VA Class:CN302

VA Class:CN400

AHFS Class:

• Benzodiazepines 28:24.08

Associated Monographs

• Alprazolam

• Chlordiazepoxide

• Clobazam

• Clonazepam

• Clorazepate

• Diazepam

• Estazolam

• Flurazepam

• Lorazepam

• Midazolam

• Oxazepam

• Quazepam

• Temazepam

• Triazolam

Benzodiazepines are used as anxiolytics, sedatives, hypnotics, anticonvulsants, and/or skeletal muscle relaxants.

Benzodiazepines are used for preoperative relief of anxiety and provision of sedation, light anesthesia, and anterograde amnesia of perioperative events; for procedural sedation; for continuous sedation in intubated and mechanically ventilated patients undergoing treatment in a critical care setting (e.g., intensive care unit [ICU]); for induction and maintenance of anesthesia; as hypnotics in the treatment of insomnia; for the management of agitation associated with acute alcohol withdrawal; and for the management of anxiety (e.g., generalized anxiety disorder, panic disorder). Benzodiazepines also are used as anticonvulsants and skeletal muscle relaxants. In addition, benzodiazepines have been used alone and as adjuncts to antipsychotic agents in the management of schizophrenia† (e.g., in patients with akathisia associated with antipsychotic therapy).429,529

All benzodiazepines have similar actions, and their use is more a reflection of the way in which the drugs have been studied and the way the manufacturers promote their use than real differences between the drugs. In general, there is no evidence that any one benzodiazepine is more effective than another if an adequate dosage is given. However, pharmacokinetic and pharmacodynamic differences have influenced the therapeutic application of these drugs.714

Anxiety and Insomnia

Benzodiazepines are used for the management of anxiety disorders and insomnia.216,217,267,271,311,312,313,321,322,323,337,338,341,342,347,283,434 These drugs appear to have a tranquilizing effect on the CNS with no appreciable effect on the respiratory or cardiovascular systems.283 Most clinicians prefer benzodiazepines to barbiturates or meprobamate for the management of anxiety and tension and to other hypnotics such as barbiturates in the management of insomnia, because benzodiazepines have a relatively low abuse potential, produce less sedation with effective anxiolytic doses, and produce less toxicity with acute overdosage. In addition, benzodiazepines generally do not induce hepatic microsomal enzymes or produce substantial changes in prothrombin time or in oral anticoagulant dosage requirements. (See Drug Interactions.) For the symptomatic treatment of anxiety or insomnia in geriatric patients and patients with liver disease, some clinicians prefer lorazepam, oxazepam, or triazolam to other benzodiazepines or barbiturates because they have a relatively short elimination half-life even in patients with liver disease, and they do not have active metabolites.

Anxiety Disorders

Benzodiazepines are used for the management of anxiety disorders, principally generalized anxiety disorder, and for the short-term relief of symptoms of anxiety or anxiety associated with depressive symptoms. Generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry (apprehensive expectation) about several life circumstances (e.g., misfortune of one's child; finances; academic, athletic, or social performance) for 6 months or longer, during which time such concerns are bothersome more often than not.372,398 When anxiety is present, it is accompanied by many signs of motor tension (e.g., trembling, twitching, shakiness, restlessness, easy fatigability), autonomic hyperactivity (e.g., shortness of breath, smothering sensation, tachycardia, palpitations, sweating, cold clammy hands, dry mouth, diarrhea, hot flushes), and vigilance and scanning (e.g., feeling keyed up or on edge, exaggerated startle response, trouble falling or staying asleep, difficulty concentrating or mind going blank because of anxiety).372,398 When such signs are associated with panic attacks, the patient may be suffering from panic disorder,372,398 which also can be treated effectively with benzodiazepines.372,373,374,375,376,378,380,381,382,383,384,385,386,387,388,389,390,391,392,393,394,395,396,397,606,607 Mild depressive symptoms commonly are associated with generalized anxiety disorder, and an associated and unrelated panic disorder or depressive disorder often is present.398

In the management of anxiety disorders and anxiety symptoms, benzodiazepines are more effective than barbiturates or meprobamate. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The efficacy of benzodiazepines for long-term use (i.e., longer than 4 months) as anxiolytics has not been evaluated.283 The need for continued therapy with benzodiazepines should be periodically reassessed.

Benzodiazepines (principally alprazolam and clonazepam, but also diazepam and lorazepam) have been used effectively in the management of panic disorder (an anxiety disorder), with or without agoraphobia.372,373,374,375,376,378,379,380,381,382,383,384,385,386,387,388,389,390,391,392,393,394,395,396,397,399,606,607 Panic disorder is characterized by recurrent, unexpected panic attacks (discrete periods of intense fear or discomfort), associated concern about having additional attacks, anxiety about the implications or consequences of the attacks, and/or a clinically important change in behavior related to the attacks.530 Panic attacks have a sudden onset, reach a peak effect rapidly (usually in 10 minutes or less), are associated with at least 4 characteristic symptoms, and often are accompanied by a feeling of imminent danger or impending doom and an urge to escape.530 Characteristic symptoms include palpitations, pounding heart, or tachycardia; sweating; trembling or shaking; dyspnea or smothering sensation; feeling of choking; chest pain or discomfort; nausea or abdominal distress; dizziness, unsteady feelings, lightheadedness, or faintness; derealization or depersonalization; fear of losing control or going crazy; fear of dying; paresthesias; and chills or hot flushes.530

Efficacy of benzodiazepines in the management of panic disorder has been established mainly in short-term (for periods of 4-10 weeks) controlled studies,372,374,375,380,386,387,388,391,394,395,396,606,607 although the drugs have been used without apparent loss of efficacy for longer periods (e.g., 8-12 months or longer) in many patients.372,376,382,607 Benzodiazepines can reduce the number of spontaneous and situational panic attacks and associated anxiety, avoidance behavior, phobic fears, somatic manifestations, and secondary disability (e.g., interference with normal work or social activities).379,386,392,393,394 Although the drugs also can reduce depressive symptomatology in many patients with panic disorder, including those who are depressed or nondepressed,388 emergence of depressive symptomatology has occurred occasionally in such patients.397

Following discontinuance of benzodiazepines, a relapse of the condition, including a rebound in panic attacks and anxiety, and/or the development of withdrawal frequently occurs.372,378,389,606,607 In one study despite gradual withdrawal over 4 weeks in patients receiving high-dose alprazolam therapy for 8 weeks, a rebound in panic attacks and anxiety occurred in 27 and 13% of patients, respectively, and a transient, mild to moderate withdrawal syndrome developed in 35% of patients, but both rebound effects and withdrawal manifestations subsided after 2 weeks.389 Additional study is needed to establish the optimum duration of benzodiazepine therapy in the management of panic disorder, and to determine the most appropriate method of tapered withdrawal of the drugs.372,385,389,390,606,607 The potential dependence liability of benzodiazepines should be considered in weighing the possible risks and benefits of therapy with the drugs in this condition.372,389,390,391,606,607

Anxiety Associated with Myocardial Infarction

Benzodiazepines (e.g., diazepam) have been used to relieve anxiety associated with acute myocardial infarction (MI); however, evidence suggests that these drugs are no more effective than placebo in managing anxiety and ischemic-type pain in patients with MI.531,532 Experts state that routine use of anxiolytics is neither necessary nor recommended in patients with acute MI.531 Morphine sulfate is considered the drug of choice for relief of pain and associated anxiety following acute MI.754 (See Uses in the Opiate Agonists General Statement 28:08.08.)

Insomnia

Benzodiazepines have been used in the management of insomnia because of their established short- and intermediate-term efficacy and relative safety.216,218,219,320,715 However, non-benzodiazepine benzodiazepine receptor agonists (e.g., zaleplon, eszopiclone, zolpidem) may be preferred in some patients because of their relatively rapid onset of effect, short duration of action, and safety profile.

While experience to date in the management of insomnia principally has been with estazolam, flurazepam, quazepam, temazepam, and triazolam, other benzodiazepines also have been used for insomnia.216,217,267,271,311,312,313,321,322,323,337,338,341,342,347 Flurazepam was the first benzodiazepine approved by the FDA for use as a hypnotic.715

The choice of a specific benzodiazepine must be individualized according to patient response and tolerance, taking into consideration pharmacokinetic and pharmacodynamic characteristics of the drug, patient age and other characteristics, and the underlying sleep disorder being treated.215,216,217,218,219,348 Benzodiazepines with a relatively short elimination half-life (e.g., triazolam) may be more likely to result in transient rebound insomnia after discontinuance207,215,216,217,218,219,220,241,242,243,244,245,246,247,248,249,250,251,262,267,313,317,318,321,323,337,338,341,342,344,345,348,400,401,418,420,421,425,429 and in pharmacodynamic tolerance and adaptation to the hypnotic effect after several weeks of therapy, with resultant diminished effectiveness during the end of each night's use (early morning insomnia) and, possibly, increased daytime anxiety.207,215,216,218,219,241,245,258,267,297,299,302,312,317,318,320,321,323,337,338,341,348 Benzodiazepines with a relatively long half-life (e.g., flurazepam, quazepam) may be more likely to result in residual daytime sedative effects and in impaired psychomotor and mental performance during continued therapy, although partial tolerance to these effects can occur.207,215,216,217,218,219,245,252,254,259,262,264,267,298,311,312,313,317,321,322,323,337,338,344,346,348,353 Differences in residual and cumulative CNS depressant effects may be particularly important in geriatric patients215,217,221,222,224,235,252,253,255,256,259,269,276,297,312,313,317,318,319,325,356,372,377 and in patients with potentially impaired elimination of the drugs and those whose job or lifestyle requires unimpaired intellectual or psychomotor function.215,217,218,257,270,279,280,297,298 Benzodiazepines with relatively slow GI absorption (e.g., temazepam) may be less effective in initial sleep induction;215,216,218,219 therefore, it has been suggested that the efficacy of such drugs may be diminished in patients whose principal symptom is initial difficulty in falling asleep (sleep-latency insomnia).216,219,245 Alterations in dosing (e.g., administering slowly absorbed drugs 1 or 2 hours before bedtime) may in part compensate for this delayed onset.216

Treatment strategies for transient (insomnia of several days' duration related to minor situational stress), short-term (insomnia of several weeks' duration usually related to stress associated with work and/or family-life conditions such as job performance, job loss, bereavement, or illness), and long-term (insomnia of prolonged duration often associated with some underlying condition such as a psychiatric disorder, chronic drug and/or alcohol dependence, or other medical condition) insomnia will differ.218 For example, in the management of transient insomnia, use of relatively low-dose therapy with a relatively rapidly eliminated benzodiazepine for one to several nights may be preferred, unless sustained sedation is desired.218 For short-term insomnia, benzodiazepines are used as an adjunct to efforts aimed at improving sleep hygiene (e.g., avoidance of caffeine, alcohol, daytime naps, or retiring to bed too early), but therapy with the drugs generally should be limited to no more than several weeks, administering the drugs intermittently (e.g., skipping a nightly dose after one or two good nights' sleep) if possible; the choice of benzodiazepine should be individualized.218 Reevaluation of the patient's condition is recommended if continued hypnotic use exceeds 2-3 weeks, since sleep disturbance may be a presenting manifestation of an underlying physical and/or psychiatric disorder.207 Such underlying disorders also could result in worsening of insomnia or the emergence of new abnormalities of mentation or behavior; however, the possibility that such effects may be associated with benzodiazepine therapy itself also should be considered.207

