Introduction

The sedative-hypnotics and anxiolytics are central nervous system depressants that also have muscle relaxant and anticonvulsant effects and are widely used in psychiatry, neurology, anesthesiology, and general medicine. The most common of these are the benzodiazepines and the new-generation nonbenzodiazepine hypnotics (i.e., zaleplon, zolpidem, and eszopiclone), which due to their better safety profiles have largely replaced the barbiturates and other older agents, particularly in the treatment of insomnia and anxiety. This group of medications also includes chloral hydrate, meprobamate, carisoprodol, glutethimide, and methaqualone. γ-Hydroxybutyrate, which has some properties associated with the sedative-hypnotics, is usually classified as a club drug.

Beyond their use in the treatment of anxiety disorders and insomnia, the benzodiazepines also are often used for the management of agitation, the treatment of seizures, as muscle relaxants, for premedication in anesthesiology, and as the mainstay of treatment for the management of medication detoxification from alcohol. The new-generation nonbenzodiazepine hypnotics are used primarily for the treatment of insomnia. The barbiturates are most commonly prescribed for the treatment of epilepsy and for anesthesia, and they can also be used for detoxification from alcohol. The older sedative-hypnotic and anxiolytic agents such as chloral hydrate, meprobamate, carisoprodol, glutethimide, and methaqualone are less commonly used nowadays.

These groups of medications have a similar mechanism of action in that they all enhance the activity of the brain’s main inhibitory neurotransmitter, γ-aminobutyric acid (GABA), leading to the opening of chloride channels and cell membrane hyperpolarization. In a simplified but clinically useful model, the central nervous system maintains a balance between inhibitory signals mediated by GABA and signals mediated by the brain’s primary excitatory neurotransmitter, glutamate. When the balance sways toward glutamate-mediated excitatory transmission, the individual experiences arousal and anxiety; conversely, GABA-mediated inhibitory transmission results in tranquility and sedation. The benzodiazepines bind to GABA _A receptors, where they enhance GABA activity. The new-generation nonbenzodiazepine hypnotics have a similar mode of action but appear to have relative selectivity to certain subunits of the GABA _A receptor, resulting in a prominent sedative-hypnotic effect and a relatively weaker anxiolytic effect. In addition, the barbiturates potentiate GABA activity at the GABA _A receptor, but may additionally exert a direct effect on opening the chloride channel. Chloral hydrate, meprobamate, carisoprodol, glutethimide, and methaqualone also appear to exert their effects through GABAergic transmission. All of these medications can be used to reduce anxiety at lower doses and to induce sleep at higher doses. Commonly used sedative-hypnotics and anxiolytic drugs, along with their approximate dose equivalencies, are included in Table 27.1 . Because all of these drugs have wide therapeutic applications and are among the most commonly used, the conceptualization of what constitutes inappropriate use of the sedative-hypnotics and anxiolytics is often difficult to determine. The use of these drugs in a fashion other than as prescribed (i.e., nonmedical use) has been defined as “misuse,” and the terms “abuse” and “dependence” have been replaced by the term “substance use disorder” in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

Despite their most common appropriate therapeutic use, nonmedical use of the sedative-hypnotics and anxiolytics can be problematic and often occurs in individuals with other substance use disorders as well as those with general psychiatric disorders. In the 2014 National Survey on Drug Use and Health, with a sample of 67,901 respondents representative of the United States, 0.1% and 0.7% of people 12 years of age or older were current nonmedical users of sedatives or tranquilizers, respectively. In the National Epidemiologic Survey on Alcohol and Related Conditions, conducted in 2001–2002 with a sample of 43,093 respondents representative of the United States, the lifetime prevalence of nonmedical use of sedatives and tranquilizers was 4.1% and 3.4%, respectively, and the lifetime prevalence of sedative and tranquilizer use disorder was 1.1% and 1.0%, respectively. In the same survey, the 12-month prevalence rates were 0.16% for sedative use disorder and 0.13% for tranquilizer use disorder. The survey reported high rates of lifetime comorbidity between sedative and tranquilizer use disorders and alcohol use disorders (odds ratios of 13.4 and 14.2, respectively), mood disorders (odds ratios of 4.9 and 4.8, respectively), anxiety disorders (odds ratios of 3.7 and 4.2, respectively), and personality disorders (odds ratios of 5.6 and 6.6, respectively). Comorbidity is likely to be even higher in clinical populations. For example, in a sample of 427 treatment-seeking individuals with alcohol use disorders, the lifetime prevalence of anxiolytic use disorder was 20% ; and in a survey of 194 patients on methadone maintenance, 47% reported a history of benzodiazepine use, and 39.8% reported a history of nonmedical benzodiazepine use. Conversely, in a sample of 30 consecutive patients undergoing inpatient detoxification from benzodiazepines because of severe benzodiazepine dependence, 100% had another lifetime substance use disorder, 33% had lifetime major depression, and 30% had lifetime panic disorder.

