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CHAPTER 183: Benzodiazepines 1215 The most common vital sign abnormalities seen in overdose are respiratory depression, hypothermia, and hypotension, with respira tory depression usually occurring first. Abnormal temperature control and respiratory depression are centrally mediated phenomena, whereas hypotension is primarily a result of decreased vascular tone. Pulse rate, pupil size, light reactivity, and nystagmus are variable. GI tract motility is slowed, resulting in delayed gastric emptying and ileus. Skin bullae, sometimes referred to as “barb blisters” or “coma blisters, ” are uncommon and may indicate nothing more than the effects of local skin pres sure, although hypoxia has been implicated as well. 14 Coma blisters are not specific to sedative-induced coma; they have been reported after surgery, 15 from other causes of coma,16 and even without coma.17 Early deaths in barbiturate overdose result from respiratory arrest and cardiovascular collapse. Common complications include hypoglycemia (perhaps due to starvation), pulmonary edema, aspiration pneumonia, and acute lung injury. Current mortality rates range between 1% and 3%; death usually results from multiple organ system failure. Lethal doses are estimates (Table 182-1), but severe poisoning can be assumed if more than 10 times the hypnotic dose has been ingested in a single exposure in a nontolerant patient. 18 As with other sedative-hypnotics, the toxic properties of barbiturates may be enhanced in the presence of benzodiazepines or alcohol. Conversely, the depressive effects may be protective in a mixed-stimulant overdose. DIAGNOSIS Laboratory evaluation in barbiturate overdose should include deter mination of glucose levels, blood chemistries, CBC, blood gas (if indicated), toxicology screen for co-ingestants, chest radiograph, and an ECG. Urine drug screens most commonly use the immunoassay methodology, and a false-positive result on the barbiturate screen has been reported with ibuprofen and naproxen. 20 If important, confirm a positive urine screen using a more accurate method, such as gas chromatography–mass spectrometry. Barbiturate serum levels are useful in establishing the diagnosis of a comatose patient; however, acute treatment decisions should be clinically based. Serum barbiturate levels reported in lethal overdoses vary widely, and measurements are not reliable in predicting clinical course after an overdose because they do not reflect brain barbiturate concentrations and may underestimate the clinical condition of a patient in the setting of polydrug exposure. 21 Barbiturate levels are also invalid in chronic barbiturate abusers who have developed physiologic tolerance and in patients with renal or hepatic disease who have decreased clearance. TREATMENT In a barbiturate overdose, the initial priorities are airway management and supportive care. Once pulmonary and cardiovascular function has been stabilized, options for increasing drug clearance are considered.  AIRWAY ASSESSMENT AND INITIAL STABILIZATION Assess the patient’s mental status and airway stability. Intubation with mechanical ventilation in severe sedative-hypnotic overdose is often required. Barbiturate toxicity results in decreased cardiac output and vascular tone, often resulting in profound hypotension. Volume expansion with IV crystalloids is the mainstay for circulatory support in the absence of cardiac failure.