The management of long-term insomnia is more complex and depends in part on the presence of any identifiable underlying condition that is a contributing factor.218 The need for therapy with hypnotic drugs such as benzodiazepines may persist despite therapy aimed at treating the underlying condition; benzodiazepine therapy also may be useful in patients with no readily identifiable cause of the insomnia and usually is combined with psychological-behavioral therapies (e.g., relaxation techniques, sleep curtailment, stimulus control therapy) aimed at modifying negative conditioning related to sleep habits.218 If hypnotic drug therapy is employed, intermittent (e.g., every third night) therapy with a benzodiazepine having a relatively long elimination half-life has been suggested; efforts generally should be made to gradually discontinue such therapy after several months.218 Data from one study comparing the effects of triazolam and behavioral therapy on sleep latency in patients with persistent sleep-onset insomnia suggest that combined use of drug and behavioral therapies may offer both immediate relief and sustained effects upon drug discontinuance;460 however, behavioral therapy is a useful alternative to drug treatment and may be preferable, given its sustained effectiveness, particularly in individuals in whom use of hypnotic agents is problematic (e.g., individuals prone to drug abuse, pregnant or breast-feeding women).460 Referral to a sleep disorders clinic may be necessary for some patients.218

Because of evidence from animal studies that the drugs can entrain circadian rhythms,225,226,237,238,239,240 benzodiazepines with a relatively short elimination half-life (e.g., triazolam) have been used for the prevention or short-term treatment of transient insomnia associated with sleep-wake schedule changes† (e.g., rapid travel across time zones [“jet lag”], rotating shift work).225,226,227,228,229,230,231,232,233,234,235,236,276,277,280 While such therapy may be useful in the management of sleep disorders associated with such schedule changes in some patients,227,228,229,230 the possibility that transient impairment of cognitive function (e.g., anterograde amnesia [“traveler's amnesia”]) may be induced by the drugs should be considered.207,233,234,235,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276,278,280,281,282,288,289,290,291,292,293,294,295,296,298,377 (See Cautions: CNS Effects.)

Because benzodiazepines suppress stage 4 sleep, diazepam has been used effectively in some studies to prevent night terrors in adults.

Procedural Sedation

Benzodiazepines (e.g., midazolam, diazepam) are used for procedural sedation, anxiolysis, and amnesia.219,611,713,821,822,823 Procedural sedation is a technique in which sedative and dissociative agents are administered with or without analgesics to allow patients to tolerate painful or unpleasant medical procedures; a depressed state of consciousness is intentionally induced while cardiorespiratory function is maintained.821,822,823 Because sedation is a continuum ranging from minimal sedation to general anesthesia, airway reflexes and cardiorespiratory function may be impaired if a deeper than intended level of sedation is produced.821,822,823 The appropriate level of sedation should be individualized according to the specific procedure and needs of the patient.822 Benzodiazepines are typically used to produce moderate to deep sedation for patients undergoing diagnostic or therapeutic procedures such as endoscopic procedures, radiologic procedures, coronary catheterization, coronary angiography, oncology procedures, and laceration repairs.609,611,713,821,822,823 Although these drugs can produce amnestic and sedative effects, they have no analgesic activity, and therefore, are usually administered in conjunction with an analgesic agent.714,821,822

Preoperative Sedation, Anxiolysis, and Amnesia

Benzodiazepines (e.g., lorazepam, midazolam, diazepam) are used preoperatively (prior to the induction of anesthesia) to relieve anxiety and produce sedation and anterograde amnesia.435,611,713 When used for this indication, benzodiazepines have been administered parenterally or orally.435,609,611,713 Benzodiazepines are particularly useful as a preoperative medication when relief of anxiety and diminished recall of events associated with the surgical procedure are desired.435 Studies have shown that diazepam, chlordiazepoxide hydrochloride (parenteral dosage form no longer commercially available in the US), or midazolam hydrochloride was as effective for preoperative sedation as opiate agonists or barbiturates and resulted in fewer undesirable effects, such as respiratory depression or hypotension. Because of midazolam's relatively rapid onset, short duration of effect, and improved local tolerance at the site of injection compared with other currently available parenteral benzodiazepines, some clinicians consider midazolam the benzodiazepine of choice for preoperative use associated with short surgical procedures.

Sedation in Critical Care Settings

Benzodiazepines (e.g., lorazepam, midazolam, diazepam) are used for sedation of intubated and mechanically ventilated patients in a critical care setting (e.g., ICU).564,611,800,801 Midazolam has a quicker onset of action than lorazepam and is generally the preferred benzodiazepine for ICU sedation; lorazepam is used less frequently and diazepam is rarely used.801

Alcohol Withdrawal

Benzodiazepines (e.g., diazepam)434 are used in the management of acute alcohol withdrawal to relieve agitation and tremor and to prevent or to provide symptomatic relief of delirium tremens and hallucinations. It has not been proven that benzodiazepines prevent hallucinations or delirium tremens; however, some studies suggest that diazepam may shorten the duration and decrease the mortality of delirium tremens.

Seizure Disorders

Status Epilepticus

Benzodiazepines (e.g., lorazepam, midazolam, diazepam) are considered the initial drugs of choice for the management of status epilepticus because of their rapid onset of action, demonstrated efficacy, safety, and tolerability.545,563,756,757,758,759,761,762,763,764,765,766,767,771

Initial treatment of status epilepticus should include standard critical care and supportive therapy (e.g., blood pressure and respiratory support, oxygen, IV access, identification and correction of underlying causes), followed by administration of a benzodiazepine.545,763,765,766 Although IV lorazepam is generally preferred because of its longer duration of action, studies generally have not identified any substantial differences between IV lorazepam, IV diazepam, and IM midazolam in terms of seizure cessation, and experts consider these therapies to be equivalent first-line options.545,763,764,765,766,767,768,769 Selection of an appropriate benzodiazepine should be individualized based on local availability, route of administration, pharmacokinetics, cost, and other factors (e.g., treatment setting).545,756,757,758,759,760,761,762,763,764,765,766,767,769 To achieve a rapid therapeutic effect, IV administration of a benzodiazepine is preferred; however, administration via other routes (e.g., IM, rectal, intranasal, buccal) may be considered when IV administration is not possible (e.g., in the prehospital setting).543,545,546,547,548,549,763,764,765,766,768,769 If seizures continue after initial therapy with a benzodiazepine, a second-line anticonvulsant agent (e.g., IV fosphenytoin or phenytoin, IV valproate sodium, IV levetiracetam, IV phenobarbital) should be administered.757,759,760,762,763,765,766 If refractory status epilepticus occurs, continuous IV infusion of anticonvulsants, IV barbiturates, or general anesthetics may be necessary.757,758,759,760,761,765,766

Other nonparenteral benzodiazepines that have been used for the treatment of status epilepticus include rectal diazepam, intranasal midazolam, and buccal midazolam; studies evaluating these benzodiazepines generally were conducted in the pediatric population.538,539,540,543,763,765,769 Potential limitations of these nonparenteral routes include difficulty with administration during an acute seizure episode, unpredictable absorption, and lack of commercially available dosage forms.765,775

Other benzodiazepines such as clonazepam and chlordiazepoxide also have been evaluated for the treatment of status epilepticus, but are infrequently used due to the unavailability of a commercially available parenteral dosage form in the US.631,766

Acute Repetitive Seizures or Seizure Clusters

Rectal diazepam and midazolam nasal spray also are used for the acute management of intermittent stereotypic episodes of increased seizure activity (also referred to as serial, cyclic, cluster, breakthrough, or crescendo seizures; acute repetitive seizures), especially for out-of-hospital management.540,544,547,550,551,773

Midazolam also is administered intranasally for the acute management of seizures, including rescue therapy for prolonged, recurrent, or cyanotic seizures.548,556,557,558,559,560,773

Adjunctive Therapy of Seizure Disorders

Benzodiazepines have been used orally as adjuncts to other anticonvulsants in the prophylactic management of partial seizures with elementary symptomatology, including those with motor symptoms (e.g., Jacksonian seizures), partial seizures with complex symptomatology (psychomotor seizures), absence (petit mal) seizures, seizures associated with Lennox-Gastaut syndrome (petit mal variant epilepsy), and akinetic or myoclonic seizures that are refractory to other drugs. Tolerance often develops to the anticonvulsant effects of benzodiazepines, which can limit their usefulness in the long-term management of seizure disorders.637,638,639,648,649,651

Skeletal Muscle Spasticity

Benzodiazepines may be useful adjuncts to rest, physical therapy, analgesics, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions. There is no convincing evidence that oral benzodiazepines are more effective than barbiturates or meprobamate in these conditions. Most studies indicate that diazepam is superior to other skeletal muscle relaxants (e.g., methocarbamol, carisoprodol) for relief of musculoskeletal pain; however, there is some evidence that diazepam is no more effective than aspirin or placebo. The benzodiazepines are useful in the short- and long-term management of skeletal muscle spasticity such as reflex spasm secondary to local pathology (e.g., trauma, inflammation), spasticity caused by upper motor neuron disorders (e.g., cerebral palsy, paraplegia), athetosis, stiff-man syndrome, strychnine poisoning, or tetanus. Diazepam is generally as effective as dantrolene sodium or baclofen for spasticity in patients with various upper motor neuron disorders. For the management of moderate muscle spasm in tetanus, parenteral diazepam in large doses may be adequate; however, in severe tetanus, neuromuscular blocking agents may be the drugs of choice. The value of diazepam in neonatal tetanus has not been established.

Cancer Chemotherapy-induced Nausea and Vomiting

Benzodiazepines (e.g., alprazolam, lorazepam) have been used in the management of nausea and vomiting associated with emetogenic cancer chemotherapy†.492,493,494,495,496,497,498,499,500,501,502,503,504,629,630 The antiemetic activity of benzodiazepines appears to be low, and their anxiolytic, sedative, and amnesic effects may account for beneficial effects in patients receiving emetogenic chemotherapy; the drugs appear to be most useful in reducing anticipatory and anxiety-related effects associated with administration of such chemotherapy.505 The American Society of Clinical Oncology (ASCO) guidelines on antiemetic therapy state that lorazepam is a useful adjunct to antiemetic drugs but is not recommended as a single-agent antiemetic.630

Delirium

Benzodiazepines, alone or combined with an antipsychotic agent, have been used in the management of delirium.533 However, the possibility that benzodiazepines may exacerbate symptoms of delirium in some patients and, when used alone, may be ineffective should be considered.533,534

There are few controlled studies that evaluated the efficacy of benzodiazepines as monotherapy for the management of delirium.533,534 Limited data suggest that benzodiazepines alone may be ineffective or at least less effective than antipsychotic agents for general cases of delirium.533,534 While there appears to be little evidence to support the use of benzodiazepine monotherapy for general delirium, the drugs may have advantages and therefore would be preferred for certain types of delirium.533 For example, benzodiazepines are the drugs of choice for the management of delirium associated with alcohol or benzodiazepine withdrawal.533

There is some evidence that combined use of a benzodiazepine and antipsychotic agent may decrease certain adverse effects and improve efficacy in certain patients with delirium (e.g., those with AIDS, those severely ill with cancer).533,535,536,537 If a benzodiazepine is used for the treatment of delirium, those with a short duration and no active metabolites (e.g., lorazepam) are preferred.533

Drug-induced Cardiovascular Emergencies

Benzodiazepines (e.g., diazepam, lorazepam) are used as adjuncts in the management of certain drug-induced cardiovascular emergencies†.696 If drug-induced cardiac arrest occurs, usual guidelines for advanced cardiovascular life support (ACLS) should be followed.696

Cocaine-induced Acute Coronary Syndrome

Benzodiazepines have been used adjunctively in patients with severe cardiovascular toxicity associated with cocaine overdose†.696 Experts state that administration of a benzodiazepine may be beneficial for cocaine-induced hypertension or chest discomfort.696

Other Uses

Parenteral diazepam also has been used to relieve agitation in the management of neonatal opiate withdrawal†.

