzodiazepine rather than a short-acting benzodiazepine in the
medically supervised taper of individuals with benzodiazepine use disorder (Grade 2C).
(See 'Medically supervised taper' above.)

We suggest cognitive-behavioral therapy as adjunctive treatment for medically supervised

taper of benzodiazepines in patients with benzodiazepine use disorder (Grade 2B). (See
'Psychosocial augmentation' above.)

We recommend weekly sessions to monitor patients who are being tapered off of
benzodiazepines in the outpatient setting. If patients cannot meet that frequently, we still
limit prescriptions for the taper to a week supply to minimize potential overuse. (See
'Monitoring and symptom management' above.)

Preventing return to use or recurrent disorder consists of avoidance of therapeutic use of

benzodiazepines when possible, and psychosocial support. No pharmacotherapy has
demonstrated efficacy. (See 'Prevention of recurrence' above.)

Use of UpToDate is subject to the Terms of Use.

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Topic 88407 Version 15.0
GRAPHICS

Schedules of controlled substances in the United States *

Medical Potential for

Schedule Examples Prescription
use? abuse/dependence

I Heroin, marijuana, LSD ¶ No Δ High Not applicable.

II Narcotics: Yes High Require a written

Codeine prescription by a
Fentanyl licensed practitioner.
Refilling of individual
Hydrocodone and
prescriptions is
hydrocodone
prohibited.
combinations (eg, with
acetaminophen)
Hydromorphone
Morphine
Methadone
Oxycodone and
oxycodone
combinations (eg, with
acetaminophen)
Tapentadol

Stimulants:
Amphetamine
Methamphetamine
Methylphenidate

Other:
Cocaine
Pentobarbital,
secobarbital

III Narcotics: Yes Less than with A prescription for a

Buprenorphine Schedule I and II drugs drug in Schedules III
Combination products through V must be
with <90 mg issued by a licensed
codeine/unit (eg, practitioner and may
acetaminophen with be communicated
codeine) orally, in writing, or by
facsimile to the
Non-narcotics: pharmacist; may be
Dronabinol
 Ketamine refilled up to five
times.
IV Narcotics: Yes Less than with
Tramadol and Schedule III drugs
combinations (eg, with
acetaminophen)

Others:
Alprazolam
Diazepam
Clonazepam
Lorazepam
Midazolam

V Preparations containing Yes Lower than with

limited quantities of certain Schedule IV drugs
narcotic and stimulant
drugs used for antitussive,
antidiarrheal, and analgesic
purposes (eg, cough
preparation with <200 mg
codeine/100 mL [eg,
Robitussin AC])

* Drugs and other substances that are considered controlled substances under the Controlled
Substances Act are divided into five schedules based upon whether they have a currently accepted
medical use in the United States and their relative abuse potential and likelihood of causing dependence
when abused.

¶ Lysergic acid diethylamide.

Δ Marijuana is classified as a Schedule I controlled substance under federal law. The definition of
Schedule I in the law indicates a lack of accepted medical use, and the designation as such in the table
reflects this statutory language. Several states have made marijuana legal for medical and/or
recreational use under state law. Marijuana's legal status is reviewed in greater detail in the UpToDate
content on the epidemiology, comorbidity, health consequences, and medico-legal status of cannabis use
and cannabis use disorder.

United States Department of Justice; Drug Enforcement Administration website https://www.dea.gov/drug-information/drug-

scheduling.

Graphic 66064 Version 10.0

Pharmacology of benzodiazepines used to treat anxiety symptoms/disorders

Onset
Adult oral Comparative Elimination
after oral
Drug total daily potency Metabolism half-life
dose
dose (mg)* (mg) ¶ (hours) Δ
(hours)

Alprazolam 0.5 to 6 0.5 1 CYP3A4 to 11 to 15

minimally
16 (older
active
adults)
Alprazolam 0.5 to 6 once 0.5 1 metabolites.
extended release daily 20 (hepatic
impairment)

22 (obesity)

Bromazepam ◊ § 6 to 30 7.5 1 CYP1A2. No 8 to 20

active
metabolite.

