Of the benzodiazepines, lorazepam is the agent with the highest level of guideline and literature support for acute use and is considered first-line therapy in the treatment of undifferentiated agitation. Much of this preference is due to its availability for administration by the PO, IM, PR, or IV route; relatively quick onset of action; and lack of active hepatic metabolites. Benzodiazepines bind to benzodiazepine-1 receptors on the postsynaptic γ-aminobutyric-A receptor, which results in increased influx of chloride ions into the postsynaptic neuron, leading to hypoexcitability and neuronal stabilization.13
The initial dose of lorazepam for acute agitation is 2 milligrams, with repeated dosing, if needed, given at least 30 minutes after the initial dose. Cumulative studied dosage is 4 milligrams over 2 to 4 hours; however, dosage regimens of up to 8 milligrams have been described.14-16 Onset of action is 0.5 to 1 hour, with a duration of 6 to 8 hours and a terminal half-life of 12.9 hours in adults that is extended to 15.9 hours in the elderly and up to 72 hours in patients with renal failure.
Lorazepam is effective in both undifferentiated and psychotic agitation, and 2 milligrams may be as effective 5 milligrams of haloperidol, with additive benefits when given in combination with other agents (except olanzapine).5,14,17 The most common adverse effect of lorazepam or other benzodiazepines is sedation, and sedation is greater than that with haloperidol alone.5,14 Lorazepam can cause respiratory depression and hypotension, particularly with repeated and high-dose administration. Another notable adverse effect is paradoxical agitation, or activation or worsening of confusion, most commonly seen in patients with delirium and in the elderly.
Typical, or First-Generation, Antipsychotics
Typical antipsychotics are also called first-generation or conventional antipsychotics, classic neuroleptics, or major tranquilizers. This class of drugs blocks dopamine receptors and is strongly associated with extrapyramidal symptoms, such as dystonias, akathisia or restlessness, and parkinsonism, and anticholinergic blockade (dry mouth, hypotension, glaucoma exacerbation, delirium). Typical antipsychotics are classified as low, intermediate, or high potency when compared to 100 milligrams of chlorpromazine (Thorazine®). Low-potency typical antipsychotics tend to be more sedating and are associated with hypotension, dizziness, and anticholinergic symptoms. High-potency medications are less sedating but are associated with extrapyramidal symptoms (Table 283-3).
Table 283-3 Potency of Typical Antipsychotics Commonly Used for Agitation |Favorite Table|Download (.pdf)
Table 283-3 Potency of Typical Antipsychotics Commonly Used for Agitation
|Generic Name||Brand Name||D2 Receptor Potency||FDA Warning or Concern||Available Routes of Administration|
|Chlorpromazine||Thorazine®||Low||QTc prolongation||PO, IM|
|Haloperidol||Haldol®||High||QTc prolongation with high-dose or IV administration||PO, IM, IV|
|Droperidol||Inapsine®||High||QTc prolongation, even with no risk factors Not approved by FDA for treatment of agitation||PO, IM, IV|
Agents commonly used for acute agitation within this class include haloperidol, fluphenazine, and chlorpromazine because these agents are available in multiple dosage forms and have decades of clinical and anecdotal data supporting their efficacy. Droperidol has historically been commonly used for agitation; however, U.S. Food and Drug Administration concerns of QTc prolongation have limited its use for this purpose.
Adverse effects limiting the use of these medications in acute agitation include sedation, hypotension, risk of extrapyramidal symptoms, and QTc prolongation and the risk of torsades de pointes. While all antipsychotics can increase the QTc interval and risk of torsades de pointes, several agents within this first-generation subclass have been implicated for adverse outcomes. Among antipsychotics used for acute agitation, haloperidol and droperidol carry additional Food and Drug Administration warnings regarding QTc prolongation, torsades de pointes, and sudden cardiac death.18,19
Neuroleptic malignant syndrome, though rare, is a potentially life-threatening adverse effect that consists of a constellation of signs including altered mental status, hyperthermia, muscular rigidity, autonomic instability, and elevated creatinine phosphokinase. Contributing factors for neuroleptic malignant syndrome may include high dose, rapid dose escalation, use of a high-potency first-generation agent, history of previous neuromuscular malignant syndrome, agitation, or dehydration.20
Common extrapyramidal symptoms encountered with the acute administration of first-generation agents include akathisia and the parkinsonian symptoms of tremor and gait disturbances. Acute dystonias, which occur less frequently but can be severe, include torticollis, laryngeal spasm, and oculogyric crisis. Acute dystonia is associated more frequently with the high-potency agents (e.g., fluphenazine, haloperidol, and droperidol). The mechanism of extrapyramidal symptoms is thought to be related to secondary acetylcholine dysregulation in response to decreased dopamine in the nigrostriatal pathway. Treat acute dystonias with anticholinergic agents such as IM or IV diphenhydramine (25 to 50 milligrams) or benztropine (2 milligrams). Coadministration of these agents with a typical IM antipsychotic to prevent dystonia and other extrapyramidal symptoms is also common practice. Be aware that diphenhydramine and benztropine carry their own risks of adverse reactions including sedation, constipation, and blurred vision.