Administration

Benzodiazepines are usually administered orally. When oral therapy is not feasible or when a rapid therapeutic effect is necessary, diazepam or lorazepam may be administered IV. Diazepam also may be given rectally.538,539,540,541,542,543,544,545,546,547,548,549,550,551 Midazolam hydrochloride is administered orally or by IM or IV injection and also has been administered intranasally† and intrabuccally†, and midazolam is administered intranasally.773 Although diazepam may also be given by deep IM injection, this route of administration is rarely justified because absorption of these drugs is slow and erratic. Chlordiazepoxide hydrochloride has also been given IV† and IM†; however, a parenteral dosage form of the drug is no longer commercially available in the US.631

Concomitant oral administration of certain benzodiazepines (e.g., midazolam, triazolam)511,516 with grapefruit juice usually should be avoided since potentially clinically important increases in hemodynamic effects can result.509,510,511 (See Drug Interactions: Grapefruit Juice.)

Dosage

Dosage of benzodiazepines must be carefully individualized, and the smallest effective dosage generally should be used (especially in geriatric or debilitated patients) to avoid oversedation. Sensitivity to the CNS depressant effects of the benzodiazepines differs among individual patients, and the patient's age, gender, physical or emotional status, and/or concurrent use of other drugs (including cigarette smoking) may alter the response.

Because of the episodic nature of anxiety, dosage may require frequent adjustments, and the drugs should generally be administered for a short period of time. The usefulness of the drug for each patient should be periodically reassessed. The effectiveness of benzodiazepines as anxiolytics for periods greater than 4 months or for panic disorder for periods greater than 4-10 weeks has not been established.

Because it is often difficult to predict how a patient will respond to a sedative agent, benzodiazepines used for procedural sedation should be titrated to effect.821,822,823

The amount of time necessary for a particular benzodiazepine and its metabolites to reach steady-state plasma concentrations should be considered when dosage adjustments are made. (See Pharmacokinetics: Elimination.)

In patients who have received prolonged (e.g., for several months) benzodiazepine therapy, abrupt discontinuance of the drug should be avoided since manifestations of withdrawal, including rebound anxiety and insomnia, can be precipitated; if the drug is to be discontinued in such patients, it is recommended that dosage be gradually tapered. (See Chronic Toxicity.) It is particularly important that benzodiazepines not be discontinued abruptly in patients with a history of a seizure disorder to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus.632 In addition, abrupt discontinuance of some benzodiazepines (e.g., those with a relatively short elimination half-life such as triazolam), even after relatively short periods of therapy (e.g., 1 week), can result in withdrawal effects such as rebound insomnia.

A boxed warning has been included in the prescribing information for all benzodiazepines describing the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with all drugs in this class.900 Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioid pain relievers, alcohol, or illicit drugs.900 Frequent follow-up with patients receiving benzodiazepines is important.900 Reassess patients regularly to manage their medical conditions and any withdrawal symptoms.900 Clinicians should assess a patient's risk of abuse, misuse, and addiction. 900 Standardized screening tools are available ([Web]).900 To reduce the risk of acute withdrawal reactions, use a gradual dose taper when reducing the dosage or discontinuing benzodiazepines.900 Take precautions when benzodiazepines are used in combination with opioid medications.900

CNS Effects

Adverse CNS effects are an extension of the pharmacologic actions of benzodiazepines and include drowsiness, ataxia, fatigue, confusion, weakness, dizziness, vertigo, and syncope. Somnolence is the principal adverse effect associated with rectal diazepam administration, occurring in 13-33% of patients.538,540,544 Adverse CNS effects usually occur during the first few days of benzodiazepine therapy and may diminish with continued therapy or reduction in dosage. Geriatric or debilitated patients, children, and patients with liver disease or low serum albumin are most likely to experience these adverse CNS effects and generally should receive decreased initial dosages of the drugs. Benzodiazepines may produce prolonged CNS depression in neonates. Reversible dementia has been reported in geriatric patients after prolonged administration of benzodiazepines. Benzodiazepines with a relatively long elimination half-life may be more likely to cause residual daytime sedative effects and impaired psychomotor and mental performance during continued therapy, although partial tolerance to these effects can occur.207,215,216,217,218,219,245,252,254,259,297 Differences in residual and cumulative CNS depressant effects among benzodiazepines may be particularly important in geriatric patients215,217,222,252,253,255,256,259,297,313,317,318,356,372,377,427,451 and in patients with potentially impaired elimination of the drugs and those whose job or lifestyle requires unimpaired intellectual or psychomotor function.215,217,218,257 There is some evidence that ataxia and the risk of falling and associated hip fracture in geriatric patients is increased with use of benzodiazepines having a relatively long elimination half-life compared with use of those having a relatively short half-life.221,222 However, in several short-term studies in geriatric patients receiving quazepam, ataxia and morning hangover did not occur more frequently with the drug relative to placebo.313,317,318,339,340 Benzodiazepine therapy should be individualized and monitored closely in geriatric patients, and the need for continued therapy with the drugs should be determined periodically.207,221,224

Amnesia

Benzodiazepines can cause amnesic effects, principally anterograde amnesia, and the magnitude and duration of these effects may vary depending on the patient (e.g., age), drug, dosage, and route of administration.207,217,223,234,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,288,289,290,291,292,293,294,295,296,297,298,312,313,336,372,377,432,488 Immediate recall usually does not appear to be affected substantially.261,271,275 Some evidence suggests that amnesic effects may be particularly likely with midazolam, triazolam, and lorazepam,207,217,234,235,261,262,263,265,266,267,268,269,270,271,272,276,277,278,279,280,288,289,290,291,292,293,294,295,296,298,336,377,470,480,481,482,486,491 although other benzodiazepines also have been reported to cause such effects.223,234,260,264,274,275,281,488 Anterograde amnesia may be particularly disturbing with triazolam,207,217,234,235,262,263,270,271,272,273,276,277,278,279,280,480,481,486,487,490 especially when relatively high doses (e.g., 0.5 mg) are used.207,217,234,263,270,271,276,277,279,280,488,489 Anterograde amnesia (“traveler's amnesia”) that occurred upon awakening and persisted for several hours has been reported in patients receiving triazolam for the prevention or treatment of insomnia associated with sleep-wake schedule changes (e.g., rapid travel across time zones [“jet lag”], rotating shift work); although behavior appeared normal in many of these patients (e.g., they performed what appeared to observers to be normal activities and they exhibited no apparent confusion or concern about memory at the time of amnesia), these patients subsequently had no recollection of the events that occurred during this period.207,234,235,280,479 Some of these patients consumed alcohol concomitantly, which also can cause anterograde amnesia.234,280 Similar anterograde amnesia has occurred in other patients receiving triazolam,270,276,277,278,279,488 and bizarre behavior has been associated with the period of amnesia in some patients.235,277,279,280 The risk of anterograde amnesia should be considered in patients receiving benzodiazepines,207,217,281 particularly when therapy with relatively high doses of triazolam is considered (e.g., for transient insomnia associated with sleep-wake schedule changes)234,235,276,277,278,279,280,284 or when the duration of drug effect is likely to exceed the intended period of sleep (e.g., when taken to induce sleep while traveling, such as during an airplane flight in which the patient will awake earlier than dissipation of hypnotic effects).207,234

Behavioral Changes and Associated Effects

Potentially serious behavioral changes and abnormal mentation occasionally have been associated with benzodiazepine use.207,258,262,269,284,285,286,287,297,372 Such effects include confusion, bizarre or abnormal behavior, agitation, hyperexcitability, auditory and visual hallucinations, paranoid ideation, panic, delirium, depersonalization, agitation, sleepwalking, and disinhibition manifested as aggression, excessive extroversion, and/or antisocial acts; in some cases, amnesia about the behavior may occur.207,258,262,269,285,286,287,297,488 Decreased inhibition may be similar to that associated with use of alcohol or other CNS depressants.207 Emergence or worsening of mental depression, including suicidal ideation, also has been associated with benzodiazepine use, principally in patients with preexisting depression.207,488 It appears that some of these behavioral effects may be dose related.207,285,286,287,298,488 There also is some epidemiologic and other evidence that the risk of some such behavioral effects may be increased with triazolam;464,465,466,467,468,469,470,471,472,473,475,476,477,480,483,484,485,486 however, a precise causal relationship rarely can be established with certainty.207

There also is a potential risk of complex sleep-related behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative-hypnotic drug, with no memory of the event), making phone calls, or preparing and eating food while asleep in patients receiving benzodiazepines.629

An analysis of spontaneous reports of adverse effects received by the FDA for triazolam and temazepam from the date of marketing through 1985 revealed that the reporting rates for confusion, amnesia, abnormal or bizarre behavior, agitation, and hallucinations were substantially higher for triazolam.464 An updated aggregate analysis of spontaneous reports in the US for the first 7 years of marketing for each drug confirmed the higher frequency associated with triazolam compared with temazepam.464 While it could not be completely ruled out that some selection factors may have contributed to the differences in reporting rates, analysis of these data with adjustment for various factors suggested that a higher occurrence of these reactions existed for triazolam; a large epidemiologic study that follows up new users for adverse reactions and includes adjustment for potentially contributing factors would be required to determine the risk factors for adverse behavioral effects associated with these and other benzodiazepines.464

Data from a limited number of patients suggest that individuals with borderline personality disorder, a history of violent or aggressive behavior, or a history of alcohol or drug abuse may be at increased risk for adverse behavioral effects with benzodiazepine use.372,606,607 Irritability, hostility, and intrusive thoughts have been reported in patients with posttraumatic stress disorder during discontinuance of alprazolam.372,606,607 While emergence of abnormalities in behavior and mentation or worsening of preexisting abnormalities may be the consequence of an underlying, possibly unrecognized, physical and/or psychiatric condition, it rarely can be determined with certainty whether such effects are drug induced, spontaneous in origin, or secondary to such underlying causes.207 Therefore, the emergence of any new behavioral sign or symptom of concern during benzodiazepine therapy requires careful and immediate evaluation.207

Seizures

When IV diazepam has been used to control absence status or Lennox-Gastaut syndrome status epilepticus, tonic status epilepticus has occurred. When oral benzodiazepines are used as adjuncts in the treatment of mixed epilepsy, increased frequency and/or severity of tonic-clonic seizures may occur, necessitating an increase in dosage of other anticonvulsants.

