Jeffrey S. Cluver, MD, Tara M. Wright, MD, and Hugh Myrick, MD
CHAPTER OUTLINE
■ PHARMACOLOGY
■ DEFINITIONS
■ ISSUES OF ABUSE AND DEPENDENCE
■ INTERVENTIONS
■ MANAGEMENT OF INTOXICATION AND OVERDOSE
■ WITHDRAWAL
■ MANAGEMENT OF WITHDRAWAL
■ TREATMENT SETTING
■ POSTWITHDRAWAL TREATMENT
■ CONCLUSIONS
Sedative–hypnotic agents have been utilized for centuries because of their ability to induce sleep. Most of the drugs in this class of medications have a mechanism of action in the central nervous system (CNS) that leads to their anxiolytic and sleep-inducing properties. Prior to 1900, agents such as chloral hydrate, bromide, paraldehyde, and sulford were used. The first barbiturate (barbital, a derivative of barbituric acid) was introduced in 1903 and soon became popular because of its ability to induce sleep and decrease anxiety. Phenobarbital was introduced in 1912, and in addition to the effects seen with barbital, this medication was also shown to have anticonvulsant properties. Despite safety and abuse issues, such as its narrow therapeutic index, tolerance, and drug interactions, phenobarbital proved to be a popular medication, and thousands of derivative compounds were developed. Today, there are less than twenty barbiturates that are available, and their clinical use has been largely supplanted by benzodiazepines.
The first benzodiazepine was synthesized in 1957. Chlordiazepoxide (Librium) and the other benzodiazepines that followed were found to be useful in the treatment of anxiety and sleep. While the properties of benzodiazepines and barbiturates are similar, the relative safety and tolerability of the benzodiazepines has led to their more widespread and lasting use. Medications in the benzodiazepine class all share a similar structure and bind to the same receptor site on the gamma-aminobutyric acid (GABA) receptor.
Barbiturates are now often categorized with other sedative–hypnotics, keeping in mind that barbiturates also act on the GABA receptor, by binding to a different subunit than the benzodiazepines. Other relatively new additions to this category of medications are the imidazopyridine derivatives (zolpidem and others), zaleplon, and eszopiclone. These medications are chemically distinct from benzodiazepines, but they also bind to the GABA receptor, at the omega subunit.
In Table 48-1, currently available sedative–hypnotic agents are listed. It has been reported that the behavioral and subjective effects (including subject-rated measures related to abuse potential) of the newer compounds are similar to those of the traditional benzodiazepines, in both individuals with a history of substance abuse and normal volunteers (1,2), and self-administration in laboratory animals has also been seen (3). Benzodiazepines and other sedative–hypnotics are often used in conjunction with other substances of abuse to enhance the effects of the other substances or to help an individual cope with unpleasant side effects of other drug use or withdrawal. Additionally, alone or when used with other CNS depressants, benzodiazepines and sedative–hypnotics can lead to respiratory depression, coma, and death. In this chapter, we focus on the management of individuals with dependence on these medications, especially in the context of withdrawal.
TABLE 48-1 CLASSES OF SEDATIVE–HYPNOTIC DRUGS: DRUG CLASSES, NONPROPRIETARY NAMES, AND TRADE NAMES
PHARMACOLOGY
As mentioned previously, the effects of benzodiazepines and other sedative–hypnotics are mediated by their binding to the GABA receptor. GABA receptors are distributed widely throughout the brain and are so named because they bind GABA, the major inhibitory neurotransmitter in the CNS. There are specific receptor subunits that are allosterically bound to the GABA receptor, and these medications act as agonists by increasing the ability of the inhibitory neurotransmitter GABA to bind to and activate the GABA-A receptor. When an agonist such as a benzodiazepine or barbiturate binds to the GABA receptor, the receptor opens its chloride channel, which then decreases neuronal excitability. Clinically, this leads to the effects of decreased anxiety, increased sedation, muscle relaxation, and increased seizure threshold. The toxic effects of these compounds are caused by excessive opening of chloride channels and can lead to respiratory depression, coma, and death. One essential difference between benzodiazepines and barbiturates is that high doses of barbiturates lead to excessive activity of GABA at the GABA-A receptor (which directly leads to respiratory depression), while high doses of benzodiazepines do not. Among the sedative–hypnotic agents, there are important differences in the onset of activity, half-life of the medication, presence of active metabolites, and specificity of the clinical effects.