Intoxication and Overdose

As noted earlier, the benzodiazepines are most commonly used as anxiolytics and sedative-hypnotics. However, there are reports of their consumption for the purpose of intoxication, which is described as similar to alcohol intoxication, leading to the saying, “benzodiazepines are the driest of martinis.” There are, however, some differences between intoxication from benzodiazepines and alcohol intoxication. For example, benzodiazepine users less commonly report the social disinhibition associated with alcohol use. Disinhibition and aggression related to benzodiazepine use is relatively rare and is more likely to occur in persons with high baseline levels of hostility as well as those with preexisting brain damage. With dose escalation, pleasurable intoxication may progress to manifestations of more profound toxicity, such as impairment in attention or memory, slurred speech, incoordination, unsteady gait, nystagmus, stupor or coma, and eventually respiratory depression. The benzodiazepines have a fairly wide therapeutic index, and overdose rarely results in death in healthy individuals. However, although safer than the barbiturates, the benzodiazepines have been associated with lethal overdoses when used alone, and especially when combined with other central nervous system depressants, such as alcohol and opioids, including buprenorphine. Recent data are very concerning, as rates of both benzodiazepine prescriptions and benzodiazepine-related overdose deaths rose considerably in the first decade of the century, and their use was involved in 30.6% of prescription drug-related overdose deaths in 2013. In addition, a recent large retrospective cohort study found an association between anxiolytic and hypnotic use and an increased risk of mortality.

The mechanism by which benzodiazepines manifest their rewarding potential is not well understood. Recent findings suggest that benzodiazepines share their reinforcing effects with other addictive drugs by activating the mesolimbic reward pathway. Laboratory studies that have tried to evaluate the rewarding properties of the benzodiazepines have found that healthy individuals have no preference for the benzodiazepines over placebo—in fact, healthy subjects have demonstrated a preference for placebo over higher doses of the benzodiazepines. However, individuals with a substance use disorder history, especially to sedatives, may be more likely to experience benzodiazepines as rewarding. In addition, there is evidence that individuals with a history of moderate alcohol consumption, anxiety, and insomnia, as well as children of alcoholics, may be more likely to experience the reinforcing effects of the benzodiazepines. Of interest though, research on the use of the benzodiazepines for the treatment of anxiety disorders in individuals with a prior history of substance use disorder found little evidence for induction of relapse to substance use. There is some evidence that benzodiazepines with a rapid onset of action such as diazepam and those with a short half-life such as alprazolam, may have a relatively more reinforcing effect, although these results are controversial. Taking the drug intravenously also has been associated with increased reinforcing effects.

When misused, the central nervous system depressants are often taken in combination with other drugs, often leading to complex and dangerous interactions. For example, individuals may use the benzodiazepines to enhance intoxication with opioids or alcohol, or to self-medicate the anxiety associated with stimulant use as well as the discomfort associated with stimulant or opioid withdrawal.

The nonbenzodiazepine hypnotics are even less likely to be taken for intoxication; however, they carry a risk of misuse, especially among individuals with other substance use disorders and psychiatric comorbidity. Although they are likely safer than the benzodiazepines, there have been reports of coma, respiratory depression, and fatal overdoses on high doses of zolpidem, especially when combined with other drugs. The barbiturates have a narrower therapeutic window in comparison with the benzodiazepines and carry more risk of dangerous central nervous system depression and death on overdose. Fatal overdose also may occur with other older agents; however, both their medical and recreational use has declined since the introduction of the benzodiazepines.

Benzodiazepine intoxication is managed according to the level of severity. Mild intoxication can be managed with supportive care and medical monitoring, while overdose is managed in an intensive care setting. Flumazenil, a benzodiazepine receptor antagonist, can be used intravenously to reverse benzodiazepine overdose. Flumazenil should be used with caution as its use may induce benzodiazepine withdrawal and increase the risk of grand mal seizures. Flumazenil also has been used in overdose related to the new-generation nonbenzodiazepine hypnotics. Because the barbiturates exert their activity independently of the benzodiazepine binding site, flumazenil does not block their effects and is not useful in barbiturate overdose.