Abrupt withdrawal of diazepam therapy in patients with epilepsy may also result in a temporary increase in the frequency and/or severity of seizures. Changes in EEG patterns with characteristic low voltage, fast activity have been observed in some patients receiving benzodiazepines but are of no known importance. Withdrawal seizures also have been reported with alprazolam; in most cases, only a single seizure occurred, but multiple seizures and status epilepticus also have been reported. All anticonvulsants, including benzodiazepines, should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus.632

Other CNS Effects

Other adverse CNS effects of benzodiazepines include headache, vivid dreams, and dysarthria. Encephalopathy reportedly occurred in patients with renal failure receiving both diazepam and flurazepam. Extrapyramidal reactions, tremor, and oral buccal dyskinesia also have been reported. Abrupt withdrawal of benzodiazepines after use in the management of anxiety may lead to increased anxiety; rebound insomnia also has occurred following abrupt withdrawal of the drugs, particularly those with a relatively short elimination half-life. Withdrawal reactions also can be precipitated by dosage tapering and inadvertent dosage reduction (e.g., forgotten dose, admission to hospital). Such effects also can emerge in the early morning or between doses of benzodiazepines with a relatively short half-life.

Paradoxical CNS stimulation resulting in talkativeness, restlessness, anxiety, mania, euphoria, tremulousness, sleep disturbances, nightmares, excitement, hyperactivity, acute rage reactions, increased muscle spasticity, and hyperreflexia may occur, usually early in benzodiazepine therapy. Excitation is particularly likely to occur in psychiatric patients and in hyperactive aggressive children. Benzodiazepine therapy usually should be discontinued if CNS stimulation occurs.

The CNS depressant effect of benzodiazepines also can result in respiratory depression.

Respiratory and Cardiovascular Effects

Parenteral administration of benzodiazepines may produce apnea, hypotension, bradycardia, or cardiac arrest, particularly in geriatric or severely ill patients and in patients with limited pulmonary reserve or unstable cardiovascular status or if the drug is administered too rapidly IV. IV diazepam has reportedly caused ventricular premature complexes and other arrhythmias when used prior to cardioversion. Death has occurred rarely shortly after initiation of alprazolam therapy in patients with severe pulmonary disease.372 Respiratory depression and apnea have been reported infrequently with benzodiazepines in patients with compromised respiratory function.

Decreased gag reflex has been reported when IV diazepam was used prior to endoscopy. During peroral endoscopic procedures, coughing, depressed respiration, dyspnea, hyperventilation, laryngospasm, and pain in the throat or chest have been reported. Although the risk of respiratory depression may be greatest with rapid IV administration or large doses of the drugs, such depression also has been reported with rectal administration. Respiratory and cardiovascular depressant effects may be caused in part by the propylene glycol present in diazepam injection, a formulation that also has been administered rectally. In clinical studies with diazepam rectal gel, respiratory depressant effects (e.g., hypoventilation)538 occurred rarely.538,540,544,550,551

Palpitation, tachycardia, shortness of breath, diaphoresis, and flushing also have been reported in patients receiving benzodiazepines.

GI and Hepatic Effects

Adverse GI effects reported in patients receiving benzodiazepines include nausea and other GI complaints, hiccups, constipation, increased appetite, anorexia, weight gain or loss, dry mouth, increased salivation and bronchial secretions, swollen tongue, and bitter or metallic taste. Animals have developed esophageal dilation after very high doses of lorazepam for prolonged periods, and patients receiving this drug should be observed for the development of GI disease. Benzodiazepines may cause elevated serum AST (SGOT), ALT (SGPT), LDH, and alkaline phosphatase and total and direct serum bilirubin; jaundice has been reported.

Hepatitis and hepatic failure have been reported during postmarketing experience with alprazolam; however, a causal relationship to the drug has not been established.372,606,607

In addition to typical benzodiazepine-associated adverse effects, rectal administration of diazepam gel may result in diarrhea538 and rarely rectal burning/pain.544

Dermatologic and Sensitivity Reactions

There is a potential risk of anaphylaxis and angioedema in patients receiving benzodiazepines; such reactions may occur as early as with the first dose of the drug.629 Urticaria, rash, pruritus, photosensitivity, immediate hypersensitivity reactions, hypotension, nonthrombocytopenic purpura, and edema may occur in patients receiving benzodiazepines. Paresthesia, Stevens-Johnson syndrome, and a lupus-like syndrome have been reported.

Local Effects

IM administration of parenteral benzodiazepines (e.g., diazepam, lorazepam, or midazolam) may result in pain. Redness, burning, induration, or muscle stiffness also has been reported with IM administration of some benzodiazepines (e.g., lorazepam).435 IV administration of benzodiazepines may result in pain or thrombophlebitis. Intra-arterial administration of diazepam and other parenteral benzodiazepines has resulted in tissue necrosis. Adverse local effects associated with IM or IV administration occur less frequently and generally are less severe with midazolam than with other currently available parenteral benzodiazepines (e.g., diazepam).288,289,290,291,295,568,569,570,571,572,573,574,575,576,577,578,579

Genitourinary and Renal Effects

Increased or decreased libido, menstrual irregularities, failure to ovulate, hyperprolactinemia, gynecomastia, and galactorrhea have been reported in patients receiving benzodiazepines. Genitourinary complaints such as urinary retention, difficulty in micturition, and urinary incontinence have occurred. Alprazolam exhibits weak uricosuric activity.372 Transient decreases in renal function have occurred after IV administration of diazepam or midazolam, and abnormal renal function test results have been reported after oral benzodiazepines.

Musculoskeletal Effects

Serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations increase after IM injection of diazepam. Body joint pains and muscle cramps also have been reported.

Hematologic Effects

A few cases of leukopenia (including neutropenia and granulocytopenia), agranulocytosis, aplastic anemia, hemolytic anemia, decreased hematocrit, eosinophilia, and leukocytosis have been attributed to benzodiazepine administration.

Ocular Effects

Conjunctivitis and visual disturbances such as diplopia, nystagmus, and blurred vision have occurred in patients receiving benzodiazepines.

Precautions and Contraindications

In September of 2020, FDA announced that it is requiring that the boxed warning, FDA's most prominent warning, be updated by adding additional information to the prescribing information for all benzodiazepines. This information will describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class. FDA is also requiring updates to the existing patient medication guides for benzodiazepines to help educate patients and caregivers about these risks. Clinicians prescribing benzodiazepines should consider the patient's condition and the other drugs being taken, and assess the risk of abuse, misuse, and addiction. Clinicians should also limit the dosage and duration of therapy to the minimum needed to achieve the desired clinical effect when prescribing benzodiazepines either alone or in combination with other drugs. In addition, a gradual taper should be used when reducing the dosage of or discontinuing benzodiazepines to reduce the risk of acute withdrawal reactions. (See Dosage and Administration: Dosage, Drug Interactions: CNS Agents, and see also Chronic Toxicity.)

Concomitant use of benzodiazepines and opiate agonists or opiate partial agonists may result in profound sedation, respiratory depression, coma, and death.700,701,703,705,706,707 Concomitant use of such drugs should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.700,703 Patients receiving benzodiazepines and/or their caregivers should be apprised of the risks associated with concomitant therapeutic or illicit use of benzodiazepines and opiates.700,703 (See Opiate Agonists and Opiate Partial Agonists under Drug Interactions: CNS Agents.)

Patients should be warned that benzodiazepines may impair ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). There also is a potential risk of complex sleep-related behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative-hypnotic drug, with no memory of the event), making phone calls, or preparing and eating food while asleep in patients receiving benzodiazepines.629 Patients also should be warned about possible effects on memory (anterograde amnesia) and to report promptly to their physician any behavioral or mental change, including disturbing thoughts and unusual manners of conduct, that develops during benzodiazepine therapy.207,470,491 (See Cautions: CNS Effects.) Benzodiazepines should be used with caution and large quantities of the drugs should not be prescribed for patients with suicidal tendencies or whose history indicates that they may increase dosage on their own initiative.

Because benzodiazepines may produce psychologic and physical dependence, patients should be advised to consult their clinician before increasing the dose of, or abruptly discontinuing, benzodiazepine therapy. (See Chronic Toxicity.)

Liver and kidney function tests and blood cell counts should be performed regularly during long-term therapy, and benzodiazepines should be administered with caution to patients with hepatic or renal disease.

Benzodiazepines should be used with caution in patients with chronic pulmonary insufficiency or sleep apnea. Facilities and age- and size-appropriate equipment for respiratory or cardiovascular assistance should be readily available whenever benzodiazepines are administered IV. The drugs should not be administered IV to patients in whom the hypnotic or hypotensive effects may be prolonged or intensified such as those with shock or coma, to patients with depressed respiration, or to those who have recently received other respiratory depressant drugs. Diazepam rectal gel should be used with caution in patients with compromised respiratory function associated with a concurrent disease process (e.g., asthma, pneumonia) or neurologic damage.538

Benzodiazepines generally should not be used in patients with depressive neuroses or psychotic reactions in which anxiety is not prominent. Many benzodiazepines are contraindicated in patients with known hypersensitivity to the drugs. Because the frequency of suicide appears to be increased in untreated patients with panic disorder, and because panic disorder may be associated with primary and secondary major depressive disorders, the usual precautions of psychotropic therapy in depressed patients or those at risk for concealed suicidal ideation should be exercised during benzodiazepine therapy for panic disorder. According to most manufacturers of benzodiazepines, the drugs are contraindicated in patients with acute angle-closure glaucoma but may be administered to patients receiving appropriate treatment for open-angle glaucoma. However, the clinical rationale for this contraindication has been questioned since benzodiazepines do not have anticholinergic effects and do not increase intraocular pressure; only one case of increased intraocular pressure after use of a benzodiazepine and other drugs has been reported.

Pediatric Precautions

FDA warns that repeated or prolonged use of general anesthetics and sedation drugs, including benzodiazepines such as lorazepam and midazolam, in children younger than 3 years of age or during the third trimester of pregnancy may affect brain development.750,753 Animal studies in multiple species, including nonhuman primates, have demonstrated that use for longer than 3 hours of anesthetic and sedation drugs that block N -methyl-d-aspartic acid (NMDA) receptors and/or potentiate γ-aminobutyric acid (GABA) activity leads to widespread neuronal and oligodendrocyte cell loss and alterations in synaptic morphology and neurogenesis in the brain, resulting in long-term deficits in cognition and behavior.750,751,752,753 Across animal species, vulnerability to these neurodevelopmental changes occurs during the period of rapid brain growth or synaptogenesis; this period is thought to correlate with the third trimester of pregnancy through the first year of life in humans, but may extend to approximately 3 years of age.750 The clinical relevance of these animal findings to humans is not known.750

While some published evidence suggests that similar deficits in cognition and behavior may occur in children following repeated or prolonged exposure to anesthesia early in life, other studies have found no association between pediatric anesthesia exposure and long-term adverse neurodevelopmental outcomes.750,752 Most studies to date have had substantial limitations, and it is not clear whether the adverse neurodevelopmental outcomes observed in children were related to the drug or to other factors (e.g., surgery, underlying illness).750 There is some clinical evidence that a single, relatively brief exposure to general anesthesia in generally healthy children is unlikely to cause clinically detectable deficits in global cognitive function or serious behavioral disorders;750,751,752 however, further research is needed to fully characterize the effects of exposure to general anesthetics in early life, particularly for prolonged or repeated exposures and in more vulnerable populations (e.g., less healthy children).750