While benzodiazepines and other sedative–hypnotics are agonists at the GABA receptor, there are also inverse agonists (such as beta-carboline) that bind to the GABA receptor but cause the chloride channels to close. Such inverse agonists can cause increased anxiety and lower the seizure threshold. A compound with a high affinity for the GABA receptor that does not exert an agonist or inverse agonist effects is flumazenil. This medication was developed and marketed to reverse the effects of benzodiazepines, including sedation and respiratory depression.
DEFINITIONS
It is worth taking a moment to clarify several definitions, especially when discussing this class of medications. Physical dependence can be defined as an altered homeostasis at several levels of drug effect and activity. Discontinuation of the drug in this state leads to symptoms resulting from a disruption of this homeostasis. Tolerance can be defined as a decreased pharmacologic effect after repeated or prolonged exposure to the drug so that higher doses are needed to achieve the same initial clinical effects. Both physical dependence and tolerance are inevitable with prolonged and regular use of medications in the class of benzodiazepines and other sedative–hypnotics. Drug misuse generally refers to inappropriate use of a medication such as the use of a higher dose than prescribed. Substance use disorder is defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria as a maladaptive pattern of substance use leading to clinically significant impairment or distress, defined by meeting multiple specified criteria within a 12-month period. (The substance use disorder category subsumes the DSM-IV’s label of both abuse and dependence and views the previous abuse and dependence criteria as various points along a continuum of maladaptive use.) Drugs with reinforcing properties, such as the ability to produce euphoria or other positive subjective experiences, are more likely to lead to a substance use disorder, though the development of physical dependence should not be equated with, or imply, the presence of a substance use disorder, although the two often coexist. Similarly, the misuse of a medication does not directly imply a substance use disorder, as may be the case in patients with severe anxiety disorders who do not achieve relief with their initially prescribed doses.
ISSUES OF ABUSE AND DEPENDENCE
Benzodiazepines have largely replaced barbiturates and other sedative–hypnotics in clinical settings, due to their preferred pharmacologic profile. Overall, there has been a trend toward decreased use of benzodiazepines and other sedative–hypnotics, but their use is still widespread. In 2009, about 118.4 million prescriptions were written for the five most commonly prescribed benzodiazepines in the United States (4), and just over 2.5% of individuals over the age of 12 reported illicit use of benzodiazepines and sedative–hypnotic medications in the past month (5). These medications are often initially prescribed for the treatment of anxiety disorders and insomnia, but their misuse (use at high doses or more frequent intervals) often leads to euphoria and disinhibition, making them desirable as drugs of abuse.
Laboratory studies involving rats and nonhuman primates demonstrate that many sedative–hypnotics are self-administered, although the benzodiazepines appear to be less reinforcing than barbiturates (6). While there have been human studies that have demonstrated the reinforcing effects of the benzodiazepines, there are notable differences among the compounds, which correlate with the agents’ onset of action. Lorazepam, alprazolam, and diazepam all appear to have a greater potential for abuse, based on their inherent properties, that is, their lipophilic properties and therefore more rapid onset of action. It is also important to note that other human studies have demonstrated that benzodiazepines do not have reinforcing effects in most individuals (7), thus suggesting that some individuals may have a vulnerability that leads to abuse.
Misuse and abuse of benzodiazepines and sedative–hypnotics is commonly seen in individuals with other substance use disorders (8). In this context, sedative– hypnotics are often used to enhance the effects of other drugs and alleviate unpleasant side effects from use or withdrawal of other substances. Benzodiazepines and other sedative–hypnotics may also be misused or abused when individuals who abuse many substances cannot obtain their substance of choice. Dependence does not often develop in this population, as the use of these substances is more likely to be intermittent and combined with other substances. The majority of patients who develop benzodiazepine and sedative– hypnotic dependence were initially being treated for problems with sleep and anxiety disorders. Individuals seeking treatment for anxiety disorders, sleep disorders, and depression are at higher risk for developing sedative–hypnotic use disorder if they have a history of substance use disorders. A family history of substance use disorders also places an individual at higher risk for developing a substance use disorder. The issue of alcohol use disorder warrants special caution because of the potential for dangerous interactions. The assumption that all individuals with alcohol use disorder have a propensity for abusing benzodiazepines or becoming dependent has been challenged (9), but the use of these medications should be closely monitored in this population.
