Jeffrey S. Cluver, MD, Tara M. Wright, MD, and Hugh Myrick, MD
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 also bind to the GABA receptor, at the omega subunit. It has been reported that the behavioral and subjective effects (including measures related to abuse potential) of the newer compounds are similar to those of the traditional benzodiazepines. 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 central nervous system (CNS) depressants, benzodiazepines and sedative–hypnotics can lead to respiratory depression, coma, and death.
The effects of benzodiazepines and other sedative–hypnotics are mediated by their binding to the GABA 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.
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.
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. The DSM-5 criteria for a substance use disorder define a maladaptive pattern of substance use leading to clinically significant impairment or distress, defined by meeting multiple specified criteria within a 12-month period. 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. These medications are often initially prescribed for the treatment of anxiety disorders and insomnia, but their misuse often leads to euphoria and disinhibition, making them desirable as drugs of abuse.
There are notable differences among the compounds that 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. Misuse and abuse of benzodiazepines and sedative–hypnotics is commonly seen in individuals with other substance use disorders. 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. 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, but the use of these medications should be closely monitored in this population.
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. 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.
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. 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, and 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, patients with known or suspected epilepsy, and in patients who have developed physiologic dependence on benzodiazepines.
Withdrawal symptoms are most often seen in patients with physiologic dependence who abruptly discontinue taking benzodiazepines and other sedative–hypnotics. 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.
While withdrawal symptoms are similar to those seen in alcohol withdrawal, 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. 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. Advanced liver disease may lead to significantly prolonged half-lives and reduced elimination rates for some benzodiazepines. 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.
Another common occurrence during withdrawal is the reemergence of symptoms of anxiety and insomnia. Initially, these rebound symptoms are perceived to be more severe and intense than the original symptoms but within several weeks return to pretreatment levels.
MANAGEMENT OF WITHDRAWAL
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. 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. 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.
When tapering patients from medications with a short half-life, consideration should be given to converting to an equivalent dose of a longer-acting agent and then gradually reducing the dose of the latter.
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, and two open-label studies also demonstrated the effectiveness of this agent in the management of complicated benzodiazepine withdrawal. Based on the initial studies, the suggested dosing of carbamazepine is in the range of 200 mg three times a day for 7 to 10 days. Carbamazepine has the distinct advantage of having low abuse potential and limited cognitive side effects, especially during short-term use. Studies have also shown gabapentin and divalproex to be effective in the treatment of alcohol withdrawal in patients who experience mild-to-moderate symptoms.
A protocol has also been developed that utilizes phenobarbital during a medically supervised withdrawal, by converting patients from other sedative–hypnotics to equivalent phenobarbital doses. This practice is not commonly employed due to the decreased use of phenobarbital in clinical settings, but it does have evidence to support its safety and efficacy.
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. 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. 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. 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.
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 and should therefore 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. 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. 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.
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.
1. Due to their inherent pharmacologic properties, benzodiazepine and other sedative– hypnotic use can lead to clinically significant and dangerous intoxication and withdrawal states.
2. There are two indications for pharmacologic intervention in individuals who are taking benzodiazepines and other sedative–hypnotics; severe intoxication and acute withdrawal.
3. Management of severe intoxication includes supportive medical care in an appropriate setting and the judicious use of flumazenil.
4. Selecting a strategy for the management of withdrawal states must include a consideration of the dose and length of time that medication has been used, the pharmacologic properties of the medication(s) being discontinued, as well as comorbid substance use and other psychiatric conditions.