Tolerance and Withdrawal

Physiological dependence requires the presence of tolerance or withdrawal. Tolerance is marked by the gradual need to use increased doses of the substance to achieve the same effect, or a diminished effect with the same dose. Tolerance to the sedative-hypnotics and anxiolytics occurs through central nervous system adaptation to the drug at the receptor level. Depending on the agent used, its dose, and the duration of use, tolerance can develop in days to months. Tolerance to the benzodiazepines is more likely to develop to the sedative-hypnotic and motor impairment effects than to the anxiolytic and short-term memory impairment effects. Tolerance can be minimized by using the medication for a short period, taking “drug holidays,” and using the lowest effective dose. Cross-tolerance can occur between the benzodiazepines and other depressant drugs, including alcohol.

Withdrawal is marked by the presence of a characteristic syndrome on cessation or reduction in the use of the substance and can be avoided or relieved by taking the same or closely related substance. Symptoms of withdrawal from the benzodiazepines resemble those of alcohol withdrawal, and are generally the result of central nervous system excitation, which is the opposite of the primary action of the drug. Withdrawal progresses from a syndrome of anxiety, insomnia, and tremor to nausea, vomiting, diaphoresis, tachycardia, hypertension, and rarely to grand mal seizures and delirium in rare, severe cases. Withdrawal usually develops after taking the benzodiazepines for months; however, milder withdrawal may emerge after days to weeks of use. Withdrawal severity correlates with the duration of use and the potency and dose of the drug taken, as well as individual susceptibility and general health status.

Syndromes that occur commonly after cessation of use of the benzodiazepines can be divided into:

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  Acute withdrawal, characterized by relatively severe symptoms emerging several hours to days following dose reduction or cessation of use. Use of short-acting agents is associated with relatively more intense but shorter duration of acute withdrawal symptoms, peaking 2 days after discontinuation, whereas longer-acting agents result in milder but longer withdrawal, peaking in 4–7 days.

  
  
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  Protracted withdrawal, characterized by ongoing anxiety and depression, as well as mild sensory and motor disturbances that can linger for months. More severe presentations such as psychotic depression also have been reported.

  
  
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  Symptom recurrence, which is the reemergence of preexisting symptoms, such as anxiety, that were previously masked by the benzodiazepine. Although often difficult to distinguish, reemerging symptoms tend to be stable over time, unlike withdrawal symptoms, which tend to subside gradually.

  
  
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  Symptom rebound, which is the exacerbation of preexisting symptoms after cessation of use, and is, therefore, a combination of genuine withdrawal and symptom reemergence.

Of note, physiological dependence (i.e., tolerance or withdrawal) may occur even when the medications are adequately used at therapeutic doses and does not necessarily indicate that a substance use disorder has developed, as defined by the DSM-5 Nonetheless, the presence of physiological dependence should alert the clinician that the individual may have developed a substance use disorder, in which case the presence of tolerance and withdrawal is associated with greater severity of the disorder. The term “addiction,” although not an official diagnostic term in the DSM-5, is commonly used to refer to the more severe forms of substance use disorder.

Benzodiazepine withdrawal can be managed by supportive measures in mild cases. In more severe cases, pharmacological detoxification is often achieved by substituting the substance with a long-acting benzodiazepine such as clonazepam or chlordiazepoxide and gradually reducing the dose over several days in inpatient detoxification programs. Intermediate-acting benzodiazepines, such as lorazepam, also are effective, and a simple taper of the original medication can also be used. Although inpatient detoxification may be needed when concurrently detoxifying from several drugs such as alcohol and opiates, a more gradual taper also can be achieved over several weeks to months in the outpatient setting. Evidence suggests that gradual detoxification is more effective than abrupt discontinuation, which is associated with a higher dropout rate. It also is recommended that the taper be slower after reaching about 50% of the original dose. An older method, using phenobarbital substitution, is less common, but is used when detoxifying individuals from the barbiturates. Because benzodiazepine or barbiturate withdrawal is associated with serious morbidity and the possibility of mortality, the clinician should evaluate individuals carefully and consider pharmacologic management of benzodiazepine withdrawal. Of other, non–sedative-hypnotic/anxiolytic medications studied for benzodiazepine detoxification, the anticonvulsant carbamazepine has the most promising data, suggesting its possible utility when used as an adjunct to the benzodiazepines, and its use also may improve drug-free outcomes. The adjunctive use of pregabalin may have a role in improving subjective sleep quality during benzodiazepine tapers.