bation with mechanical ventilation in severe sedative-hypnotic overdose is often required. Barbiturate toxicity results in decreased cardiac output and vascular tone, often resulting in profound hypotension. Volume expansion with IV crystalloids is the mainstay for circulatory support in the absence of cardiac failure. If fluid resuscitation fails to correct hypoten sion, administer vasopressors such as dopamine or norepinephrine. Hypothermia between 30°C (86°F) and 36°C (96.8°F) is common and should be monitored via continuous core temperature and treated with rewarming measures.  ACTIVATED CHARCOAL A single dose of activated charcoal should be given to cooperative, clinically stable patients who present within 1 hour of acute oral overdose. Current consensus guidelines are to consider multidose activated char coal if a patient has ingested a life-threatening amount of phenobarbital.23 A typical adult regimen for multidose activated charcoal is an initial dose of 50 to 100 grams PO followed by 12.5 to 25 grams PO every 4 hours. Concurrent administration of cathartic agents remains unproven and is discouraged (see Chapter 176, “General Management of Poisoned Patients”). Careful attention to and monitoring of the patient’s airway is important to decrease the risk of aspiration or bowel obstruction.  FORCED DIURESIS AND URINARY ALKALIZATION Forced diuresis is not recommended because of the risks of sodium and fluid overload and lack of proven efficacy. Urinary alkalization (see Chapter 176) does enhance the clearance of phenobarbital and primidone (which is metabolized to phenobarbital). This treatment is less effective than multidose activated charcoal in reducing serum levels, does not improve clinical outcomes, and is not effective for shorter-acting barbiturates. 24 In barbiturate poisoning, urinary alkalization is not a first-line treatment and has only a minor, if any, role.25,26  EXTRACORPOREAL ELIMINATION Hemodialysis, hemoperfusion, and hemodiafiltration can enhance elimination of phenobarbital, but are reserved for patients who are deteriorating despite aggressive supportive care. 26-28 These modalities are not useful for poisoning from barbiturates other than phenobarbital. Exchange transfusion has also been reported to be useful in neonatal phenobarbital toxicity.  DISPOSITION AND FOLLOW-UP Mild to moderate barbiturate intoxication responds well to general supportive care, including a single dose of activated charcoal, as long as potential benefits outweigh aspiration risk. Improvement in neurologic status and vital signs over 6 to 8 hours signals eventual patient discharge or transfer. When indicated, obtain mental health assessment. For a longacting agent such as phenobarbital, serial serum levels should be obtained during the initial 6 hours after an overdose before concluding the patient can be safely discharged or transferred. Evidence of toxicity after 6 hours will require hospital admission, and patients with severe toxicity should go to the intensive care unit. Consult with a medical toxicologist or local poison center to assist in the care of severe barbiturate-poisoned patients. BARBITURATE WITHDRAWAL SYNDROME Abrupt discontinuation of barbiturates in a chronically dependent user will produce withdrawal symptoms similar to alcohol or benzodiaz epine withdrawal. Clinical manifestations will range from anxiety and restlessness to hallucinations, delirium, and/or generalized seizures. Severe symptoms in the ED can be treated with benzodiazepines or barbiturates, but due to the associated mortality, gradual in-hospital detoxification is needed. REFERENCES The complete reference list is available online at www.TintinalliEM.com.

