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Chapter 16. Benzodiazepines and Other Sedatives and Hypnotics

Adam Bisaga, M.D.
DOI: 10.1176/appi.books.9781585623440.350267

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In this chapter I will discuss treatment strategies for individuals who abuse or are dependent on benzodiazepines and other medications that have sedative-hypnotic properties; that is, individuals who meet DSM-IV-TR criteria for sedative, hypnotic, or anxiolytic use disorders (American Psychiatric Association 2000). Benzodiazepines are the most frequently prescribed class of psychotropic agents. About 100 million prescriptions are written annually for benzodiazepines, and 3%–4% of adults in the United States and Canada are taking them at any one time (Neutel 2005; Paulose-Ram et al. 2004). Medications included in this class are used in a wide range of psychiatric and medical conditions, including anxiety disorders, sleep disorders, seizure disorders, movement disorders, and muscle spasticity. Sedative and anxiolytic properties of these medications are used in the symptomatic treatment of anxiety and agitation associated with other psychiatric and neurological disorders, including psychotic, mood, and cognitive (dementia, delirium) disorders (Hollister et al. 1993). Sedative and hypnotic properties of these medications have a variety of uses in anesthesiology and emergency medicine. These medications are also used for the symptomatic treatment of syndromes related to abuse of other drugs, such as agitation secondary to intoxication with stimulants, as well as signs and symptoms associated with withdrawal from alcohol, sedative-hypnotics, or opiates.

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FIGURE 16–1. Schematic representation of the GABAA receptor complex.(A) Each GABAA receptor contains five transmembrane subunits arranged in a circle around the channel. Many different subunits have been identified to date, which are grouped into several classes. Most receptors include two subunits, two subunits, and a , , , , or subunit (Mohler et al. 2002). (B) View from the extracellular space of the most commonly encountered receptor subtype with the location of the benzodiazepine and low-affinity GABA sites. This receptor has high affinity for benzodiazepines, mediating its sedative, amnestic, anticonvulsant, and reinforcing effects. It also has a high affinity site for flumazenil and zolpidem. BZ = benzodiazepine; Cl = chloride ion; GABA = -aminobutyric acid.

FIGURE 16–2. Suggested sequenced treatment strategies for individuals with a primary psychiatric disorder who developed sedative-hypnotic use disorder.

FIGURE 16–3. Suggested sequenced treatment strategies for individuals with a primary substance use disorder who developed sedative-hypnotic use disorder.GABA = -aminobutyric acid.
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TABLE 16–1. Sedative-hypnotic and anxiolytic medication categories available, with approximate clinically equivalent doses and pharmacokinetic properties
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TABLE 16–2. Pharmacological effects associated with specific subunits and receptor subunit selectivity for specific pharmacological agents
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TABLE 16–3. Groups of patients who are using sedative-hypnotic medications
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TABLE 16–4. Suggested treatment recommendations, according to the level of risk, for patients with a history of substance use disorders who may benefit from treatment with sedative-hypnotics
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Benzodiazepines and other sedative-hypnotics with a common mode of action at -aminobutyric acid (GABA)A receptors are highly useful medications for treatment of anxiety and insomnia as well as other disorders in psychiatry, neurology, and anesthesiology.

The abuse liability of benzodiazepines and the risk of developing DSM-IV-TR sedative-hypnotic use disorders are generally low. This also pertains to patients who are treated with sedative-hypnotics for an extended period of time and develop physical dependence.

Patients who are chronically prescribed benzodiazepines or other sedative-hypnotics should always be monitored both for the development of adverse side effects and the behavioral changes suggestive of a substance use disorder.

Signs of emerging abuse or dependence include 1) the development of excessive tolerance to the primary effect, with frequent requests for dose escalation; 2) continued and escalating use despite the presence of impairing adverse effects (e.g., excessive sedation); 3) use of medication to obtain euphoric effects; 4) preoccupation with medication and reported inability to function without it; and 5) additional use of illicit drugs and excessive use of alcohol.

Patients who meet DSM-IV-TR criteria for sedative-hypnotic use disorder often have other drug or alcohol use disorders, which are frequently the presenting problem. Thus, patients presenting with any substance use disorder should always be screened for sedative-hypnotic use, abuse, or dependence.

It is preferable not to prescribe benzodiazepines or other sedative hypnotics as a first choice to treat psychiatric disorders in patients with a history of current alcohol or drug use disorders. These patients are at greater risk of developing benzodiazepine use disorder, and, often, other medications with lower abuse liability can be used.

History of substance use disorder is not an absolute contraindication to treatment with sedative-hypnotics. Benzodiazepines are useful for detoxification from alcohol and opioids. Patients with anxiety disorder or insomnia who show resistance to other treatments can often be treated safely, along with careful monitoring for the emergence of signs of abuse or dependence.

The presence of benzodiazepine or other sedative-hypnotic use in patients with alcohol or drug use disorders should prompt a careful history to look for co-occurring mood, anxiety, or sleep disorders, given that appropriate treatment for these conditions may reduce or eliminate the need for benzodiazepines.

Patients who may no longer benefit from sedative-hypnotic medications, those who cannot be stabilized on the alternative dosing regimen, and those who primarily abuse the medication to achieve euphoria require medication discontinuation and treatment to prevent relapse.

Detoxification from benzodiazepines in individuals who were maintained on them for a long time can be best accomplished by substituting an agent with slow absorption and a long half-life (e.g., clonazepam, chlordiazepoxide), followed by a very slow (i.e., several months), gradual taper.

Inpatient detoxification may be indicated in individuals with substance use disorders who are physically dependent on several substances (sedatives, anxiolytics, opiates, or alcohol).

In the last phase of detoxification, stabilization on a very low dose of tapered medication may be warranted. Furthermore, during the final stage of detoxification, intensive behavioral therapy and adjunctive medication (e.g., carbamazepine, valproate, or imipramine) may be added to facilitate transition to complete abstinence. This treatment should be maintained for several weeks or months afterward to prevent early relapse and solidify extended abstinence.

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A number of benzodiazepines have been precribed to treat insomnia. Which of the following has the longest elimination half-life (excluding active metabolites)?
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