Results from an observational study (the Pediatric Anesthesia Neurodevelopment Assessment [PANDA] study) and preliminary results from an ongoing multicenter, randomized trial (the General Anesthesia Compared to Spinal Anesthesia [GAS] trial) provide some evidence that a single, relatively brief exposure to general anesthesia in generally healthy children is unlikely to cause clinically detectable deficits in global cognitive function or serious behavioral disorders.750,751,752 The PANDA study compared global cognitive function (as measured by intelligence quotient [IQ] score) of children 8-15 years of age who had a single anesthesia exposure for elective inguinal hernia surgery before the age of 3 years with that of a biologically related sibling who had no anesthesia exposure before the age of 3 years.750,752 All of the children had a gestational age at birth of at least 36 weeks, and sibling pairs were within 3 years of being the same age.750,752 Children who underwent the elective procedure were mostly males (90%) and generally healthy.750,752 The mean duration of anesthesia was 84 minutes; 16% of those receiving anesthesia had exposures exceeding 2 hours.750 The study found no substantial difference in IQ score between children who had a single anesthesia exposure before the age of 3 years and their siblings who had not.750,752 The GAS trial was designed to compare neurodevelopmental outcomes in children who received general anesthesia with those in children who received awake regional (caudal and/or spinal) anesthesia for inguinal herniorrhaphy before they reached a postmenstrual age of 60 weeks (with a gestational age at birth of more than 26 weeks); the primary outcome was the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale IQ at 5 years of age.750,751 In an interim analysis at the age of 2 years, no difference in composite cognitive score (as measured by the Bayley Scales of Infant and Toddler Development III) was detected between children who had received sevoflurane anesthesia of less than 1 hour's duration (median duration: 54 minutes) compared with those who had received awake regional anesthesia.750,751

Anesthetic and sedation drugs are an essential component of care for children and pregnant women who require surgery or other procedures that cannot be delayed;750,753 no specific general anesthetic or sedation drug has been shown to be less likely to cause neurocognitive deficits than any other such drug.750 Pending further accumulation of data in humans from well-designed studies, decisions regarding the timing of elective procedures requiring anesthesia should take into consideration both the benefits of the procedure and the potential risks.750 When procedures requiring the use of general anesthetics or sedation drugs are considered for young children or pregnant women, clinicians should discuss with the patient, parent, or caregiver the benefits, risks (including potential risk of adverse neurodevelopmental effects), and appropriate timing and duration of the procedure.750,753 FDA states that procedures that are considered medically necessary should not be delayed or avoided.750,753

Pregnancy and Lactation

Pregnancy

Benzodiazepines can cause fetal harm when administered to pregnant women. Results of retrospective studies suggest an increased risk of congenital malformations in infants of mothers who received benzodiazepines (e.g., chlordiazepoxide, diazepam) during the first trimester of pregnancy. An increase in fetal heart rate has occurred after diazepam use during labor. Hypoactivity, hypotonia, hypothermia, apnea, feeding problems, impaired metabolic response to cold stress, hyperbilirubinemia, and kernicterus have been reported in neonates born to mothers who received large doses of diazepam (generally greater than 30 mg) shortly before delivery. Infants of mothers who chronically ingested benzodiazepines during pregnancy have been reported to have withdrawal symptoms. Neonatal flaccidity, respiratory and feeding difficulties, and hypothermia have been reported in infants born to women who received benzodiazepines late in pregnancy.538 Since the use of anxiolytics is rarely urgent, their use during the first trimester of pregnancy should almost always be avoided. Benzodiazepines used solely as hypnotics (flurazepam, temazepam, triazolam) are contraindicated during pregnancy.

Although there is an association between anticonvulsant drug use in pregnant women with seizure disorders and an increased incidence of teratogenic effects in children born to such women, anticonvulsant therapy should not be discontinued in women in whom the drugs are administered to prevent seizures because of the strong possibility of precipitating status epilepticus and the attendant hypoxia and threat to life.538 In cases where the severity and frequency of the seizure disorder are such that removal of the anticonvulsant does not pose a serious threat to the patient, discontinuance of the drug may be considered prior to and during pregnancy.538 However, it cannot be said with confidence that even mild seizures do not pose some hazard to the developing embryo or fetus.538 In general, benzodiazepines should be considered for use as anticonvulsant therapy in women of childbearing potential, and more specifically during known pregnancy, only when the clinical situation warrants the risk to the fetus.538

Based on animal data, repeated or prolonged use of general anesthetics and sedation drugs, including benzodiazepines such as lorazepam and midazolam, during the third trimester of pregnancy may result in adverse neurodevelopmental effects in the fetus.750,753 The clinical relevance of these animal findings to humans is not known; the potential risk of adverse neurodevelopmental effects should be considered and discussed with pregnant women undergoing procedures requiring general anesthetics and sedation drugs.750 (See Cautions: Pediatric Precautions.)

The possibility that a woman of childbearing potential may be pregnant at the time benzodiazepine therapy is initiated should be considered.538 Patients should be advised that if they become pregnant or intend to become pregnant during benzodiazepine therapy, they should communicate with their clinician about the desirability of discontinuing the drug.538

Lactation

Since many benzodiazepines are distributed into milk and because of the potential for adverse reactions from the drugs in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Some benzodiazepines (e.g., alprazolam, clobazam, diazepam, estazolam, midazolam, triazolam) are metabolized by cytochrome P-450 (CYP) isoenzymes, predominantly by CYP3A4 and/or CYP2C19.372,538,609,610,625,632 Clearance of these benzodiazepines may be reduced by drugs or foods that inhibit CYP3A4 (e.g., some azole antifungals, some macrolide antibiotics, HIV protease inhibitors, some calcium-channel blocking agents, some selective serotonin-reuptake inhibitors [SSRIs], nefazodone, grapefruit juice) or inhibit CYP2C19 (e.g., fluvoxamine, omeprazole, ticlopidine), possibly resulting in enhanced or prolonged benzodiazepine effects.372,609,610,625,632,642 Conversely, concomitant use of these benzodiazepines with drugs that induce CYP3A4 (e.g., carbamazepine, phenobarbital, phenytoin, rifampin) may decrease plasma concentrations of the benzodiazepines.372,609,625

Antihistamines

Concomitant administration of temazepam and diphenhydramine in a pregnant woman at the end of the third trimester has been associated with violent intrauterine fetal movements within several hours after maternal ingestion of the drugs; within 8 hours, the infant was delivered stillborn.211 Reproduction studies in rabbits have suggested that concomitant administration of these drugs markedly increases perinatal mortality; neonatal deaths were associated with increased irritability and seizures.211

Anti-infective Agents

Antifungal Agents

Concomitant use of some benzodiazepines (e.g., alprazolam, clobazam, estazolam, midazolam, triazolam) with some azole antifungal agents (e.g., fluconazole, itraconazole, ketoconazole) may result in increased plasma concentrations and systemic exposure of these benzodiazepines.207,562,611,625,632 Following concomitant administration of oral midazolam with itraconazole or ketoconazole, large increases in the peak plasma concentration (up to 240 or 309%, respectively) and area under the serum concentration-time curve (AUC) (up to 980 or 1490%, respectively) of midazolam were observed.609 When alprazolam was given concomitantly with itraconazole or ketoconazole, increases of 2.7- or 4-fold, respectively, in the AUC of alprazolam were observed.372 In healthy adults receiving multiple doses of itraconazole (200 mg daily for 6 days), the elimination half-life of alprazolam was increased by 260% and AUC was increased by 270% following administration of a single 0.8-mg dose of alprazolam; substantial changes in psychomotor function (e.g., sleepiness) were also noted.562 Administration of a single 200-mg dose of itraconazole given 3, 12, or 24 hours prior to or simultaneously with a single 0.25-mg dose of triazolam increased the peak plasma concentration of triazolam by 140-180% and AUC of triazolam by 300-500%, depending on ingestion time of the dose, while the elimination half-life of triazolam was increased by 300%.562 When oral midazolam was administered concomitantly with fluconazole in healthy adults, the peak plasma concentration and AUC of midazolam were increased by 150 and 250%, respectively.609

Alprazolam, estazolam, and triazolam are contraindicated in patients receiving concomitant therapy with potent CYP3A inhibitors such as ketoconazole and itraconazole;372,610,625 concomitant use of other azole antifungal agents that are considered potent CYP3A inhibitors is not recommended.372,610 Because of the potential for intense and prolonged sedation and respiratory depression, oral midazolam should be administered only when absolutely necessary and with extreme caution (e.g., with appropriate equipment and personnel available to respond to respiratory insufficiency) in patients receiving ketoconazole or itraconazole.562,609

Antimycobacterial Agents

Isoniazid

Concomitant use of isoniazid with triazolam has been shown to increase the peak plasma concentration and half-life of triazolam by 20 and 31%, respectively, and decrease clearance of triazolam by 42%.610 Caution is advised when triazolam or other benzodiazepines that are metabolized by the CYP3A isoenzyme (e.g., alprazolam, estazolam) are used concomitantly with isoniazid.372,610,625

Antiretroviral Agents

HIV Protease Inhibitors

Because of the potential for intense and prolonged sedation and respiratory depression, the manufacturers of HIV protease inhibitors (e.g., atazanavir, darunavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir) state that concomitant use of these agents with midazolam or triazolam is contraindicated.614,616,617,618,619,620,621,622,627

Concomitant use of HIV protease inhibitors (e.g., fosamprenavir, ritonavir, saquinavir) with certain other benzodiazepines (e.g., alprazolam, clorazepate, diazepam, flurazepam) also may result in increased concentrations of the benzodiazepine.614,620,622 While the clinical importance of the interaction is unknown, a reduction in dosage of the benzodiazepine may be needed.614,620,622

Nonnucleoside Reverse Transcriptase Inhibitors

Concomitant use of efavirenz with midazolam or triazolam624 and of delavirdine with alprazolam, midazolam, or triazolam623 should be avoided because of the potential for the nonnucleoside reverse transcriptase inhibitor (NNRTI) to decrease metabolism of the benzodiazepine and result in intense or prolonged sedation or respiratory depression.623,624

Macrolide Antibiotics

Concomitant use of erythromycin decreases clearance of midazolam508,562,611 and triazolam212,213,214,562 and could increase the pharmacologic effects of these benzodiazepines.212,213,214,508,562,611 Available data also suggest that some macrolide antibiotics (i.e., erythromycin, clarithromycin) might interact with alprazolam.372 In addition, it might be anticipated that erythromycin could interfere with the metabolism of estazolam.625

Patients receiving benzodiazepines that are metabolized by the CYP3A isoenzyme concomitantly with some macrolide antibiotics (i.e., erythromycin, clarithromycin) should be monitored closely; reduction in the benzodiazepine dosage may be necessary.372,508,609,610,625

Cardiovascular Agents

Amiodarone

Although specific drug interaction studies are not available, concomitant use of amiodarone with some benzodiazepines (e.g., alprazolam, triazolam) may result in decreased metabolism of the benzodiazepine; caution is advised.372,610

Calcium-channel Blocking Agents

Concomitant use of diltiazem or verapamil with oral midazolam results in increased plasma midazolam concentrations and may lead to increased and prolonged sedation and respiratory depression.609 If midazolam is used concomitantly with diltiazem or verapamil, caution is advised and dosage reduction of midazolam may be necessary.609