and restlessness to hallucinations, delirium, and/or generalized seizures. Severe symptoms in the ED can be treated with benzodiazepines or barbiturates, but due to the associated mortality, gradual in-hospital detoxification is needed. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Benzodiazepines Dan Quan INTRODUCTION Benzodiazepines, to varying degrees, have in common six major phar macologic effects: sedative, hypnotic, anxiolytic, amnestic, anticonvul sant, and muscle relaxant.1 Benzodiazepines are commonly used for the short-term treatment of anxiety, insomnia, seizures, and withdrawal CHAPTER Tintinalli_Sec15_p1187-1332.indd 1215 8/2/19 8:39 PM

to varying degrees, have in common six major phar macologic effects: sedative, hypnotic, anxiolytic, amnestic, anticonvul sant, and muscle relaxant.1 Benzodiazepines are commonly used for the short-term treatment of anxiety, insomnia, seizures, and withdrawal CHAPTER Tintinalli_Sec15_p1187-1332.indd 1215 8/2/19 8:39 PM 1216 SECTION 15: Toxicology from alcohol or sedative-hypnotic agents. 2-5 The long-term benefits of benzodiazepines for psychiatric disorders are controversial. 6,7 Mid azolam, a benzodiazepine with a short duration of action, is also used for procedural sedation and general anesthesia (Table 183-1). Isolated benzodiazepine overdose has low mortality, and death is rare.8 However, increased rates of morbidity do result from mixed overdose, especially in combination with opioids. Isolated overdose with highpotency short-acting agents, such as alprazolam, temazepam, and triazolam, is associated with higher incidences of intensive care unit admissions, coma, and mechanical ventilation with toxicity compared to other benzodiazepines, such as diazepam. 9 A review of suicide by TABLE 183-1 Benzodiazepines Generic Name Time to Peak Effect (hours)† Elimination Half-Life (hours) ‡ Duration of Action (hours) Active Metabolite Half-Life (hours) Oral Dose Equivalents in Milligrams to Diazepam 10 Milligrams Short Acting Alprazolam * 1–2 6–12 4-7 No 0.5 Midazolam* IV 1–2 min IM 10–15 min PO 0.5–1 3–6 IV 2 IM 4–6 PO 4–6 Yes 5 Oxazepam * 0.3–0.5 5–10 3–6 No 20 Tetrazepam 1–3 15 6–8 No 50–100 Triazolam* 0.25–0.5 2–5 6–7 No 0.25–0.50 Intermediate Acting Bromazepam 1–3 10–20 <12 Yes 5–6 Cinolazepam 0.5–2 9 9 No 40 Estazolam* 1 10–24 <12 No 1–2 Flunitrazepam 0.25–0.3 18–24 4–6 Yes (36–200) 1 Loprazolam 0.5–4 6–12 <12 No 1–2 Lorazepam* IV 5–20 min 9–16 6–8 No 1 IM 20–30 min PO 0.5–1 Lormetazepam 0.5–2 10–12 <12 No 1–2 Nimetazepam 0.25–0.5 14–30 <12 No 5 Nitrazepam 0.5–5 16–48 <12 No 10 Premazepam 2 10–13 <12 No 3.75 Temazepam* 1.5 9–12 5–20 No 20 Long Acting Chlordiazepoxide* 2 5–30 5–30 Yes (36–200) 25 Clonazepam* 0.3–0.5 20–80 <12 No 0.5 Clorazepate* 1–2 48 8–24 Yes (36–200) 15 Cloxazolam 2–5 65 18–50 No 1–2 Diazepam* IV 1–5 min 20–50 IV 0.25–1 Yes (36–200) 10 PO 15–45 min   PO 12–24 PR 5–45 min Flurazepam* 0.5–1 2 12 Yes (50–100) 15–30 Flutoprazepam 0.5–2 60–90 24 Yes 2–3 Halazepam 1–3 — 12–24 Yes (30–100) 20–40 Ketazolam 2.5–3 30–100 12–24 Yes (36–200) 15–30 Medazepam — 36–150 10–12 Yes (36–200) 10 Nordazepam 2 40–50 12–14 Yes (50–120) 10 Phenazepam 1.5–4 60 12 Yes 1 Pinazepam 1–2 20–25 12–24 Yes (40–100) 20 Prazepam 2–6 40–80 12–24 Yes (36–200) 10–20 Quazepam* 0.5–2 27–41 12–24 Yes (28–80) 20 *Available in the United States. †After oral ingestion, unless otherwise specified. ‡Parent compound. self-poisoning found that temazepam was 10 times more toxic (fatal toxicity index) and 13 times more lethal (case fatality index) than diazepam.10 In the ED, parenteral administration of benzodiazepines may result in significant complications, particularly respiratory depression and hypotension, especially when combined with opioids or other sedatives. PHARMACOLOGY Benzodiazepines stimulate the α subunit of the postsynaptic γ-aminobutyric acid (GABA A) receptor in the CNS. Stimulation of this receptor affects the ligand-gated chloride channel on the cell membrane, Tintinalli_Sec15_p1187-1332.indd 1216 8/2/19 8:39 PM