The literature on physiological dependence to the new-generation nonbenzodiazepine hypnotics has been scarce. Tolerance and withdrawal from these drugs have been reported but appear to be relatively rare, as compared with the benzodiazepines, possibly due to their relative selectivity at the GABA _A receptor. Caution, however, is advised, as there have been reported cases of withdrawal seizures, as well as withdrawal delirium and psychosis, after discontinuation of the use of the new-generation nonbenzodiazepine hypnotics. A detoxification regimen similar to that used with the benzodiazepines and barbiturates has been suggested in managing withdrawal from these agents.

Withdrawal from the barbiturates and other older agents is associated with a clinical picture comparable to that of the benzodiazepines and may lead to withdrawal seizures as well as delirium. Treatment includes detoxification with phenobarbital, a benzodiazepine, or by a gradual taper of the original substance.

Substance Use Disorder

The DSM-5 ¹ offers a clear definition of substance use disorder that applies to most classes of substances of abuse (the exception is drugs that do not haven an established withdrawal syndrome), including the sedative-hypnotics and anxiolytics.

Evaluating for sedative, hypnotic, and anxiolytic use disorder when a patient has been prescribed the medication by a physician is potentially difficult. For example, if an individual manifests psychosocial deterioration, it is often difficult to determine whether it is related to a substance use disorder or the result of an undertreated anxiety disorder. The trajectory of the patient’s level of functioning may be a good clinical barometer—if their level of functioning improves with the use of a benzodiazepine, then it is likely that the prescribed substance is beneficial. Conversely, the patient’s demand for increasing doses of the medications despite deteriorating psychosocial functioning is one indication that a substance use disorder may have developed. The patient’s level of functioning can be evaluated by accessing previous records, as well as collateral information and involvement of significant others, after obtaining the patient’s consent.

Other indicators of the presence of a substance use disorder are reports of loss of prescriptions, running out of the medication, obtaining the medication from several prescribers, and other signs of loss of control over use of the substance. Even when these signs are present, the physician should consider the possibility that the behavior could be related to the patient’s efforts to obtain a medication that they need for a genuine disorder. In such instances, with adequate treatment of the underlying psychiatric disorder, this behavioral pattern should resolve. Naturally, there is no simple strategy to managing these complex clinical situations, and in all cases the clinician should clarify the reasons for the patient’s use of these agents, evaluate the risk/benefit ratio of prescribing, and subsequently use clinical judgment to develop a reasonable treatment plan in collaboration with the patient.

A common clinical dilemma revolves around whether a physician should prescribe benzodiazepines to individuals with a history of other (nonbenzodiazepine) substance use disorders. Although their use is unquestionably of great value in detoxification from alcohol and other substances, their value as anxiolytics and sedative-hypnotics in this patient population is difficult to determine. The prudent course seems to be that although the benzodiazepines should not be absolutely contraindicated in patients with a history of substance use disorders, since some individuals may in fact benefit from treatment with benzodiazepines without misusing them, special care should be exercised and, if possible, the benzodiazepines should not be the first line of treatment. When prescribed, their use should be monitored and the clinical course followed over time for signs of a substance use disorder.

Treatment of sedative-hypnotic and anxiolytic use disorder usually involves successful detoxification, followed by psychosocial interventions aimed at achieving long-term abstinence. People with sedative-hypnotic and anxiolytic use disorder often have other co-occurring substance use disorders and psychiatric disorders, which should be screened for, adequately diagnosed, and concurrently treated. There are no agents approved by the US Food and Drug Administration (FDA) for the long-term treatment of benzodiazepine use disorder. However, pharmacologic strategies are being investigated to target achieving abstinence from the benzodiazepines. Agents that have shown promising potential include the benzodiazepine antagonist flumazenil although further study is clearly needed, as its use may carry a high risk of precipitating seizures in patients with physiological dependence. Other promising agents include the anticonvulsants carbamazepine and valproate. Although controversial, maintenance substitution treatment with a long-acting agent, such as clonazepam, also has been suggested. Long-acting benzodiazepines may provide adequate relief from low-grade anxiety, which may be a trigger to relapse to other benzodiazepine and alcohol use. These strategies, although interesting and promising, are still in their investigational stages, and data supporting their safety and efficacy are limited.

Data on the new-generation nonbenzodiazepine hypnotics have been scarce; however, there is emerging evidence that they do carry a risk of substance use disorder, especially among individuals with other substance use disorders and psychiatric comorbidity. Although use disorder related to these medications seems to be less likely than with the benzodiazepines, caution should nonetheless be exercised with their prolonged use. Since the introduction of the benzodiazepines, use of the barbiturates and other older agents has been declining, and use disorders related to these agents are relatively rare.