Although specific drug interaction studies are not available, clinically important decreases in the metabolism and clearance of other benzodiazepines metabolized by the CYP3A isoenzyme (e.g., alprazolam, estazolam, triazolam) may occur when these benzodiazepines are used concomitantly with some calcium-channel blocking agents (e.g., diltiazem, verapamil); caution is advised.372,610,625 Drug interactions also are possible when some benzodiazepines (e.g., alprazolam, estazolam, triazolam) are used concomitantly with nicardipine or nifedipine.372,610,625

Digoxin

Limited evidence suggests that diazepam may reduce the renal excretion of digoxin, resulting in an increased plasma half-life of the cardiac glycoside and possible digoxin toxicity.200,208 Digoxin toxicity has been reported in one geriatric patient who was receiving alprazolam and digoxin concurrently; serum digoxin concentrations increased threefold in this patient following initiation of alprazolam therapy, but returned to within normal limits following discontinuance of the benzodiazepine.209 Although the exact mechanism for the effect of benzodiazepines on the renal excretion of digoxin has not been clearly established, increased plasma protein binding of digoxin and/or an effect of benzodiazepines on the renal tubular transport of digoxin have been suggested.208,209 Pending further accumulation of data, serum digoxin concentrations should be monitored and patients should be carefully observed for signs and/or symptoms of digoxin toxicity during concomitant therapy with benzodiazepines and digoxin.200,208,209 Dosage reduction of digoxin may be necessary in some patients receiving concomitant therapy.200,209

CNS Agents

CNS Depressants

Additive CNS depression may occur when benzodiazepines are administered concomitantly with other CNS depressants, including other anticonvulsants, opiates, and alcohol. If benzodiazepines are used concomitantly with other depressant drugs, caution should be used to avoid overdosage. Patients receiving benzodiazepines should be advised to avoid alcohol.700

Anticonvulsants

In patients receiving clonazepam and phenytoin concurrently, plasma concentrations of phenytoin may decrease; patients receiving these drugs concurrently should be closely observed.

Concurrent administration of carbamazepine with alprazolam or clonazepam has been shown to increase the rate of metabolism and decrease plasma concentrations of these benzodiazepines. In one study, administration of a single 0.8-mg dose of alprazolam after 10 days of low-dose carbamazepine (300 mg daily) resulted in a 2.4-fold increase in oral clearance of alprazolam and decreased the elimination half-life of alprazolam from 17.1 hours to 7.7 hours.372

Concomitant administration of oral midazolam with phenytoin or carbamazepine has been shown to decrease the peak plasma concentration and AUC of midazolam by about 93-94%.609

In a limited number of healthy men, concurrent use of valproate (250 mg twice daily orally, for 3 days) with a single 2-mg IV dose of lorazepam reportedly decreased total clearance of lorazepam by 40% and increased plasma concentration of the benzodiazepine approximately twofold (that persisted for at least 12 hours after dosing) compared with administration of lorazepam alone.435 The dosage of lorazepam should be reduced by approximately 50% when administered concomitantly with valproate.435

Antidepressants

Nefazodone

Concomitant use of nefazodone with some benzodiazepines (e.g., alprazolam, triazolam) results in clinically important increases in plasma concentrations of the benzodiazepine.372,610 Concomitant use of triazolam and nefazodone should be avoided.610 If alprazolam is used concomitantly with nefazodone, caution is advised and reduction of the alprazolam dosage should be considered.372 Although specific drug interaction studies are not available, concomitant use of estazolam with nefazodone would be expected to increase plasma concentrations of estazolam.625

Selective Serotonin-reuptake Inhibitors

Concomitant use of some SSRIs (e.g., fluoxetine, fluvoxamine) with alprazolam has been reported to decrease clearance and increase plasma concentrations of alprazolam and impair psychomotor performance.372 In one study, peak plasma concentrations of alprazolam were doubled, half-life of alprazolam was increased by 71%, and clearance of the drug was reduced by 49% when alprazolam was given concomitantly with fluvoxamine.372,613 When alprazolam was given concomitantly with fluoxetine, the peak plasma concentration and half-life of alprazolam were increased by 46 and 17%, respectively, and clearance of alprazolam was reduced by 21%.372 Caution is advised if fluvoxamine or fluoxetine is used concomitantly with alprazolam, midazolam, or triazolam.372,610,613 If fluvoxamine is used concomitantly with alprazolam, reduction of the alprazolam dosage also should be considered.372,613

Although specific drug interaction studies are not available, concomitant use of estazolam with fluvoxamine would be expected to result in increased plasma concentrations of estazolam.625 In one study, concomitant use of estazolam (2 mg daily) and fluoxetine (20 mg twice daily) for 7 days did not appear to affect the peak plasma concentration or AUC of estazolam.625

The clearance of diazepam was reduced by 65% and that of its active metabolite N -desmethyldiazepam could not be determined during concomitant administration with fluvoxamine in one study.613 Concomitant use of diazepam and fluvoxamine generally should be avoided.613

The clearance of benzodiazepines that are metabolized by glucuronidation (e.g., lorazepam, oxazepam, temazepam) is unlikely to be affected by fluvoxamine.613

In vitro studies suggest a possible interaction between triazolam and sertraline or paroxetine; caution is advised if these drugs are used concomitantly.610 Although in vitro data also suggest the possibility of an interaction between alprazolam and sertraline or paroxetine, no substantial changes in alprazolam pharmacokinetics were evident in one study involving multiple-dose administration of sertraline (50-150 mg daily) and single-dose administration of alprazolam (1 mg).372 Nonetheless, the manufacturers of alprazolam state that caution is advised when alprazolam is used concomitantly with sertraline or paroxetine.372,606,607

Tricyclic Antidepressants

Although some studies showed no substantial alteration of tricyclic antidepressant plasma concentrations during simultaneous administration of benzodiazepines, one study indicated that the elimination half-life and steady-state plasma concentrations of amitriptyline may be increased in patients receiving diazepam. In addition, steady-state plasma concentrations of imipramine and desipramine reportedly were increased by 31 and 20%, respectively, in patients receiving these antidepressants concomitantly with alprazolam (up to 4 mg daily).372 The clinical importance of these possible interactions has not been determined. There have been reports of impaired motor function when tricyclic antidepressants were used with benzodiazepines, but these have not been confirmed and the drugs have often been administered concomitantly without adverse effects.

Antipsychotic Agents

Clozapine

Severe hypotension (including absence of measurable blood pressure), respiratory or cardiac arrest, and loss of consciousness have been reported in several patients who received benzodiazepines (i.e., diazepam, flurazepam, lorazepam) concomitantly with or before clozapine therapy. 529,591,592,593,595,597,598,600 Such effects occurred following administration of 12.5-150 mg of clozapine concurrently with or within 24 hours of the benzodiazepine, but patients generally have recovered within a few minutes to hours, usually spontaneously;592,593,597,598 the reactions usually developed on the first or second day of clozapine therapy.592,593,597,598 Although a causal relationship has not definitely been established and such effects also have been observed in clozapine-treated patients who were not receiving a benzodiazepine concomitantly, 591,597,599 death resulting from respiratory arrest reportedly has rarely occurred when a benzodiazepine (e.g., lorazepam) was used concomitantly with clozapine.435,594 An increased incidence of dizziness and sedation and greater increases in liver enzyme test results also have been reported when benzodiazepines and clozapine were used concomitantly.593,596

The manufacturers of lorazepam and clozapine recommend caution when clozapine is initiated in patients receiving benzodiazepine therapy.435,591,599 However, some clinicians advise that, pending further accumulation of data, greater precaution should be exercised.597,598 These clinicians recommend that because initial titration of clozapine may cause respiratory arrest requiring resuscitation, which may be potentiated by recent benzodiazepine therapy, these latter drugs should be discontinued for at least 1 week prior to initiating clozapine therapy.597,598

Other Antipsychotic Agents

Respiratory depression, stupor, and/or hypotension have been reported rarely in patients receiving lorazepam concomitantly with loxapine. 435 In addition, apnea, coma, bradycardia, arrhythmia, cardiac arrest, and death have occurred in patients receiving lorazepam and haloperidol concomitantly.435 The manufacturer of lorazepam states that lorazepam should be used with caution in patients receiving haloperidol or loxapine because concomitant administration of these drugs has not been evaluated systematically.435

Opiate Agonists and Opiate Partial Agonists

Concomitant use of benzodiazepines with opiate agonists or opiate partial agonists may result in profound sedation, respiratory depression, coma, and death.700,701,703,705,706,707 Epidemiologic studies have shown that a substantial proportion of fatal opiate overdoses involve the concurrent use of benzodiazepines.700,701,705,706,707,711

Whenever possible, concomitant use of opiate agonists or partial agonists and benzodiazepines should be avoided.708,709,710,711 Opiate antitussive agents should be avoided in patients receiving benzodiazepines,700,704 and concomitant use of opiate analgesics and benzodiazepines should be reserved for patients in whom alternative treatment options are inadequate.700,703 (See Cautions: Precautions and Contraindications, in the Opiate Agonists General Statement 28:08.08.) If a decision is made to prescribe opiates and benzodiazepines concomitantly, the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.700,703 If a benzodiazepine is required for any indication other than epilepsy in a patient receiving opiate therapy, the drug should be initiated at a lower dosage than indicated in the absence of opiate therapy and titrated based on clinical response.700 In patients receiving benzodiazepines, opiate analgesics should be initiated at a reduced dosage and titrated based on clinical response.700 Some experts state that consideration should be given to offering the opiate antagonist naloxone when opiates are prescribed for patients at increased risk of opiate overdosage, including those receiving benzodiazepines concomitantly.709,712

Cyclosporine

Although specific drug interaction studies are not available, concomitant use of cyclosporine with some benzodiazepines (e.g., alprazolam, triazolam) may result in decreased metabolism of the benzodiazepine; caution is advised.372,610

Disulfiram

Concurrent administration of disulfiram and benzodiazepines may result in inhibition of metabolism of some benzodiazepines. Disulfiram has reduced the plasma clearance and increased the plasma half-lives of chlordiazepoxide and diazepam during concomitant administration.200,201 It is likely that other benzodiazepines that undergo oxidative metabolism (e.g., alprazolam, clonazepam, clorazepate, estazolam, flurazepam, triazolam) would also interact with disulfiram.200 Benzodiazepines metabolized by glucuronide conjugation (e.g., lorazepam, oxazepam, temazepam) are probably not affected by disulfiram.200,201 Patients should be closely observed for evidence of enhanced benzodiazepine response during concomitant therapy with disulfiram; some patients may require reduction in benzodiazepine dosage.200

Ergot Alkaloids

Although specific drug interaction studies are not available, concomitant use of ergotamine with some benzodiazepines (e.g., alprazolam, triazolam) may result in decreased metabolism of the benzodiazepine; caution is advised.372,610

GI Drugs

Antacids

Concurrent administration of chlordiazepoxide or diazepam with antacids such as aluminum and magnesium hydroxides may decrease the rate, but not the extent, of GI absorption of chlordiazepoxide or diazepam. Concurrent administration of antacids and clorazepate may decrease the rate and extent of conversion of the latter drug to desmethyldiazepam, and these drugs should not be given concurrently.

