Day # 85: Agitation - Pharmacological Management

Previously we covered an overview of agitation which included an introduction, approach to assessment, tips on verbal de-escalation, and considerations for physical restraints. If you haven't already read that post then I recommend reading it before you proceed. Today we will discuss pharmacological interventions for agitation.

Today's Content Level: Intermediate, Advanced

INTRODUCTION

•Pharmacological interventions are used in agitated patients when behavioral approaches such as verbal de-escalation have failed to calm the patient and there is still an acute safety risk.

•Pharmacological management of agitation is sometimes called rapid tranquilization (RT). The term "chemical restraint" should not be used.

Goals for pharmacological intervention are the following:

• Ensure safety: reduce risk of harm to self and others.

• Reduce suffering: calm the patient to reduce psychological or physical suffering. Goal should be to calm but not over-sedate.

• Enable patient to participate: de-escalate patient to the point they can eventually participate in the assessment and treatment plan.

• "Do no harm": give safe treatment regimes as well as appropriate monitoring after medications are given.

Considerations for pharmacological management includes:

• If able, assess to see if there may be a medical cause of the agitation.

• First attempt non-pharmacologic interventions as discussed on day #83. Offer medications early during these interventions, give options, and ask patient their preference of type and route of medication.

• Always have a working diagnosis to guide medication choice. Remember that acute behavioral disturbance can occur in the context of medical illness, substance abuse, currently prescribed medications, psychiatric illness (delusions or hallucinations), or a personality disorder. For example, you will treat agitation in untreated schizophrenia (antipsychotics) differently then you would in someone in acute alcohol withdrawal (benzodiazepines). You would also avoid benzodiazepines in someone intoxicated with alcohol as you will potentiate the intoxication.

• If able, optimize their regular prescription and avoid concomitant use of two or more antipsychotics (antipsychotic polypharmacy) on the basis of increased risk of QTc prolongation.

• Special populations: Pediatrics-> Avoid first-generation antipsychotics due to increased risk of extrapyramidal symptoms 1. Olanzapine is generally preferred. Also consider that benzodiazepines are more often associated with paradoxical increase in agitation in kids 2. Elderly-> Antipsychotics should be used with caution due to increased risk of short-term mortality from all causes 3. Also benzodiazepines are associated with increased risk of dementia, falls, and respiratory depression in the elderly.

• If physical restraints are required, use IM or IV medications immediately following the restraint as the goal is to discontinue the restraint as soon as the agitation improves.

• Once a medication is administered frequently assess the patient and monitor vital signs (VS). VS should be monitored every 15 minutes for 1 hour, and then hourly until the patient is ambulatory. Patients who refuse to have their VS monitored should be observed for signs of general well-being, over-sedation, fever, hypoxia, or hypotension.

CHOICE OF MEDICATION

•If you are a medical student and need a refresher on antipsychotic and sedative medications, please refer back to these posts (Intro to Antipsychotics; General SE of antipsychotics; Specific antipsychotics; Benzodiazepines)

Oral Treatment Options (PO or SL)

• If able, optimize regular prescription (ex: give extra dose of current antipsychotic).

• First Generation Antipsychotics (FGAs) -> Commonly used meds includes Haloperidol (PO; onset 120-360 mins; typically 5mg); Chlorpromazine (PO; onset 60-240 mins); and Fluphenazine 4. Haloperidol is often given with antihistamine (25-50mg benadryl or 25-50mg promethazine) for prophylaxis of extrapyramidal symptoms (EPS) or as a "B52" (Haldol-5mg, Benadryl-50mg, Lorazepam-2mg). Pre-treatment ECG and avoidance of antipsychotic poly-pharmacy recommended due to higher risk of QTc prolongation.

• Second Generation Antipsychotics (SGAs)-> Commonly used meds include Olanzapine (PO or SL; onset ~360 mins); Risperidone (PO or SL; onset ~60 mins); Quetiapine (PO; onset 360-480 mins); and Ziprasidone (PO; onset 360-480 mins). Olanzapine highly effective. Risperidone considered as effective as haloperidol, especially in combination with lorazepam. Quetiapine may result in hypotension. Ziprasidone use is limited by severity of QTc prolongation.