INTERVENTIONS
In general, there are two clear indications for pharmacologic intervention in individuals who are taking benzodiazepines and other sedative–hypnotics and meet criteria for a use disorder. In a state of intoxication, a patient may require monitoring and even intervention to ensure a safe recovery. In patients experiencing acute withdrawal, pharmacologic management is often recommended because of the risk of serious consequences, including seizures and delirium tremens. The decision as to whether or not a benzodiazepine or other sedative–hypnotic should be continued is also important to consider in any patient who is prescribed these medications. In general, if there is a clear diagnosis, benefit from the treatment, minimal side effects, and no evidence of abuse or misuse, then the medication should be continued (10). Sedative–hypnotics are commonly recommended for the shortest period of time possible, and these medications are often seen as short-term therapies that should be discontinued as soon as the clinical situation permits. Guidelines for benzodiazepine prescribing have been published by the American Psychiatric Association (11).
MANAGEMENT OF INTOXICATION AND OVERDOSE
The signs and symptoms of benzodiazepine and sedative– hypnotic intoxication are very similar to those of alcohol intoxication. Severe intoxication can lead to respiratory depression, coma, and death, especially with the barbiturates and other older, nonbenzodiazepine agents. Benzodiazepine intoxication, even in the situation of an overdose, rarely leads to death, unless the benzodiazepines are combined with other CNS depressants. The management of acute intoxication is mostly supportive, with special attention to airway management, as respiratory depression is the most likely cause of death in overdose. In overdose, it is also critical to know what other psychoactive agents (especially CNS depressants) may have been acutely or chronically ingested. Flumazenil can be used in the case of benzodiazepine intoxication and overdose, but its use is limited by the risk of precipitating withdrawal symptoms, including seizures if this is not used with caution. Flumazenil can be considered in patients who have confirmed or suspected benzodiazepine toxicity, who have lost consciousness or are at risk of losing consciousness, and who may require intubation. Flumazenil should be avoided in patients who have also recently ingested medications or substances that lower the seizure threshold, in patients with known or suspected epilepsy, and in patients who have developed physiologic dependence on benzodiazepines. Because of the risk of adverse events related to the administration of flumazenil, it should be administered in the lowest possible doses for the shortest period of time required and in a medical setting where resuscitation equipment and appropriately trained health care personnel are present (12–15).
WITHDRAWAL
Withdrawal symptoms are most often seen in patients with physiologic dependence who abruptly discontinue taking benzodiazepines and other sedative–hypnotics (16). Withdrawal may be precipitated unintentionally when an individual stops taking a prescribed medication or is unable to obtain the sedative–hypnotic from illicit sources. Withdrawal may also be initiated by a provider due to concerns of misuse, abuse, psychological dependence, or other substance use disorders. In some cases, the decision is made to stop benzodiazepines because of side effects, such as memory impairment or behavioral problems. Individuals are likely to develop withdrawal symptoms when they have been taking high doses of sedative–hypnotics or if they have been taking low or moderate doses for a prolonged period of time (6,17).
While withdrawal symptoms are similar to those seen in alcohol withdrawal (Table 48-2), the signs and symptoms of withdrawal manifest differently in each patient, because of characteristics like age and overall state of health and the unique pharmacologic properties of each medication (18). The half-life of the medication, and its active metabolites, is of particular importance, especially when discussing the onset of withdrawal symptoms. Withdrawal from agents with short half-lives usually begins within 12 to 24 hours and reaches peak intensity within 1 to 3 days. With longer-acting agents, withdrawal symptoms may begin later and not peak until 4 to 7 days after discontinuation. Symptoms may then continue for several more days or even weeks depending on the half-life of drug. The onset and duration of withdrawal symptoms depend on the intrinsic pharmacokinetic properties (i.e., half-life) of the agent itself as well as extrinsic factors that impact the metabolism and effective half-life of the agent, such as the inhibition or induction of cytochrome p450 enzymes, patient age, and preexisting liver disease. Advanced liver disease may lead to significantly prolonged half-lives and reduced elimination rates for benzodiazepines requiring oxidative metabolism prior to glucuronidation (i.e., diazepam, clonazepam, chlordiazepoxide, alprazolam) due to the impairment of the oxidative process. Impairment of the oxidative process and resulting prolongation of the half-lives of these benzodiazepines may also occur due to advanced age (19,20). As one example of cytochrome p450 enzyme effects, norfluoxetine (a metabolite of fluoxetine) may lead to the inhibition of the liver microsomal system responsible for alprazolam metabolism, resulting in clinically significant changes in the half-life and clearance of this benzodiazepine (19). Lorazepam, oxazepam, and temazepam can be conjugated directly and are often the preferred agents in situations where there are concerns about liver function, age, and medication interactions.
