Sedative, Hypnotic, or Anxiolytic (Benzodiazepine) Withdrawal

Sedative, Hypnotic, or Anxiolytic (Benzodiazepine) Withdrawal

Sedative, Hypnotic, or Anxiolytic (Benzodiazepine) Withdrawal

Primer

Sedative, Hypnotic, or Anxiolytic Withdrawal is a withdrawal syndrome that occurs after a marked decrease in or cessation of intake after several weeks or more of regular use of substances such as benzodiazepines, benzodiazepine-like drugs (e.g. - zolpidem, zaleplon), carbamates (e.g. - glutethimide, meprobamate), barbiturates (e.g. - phenobarbital, secobarbital), and/or barbiturate-like hypnotics (e.g. - glutethimide, methaqualone). This class also includes all prescription sleeping medications and almost all prescription anti-anxiety medications. Non-benzodiazepine anti-anxiety agents (e.g. - buspirone, gepirone) are not included in this class because they are not associated with significant misuse. The withdrawal syndrome is characterized by symptoms similar to alcohol withdrawal and includes symptoms such as autonomic hyperactivity and psychomotor agitation.

Epidemiology

The prevalence of sedative, hypnotic, or anxiolytic withdrawal is unknown.^[1]

Prognosis

The timing and severity of the withdrawal syndrome will differ depending on the specific substance and its pharmacokinetics and pharmacodynamics.
- For example, withdrawal from short-acting substances with no active metabolites (e.g. - triazolam) can begin within hours after it is stopped.
- Other short half-life (e.g. - 10 hours or less) medications such as lorazepam, oxazepam, and temazepam can produce withdrawal symptoms within 6 to 8 hours, and will peak in intensity on the second day and improve by the fourth or fifth day.
- Substances with long-acting metabolites (e.g. - diazepam) may not produce withdrawal for 1 to 2 days or even longer (1 week!) after stopping, and withdrawal symptoms may not peak in intensity until the second week.^[2]
- For substances with longer half-lives (e.g., diazepam), , and de crease markedly during the third or fourth week. There may be additional longer-term symptoms at a much lower level of intensity that persist for several months.
Similar to alcohol withdrawal, the withdrawal from this class of medications can also progress to a life-threatening delirium.^[3]

Risk Factors

Longer substance use, plus higher dosages results in a higher risk for severe withdrawal.^[4]
- However, withdrawal has also been reported with low doses (e.g. - 15 mg of diazepam) when taken daily for several months.
- Doses of approximately 40 mg diazepam (or its equivalent) are more likely to produce clinically relevant withdrawal symptoms
- Ultra high doses (e.g. - 100 mg diazepam) are more likely to be followed by withdrawal seizures or delirium.

DSM-5 Diagnostic Criteria

Criterion A

Cessation of (or reduction in) sedative, hypnotic, or anxiolytic use that has been prolonged.

Criterion B

At least 2 of the following, developing within several hours to a few days after the cessation of (or reduction in) sedative, hypnotic, or anxiolytic use described in Criterion A:

Autonomic hyperactivity (e.g. - sweating or pulse rate greater than 100 beats per minute)
Hand tremor
Insomnia
Nausea or vomiting
Transient visual, tactile, or auditory hallucinations or illusions
Psychomotor agitation
Anxiety
Grand mal seizures

Criterion C

The signs or symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

Criterion 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.

Specifiers

Specifier

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.

Signs and Symptoms

A grand mal seizure may occur in as many as 20 to 30% of individuals undergoing untreated withdrawal from these substances.^[5]
In severe withdrawal, visual, tactile, or auditory hallucinations or illusions may occur, but are usually in the context of an episode of delirium.^[6]

Screening and Rating Scales

Withdrawal from these substances can be monitored similarly to alcohol withdrawal using tools such as the CIWA.

Alcohol Withdrawal Tools and Scales

Name	Rater	Description	Download
CIWA-Ar	Clinician	The CIWA–Ar (revised) measures 10 symptoms. Scores of less than 8 to 10 indicate minimal to mild withdrawal. Scores of 8 to 15 indicate moderate withdrawal (marked autonomic arousal); and scores of 15 or more indicate severe withdrawal. It takes approximately 2 minutes to perform.	Download
PAWSS	Clinician	The PAWSS is the first validated tool for the prediction of severe alcohol withdrawal syndrome in the medically ill and its use may aid in the early identification of patients at risk for complicated withdrawal, allowing for prophylaxis before severe alcohol withdrawal syndromes occur.	Download

CIWA

The Clinical Institute Withdrawal Assessment (CIWA) was developed in Toronto, Canada in the 1980s.^[7] It is considered the gold-standard for measurement of alcohol withdrawal symptoms, and is used in the treatment of alcohol withdrawal in an inpatient setting. Whenever a patient scores > 10 on the CIWA, they should be given either lorazepam or diazepam.

