Pharmacologic Treatment

Pharmacologic treatment options are based on current understanding of agitation pathophysiology. The main neurochemical considerations include dopamine and norepinephrine hyperactivity and serotonin and GABA hypoactivity.⁴ As such, antipsychotics and benzodiazepines have emerged as the main evidence-based options. Oral medications are considered first in the treatment of mild to moderate agitation, while severe agitation often requires rapid improvement with parenteral medication to calm the person, assist them in regaining self-control, and quell the risk of harm.^18-23 In rare cases of extremely severe agitation, quick acting parenteral medications have been used for sedation when a less invasive outcome isn't sufficient to prevent harm to self or others. Tables 2 and 3 summarize medication options recommended by existing guidelines and expert consensus.^18-37

TABLE 2 Oral medication options recommended for the management of mild to moderate agitation and aggression in adults^18-37

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TABLE 3 Parenteral and inhaled medication options recommended for the management of moderate to severe agitation and aggression in adults^18-37

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Antipsychotics

Antipsychotics are the preferred initial treatment choice in the presence of a psychiatric etiology or CNS depressant intoxication. Recommended antipsychotics include haloperidol, droperidol, loxapine, olanzapine, ziprasidone, aripiprazole, asenapine, risperidone, and quetiapine with second-generation antipsychotics (SGAs) preferred to first-generation antipsychotics.^18-23 Chlorpromazine has historically been used for agitation in single oral or IM doses of 25 to 50 mg, repeated at 1 hour if needed and then administered every 4 to 6 hours up to a recommended maximum of 200 mg/d. Its use is limited by lack of primary evidence, IM availability in a glass ampule requiring use of a filter needle, significant risk of hypotension, sedation, decreased seizure threshold, and slow time to effect.^18,21,37

Fluphenazine has also been used in IM doses of 1.25 to 5 mg administered every 6 to 8 hours up to a maximum of 10 mg/d because of availability of quick-acting formulations, but the IM formulation is only supplied in multidose vials thus limiting its ability to be stored in certain automated dispensing machines for quick access. Despite possibility of chlorpromazine and fluphenazine availability in times of drug shortages of more evidenced-based options, their use carries feasibility and safety issues and is not supported in guidelines.^18-23

Oral Antipsychotics

There have been few studies evaluating oral antipsychotics for agitation. Existing data are reviewed here. Oral haloperidol has evidence for reducing agitation, but data are limited by small sample size and uncontrolled use of concurrent IM lorazepam.^20,21,38

Oral haloperidol was also compared to various oral SGAs, including risperidone, quetiapine, olanzapine, and aripiprazole. Studies^39-41 reveal similar efficacy between groups, with more extrapyramidal symptoms (EPS) observed in the haloperidol group. Of note, oral ziprasidone is not recommended because of lack of primary evidence in agitation treatment as well as practicality issues including slow peak effect time of 6 to 8 hours and need to administer with food. As above, aripiprazole is recommended as an evidenced-based option for oral treatment of acute agitation, but, like ziprasidone, clinicians should consider the time to peak effect of 3 to 5 hours.

Alternative formulations including sublingual asenapine, and orally disintegrating tablet formulations of olanzapine and risperidone were also studied. Asenapine is the only sublingual option with support from a small randomized controlled trial showing significant reduction in agitation at 2 hours as compared with placebo.⁴² Finally, data from open label trials^43,44 supports the efficacy of olanzapine and risperidone orally disintegrating tablet formulations similar to that of traditional oral antipsychotic formulations.

Parenteral Antipsychotics

IM haloperidol has been used for the management of severe agitation since the 1950s. Its efficacy was demonstrated in multiple randomized double-blind studies^20,21,45-47 with data indicating comparable efficacy to IM lorazepam, IM olanzapine, and IM ziprasidone. However, evidence shows IM haloperidol monotherapy carries a greater risk of EPS compared to IM SGAs, and guidelines recommend combination with a benzodiazepine or promethazine over its use alone.^20,21,46 Of note, more recent guidance from 2020 recommends the combination of haloperidol with diphenhydramine for the prevention of EPS.¹⁹

IM droperidol use has fluctuated over the years because of supply issues and a 2001 boxed warning for QTc prolongation.⁴⁸ There is evidence to support comparable efficacy to IM haloperidol but with less need for redosing. However, safety concerns for hypotension were more frequent with droperidol.^20,49 Droperidol's cardiac safety has been further assessed with data from a large prospective observational study showing 1.3% of participants experienced QTc prolongation but no cases of torsade de pointes were observed. These findings are limited by uncontrolled use of either IM or IV droperidol as well as concurrent QTc prolonging medications.⁵⁰ Finally, a Cochrane review⁵¹ published in 2016 determined parenteral droperidol to be safe and effective in the treatment of acute agitation.

