Time to retire haloperidol?

Benzodiazepines. Lorazepam offers an attractive alternative to haloperidol without the risk of EPS.^2,4,8 However, lorazepam alone may be perceived as less efficacious than a haloperidol “cocktail” because it represents less overall medication. Some evidence has suggested that lorazepam, 4 mg, might be the most appropriate dose, although it has only rarely been studied in clinical trials of acute agitation.³ Midazolam is another IM benzodiazepine alternative to IM haloperidol that has been shown to achieve more rapid sedation than either haloperidol or lorazepam,^44,45 although it can cause substantial anterograde amnesia and also has an FDA black-box warning for respiratory depression associated with IV administration.

Respiratory depression is frequently cited as an argument against using lorazepam for agitation, as if the therapeutic window is extremely narrow with ineffectiveness at 2 mg, but potential lethality beyond that dose. In fact, serious respiratory depression with lorazepam is unlikely in the absence of chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, or concomitant alcohol or other sedative use.⁴⁶ Case reports have documented therapeutic lorazepam dosing of 2 to 4 mg every 2 hours up to 20 to 30 mg/d in patients with manic agitation.⁴⁷ Even in patients with COPD, significant respiratory depression tends not to occur at doses <8 mg.⁴⁸ A more evidence-based concern about lorazepam dosing is that 2 mg might be ineffective in patients with established tolerance. For example, 1 report described a patient in acute alcohol withdrawal who required dosing lorazepam to 1,600 mg within 24 hours.⁴⁹ Collectively, these reports suggest that lorazepam has a much wider therapeutic window than is typically perceived, and that dosing with 3 to 4 mg IM is a reasonable option for agitation when 2 mg is likely to be inadequate.

Paradoxical disinhibition is another concern that might prevent benzodiazepines from being used alone as a first-line intervention for emergency treatment of agitation. However, similar to respiratory depression, this adverse event is relatively rare and tends to occur in children and geriatric patients, individuals intoxicated with alcohol or other sedatives, and patients with brain injury, developmental delay, or dementia.^23,46 Although exacerbation of aggression has not been demonstrated in the RCTs examining benzodiazepines for agitation reviewed above, based on other research, some clinicians have expressed concerns about the potential for benzodiazepines to exacerbate aggression in patients with impulse control disorders and a history of violent behavior.⁵⁰

The 2005 Expert Consensus Panel for Behavioral Emergencies⁵¹ recommended the use of lorazepam alone over haloperidol for agitation for patients for whom the diagnosis is unknown or includes the following:

• stimulant intoxication
• personality disorder
• comorbid obesity
• comorbid cardiac arrhythmia
• a history of akathisia and other EPS
• a history of amenorrhea/galactorrhea
• a history of seizures.

In surveys, patients have ranked lorazepam as the preferred medication for emergency agitation, whereas haloperidol was ranked as one of the least-preferred options.^51,52

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