ally when combined with opioids or other sedatives. PHARMACOLOGY Benzodiazepines stimulate the α subunit of the postsynaptic γ-aminobutyric acid (GABA A) receptor in the CNS. Stimulation of this receptor affects the ligand-gated chloride channel on the cell membrane, Tintinalli_Sec15_p1187-1332.indd 1216 8/2/19 8:39 PM CHAPTER 183: Benzodiazepines 1217 altering the transmembrane resting potential to below stimulation threshold and rendering the postsynaptic neuron less excitable. Stimulation of this GABA A receptor leads to inhibitory effects throughout the neuraxis, producing the typical clinical effects of sedation, anxiolysis, anticonvulsant activity, and striated muscle relaxation. In general, benzodiazepines are well absorbed from the GI tract. The onset of action after oral ingestion is limited more by the rate of absorption from the GI tract than by the relatively rapid passage from the bloodstream into the brain. With the exception of lorazepam and midazolam, IM injection of benzodiazepines results in unpredictable absorption. IV administration of midazolam and lorazepam has an onset of action in 1 to 5 minutes. Diazepam may be administered rec tally, and midazolam may be administered intranasally or intrabuccally, with variable rates of absorption by those routes. Benzodiazepines are relatively lipid soluble, with some variation among the agents. Increased lipid solubility is associated with more rapid diffusion across the blood–brain barrier. After single doses, the more highly lipophilic benzodiazepines have a shorter onset of action but also a shorter duration of activity. This short duration of activity occurs because of rapid egress of the drug from the brain and bloodstream into inactive tissue storage sites. For this reason, the serum halflife is not a good indicator of the duration of action in an acute ingestion. Benzodiazepine derivatives undergo hepatic metabolism through different pathways depending on the agent. Hepatic biotransformation occurs through either oxidation or conjugation; both pathways may be used by some derivatives. Oxidation often produces active metabolites that prolong the pharmacologic effects of the parent compounds. Oxidation is more susceptible to impairment by such factors as disease states (chronic liver disease), demographic characteristics (advanced age), and concurrent treatment with drugs that affect metabolism (estrogen, iso niazid, ethanol, ketoconazole, cimetidine, and phenytoin). Conjugation is a rapid process that generally produces inactive metabolites. Examples of agents that undergo conjugation primarily include lorazepam, oxaz epam, and temazepam. These agents may be safer in susceptible groups such as patients with hepatic dysfunction. There is conflicting evidence on how benzodiazepines affect fetal development. 11-13 In general, cohort studies have not found an increase in congenital malformations, whereas case-control studies show a small increase (especially for cleft lip and palate). This difference is ascribed to the higher sensitivity of case-control studies in identifying an association with specific conditions. The effect on fetal outcome of large doses of benzodiazepines taken for suicide attempts by pregnant women is not clear. Retrospective reviews of overdose with four different benzodiaz epines, albeit with relatively small numbers, did not find an increased incidence of congenital abnormalities in the offspring. 14-18 Nearly all benzodiazepines enter breast milk, and therefore, caution should be exercised in patients taking benzodiazepines. 11,12 Administration of benzodiazepines in the elderly or in patients with comorbid conditions (such as hepatic dysfunction) may be associated with more complications.