Despite strong clinical evidence supporting efficacy in acute agitation, droperidol is no longer U.S. FDA–approved for this use.18 The FDA warning includes reports of death from QTc prolongation even with use at low dosage and in patients with no cardiac risk factors. These risks led to removal of the drug from the European markets. Droperidol is still available in the United States and is Food and Drug Administration–approved for perioperative nausea and vomiting and is to be used only when other treatment methods fail. The maximum initial dosage is 2.5 milligrams given IV or IM, with repeat doses of 1.25 milligrams given until desired effect is achieved.
Haloperidol also carries an additional warning from the U.S. FDA regarding QTc prolongation, specifically related to IV administration, and by any route at dosages higher than recommended,21 most commonly defined as >35 milligrams/d or single doses of 20 milligrams or greater. Data supporting this warning include 73 cases of torsades de pointes, including 11 fatalities.19 It is also important to note that, while used in common practice, haloperidol is not Food and Drug Administration–approved for IV administration. If used IV, doses of 2 to 10 milligrams have been studied, with repeat dosing every 15 to 30 minutes as needed to achieve calming effects, and subsequent administration of 25% of the required bolus dosing. Use the lowest effective single and cumulative dose. Continuous cardiac monitoring should be maintained after IV dosing.
IM haloperidol is often used for acute agitation and is considered second only to lorazepam as standard-of-care therapy.22 Doses between 2.5 and 10 milligrams have been evaluated in clinical trials as either the primary medication or active comparator, with the most common dosage of 5 milligrams initially, with repeated dosing in 1 to 2 hours as needed. Coadministration with lorazepam has additive calming effects but a higher incidence of sedation.
Fluphenazine IM is an additional injectable, high-potency, first-generation antipsychotic option. Its efficacy is generally considered interchangeable with haloperidol.23 The average dosing of IM fluphenazine is 2.5 to 5 milligrams per injection, with a recommended dosing range of 1.25 to 10 milligrams per injection.22
Chlorpromazine, a low-potency, first-generation antipsychotic agent, may also be administered PO or IM at doses of 12.5 to 25 milligrams initially, with repeat doses of 25 to 50 milligrams given if necessary to calm agitation.24 Chlorpromazine may also be given IV, although this is seldom done in clinical practice for the treatment of acute agitation. While this agent does not carry a formal bolded U.S. FDA warning, its label still advises cardiac monitoring, because QTc prolongation is a concern.25 Additionally, frequent monitoring of vital signs and orthostatic blood pressure is recommended with acute administration because hypotension, tachycardia, and sedation are common and can be profound. These adverse effects limit the usefulness of this agent in acute agitation.
Atypical, or Second-Generation, Antipsychotics
Atypical antipsychotics are also called second-generation antipsychotics. These agents block dopamine receptors, but their precise action is not known. Atypical antipsychotics are less likely than typical antipsychotics to cause extrapyramidal symptoms or neuroleptic malignant syndrome and have lower rates of tardive dyskinesia. These features have served to propel them to first-line therapy within the field of psychiatry. Another advantage of atypical antipsychotics is the decreased need for coadministration of medications to combat adverse anticholinergic effects. Less need for concomitant benzodiazepines is also an advantage, especially in the elderly.
Several agents in this class can be given orally or IM. Oral disintegrating tablets of olanzapine and risperidone, oral solution of risperidone, and IM preparations of olanzapine, ziprasidone, and aripiprazole have all been studied specifically for use in acute agitation. Additionally, quetiapine is effective for agitation in delirious critical care patients.26 Table 283-4 outlines dosage forms for the available options in this class.