There are 2 SGAs, olanzapine and ziprasidone, with IM formulations indicated for the management of agitation. Ziprasidone was FDA-approved in 2002 with double-blind randomized controlled trial support for use.⁵² Furthermore, IM ziprasidone has been shown to be at least as effective, if not more effective than IM haloperidol in some studies, with similar risk for QTc prolongation but less EPS.^53-56

Olanzapine became available for IM use in 2004 and is supported by data from randomized controlled trials and a meta-analysis concluding it as a safe and effective option with comparable efficacy but less EPS than IM haloperidol.^3,57 It was also comparable in efficacy to haloperidol/promethazine and haloperidol/benzodiazepine combinations. Data^58-61 suggest more frequent need for redosing in IM olanzapine groups, which raised concern for respiratory suppression. A 2011 observational study⁶² investigating haloperidol, olanzapine, and ziprasidone revealed similar lengths of stay among these IM formulations.

There are 3 IV antipsychotic options that include droperidol, haloperidol, and olanzapine. However, these medications have been shown to produce a main outcome of sedation versus calming. IV droperidol appears to have more evidence versus haloperidol, but neither were studied in a well-designed trial and data were not controlled for route of administration.^51,63,64 IV olanzapine was shown to be effective for sedation in ED settings but with significant risk of adverse respiratory events.^65,66 In conclusion, IV droperidol and olanzapine are recommended as last-line medication options for severe agitation and aggression requiring rapid sedation. The concerns for cardiac and respiratory safety necessitate electrocardiogram monitoring and use only in settings with resuscitation capacity, resulting in some hospitals restricting droperidol and olanzapine to IM use only.²⁰

Inhaled Antipsychotic

Inhaled loxapine was FDA-approved in 2012 with data^20,67 showing significant improvement in agitation scores at 20 minutes lasting until 2 hours posttreatment compared to placebo but with greater frequency of side effects including altered taste and throat irritation.

A recent randomized trial⁶⁸ comparing inhaled loxapine to IM aripiprazole concluded that inhaled loxapine resulted in quicker onset of effects. Of note, IM aripiprazole is not available in the United States and these data may not be extrapolated to comparisons with other IM antipsychotic injections because of pharmacokinetic differences. Inhaled loxapine is to be used with a patient's cooperation under Risk Evaluation and Mitigation Strategies guidance, and its use is further limited by high cost. It is contraindicated in certain respiratory conditions and may only be used in settings in which staff monitor patients with chest auscultation every 15 minutes for 1 hour and have a short-acting beta-agonist bronchodilator available for rescue use.²⁷

In conclusion, oral SGAs and haloperidol/lorazepam combinations are appropriate noninvasive options for mild to moderate agitation. Unfortunately, as seen in our clinical case, the window of opportunity for offering oral medication to a patient with agitation closes if timely de-escalation strategies are not employed. Therefore, we are left with few options to manage severe agitation outside of invasive medications. If agitation does progress to severe levels with imminent risk of harm, IM olanzapine, ziprasidone or haloperidol/lorazepam combinations are reasonable options while weighing risks of hypotension, metabolic complications, QTc prolongation, and EPS.

Benzodiazepines

Benzodiazepine monotherapy is recommended as the initial treatment choice in the presence of stimulant intoxication or unknown etiology.¹⁸ Lorazepam and midazolam have emerged as evidence-based options and have desirable pharmacokinetic properties, including reliable absorption, rapid onset of action, and minimal accumulation of drug. Although diazepam is used, this practice is not supported by guidelines because of limited evidence, risk of drug accumulation with oral and IM administration, erratic absorption, and likelihood of injection site pain with IM administration.^20,37

Overall, there is less evidence to support the use of oral monotherapy with benzodiazepines as compared to oral SGA monotherapy. Recommendations are mainly limited to lorazepam and based on a small study²⁰ that revealed comparable reduction in agitation to haloperidol. Data were not controlled for redosing and route of administration.⁶⁹ Based on available evidence and favorable pharmacologic properties, oral lorazepam monotherapy is regarded as an option for the management of acute agitation and aggression when the risks of an antipsychotic are unacceptable, as is the case in stimulant intoxication.