PAWSS

The Prediction of Alcohol Withdrawal Severity Scale (PAWSS) is a validated screening tool that uses a combination of symptoms and signs to identifying patients at risk of developing severe alcohol withdrawal syndrome (i.e., withdrawal hallucinosis, withdrawal-related seizures, and delirium tremens).^[8]^[9]
The use of this tool is particularly important, as the CIWA does not indicate the probability that the patient will develop severe withdrawal syndrome, and only indicates whether the patient is experiencing withdrawal symptoms. This is particularly important for identifying high risk patients who may need more intensive medical management or prophylaxis.

Pathophysiology

Similar to alcohol withdrawal, the mechanism behind withdrawal symptoms is thought to be due to an imbalance between GABA (decreased) and glutamate (increased).

Differential Diagnosis

Other medical disorders
- The symptoms of sedative, hypnotic, or anxiolytic withdrawal can mimic other medical conditions (e.g. - hypoglycemia, diabetic ketoacidosis). If seizures are present in the sedative, hypnotic, or anxiolytic withdrawal, the differential diagnosis should also include the various causes of seizures (e.g. - infections, head injury, poisonings).
Essential tremor
- Essential tremor, a disorder that frequently runs in families, may erroneously suggest the tremulousness associated with sedative, hypnotic, or anxiolytic withdrawal.
Alcohol withdrawal
- Alcohol withdrawal can have a syndrome very similar to that of a sedative, hypnotic, or anxiolytic withdrawal.
Other sedative-, hypnotic-, or anxiolytic-induced disorders
- Sedative, hypnotic, or anxiolytic withdrawal is different from the other sedative-, hypnotic-, or anxiolytic- induced disorders (e.g. - sedative-, hypnotic-, or anxiolytic-induced anxiety disorder, with onset during withdrawal) because the symptoms in the induced disorders predominate in the clinical presentation and are severe enough to warrant additional clinical attention.
Anxiety disorders
- Recurrence or worsening of a primary anxiety disorder can produce a syndrome similar to sedative, hypnotic, or anxiolytic withdrawal. Withdrawal is more likely with an abrupt reduction in the dosage of a sedative, hypnotic, or anxiolytic medication. When a gradual taper is occuring, differentiating a withdrawal syndrome from an anxiety disorder can be difficult. Similar to alcohol, lingering withdrawal symptoms (e.g. - anxiety, moodiness, and trouble sleeping) can be mistaken for non-substance/medication-induced anxiety or depressive disorders (e.g. - generalized anxiety disorder).

Investigations

If there is a clinical suspicion for other medical disease or conditions (e.g. - delirium, head injury), other relevant lab tests and investigations should be ordered, as per the differential diagnosis above.

Physical Exam

Vital sign changes with autonomic instability, tremors, and psychomotor agitation may be present.^[10]
Hyperreflexia may also be present in benzodiazepine withdrawal.^[11]

Treatment

See main article: Alcohol Withdrawal: Treatment

The approach to withdrawal for substances in this class is similar to treating alcohol withdrawal.

Guidelines

See also: Psychiatry Clinical Practice Guidelines (CPGs)

Benzodiazepine Use Guidelines

Guideline	Location	Year	PDF	Website
Deprescribing.org	Canada	2018	• For Patients • For Prescribers	• For Patients • For Providers
Canadian Guidelines on Benzodiazepine Receptor Agonist Use Disorder Among Older Adults	Canada	2019	PDF	Link
Australian Prescriber	Australia	2015	-	Link

Resources

For Patients

For Providers

Articles

Research

¹⁾ American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.

²⁾ American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.

³⁾ American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.

⁴⁾ American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.

⁵⁾ American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.

⁶⁾ American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.

⁷⁾ Sullivan, J. T., Sykora, K., Schneiderman, J., Naranjo, C. A., & Sellers, E. M. (1989). Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA‐Ar). Addiction, 84(11), 1353-1357.

⁸⁾ Goodson, C. M., Clark, B. J., & Douglas, I. S. (2014). Predictors of severe alcohol withdrawal syndrome: a systematic review and meta‐analysis. Alcoholism: Clinical and Experimental Research, 38(10), 2664-2677.

⁹⁾ Wood, E., Albarqouni, L., Tkachuk, S., Green, C. J., Ahamad, K., Nolan, S., ... & Klimas, J. (2018). Will This Hospitalized Patient Develop Severe Alcohol Withdrawal Syndrome?: The Rational Clinical Examination Systematic Review. JAMA, 320(8), 825-833.

¹⁰⁾ American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.

¹¹⁾ Newman RK, Stobart Gallagher MA, Gomez AE. Alcohol Withdrawal. [Updated 2020 Dec 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing

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