ies in the offspring. 14-18 Nearly all benzodiazepines enter breast milk, and therefore, caution should be exercised in patients taking benzodiazepines. 11,12 Administration of benzodiazepines in the elderly or in patients with comorbid conditions (such as hepatic dysfunction) may be associated with more complications. Those with hepatic dysfunction can have impaired metabolism, causing increased clinical effects. Elderly patients taking benzodiazepines are at increased risk for falls, cognitive impair ment, delirium, fractures, and motor vehicle accidents. 13,19 Drug–drug interactions with benzodiazepines occur mainly with drugs that affect the cytochrome P450 pathway , specifically CYP3A4 and CYP2C19. For example, drugs such as ketoconazole or cimetidine are CYP3A4 inhibitors and may increase benzodiazepine blood levels, increasing their duration of action and/or clinical effect. Benzodiaz epines themselves have not been implicated in affecting cytochrome P450 enzymes and, therefore, are unlikely to interfere with metabolism of other agents. CLINICAL FEATURES The clinical presentation of benzodiazepine intoxication is nonspecific and may be highly variable because of the frequent co-ingestion of other agents. Except for additive effects, drug interactions of benzodiazepines with other sedative-hypnotics are unusual. The predominant manifestations of benzodiazepines are neuro logic and are characterized by somnolence, dizziness, slurred speech, confusion, ataxia, incoordination, and general impairment of intellectual function. Prolonged coma is atypical and should prompt suspicion of intoxication with other agents or a nontoxicologic explanation. Neuro logic effects of benzodiazepines may be prolonged or enhanced in the elderly, the young, and in those with protein deficiency or hepatic disease. Paradoxical reactions, including excitement, anxiety, aggression, hostile behavior, rage, and delirium, have been reported but are quite uncommon. Paradoxical reactions may occur more with hyperactive children and in psychiatric patients. Benzodiazepines may have a dis inhibiting effect, which, in the presence of various extrinsic factors, can lead to such actions as aggressive or hostile behavior. Other effects that have been reported and that have unclear etiologies include headache, nausea, vomiting, chest pain, joint pain, diarrhea, and incontinence. Benzodiazepines may cause short-term anterograde amnesia; this effect may be desired, especially in procedural sedation. 13 Agents most often associated with anterograde amnesia are lorazepam, midazolam, and triazolam, although this may occur with the other benzodiazepines. Uncommonly, respiratory depression and hypotension may occur, generally with either parenteral administration or in the presence of co-ingestants. IV administration is more likely to cause serious cardio respiratory effects with rapid administration. In addition, the elderly and those with underlying cardiorespiratory disease are more susceptible to adverse effects of IV administration. Propylene glycol as a diluent in parenteral preparations of diaz epam and lorazepam may cause severe metabolic acidosis (lactic acidosis), nephrotoxicity, and hyperosmolar states when infused at doses >1 milligram/kg per day for an extended period of time. 20,21 During such treatment, an osmolar gap >10 is predictive of elevated propylene glycol concentrations. 21 Treatment of propylene toxicity is generally supportive but may require hemodialysis.22 Extrapyramidal reactions have been associated with the use of mid azolam. Various allergic, hepatotoxic, and hematologic reactions also have been reported, but they are infrequent.

ive of elevated propylene glycol concentrations. 21 Treatment of propylene toxicity is generally supportive but may require hemodialysis.22 Extrapyramidal reactions have been associated with the use of mid azolam. Various allergic, hepatotoxic, and hematologic reactions also have been reported, but they are infrequent. In general, benzodiaz epines have no long-term organ system toxicity other than that which can be ascribed to indirect effects from neurologic or cardiorespiratory depression. DIAGNOSIS Toxicologic testing in benzodiazepine ingestion is of limited value. Serum benzodiazepine levels do not correlate well with the clinical state, so serum level measurement is not routinely indicated. Qualitative testing with urine drug screens is typically designed to identify major metabolites of most benzodiazepines, such as oxazepam, temazepam, or nordiazepam, and not the parent compound. 23 Depending on the antibody specificity used in the immunoassay, a false-negative test can occur and is commonly seen with midazolam and flunitrazepam. A urine benzodiazepine screen can usually detect a short-acting agent (e.g., lorazepam) up to 3 days and a long-acting agent (e.g., diazepam) up to 30 days after ingestion. Thus, detection of a benzodiazepine agent taken in the recent past may not correctly identify the toxicologic cause of the patient’s current condition. False-positive benzodiazepine urine drug screens have been reported with oxaprozin and sertraline, although improved immunoassay techniques have reduced this poten tial interference. 