There have been relatively limited studies published supporting the use of IM benzodiazepines, but data^20,70 appear more robust for lorazepam and midazolam as compared with other benzodiazepines. Specifically, IM lorazepam revealed a similar reduction in agitation scores as compared to IM haloperidol in 2 randomized controlled trials but redosing was not controlled.^20,46,69 IM midazolam has shown a quicker onset and shorter duration of action as compared with other IM options including lorazepam, haloperidol, and haloperidol/promethazine combination.^47,71 However, the short duration of action was highlighted as problematic in a study⁷² that showed more patients in the midazolam group with agitation at 45 minutes posttreatment as compared to ziprasidone and droperidol.

IV benzodiazepine formulations include lorazepam and midazolam and have been used in practice for the main therapeutic effect of sedation as opposed to calming. IV lorazepam monotherapy and IV midazolam monotherapy are considered comparable in effect to IV droperidol, but with more need for redosing in benzodiazepine groups.^63,73,74 Of note, the midazolam group did experience more frequent respiratory suppression as compared to droperidol.⁷³ Based on this limited data and CNS depressant potential, IV lorazepam and midazolam are reserved for last-line use for rapid sedation in severe agitation and aggression in situations where antipsychotic risks are unacceptable and only in settings with resuscitation capacity.

Medication Combinations

Approximately 25% of patients don't respond to initial treatment.²⁰ Therefore, various combination regimens have been studied. Oral risperidone/lorazepam and oral haloperidol/lorazepam combinations are considered safe and effective for mild to moderate agitation.^38,69,75,76 For moderate to severe agitation, the IM haloperidol/lorazepam combination is considered more effective than either drug alone and with less risk of EPS versus haloperidol monotherapy.^70,77,78 The haloperidol/promethazine combination is also considered more effective than haloperidol alone, but parenteral promethazine use is discouraged because of its irritant-like properties, especially when used intravenously.^79,80 Benztropine has been used to treat EPS, namely acute dystonia, but guidelines do not recommend this as prophylaxis in combination with haloperidol for the treatment of acute agitation.^18-23,37 Lastly, IM haloperidol combinations have been largely regarded as comparable to IM olanzapine monotherapy.^59-61,81 However, a Cochrane review⁵⁸ concluded the haloperidol/promethazine combination resulted in less need for redosing as compared with olanzapine.

As seen in the patient case, H.N.'s agitation progressed to a severe level requiring administration of parenteral medication to reestablish safety. Haloperidol was chosen and administered with lorazepam, which was appropriate to minimize risk of EPS. Other options would have been appropriate as well, such as IM olanzapine or ziprasidone monotherapy.

Other Medications

Two alternative parenteral medications used for sedation in severe agitation include ketamine and dexmedetomidine. IM or IV ketamine is considered to have superior sedation with quicker onset as compared to parenteral haloperidol, midazolam, and lorazepam in prospective observational and retrospective studies.⁸² However, ketamine use carries the risk of tachycardia, hypertension, and need for intubation and is typically restricted to ED or intensive care unit settings in patients with extreme agitation unresponsive to benzodiazepines and/or antipsychotics.^83,84

Dexmedetomidine is considered a superior IV option for sedation in medical intensive care unit settings but is not recommended for use in the ED because of significant risk for hypotension.²⁰ Both parenteral ketamine and dexmedetomidine cause rapid sedation versus calming. Because of this, they are rarely recommended for the routine management of acute agitation and aggression, but they are valuable options for severe refractory agitation with imminent risk of harm.²⁰

Drug Shortages

What happens when the medication of choice is unavailable due to a drug shortage?

Drug shortages are defined and cataloged by both the FDA and American Society of Health-System Pharmacists.⁷ According to their databases, many of the drugs used for the management of agitation have recently been the subject of a shortage, including: haloperidol tablets, haloperidol injection, droperidol injection, lorazepam tablets, lorazepam injection, midazolam injection, promethazine injection, dexmedetomidine injection, and ketamine injection. At the time this article was written many of these medications remain affected by shortage.^85,86

Drug shortages tend to impact older, generic, and/or parenteral medications. Reasons for this are multifactorial and include production delays, lack of manufacturing capacity, decreased profitability, and manufacturer quality management problems.⁷ Unfortunately, clinicians rely on many older, generic, and/or parenteral medications in the management of acute agitation and aggression, making this especially problematic in these high acuity situations.