Cimetidine

Concomitant administration of some benzodiazepines (e.g., alprazolam, chlordiazepoxide, clobazam, clorazepate, diazepam, midazolam, triazolam) and cimetidine may result in decreased benzodiazepine plasma clearance and increased plasma half-lives and concentrations of these benzodiazepines.200,202,203,204,205,206,207,372,507,611,643 Cimetidine reduces plasma clearance of benzodiazepines that undergo oxidative metabolism, apparently via inhibition of hepatic microsomal enzymes involved in oxidative metabolism.200,202,203,210 Consequently, the elimination of clonazepam, estazolam, and flurazepam may also be similarly affected by cimetidine.200,625 Benzodiazepines metabolized by conjugation with glucuronic acid (e.g., lorazepam, oxazepam, temazepam) do not appear to be affected by concomitant cimetidine therapy.200,205,210 Although an increased sedative effect has been observed in some patients receiving concomitant therapy with a benzodiazepine and cimetidine,202 the degree to which the pharmacologic response to the benzodiazepine may be increased is not well established.200,206,507 Benzodiazepine dosage reduction may be necessary in patients receiving concomitant therapy with cimetidine.200,372,610 Altered benzodiazepine response may occur following initiation or discontinuance of cimetidine therapy in patients receiving affected benzodiazepines.200

Ranitidine

There have been reports of increased systemic availability of benzodiazepines (e.g., oral midazolam, triazolam) when these benzodiazepines were administered concomitantly with ranitidine.609,610 The mechanism has not been fully elucidated.610,626

Grapefruit Juice

Concomitant oral administration of grapefruit juice with midazolam509,510 or triazolam511 has been reported to increase bioavailability of the drugs.509,510 The interaction between grapefruit juice and benzodiazepine bioavailability appears to result from inhibition, probably prehepatic,509,513,514,515,516,517,518,519,520,521 of the cytochrome P-450 enzyme system by some constituent(s) in the juice.510,511,512,513,514,515,516,517,518,519,520,521,523,524,525,526,527,528 Following oral administration of these benzodiazepines,509,510,511,516 such prehepatic inhibition of drug metabolism by grapefruit juice appears mainly to involve the CYP3A4 isoenzyme, principally within the small intestinal wall (e.g., in the jejunum), thus increasing systemic availability of these drugs.509,510,511,516 (See Grapefruit Juice under Drug Interactions: Drugs and Foods Affecting Hepatic Microsomal Enzymes, in Cyclosporine 92:44.)

Hormonal Contraceptives

In a limited number of healthy women, concurrent use of an oral estrogen-progestin contraceptive (1 mg of norethindrone acetate and 50 mcg of ethinyl estradiol daily for at least 6 months) with a single 2-mg IV dose of lorazepam decreased half-life of lorazepam by 55% and increased volume of distribution by 50%, resulting in an almost 3.7-fold increase in total clearance of lorazepam.435 Dosage of lorazepam may need to be increased when administered to women receiving oral contraceptives.435

Concomitant use of oral contraceptives with alprazolam or triazolam has been shown to decrease clearance of these benzodiazepines.372,610 In one study, the peak plasma concentration and elimination half-life of alprazolam were increased by 18 and 29%, respectively, and clearance of alprazolam was decreased by 22% when oral contraceptives were given concomitantly.372 Similar results were observed in a study with triazolam; the peak plasma concentration and elimination half-life of triazolam were increased by 6 and 16%, respectively, and clearance of triazolam was decreased by 32% when oral contraceptives were given concomitantly.610 Caution is advised when alprazolam or triazolam is used concomitantly with oral contraceptives.372,610

Clobazam may reduce the efficacy of some hormonal contraceptives (e.g., oral or other hormonal contraceptives) that are metabolized by CYP3A4.632,641 Additional nonhormonal forms of contraception are recommended in women receiving hormonal contraceptives during clobazam therapy and for 28 days following discontinuance of the drug.632

Levodopa

A few levodopa-treated patients experienced decreased control of parkinsonian symptoms when chlordiazepoxide hydrochloride or diazepam was added to their therapeutic regimen. Therefore, benzodiazepines should be administered with caution to patients receiving levodopa.

Probenecid

In a limited number of healthy adults, concurrent use of probenecid (500 mg every 6 hours) with a single 2-mg IV dose of lorazepam increased the half-life of lorazepam by 130% and decreased its clearance by 45%.435 Dosage of lorazepam should be reduced by 50% when administered concomitantly with probenecid.435

Scopolamine

An increased incidence of sedation, hallucinations, and irrational behavior has been reported in patients receiving lorazepam injection concomitantly with scopolamine.435 The manufacturer of lorazepam states that the benzodiazepine should be used with caution in patients receiving scopolamine, because concomitant administration of these drugs has not been evaluated systematically.435

Smoking

Cigarette smoking may decrease the sedative effects of usual doses of benzodiazepines. Clearance of benzodiazepines may be increased in smokers compared with nonsmokers.625 Plasma alprazolam concentrations reportedly are decreased by up to 50% in cigarette smokers compared with nonsmokers.372

Laboratory Test Interferences

Pregnancy Test

Chlordiazepoxide may cause a false-positive reaction in the Gravindex^® pregnancy test.

Tests for Urinary Steroids and Alkaloids

Chlordiazepoxide reportedly interferes with the Zimmerman reaction for urinary 17-ketosteroids, resulting in falsely elevated or decreased concentrations. Chlordiazepoxide and diazepam may interfere with urine alkaloids determined by the Frings thin layer chromatography procedure, resulting in falsely elevated readings.

Tests for Urinary Glucose

False-negative reactions for glucose in the urine may occur in patients receiving diazepam when the test is performed with Clinistix^® and Diastix^®, but not with Tes-Tape^®.

Acute Toxicity

Manifestations

Benzodiazepine overdosage may result in somnolence, impaired coordination, slurred speech, confusion, coma, and diminished reflexes. Hypotension, seizures, respiratory depression, and apnea also may occur. Although cardiac arrest has been reported, death from overdosage of benzodiazepines in the absence of concurrent ingestion of alcohol or other CNS depressants is rare. Most patients recover rapidly.

Treatment

Treatment of benzodiazepine intoxication consists of general supportive therapy. Flumazenil, a benzodiazepine antagonist, can be used in the management of benzodiazepine overdosage, but the drug is an adjunct to, not a substitute for, appropriate supportive and symptomatic therapy. (See Flumazenil 28:92.) The possibility that the antagonist could precipitate withdrawal (e.g., seizures) in benzodiazepine-dependent individuals should be considered.696

If ingestion of the benzodiazepine is recent and the patient is fully conscious, emesis should be induced. If the patient is comatose, gastric lavage may be done if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Activated charcoal and a saline cathartic may be administered after gastric lavage and/or emesis to remove any remaining drug. Pulse, respiration, and blood pressure should be monitored and the patient should be closely observed. IV fluids should be administered and an adequate airway maintained. Hypotension may be controlled, if necessary, by IV administration of norepinephrine or metaraminol. Although some manufacturers recommend use of caffeine and sodium benzoate to combat CNS depression, most authorities believe caffeine and other analeptic agents should not be used, because these drugs have questionable benefit and transient action. Instead, administration of flumazenil, if indicated, generally would be preferred. Hemodialysis is not useful in the treatment of benzodiazepine overdosage.

Chronic Toxicity

Tolerance and psychologic and physical dependence may occur following prolonged use of benzodiazepines. The possibility that such effects also may occur following short-term use of benzodiazepines, particularly at high dosages, also should be considered. Symptoms of benzodiazepine dependence are similar to barbiturate dependence or chronic alcoholism and may include drowsiness, ataxia, slurred speech, and vertigo.

Sudden discontinuance of benzodiazepines in physically dependent patients (usually patients who have received excessive doses for an extended period of time but also occasionally with therapeutic dosages for relatively short periods) may produce severe withdrawal symptoms including anxiety, agitation, tension, dysphoria, anorexia, insomnia, sweating, vomiting, diarrhea, blurred vision, irritability, memory impairment, impaired concentrating ability, clouded sensorium, paresthesias, ataxia, tremors, muscle and abdominal cramps, heightened sensory perception, hallucinations, acute psychosis, decreased appetite/weight loss, and seizures which are clinically indistinguishable from tonic-clonic seizures. In addition, milder withdrawal symptoms such as dysphoria and insomnia have been reported following abrupt discontinuance of benzodiazepines in patients receiving therapeutic dosages for several months. It may be difficult to distinguish between withdrawal symptoms and those that are manifestations of illness return or rebound, although their management may differ. Because some benzodiazepines and their metabolites have long elimination half-lives, withdrawal symptoms may not occur until several days after the drugs have been discontinued.

Treatment of benzodiazepine physical dependence consists of cautious and gradual withdrawal of the drug using a dosage tapering schedule. Gradual dosage tapering is particularly important in patients with a seizure history. Occasionally, temporary reinstitution of benzodiazepine therapy at dosages adequate to suppress withdrawal symptoms may be necessary.

Pharmacology

The exact sites and mode of action of the benzodiazepines have not been fully elucidated, but the effects of the drugs appear to be mediated through the inhibitory neurotransmitter γ-aminobutyric acid (GABA).313,320,365,366,367,368,369,632 The drugs appear to act at the limbic, thalamic, and hypothalamic levels of the CNS, producing anxiolytic, sedative, hypnotic, skeletal muscle relaxant, and anticonvulsant effects. Benzodiazepines are capable of producing all levels of CNS depression—from mild sedation to hypnosis to coma.

Specific binding sites with high affinity for benzodiazepines have been detected in the CNS,313,320,326,327,328,329,330,331,332,358,359,360,361,362,363,364,365,366,367,368,369,370,406 and the affinity of these sites for the drugs is enhanced by both GABA and chloride.320 The sites and actions of benzodiazepines within the CNS appear to involve a macromolecular (oligomer or possibly a tetramer) complex (GABA_A-receptor-chloride ionophore complex) that includes GABA_A receptors (GABA recognition sites), high-affinity benzodiazepine receptors, and chloride channels,320,357,358,359,360,361,362,363,364,365,366,367,368,369,370 although precise relationships between the sites of action of benzodiazepines and GABA-regulated (-gated) chloride channels remain to be more fully elucidated.320,365 Allosteric interactions of central benzodiazepine receptors with GABA_A receptors and subsequent opening of chloride channels appear to be involved in eliciting the CNS effects of the drugs; the benzodiazepine receptors act as modulatory sites on the complex.320,357,358,359,360,361,362,363,364,365,366,367,368,369,370 Some evidence suggests that benzodiazepine receptor sites are heterogeneous, with at least 2 CNS subtypes (type 1 [BZ₁] and type 2 [BZ₂] benzodiazepine receptors) being described to date.313,318,326,327,328,329,330,331,332,365,371 While quazepam and 2-oxoquazepam (an active metabolite), like halazepam (another 1- N -trifluoroethyl derivative [no longer commercially available in the US]) but unlike other currently available benzodiazepines, exhibit relative selectivity for type 1 receptors (2-oxoquazepam is the most potent and selective of the three),313,317,318,326,327,328,329,330,331,371 the clinical importance, if any, of this finding remains to be established.313,327,328 Some evidence suggests that such selectivity may be responsible for the reduced ataxic effect of quazepam observed in animal studies;313,318,326,329,331,365 the possibility that the spectrum of other benzodiazepine-induced effects may be narrowed by such selectivity also has been suggested.318,326,327,357

Clobazam, a 1,5-benzodiazepine, has been shown to have a broader spectrum of anticonvulsant activity and an improved adverse effect profile (e.g., less sedative effects) compared with the traditional 1,4-benzodiazepines (e.g., diazepam, lorazepam); these differences have been attributed to differences in binding affinity for the GABA_A receptor.632,635,636,639,648 Because the active metabolite of clobazam, N -desmethylclobazam, is extensively metabolized by cytochrome P-450 (CYP) 2C19, genetic polymorphism of CYP2C19 can result in possible increased concentrations of the active metabolite.632 Systemic exposure to N -desmethylclobazam is approximately 3-5 and 2 times higher in poor (CYP2C19*2/*2) and intermediate (CYP2C19*1/*2) metabolizers of CYP2C19, respectively, than in extensive (CYP2C19*1/*1) metabolizers.632 The frequency of poor CYP2C19 metabolizers in the population varies widely depending on ethnic or racial background.632

Anxiolytic and possibly paradoxical CNS stimulatory effects of benzodiazepines are postulated to result from release of previously suppressed responses (disinhibition). After usual doses of benzodiazepines for several days, the drugs cause a moderate decrease in rapid eye movement (REM) sleep. REM rebound does not occur when the drugs are withdrawn. Stage 3 and 4 sleep are markedly reduced by usual doses of the drugs; the clinical importance of these sleep stage alterations has not been established.