Table 283-4 Dosage Form Availability for Selected Antipsychotic Agents |Favorite Table|Download (.pdf)
Table 283-4 Dosage Form Availability for Selected Antipsychotic Agents
|Antipsychotic||Oral Solution||Orally Disintegrating Tablet||IM Injection||Tablets or Capsules||IV|
Risperidone (Risperdal®) has been studied in both ED and psychiatric settings for the treatment of acute agitation. It is not available as an IM preparation, but the oral liquid or rapid oral dispersible tablet (M-Tab®) is comparable to IM haloperidol with and without concomitant lorazepam. It is effective beginning 30 to 60 minutes after administration and has lower rates of extrapyramidal symptoms and sedation than haloperidol.6,7 It also has comparable efficacy to olanzapine PO and IM, but with a longer time to onset of effect.8,27
Olanzapine (Zyprexa®) is available as a rapidly dissolving oral tablet (Zydis®) and an IM preparation. It is as effective as haloperidol or risperidone, with less extrapyramidal symptoms than haloperidol, but with more hypotension than risperidone.8,27,28 Olanzapine given either orally or IM has a faster onset of action than IM haloperidol or oral risperidone, with effect beginning within 15 minutes after administration.8
Hypotension with IM olanzapine is a serious adverse effect and has led to fatalities in patients coadministered benzodiazepines or chlorpromazine.29 The product information for olanzapine warns against coadministration with benzodiazepines, because life-threatening sedation and hypotension can occur 1 hour after administration of lorazepam 2 milligrams IM.30 While recommendations differ, it is best to wait 1 to 2 hours between administering benzodiazepines with IM olanzapine, and if coadministering with oral olanzapine, monitor blood pressure frequently.
Ziprasidone (Geodon®) is available in an IM preparation and has been compared with haloperidol for the treatment of patients with bipolar disorder or schizophrenia. Doses of 20 milligrams IM are comparable to 5 milligrams of IM haloperidol.31,32 A potential barrier to use for ziprasidone is its effects on QTc prolongation. In a direct-comparative study, IM ziprasidone was found to increase QTc approximately 9 to 14 milliseconds longer than four other antipsychotic agents, including haloperidol.33 As a result, ziprasidone is contraindicated in patients with a known history of QTc prolongation, recent myocardial infarction, or uncompensated heart failure, or who are taking other medications known to prolong the QTc interval. If possible, magnesium and potassium levels should be obtained and corrected prior to administration of ziprasidone, and the drug should be discontinued in patients with a QTc >500 milliseconds.31-33 This warning has limited its use for acute agitation in the ED.
IM aripiprazole (Abilify®) is effective for acute agitation when compared with IM haloperidol, with onset of response within 1 hour. Patients treated with aripiprazole had lower rates of extrapyramidal symptoms when compared with patients treated with haloperidol, but a higher incidence of headache.34,35 No studies have researched the utility of oral aripiprazole in the management of acute agitation. The dose of IM aripiprazole is 9.75 milligrams per injection, with a maximum dose of 30 milligrams per day. Aripiprazole is not recommended for use in children or adolescents with acute agitation due to an increased rate of akathisia in this patient group.36
Quetiapine is an atypical antipsychotic that has shown benefits for agitation associated with delirium in a critical care population.37 Dosing ranges from 12.5 to 200 milligrams twice daily, and the most common adverse effects include somnolence and hypotension. Quetiapine has not been studied specifically for the treatment of undifferentiated or psychotic agitation in adults. Dosage forms are limited to oral tablets.
The most commonly used antihistamines for the treatment of agitation include diphenhydramine and hydroxyzine. Diphenhydramine is available in both liquid and parenteral dosage forms, but carries a higher rate of sedation and anticholinergic burden than hydroxyzine or other agents for agitation. Efficacy most supports the use of antihistamines in the treatment of anxiety in pediatric and adolescent patients, but antihistamines may be used as a single agent or adjunctive therapy in a generally agitated patient, particularly if the symptoms are anxiety driven.38
Anticonvulsants have been studied as agents for agitation, particularly in the acutely aggressive patient, as well as for anxiety. Gabapentin has shown some efficacy as adjunctive therapy of agitation in patients with major mental illnesses,39 as well as some benefits in anxiety or agitation associated with dementia. Overall efficacy, however, is considered to be modest.40 In patients with bipolar disorder, it is reasonable to consider valproic acid/divalproex as a treatment option for agitation because it can be "loaded" (i.e., dosed in a fashion that promotes efficacy for bipolar agitation quickly) and often produces calm and sedation as adverse effects.41 Other anticonvulsants indicated for bipolar disorder such as carbamazepine or lamotrigine must be titrated to effect to avoid Stevens-Johnson syndrome and other adverse effects, therefore limiting their use in acute agitation associated with bipolar disorder. The same limitation applies for lithium as well, rendering it ineffective in acute symptom management.
Clonidine, a centrally acting α2-agonist, has historically been tried to combat acute agitation. Unfortunately, hypotension and bradycardia, along with mixed data for efficacy in this patient group, limit its use. However, the sedative agent dexmedetomidine, also an α2-agonist, has gained attention for use in acute agitation in the intensive care unit setting.42 It is currently under investigation for use in alcohol detoxification in intensive care unit patients as well. It is further hypothesized that the potential benefits of quetiapine and risperidone may be, in part, due to their alpha-agonist effects.37 Although clonidine and dexmedetomidine are potentially of benefit, the current literature supports limiting them to adjunctive or alternative strategies.