TABLE 48-2 SEDATIVE–HYPNOTIC WITHDRAWAL SYMPTOMS
Another common occurrence during withdrawal is the reemergence of symptoms of anxiety and insomnia, which has been found to occur in 60% to 80% of benzodiazepine-dependent patients who were initially treated for these disorders (21–25). Initially, these rebound symptoms are perceived to be more severe and intense than the original symptoms but within several weeks return to pretreatment levels. Although there is some debate as to the validity of the “protracted abstinence syndrome,” these symptoms are thought to persist for weeks to months and even years. Smith and Wesson (26) suggest that receptor-mediated changes lead to worsening of withdrawal symptoms when patients are tapered from the remaining, low-dose, medication. Prolonged or protracted withdrawal symptoms may include anxiety; sensitivity to light, sound, and touch (27); and tinnitus (28). In contrast to symptom reemergence, protracted withdrawal symptoms often wax and wane and slowly resolve with continued abstinence.
It has been estimated that up to 50% (29) of regular benzodiazepine users will experience clinically significant signs of withdrawal with sudden discontinuation. The duration of treatment necessary to cause withdrawal symptoms is unclear. Some sources suggest that it may take as little as 4 to 6 weeks (30), while rebound insomnia has been seen after just 2 weeks of daily drug use (31).
MANAGEMENT OF WITHDRAWAL
The decision to discontinue or taper sedative–hypnotic drugs should be discussed at length with patients, with education provided about the reasons for discontinuation, the signs and symptoms that they are likely to experience, and the risks and benefits of the available withdrawal strategies. There are several strategies that may be employed in the management of sedative–hypnotic withdrawal. The approach with the most data to support its safety and efficacy includes slowly tapering a medication over a prolonged period of time to minimize the withdrawal symptoms. One benefit of this strategy is that it can be safely completed in an outpatient setting. Modest evidence exists to support more acute and rapid medically supervised withdrawals, similar to the approach taken in alcohol withdrawal treatment, though this is generally not as well tolerated as a prolonged taper (32). The later approach also requires close observation and monitoring and thus should only be undertaken in an inpatient setting. Emerging evidence that supports the use of certain anticonvulsants for the treatment of alcohol withdrawal suggests that there may be a role for the use of similar agents in the treatment of sedative–hypnotic withdrawal (32–34). The use of phenobarbital in the setting of an acute medically supervised withdrawal has also been studied, though the evidence to support this treatment is limited and somewhat dated. A mention will also be made of the work that has been done on the use of flumazenil in the management of benzodiazepine withdrawal.
Benzodiazepine Taper
The approach with the most data to support its safety and efficacy is to initiate a taper that uses decreasing doses of the therapeutic agent over the course of 4 to 12 weeks (35,36). This is most often used in settings of long-term use and physical dependence, where there is not an urgent need to discontinue the current medication. While this method could be used in settings where there are issues of misuse, abuse, or dependence, this approach is not recommended because it would provide the patient with continued doses of the drug for a period of weeks to months. In order for this strategy to be effective, the patient must be able to follow complex dosing regimens, adhere to regular follow-up appointments, and be free of other active substance use disorders. It is recommended that as lower doses are achieved, the dose reduction at each stage should be more modest, especially if short half-life drugs are being prescribed. More frequent dosing intervals can also be used in the later stages to help prevent the emergence of any withdrawal symptoms.
There is an increased likelihood of withdrawal symptoms with medications with a short half-life, even during prolonged tapers. Thus, a derivation of the above withdrawal strategy involves conversion of the therapeutic agent to an equivalent dose of a longer-acting agent and then a gradual reduction in the dose of the latter, using the principles described above. Agents such as clonazepam (37) and chlordiazepoxide are especially good choices given their slower onset of action and therefore relatively limited abuse potential.