24,25 TREATMENT  GENERAL MEASURES Benzodiazepines often are ingested with other agents, and the history is frequently inaccurate. Therefore, in patients with depressed or altered mental status, other metabolic and toxicologic possibilities should be considered (see Chapter 176, “General Management of Poisoned Patients”). Do not induce emesis in benzodiazepine overdose because mental status depression may develop and increase the risk for pulmonary aspiration. Activated charcoal binds benzodiazepines effectively and may be considered. Aspiration risk should be weighed against the benefits of treatment for an ingestion that rarely causes major morbidity in isolated overdose. The combination of rapid absorption and high level of protein bind ing render gastric lavage, elimination enhancement by forced diuresis, Tintinalli_Sec15_p1187-1332.indd 1217 8/2/19 8:39 PM

isk should be weighed against the benefits of treatment for an ingestion that rarely causes major morbidity in isolated overdose. The combination of rapid absorption and high level of protein bind ing render gastric lavage, elimination enhancement by forced diuresis, Tintinalli_Sec15_p1187-1332.indd 1217 8/2/19 8:39 PM 1218 SECTION 15: Toxicology TABLE 183-3 Clinical Features of Benzodiazepine Withdrawal Psychiatric Anxiety and nervousness* Restlessness and irritability* Insomnia and nightmares* Paranoia Hallucinations Delirium Neurologic Muscle twitching and tremors * Cognition and memory impairment* Perceptual distortions Hyperacusis and photophobia * Seizures* Autonomic Tachycardia* Hypertension Diaphoresis Nausea and vomiting Headache *Common features. hemodialysis, and hemoperfusion ineffective. Monitor neurologic and respiratory status and provide mechanical ventilation if necessary. Aspiration pneumonitis may be caused by severe respiratory and neurologic depression.  BENZODIAZEPINE ANTAGONIST Flumazenil is a unique selective antagonist of the central effects of benzodiazepines, although there have been inconclusive claims that it may be effective in reversing the neurologic toxicity from other drugs. Potential clinical applications include the reversal of coma in benzodiazepine overdose and reversal of iatrogenic benzodiazepine-induced sedation during procedural sedation. 23,27 Its use in benzodiazepine toxicity may obviate the need for tracheal intubation and respiratory support.28,29 However, some toxicologists advocate that flumazenil has limited utility in the ED, noting it is useful mainly in reversing the effects of shortacting benzodiazepines administered for diagnostic and therapeutic procedures. 30 Even in such cases, management is usually accomplished safely and easily by allowing the effects of the benzodiazepine to subside without antidotal administration. 29 Although the plasma elimination half-life of flumazenil is approximately 1 hour, its duration of action is variable and depends on the dose of flumazenil and the benzodiazepine administered. Recurrent benzodiazepine toxicity may result once the effects of flumazenil have worn off. 29 This is less likely for a benzodi azepine with a short duration of action, such as midazolam. The dose of flumazenil is 0.2 milligram IV , which can be repeated every minute, titrated according to response or to a total dose of 3 milligrams. Several considerations should limit the empiric administration of flumazenil to a poisoned patient ( Table 183-2). There is a higher inci dence of side effects, albeit generally minor (agitation, nausea, vomiting, abdominal pain), when flumazenil is administered to an unconscious patient presenting to the ED. 28,31 Of greater importance, generalized seizures have occurred in patients given flumazenil after co-ingestions of benzodiazepines and seizure-inducing agents, particularly cyclic antidepressants. 31,32 Seizure activity after flumazenil administration also has occurred in patients physically dependent on benzodiazepines and in patients receiving benzodiazepines for control of a seizure disorder. The putative explanation for this convulsive activity is either the reversal of the cerebroprotective and anticonvulsive effects of benzodiazepines or the precipitation of a benzodiazepine withdrawal syndrome. Flumazenil-precipitated seizures in patients who are chronically tak ing benzodiazepines should be treated aggressively with another GABA receptor agonist because the benzodiazepine site on the receptor is antagonized. Anticonvulsants such as phenobarbital or propofol are recommended for flumazenil-induced seizures. Careful monitoring of the patient’s respiratory and mental status is necessary during treatment and may require securing the airway.

