Past history and a differential diagnosis will help guide the treatment of acute agitation. A past history of response to an agent is not a guarantee of future performance but should be strongly considered, barring any new information that would contraindicate its use. One possible source of confusion is the multifactorial etiology for agitated behavior. This requires assessment of the patient for possible comorbidities, such as somatic conditions or other psychiatric conditions, or adverse effects of medications, such as akathisia. For example, co-occurring substance abuse, depen-dence, and intoxication increase the risk of violent behavior (2). The presence of hallucinations and delusions, neuropsychiatric deficits and poor impulse control, underlying character pathology, and a chaotic environment increase risk and further complicate both assessment and treatment (3). Potential somatic conditions must be ruled out, especially in a patient who ordinarily has not been aggressive in the past.

Special consideration needs to be made for patients who may be in acute alcohol or sedative withdrawal. Sedating agents that reduce the seizure threshold, such as antipsychotics, may render the situation worse. Agents that are cross-tolerant with alcohol are preferred—not only are they sedating, but if the agitation is directly related to a withdrawal state, agents will treat the source of the abnormal behavior. The use of amobarbital (Amytal) entails the risk of respiratory depression and has essentially been supplanted by the availability of lorazepam. Other benzodiazepines, such as diazepam or chlordiazepoxide, although often used orally, are not reliably absorbed when administered intramuscularly. Benzodiazepines also can result in a decrease in respiratory drive, particularly in patients with a history of lung disease or sleep apnea, but they are otherwise relatively well tolerated. Advantages for lorazepam in particular include its relatively short half-life and lack of active metabolites, making it the dominant choice in patients whose agitation is secondary to acute alcohol withdrawal. Disadvantages include the potential for behavioral disinhibition, which, although uncommon, may paradoxically increase agitation (4). A disadvantage with using intramuscular lorazepam in a patient with a core psychotic illness is the lack of substantial antipsychotic effect. Long-term use of a benzodiazepine will also result in physiologic tolerance, leading to potential rebound anxiety or agitation in between doses or when doses are missed. Abrupt withdrawal of benzodiazepines is associated with a risk for epileptic seizures.

The alternatives to using benzodiazepines are the antipsychotics, many of which are available in intramuscular form. Clinicians have many years of experience using first-generation antipsychotics. They universally cause sedation given a high enough dose, and many different intramuscular preparations are available. Low-potency agents such as chlorpromazine can be contrasted with high-potency agents such as haloperidol in terms of propensity for sedation, postural hypotension, anticholinergic effects, and decrease in the seizure threshold. A considerable disadvantage of these agents is their risk for causing extrapyramidal side effects, including akathisia, which can be confused with the underlying agitation, and acute dystonia, which will lead to substantial problems in terms of convincing the patient to continue with medication. Commonly used is a combination of haloperidol and lorazepam, supported by a double-blind, randomized clinical trial that compared intramuscular haloperidol 5 mg, intramuscular lorazepam 2 mg, or both in combination in 98 psychotic, agitated, and aggressive patients (73 men and 25 women) prospectively enrolled during an 18-month period in emergency departments in five university or general hospitals (5). Patients in each treatment group received one to six injections of the same study drug within 12 hours, based on clinical need. They were evaluated hourly after the first injection until at least 12 hours after the last injection. Effective symptom reduction was achieved in each treatment group, with significant mean decreases from baseline at every hourly Agitated Behavior Scale evaluation (a 14-item observational scale in which each item is rated as either absent, slight, moderate, or extreme), but the patients assigned to combination treatment experienced more rapid tranquilization. Side effects did not differ significantly among treatment groups, although patients receiving haloperidol alone tended to have more extrapyramidal system symptoms.