Benzodiazepines appear to produce skeletal muscle relaxation predominantly by inhibiting spinal polysynaptic afferent pathways, but the drugs may also inhibit monosynaptic afferent pathways. The drugs may inhibit monosynaptic and polysynaptic reflexes by acting as inhibitory neuronal transmitters or by blocking excitatory synaptic transmission. The drugs may also directly depress motor nerve and muscle function.

In animals, benzodiazepines protect against seizures induced by electrical stimulation and by pentylenetetrazol; benzodiazepines appear to act, at least partly, by augmenting presynaptic inhibition. The drugs suppress the spread of seizure activity but do not abolish the abnormal discharge from a focus in experimental models of epilepsy. In usual doses, benzodiazepines appear to have very little effect on the autonomic nervous system, respiration, or the cardiovascular system.

Pharmacokinetics

Absorption

Benzodiazepines are generally well absorbed from the GI tract. Following IM administration of diazepam, absorption is slow and erratic. Absorption of lorazepam and midazolam hydrochloride after IM administration appears to be rapid and complete. Following oral administration of clorazepate dipotassium, it appears that most of the drug is rapidly decarboxylated in the GI tract and is absorbed as desmethyldiazepam (nordiazepam). The rate of decarboxylation of clorazepate decreases as gastric pH increases. Flurazepam undergoes first-pass metabolism in the liver, and plasma concentrations of the parent compound are minimal after oral administration. Plasma concentrations of the benzodiazepines and their metabolites (which in general are active) exhibit considerable interpatient variation, and therapeutic plasma concentrations are difficult to define.

Following oral administration of usual doses of flurazepam, onset of hypnotic action is 15-45 minutes, and the duration of action is 7-8 hours. In general, orally administered benzodiazepines produce anxiolytic, skeletal muscle relaxant, and anticonvulsant effects after the first dose; however, these effects may increase until steady-state plasma concentrations are achieved. After IV administration of single doses of diazepam or lorazepam, the onset of anticonvulsant, anxiolytic, or sedative action occurs in 1-5 minutes; after usual doses of IV diazepam, the duration of action is 15 minutes-1 hour, and after IV lorazepam, the duration of action is 12-24 hours. Following repeated doses of IV diazepam, prolonged duration of sedative action may occur, because of the presence of its long-acting metabolites. Following IV administration of usual doses of midazolam hydrochloride, the onset of sedative, anxiolytic, and amnesic action usually occurs within 1-5 minutes. The duration of action following IV administration of midazolam is usually less than 2 hours; however, the pharmacologic effects may persist up to 6 hours in some patients and the duration of action appears to be dose related. After IM administration, the onset of action of lorazepam is 15-30 minutes, and the duration of action is 12-24 hours. Following IM administration of midazolam hydrochloride, onset of action occurs within 5-15 minutes but may not be maximal until 20-60 minutes; the duration of action usually is about 2 hours (range: 1-6 hours).

Midazolam appears to be rapidly and well absorbed transmucosally following intrabuccal administration.548,555 The drug also appears to be rapidly and well absorbed transmucosally following intranasal administration;548,556,557,558,560 however, the effect of increased nasal discharge and mucus production on intranasal midazolam absorption is unknown, and breathing may discharge drugs that are administered intranasally.548,559

Diazepam is rapidly and well absorbed systemically following rectal administration as a gel or solution (e.g., using parenteral formulations).538,539,540,543 Peak plasma or serum concentrations generally are achieved within 5-90 minutes following rectal administration of these formulations, with bioavailabilities averaging 80-102%.538,539,540,543 Diazepam is less predictably absorbed systemically following rectal administration as suppositories (e.g., bioavailability of 67-84%), exhibiting slow and variable absorption.539,540,541,542,543 When a single 15-mg dose was administered rectally as a commercially available viscous gel (Diastat^®) in healthy adults pretreated with an enema to ensure an empty rectum,539 plasma diazepam concentrations exceeded 200 ng/mL within 15 minutes and reached an initial peak of 373 ng/mL at 45 minutes and a second peak of 447 ng/mL at approximately 70 minutes.539 The manufacturer states that peak plasma concentrations of the drug are achieved within 1.5 hours following rectal administration of the gel in adults.538 In the healthy adults who received a single 15-mg rectal dose of diazepam following pretreatment with an enema,539 the absolute systemic bioavailability averaged about 90% (range: 71-110%).538,539 Peak plasma concentrations of the desmethyl metabolite in these adults averaged 62 ng/mL and were achieved 68 hours after rectal administration; areas under the plasma concentration-time curve (AUCs) and peak plasma concentrations for this metabolite were similar with rectal or IV administration.539 The elimination half-lives for diazepam and desmethyldiazepam averaged about 45-46 and 71-99 hours, respectively, following rectal administration of the gel in healthy adults.538,539 The pharmacokinetics of diazepam rectal gel in pediatric patients have not been determined,538,539 although some evidence suggests that more rapid absorption may be likely.539

Clobazam is rapidly and almost completely absorbed following oral administration; peak plasma concentrations of the drug are achieved within 0.5-4 hours after single- or multiple-dose administration.632 The main circulating metabolite, N -desmethylclobazam, is pharmacologically active with potency estimates ranging from one-fifth to equal potency of the parent drug; therefore, the active metabolite may contribute to the efficacy and tolerability of the drug.632,635,639 At therapeutic dosages, plasma concentrations of N -desmethylclobazam are approximately 3-5 times higher than those of clobazam.632,642

Distribution

Benzodiazepines are widely distributed into body tissues and cross the blood-brain barrier. Following IV administration of diazepam, there is an early, rapid decline in plasma concentrations of the drug, principally associated with distribution into the tissues. After IV administration of lorazepam, plasma concentrations decline less rapidly. Generally, benzodiazepines and their metabolites cross the placenta; the concentration of diazepam in the fetal circulation has been reported to be equal to or greater than maternal plasma drug concentrations. The drugs and their metabolites are distributed into milk.

Benzodiazepines and their metabolites are highly bound to plasma proteins.

Elimination

Elimination half-lives (t_½s) of benzodiazepines and their metabolites exhibit wide interpatient variation. (See Table 1.)

Geriatric patients and patients with liver disease may have prolonged elimination half-lives of all benzodiazepines and their metabolites, except possibly lorazepam, oxazepam, temazepam, and triazolam. However, limited data in healthy geriatric individuals (average age: 69 years) receiving single doses (0.125 or 0.25 mg) of triazolam indicate that values for peak plasma concentration and AUCs are increased and clearance decreased by an average of approximately 50% compared with values in younger adults (average age: 30 years).451 Evidence suggesting accumulation of triazolam (as determined by benzodiazepine receptor binding activity) with prolonged (i.e., 4 weeks) administration in geriatric individuals also has been reported.459 In premature and newborn infants, the half-lives of diazepam are longer than in adults and older children. Steady-state plasma concentrations of benzodiazepines and their metabolites are reached after administration of a fixed dosage for approximately 5 elimination half-lives. Plasma concentrations of metabolites with long half-lives may be greater than those of the unchanged drugs.

Benzodiazepines are metabolized in the liver. Lorazepam, oxazepam, temazepam, and the hydroxylated metabolites of chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam (no longer commercially available in the US), midazolam, quazepam, and triazolam are conjugated with glucuronic and/or sulfuric acid; these inactive conjugates are excreted principally in urine. Benzodiazepines are not appreciably removed by hemodialysis.

Chemistry

Alprazolam, chlordiazepoxide, clobazam (see 28:12.08), clonazepam (see 28:12.08), clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, and triazolam are benzodiazepines that are used as anxiolytics, sedatives, hypnotics, anticonvulsants, and/or skeletal muscle relaxants. Benzodiazepines are subject to control under the Federal Controlled Substances Act of 1970.

Benzodiazepines contain a benzene ring structure fused to a 7-membered diazepine ring.648 The classic benzodiazepines (e.g., chlordiazepoxide, clonazepam, diazepam, lorazepam) are referred to as 1,4-benzodiazepines because they contain nitrogen atoms at positions 1 and 4 on the diazepine ring.648 Clobazam, a 1,5-benzodiazepine, differs structurally from 1,4-benzodiazepines in that its nitrogen atoms are at positions 1 and 5 and a keto group occupies the 4 position on the diazepine ring; clobazam is the only 1,5-benzodiazepine that is currently used in clinical practice.632,635,650,651 Commercially available 1,4-benzodiazepines, except alprazolam, chlordiazepoxide, estazolam, midazolam, quazepam, and triazolam, have the same characteristic structure but differ in the substitutions at the R¹, R³, R⁷, and R^2' positions.

Comparative Structures of Benzodiazepines

In chlordiazepoxide, a 1,4-benzodiazepine-4-oxide, a methylamino group replaces the ketone at the 2 position, and a chlorine atom is at R⁷. In alprazolam, estazolam, and triazolam, triazolobenzodiazepines, a triazolo ring is formed by the addition of a ring to the benzodiazepine nucleus at the 1 and 2 positions, and a chlorine atom is at R⁷; triazolam also has a chlorine atom at R^2'. In midazolam, an imidazobenzodiazepine, an imidazole ring fused at positions 1 and 2 of the benzodiazepine nucleus replaces the ketone at position 2 of the nucleus; midazolam has a fluorine atom at R^2' and a chlorine atom at R⁷. Quazepam, a 1,4-benzodiazepine-2-thione, has a sulfur atom rather than a ketone at position 2 of the nucleus; the drug also has a trifluoroethyl group at R¹, a fluorine atom at R^2', and a chlorine atom at R⁷.312,313,317,318 The presence of the trifluoroethyl group (1- N -trifluoroethyl derivative) distinguishes halazepam (no longer commercially available in the US) and quazepam from other currently available benzodiazepines and results in relative selectivity for type 1 (BZ₁) benzodiazepine receptors.313,317,318,326,327,328,329,330,331,365 (See Pharmacology.)

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