er GABA receptor agonist because the benzodiazepine site on the receptor is antagonized. Anticonvulsants such as phenobarbital or propofol are recommended for flumazenil-induced seizures. Careful monitoring of the patient’s respiratory and mental status is necessary during treatment and may require securing the airway. Another reason to avoid empiric administration of flumazenil in overdose patients is that the history is often unreliable or unavailable. The apparent overdose may be caused instead by an intracranial mass lesion. Flumazenil is contraindicated in patients with a suspected elevation of intracranial pressure, such as in severe head injury, due to its adverse effect on cerebral hemodynamics. DISPOSITION AND FOLLOW-UP Indications for observation or hospital admission include significant alterations in mental status, respiratory depression, and hypotension. If mental status depression persists or is profound, other agents or conditions must be considered. Although many clinicians use the 6-hour principle for observation of stable patients after ingestion, there is insufficient evidence to recommend a specific duration for an appropriate ED observation period. BENZODIAZEPINE WITHDRAWAL Benzodiazepine dependence can develop after long-term use—usually 6 to 12 months—and typically develops without tolerance (e.g., the absence of needing to increase dose to obtain the same effect). 33 Such patients are at risk for withdrawal upon sudden cessation. Withdrawal symptoms usually start within 2 to 3 days for short-acting benzodiaz epines and 5 to 10 days for longer-acting ones. Benzodiazepine with drawal is characterized by nervous system hyperactivity ( Table 183-3). Seizures are common in benzodiazepine withdrawal upon sudden discontinuation. Withdrawal symptoms tend to be more severe with short-acting agents. Alprazolam withdrawal has some unique features compared with other benzodiazepine withdrawal syndromes. 34 Delirium and psychosis are more common, and hyperadrenergic states characterized by intermittent episodes of hypertension with sinus tachycardia have been reported. To prevent withdrawal, benzodiazepine dosing should be slowly reduced over 4 to 6 weeks, or even longer when a patient is tolerant to a long-acting agent such as diazepam. 33 Dose reduction is guided by the patient’ s ability to tolerate symptoms. Treatment of benzodiazepine withdrawal can obviously be done by reinstituting the drug and then embarking on a slow taper. Most ben zodiazepines can be substituted by others for treatment of withdrawal symptoms with the apparent exception of alprazolam withdrawal, in which cases clonazepam is recommended since lorazepam, diazepam, and chlordiazepoxide are ineffective. 34 Alternative nonbenzodiazepine treatment includes antidepressants (e.g., trazodone), mood stabilizers (e.g., carbamazepine), anxiolytic agents (e.g., pregabalin or gabapentin), and β-blockers (e.g., propranolol). 35,36 Antihistaminic agents may be useful, and diphenhydramine, hydroxyzine, or promethazine have been effective. Patients with severe benzodiazepine withdrawal (i.e., experiencing seizures, delirium, and psychosis) should be admitted for stabilization on appropriate medications. 37,38 For patients with less severe withdrawal, reinstituting the benzodiazepine is recommended, with a suggestion to switch to a long-acting agent at an equivalent dose. 38 Outpatient followup with taper can then be done. REFERENCES The complete reference list is available online at www.TintinalliEM.com.

medications. 37,38 For patients with less severe withdrawal, reinstituting the benzodiazepine is recommended, with a suggestion to switch to a long-acting agent at an equivalent dose. 38 Outpatient followup with taper can then be done. REFERENCES The complete reference list is available online at www.TintinalliEM.com. TABLE 183-2 Contraindications to Flumazenil •   Overdose of unknown agents •   Suspected or known physical dependence on benzodiazepines •   Suspected cyclic antidepressant overdose •   Co-ingestion of seizure-inducing agents •   Known seizure disorder •   Suspected increased intracranial pressure Tintinalli_Sec15_p1187-1332.indd 1218 8/2/19 8:39 PM