Short-acting benzodiazepines, like the triazolobenzodiazepines, alprazolam and triazolam, warrant special consideration. These agents may have a higher binding affinity at a subpopulation of benzodiazepine GABA receptors that are not targeted by other benzodiazepines (38). Because of this, other benzodiazepines may not have fully effective cross-tolerance and therefore may be less effective when they are used for tapering and withdrawal. There are case reports that suggest that clonazepam can be used effectively for the treatment of triazolobenzodiazepine withdrawal (37), while others have reported distinct withdrawal symptoms with alprazolam (18,39).
Anticonvulsants
Another strategy for the treatment of withdrawal is the use of carbamazepine. This anticonvulsant has been shown to be as effective as oxazepam in the treatment of alcohol withdrawal (40), and two open-label studies also demonstrated the effectiveness of this agent in the management of complicated benzodiazepine withdrawal (41,42). One multisite, placebo-controlled study suggested that carbamazepine could also be effective for the treatment of alprazolam withdrawal, but the findings were limited by a high dropout rate. Based on these initial studies, the suggested dosing of carbamazepine is in the range of 200 mg three times a day for 7 to 10 days. Clinical experience suggests that this strategy is effective, but because of the potential for serious adverse events during sedative–hypnotic withdrawal, patients should be monitored closely, and benzodiazepines should be used as needed, especially for elevated vital signs or other uncontrolled symptoms. Carbamazepine has the distinct advantage of having low abuse potential and limited cognitive side effects, especially during short-term use. These properties make carbamazepine an attractive option in patients who are beginning a treatment program while also undergoing medically supervised withdrawal.
Studies have also shown gabapentin and divalproex to be effective in the treatment of alcohol withdrawal in patients who experience mild to moderate symptoms (33). While these medications have not been directly studied in the context of sedative–hypnotic withdrawal, there is reason to suggest that these agents could be used in this context. The activity of alcohol and other sedative–hypnotics, especially benzodiazepines, is similar as they act at a common receptor. Both gabapentin and divalproex compare favorably to carbamazepine in terms of research supporting their use in the treatment of alcohol withdrawal. This suggests that these agents could also be efficacious in the treatment of the symptoms of sedative–hypnotic withdrawal, but there is little direct evidence to support their use in this context.
Phenobarbital
Smith and Wesson (43,44) elucidated a protocol for utilizing phenobarbital for medically supervised withdrawal by converting patients from other sedative–hypnotics to equivalent phenobarbital doses. The starting daily dose of phenobarbital should be based on the patient’s drug use during the previous month. In cases when this is not known, a pentobarbital challenge test (45) can be used to determine the starting dose. (The maximum starting dose is 500 mg daily.) The daily dose should be administered in divided doses, three times a day, and then tapered by 30 mg a day. Signs of phenobarbital intoxication are similar to those seen with other sedative–hypnotics and include slurred speech, ataxia, and nystagmus. If signs and symptoms of intoxication are present, then the total daily dose should be decreased by 50% or more and the patient reassessed at frequent intervals until the intoxication resolves.
Flumazenil
Another treatment strategy for managing benzodiazepine withdrawal that is being studied involves the use of flumazenil (46–50). The data on the use of flumazenil are limited and still emerging, but published reports and studies suggest that parenteral and subcutaneous flumazenil may be effective in the management of benzodiazepine withdrawal. As described above, flumazenil is used to counteract benzodiazepine toxicity and can precipitate severe withdrawal, so the use of this agent to manage withdrawal is not intuitive and warrants explanation. While flumazenil is generally thought of as a pure antagonist, it acts as a partial agonist with weak affinity at the benzodiazepine receptor site. Explanations for flumazenil’s potential efficacy in the treatment of withdrawal symptoms include flumazenil-induced changes in receptor sensitivity and binding affinity, though the exact mechanism of action in ameliorating withdrawal symptoms is not clear (51,52). The evidence supporting the use of flumazenil is preliminary at this point—there is not a consensus on the efficacy of this treatment and therefore no generally agreed upon strategy for dosing. Factors that may limit the use of this strategy include the method of administration of the medication and the treatment setting, as intravenous infusion would necessitate an appropriately monitored environment such as an inpatient unit.