Staff Preparedness

Drug shortages impair staff preparedness by forcing the clinician to use alternatives that may be unfamiliar, have increased side effect risk, or inferior efficacy. American Society of Health-System Pharmacists recommends preparing and responding to drug shortages through use of operational and therapeutic assessments.⁷ An operational assessment is used to determine the extent and impact of the shortage by working with the pharmacy and inventory specialists to account for current inventory and expected duration and impact of the shortage. A clinician may also access this information directly through the FDA or American Society of Health-System Pharmacists databases and receive alerts regarding shortages.^85,86

A therapeutic assessment involves prioritizing patient populations for which to allocate available resources.⁷ This would include identifying areas of the facility and patient populations with higher incidence of agitation than others. This may differ depending on the facility, but the ED and inpatient psychiatry units are generally considered high-risk areas.²¹ These areas may benefit from outreach and education about the potential implications of drug shortages.

Therapeutic assessment also involves identifying feasible treatment alternatives. First, staff shouldn't underestimate the usefulness of screening tools and nonpharmacologic intervention. For example, using the Overt Agitation Severity Scale may promptly identify signs of agitation, and the Brøset Violence Checklist may indicate a higher risk for aggression. This can signal the need to prioritize early verbal de-escalation and environment modification. It may even create safe opportunities for therapeutic rapport building and collaborative decision making on medication options prior to escalation. Therefore, proper use of these interventions may prevent escalation to severe agitation, spare the need for parenteral medications, and minimize the impact of drug shortages in practice.

When determining alternative medication options, the clinician should be aware of the evidence for medication efficacy and safety. Overall, guideline and expert consensus consider multiple options effective for mild to moderate agitation as well as moderate to severe. These are included in Tables 2 and 3, respectively. There are also various safety concerns that may make one option more desirable. The route of administration is an important consideration, and facility resources in different areas may limit which medication routes are able to be used. For example, IV administration of olanzapine, haloperidol, droperidol, midazolam, and lorazepam are restricted to use in settings with resuscitation capacity, such as in a person with established IV access for treatment of delirium on a medical floor.

Another important consideration in the management of agitation and aggression includes conserving parenteral medication.⁷ For example, a person requiring IM olanzapine to treat severe agitation should be de-escalated to oral antipsychotic as appropriate. Staff should also be aware of supply shortages, such as sterile water which is necessary for administering certain parenteral medications like olanzapine and ziprasidone. Additionally, parenteral haloperidol combinations with a benzodiazepine or diphenhydramine are frequently used as standard treatment for moderate to severe agitation, but these medications may be in short supply. It should be noted that the combination of 3 IM drugs such as a first-generation antipsychotic, benzodiazepine, and an antihistamine is not supported by evidence and may even be regarded as wasteful given the drug shortages faced in practice.^7,18-23

Finally, the clinician should prepare their next step if a patient has an insufficient response to initial treatment. In general, available guidelines/recommendations^18,23 suggest redosing with the initial treatment at least once for insufficient response and then adding a benzodiazepine or switching to alternative such as haloperidol, benzodiazepine, promethazine, or diphenhydramine combination if not initially used. Screening tools such as the Positive and Negative Syndrome Scale-Excited Component may assist the clinician in determining need for additional medication. In this way, the assessment becomes more objective, and the unnecessary use of medication may be spared.

In the case of H.N., the inpatient psychiatry team is preparing to discuss a treatment plan, given the above described drug shortage of haloperidol. They scan the interview room for safety risks and means of egress. H.N. presents to the team as awake and alert, and a Behavioural Activity Rating Scale screen reflects calmness with redirection. The team concludes mild to moderate agitation is present with spikes when discussing substance use. They employ verbal de-escalation and reassure H.N. that these nonpharmacologic interventions will be used throughout admission. Finally, they discuss use of oral risperidone/lorazepam combination for mild to moderate agitation. This decision is appropriate given history of insufficient response to oral risperidone monotherapy. Additionally, the use of lorazepam would be limited to the inpatient controlled environment and would not be used long-term to minimize any risk of reinforcing a substance use disorder. This plan may establish safe and effective oral risperidone dosing necessary to achieve stabilization and facilitate transition to long-acting injectable risperidone or paliperidone for improved treatment adherence and future agitation risk mitigation. They make H.N. aware that everyone's safety is of the utmost importance and that IM olanzapine will be used for severe agitation with the availability of seclusion and restraints as a last-line option. They are transparent with H.N. and despite need for frequent redirection and de-escalation, H.N. leaves the room to voluntarily take a dose of oral medication.