Chlordiazepoxide § 5 to 100 10 1 CYP3A4 to 30 to 100

active
Prolonged in
metabolites.
older adults
and hepatic
impairment

Clonazepam 0.5 to 4 0.25 to 0.5 0.5 to 1 CYP3A4. No 18 to 50

active
metabolite.

Clorazepate 15 to 60 7.5 0.5 to 1 CYP3A4 to 36 to 200

active
metabolite.

Diazepam 4 to 40 5 0.25 to 0.5 CYP2C19 and 50 to 100

3A4 to active
Prolonged in
metabolites.
older adults
and renal or
hepatic
impairment

Lorazepam 0.5 to 6 1 0.5 to 1 Non-CYP 10 to 14

immediate release glucuronidation
0.5 to 4
in liver. No
(hypnotic)
active
metabolite.

Lorazepam 1 to 6 mg ¥ 1 0.5 to 1 Non-CYP 13 to 27

extended release glucuronidation
 in liver. No
active
metabolite.

Oxazepam 30 to 120 15 to 30 1 to 2 Non-CYP 5 to 15

glucuronidation
15 to 30
in liver. No
(hypnotic)
active
metabolite.

Prazepam ◊ § 15 to 60 15 2 to 3 CYP3A4 to 30 to 200

active
Prolonged in
metabolites.
older adults

Data on drug metabolism and activity of metabolite(s) are for assessment of potential for CYP drug
interactions and risk of accumulation. Risk of accumulation is greater, and dose reduction necessary, for
older or debilitated adults and for patients with renal or hepatic insufficiency.

* Range of usual total daily dose for treatment of adults with anxiety or panic disorder typically given in
divided doses two to four times daily.

¶ Important: Data shown are approximate equal potencies relative to lorazepam 1 mg orally and are NOT
recommendations for initiation of therapy or for conversion between agents.

Δ Half-life of parent drug and pharmacologically active metabolite, if any.

◊ Not available in the United States.

§ Use only when other preferred agents are unavailable or not tolerated.

¥ To be used only when converting from immediate release lorazepam. Total daily dose is equal to the
current total daily dose of immediate release lorazepam. Dose is given once daily in the morning after
discontinuing immediate dose lorazepam tablets the night before.

Graphic 65653 Version 13.0

Contributor Disclosures
Tae Woo Park, MD, MSc No relevant financial relationship(s) with ineligible companies to
disclose. Murray B Stein, MD, MPH Equity Ownership/Stock Options: EpiVario [Substance use disorders
and PTSD]; Oxeia Biopharmaceuticals [Traumatic brain injury]. Consultant/Advisory Boards: Acadia
Pharmaceuticals [Anxiety and traumatic stress-related disorders]; BigHealth [Anxiety and traumatic stress-
related disorders]; Biogen [Anxiety and traumatic stress-related disorders; mood disorders]; Bionomics
[Anxiety and traumatic stress-related disorders]; Boehringer-Ingelheim [Anxiety and traumatic stress-
related disorders]; Cerevel Therapeutics [Anxiety and traumatic stress-related disorders]; Delix
Therapeutics [Anxiety and traumatic stress-related disorders]; EmpowerPharm [Anxiety and traumatic
stress-related disorders]; Engrail Therapeutics [Anxiety and traumatic stress-related disorders]; Janssen
[Anxiety and traumatic stress-related disorders]; Jazz Pharmaceuticals [Anxiety and traumatic stress-
related disorders]; Lykos Therapeutics [Anxiety and traumatic stress-related disorders]; Otsuka [Anxiety
and traumatic stress-related disorders]; Oxeia Biopharmaceuticals [Traumatic brain injury]; PureTech
[Anxiety and traumatic stress-related disorders]; Roche/Genentech [Anxiety and traumatic stress-related
disorders]; Sage Therapeutics [Anxiety and traumatic stress-related disorders; mood disorders]. Other
Financial Interest: Biological Psychiatry [Deputy Editor]; Depression and Anxiety [Editor-in-chief]. All of the
relevant financial relationships listed have been mitigated. Michael Friedman, MD No relevant financial
relationship(s) with ineligible companies 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.

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