Protracted Withdrawal Symptoms
One additional consideration is the treatment of residual symptoms of withdrawal in the days and weeks following the discontinuation of the medication used to manage the withdrawal. The phenomenon of prolonged or protracted withdrawal has been commented on and studied in a limited way to date, but parallels could be drawn with the work done on understanding the nature and effective treatment of protracted alcohol withdrawal symptoms. There are no definitive pharmacologic options for the treatment of protracted benzodiazepine withdrawal symptoms, and this is a subject that is in need of further investigation and understanding. Pharmacologic strategies with antihistamines, alpha adrenergic agents, anticonvulsants, buspirone, and others have been described, but there is not an evidence base to support the use of a particular agent or strategy (53–56).
TREATMENT SETTING
While discussing with the patient the pharmacologic strategy for the treatment of withdrawal, a decision must also be made regarding the setting in which the withdrawal will be treated. While inpatient treatment is often optimal because of the close observation and controlled environment, this is often not feasible due to limited accessibility to inpatient resources and cost considerations. Therefore, inpatient treatment of withdrawal should be limited to cases in which the patient is medically compromised or a high risk of the patient developing severe symptoms, such as seizures, exists. This may be the case in patients who have been taking high doses of sedative–hypnotics for a long period of time and who require a rapid medically supervised withdrawal. Medically supervised withdrawal on an inpatient basis may also be appropriate if the patient has been taking multiple sedative–hypnotics or is alcohol dependent. Patients who have a history of experiencing severe withdrawal when they have previously stopped using sedative–hypnotics are also at high risk for having their withdrawal complicated by serious side effects.
Medically supervised outpatient withdrawal is reasonable if the patient does not appear to be at risk for severe withdrawal, especially if the method of slowly reducing the sedative–hypnotic dose can be utilized. If outpatient management is undertaken, the patient should be given clear instructions and close follow-up appointments. If a gradual dose reduction approach is employed, it is recommended that the patient be seen each time there is a dose reduction, and if this is not possible, then there should be a mechanism by which the patient can access the provider to address any questions or concerns. It is preferable for the patient to have some level of supervision by friends or family, but this is not always possible. Urine drug screens and clinical and laboratory assessments for the use of alcohol should be utilized to monitor for complications that could arise from the concomitant use of other substances.
POSTWITHDRAWAL TREATMENT
Medically supervised withdrawal should not be seen as definitive treatment in the case of sedative–hypnotic use disorder. This is the first step in the management of patients who often have other substance use disorders, anxiety and sleep disorders, and other co-occurring medical and psychiatric disorders. In the case of other substance use disorders, a treatment plan should include co-occurring medically supervised withdrawal from other substances and substance use disorder treatment in an appropriate setting. When treating patients with underlying anxiety and sleep disorders, other pharmacologic and psychotherapeutic treatments, particularly cognitive–behavioral therapy, should be initiated to counter any reemerging symptoms that may be experienced following withdrawal, which may help to reduce the risk of relapse (57–59). Other co-occurring psychiatric disorders should also be addressed during, or soon after, withdrawal. Failure to stabilize anxiety, sleep, or other co-occurring conditions will likely lead to higher rates of relapse due to patient discomfort, limited compliance, and inability to effectively engage in the early stages of rehabilitative treatment.
CONCLUSIONS
Sedative–hypnotic medications have been used for many years for a variety of disorders and symptoms. Today, benzodiazepines are by far the most commonly used sedative– hypnotics, and their use is widespread. The appropriate use of benzodiazepines requires a clear understanding of the medications, an accurate diagnosis and treatment plan, and close monitoring. Most users of sedative–hypnotic medications take their medications as prescribed and do not misuse, abuse, or develop dependence. Physical dependence may be unavoidable in cases of prolonged use; therefore, benzodiazepines should be prescribed for the shortest period of time that is clinically reasonable. In most cases, tapering of the drug over several weeks is an effective way to avoid withdrawal symptoms. Potential withdrawal signs and symptoms should be initially discussed with patients before treatment is initiated. In other cases, a more rapid withdrawal is needed, often because of misuse, benzodiazepine or sedative–hypnotic use disorder, or other substance use disorders. Prescribers must be aware of the risks inherent in prescribing benzodiazepines and other sedative–hypnotics, but they should be careful not to withhold treatment when appropriate. If providers and patients are well informed and openly discuss the risks and benefits of these medications, and they are prescribed at reasonable doses, sedative–hypnotics can be used safely and effectively for the treatment of a number of otherwise disabling conditions.
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