• Lorazepam-> PO or SL; onset 60-360 mins; typically 1-2mg. Can be used alone or in combination with antipsychotic. Sedative effects may result in respiratory depression, so avoid in respiratory disease. It can also contribute to delirium, so avoid in the elderly.

• Diphenhydramine-> PO; onset 60-180 mins. Often used in combination with haloperidol and lorazepam for acute physical aggression (B52). May ameliorate risk of EPS from haloperidol. Avoid in elderly because of anticholinergic effects.

• Hydroxyzine-> PO; onset 15-30 mins. Commonly prescribed as a non-benzodiazepine anxiolytic because of its rapid absorption.

• Trazodone-> PO; onset 60-120 mins. Low doses are used 12.5-50mg. May be beneficial in geriatric patients in whom benzodiazepines carry a risk of delirium and antipsychotics carry cardiac risk. May result in hypotension.

Parenteral Treatment Options (IM or IV)

• First Generation Antipsychotics (FGA) -> Haloperidol -> IM or IV; onset 30-60 and 15-30 mins respectively; typically 5mg. Poorly tolerated if given alone. Give with antihistamine (25-50mg benadryl or 25-50mg promethazine) for prophylaxis of EPS or as a "B52". Pre-treatment ECG and avoidance of antipsychotic poly-pharmacy recommended due to higher risk of QTc prolongation. IM preparation has the highest risk of EPS. IV preparation has the highest risk of QTc prolongation. Combination of IM haloperidol and IM lorazepam found to be similar in efficacy to IM olanzapine 5. Chlorpromazine-> IM; onset 15-30 mins. May result in severe hypotension. Also has been associated with a local site reaction and abscess formation. Fluphenazine-> IM; onset 30-60 mins.

• Second Generation Antipsychotics (SGAs) -> Olanzapine-> IM; onset 15-45 mins. Most effective when compared to haloperidol, ziprasidone, and aripiprazole 6. Do not co-administer with lorazepam or other benzodiazepines due to high risk of respiratory depression. The risk is even higher if alcohol has been consumed 7. Ziprasidone-> IM; onset 60 mins. Use is limited by severity of QTc prolongation. Also see aripiprazole in the next section.

• Benzodiazepines -> Can be used alone or in combination with antipsychotic. Sedative effects may result in respiratory depression, so avoid in respiratory disease. Have flumazenil available in case of benzodiazepine-induced respiratory depression. It can also contribute to delirium, so avoid in the elderly. Lorazepam-> IM or IV; onset 60-90 and <10 mins respectively; typically 2mg. Midazolam-> IM or IV; <15 and <5 minutes respectively. Most trials suggest midazolam is probably more effective than lorazepam but may cause higher incidence of over-sedation / respiratory depression.

• Diphenhydramine-> IM or IV; <10 mins. Often used in combination with haloperidol and lorazepam for acute physical aggression (B52). May ameliorate risk of EPS from haloperidol. Avoid in elderly because of anticholinergic effects.

Less Commonly Used and/or Emerging Use

• Loxapine-> typically 10mg. First generation antipsychotic (FGA). Evidence for inhaled loxapine. Requires co-operation of the patient. Bronchospasm is a known rare adverse effect. Recent study showed faster response time and no difference in safety compared to IM aripiprazole. 8

• Aripiprazole-> PO or SL or IM; Less hypotension than olanzapine but probably less effective 9. One study showed IM aripiprazole has similar efficacy to haloperidol and other antipsychotics in reducing agitation 10. Other studies have shown haloperidol to be more effective.

• Ketamine-> NAS, IM, IV; Though not commonly used, emerging evidence showing it can be useful for acute agitation. One study showed IM ketamine was effective, with minimal adverse effects, in a group of patients who failed to respond to IM antipsychotics 11. Another showed that ketamine controlled agitation faster than standard agents 12. Caries small risk of dissociation and theoretically may worsen agitation and psychosis in patients with primary psychotic disorders.

CONCLUSION

I hope this lesson was a helpful resource on the pharmacological treatment options for agitation. Next lesson we will cover an important topic relevant to emergency psychiatry in addition to many other fields: alcohol withdrawal.

Resources for today's post include The Maudsley Prescribing Guidelines in Psychiatry, Pocket Psychiatry, Kaplan and Sadock Synopsis of Psychiatry, and the articles referenced in the lesson.

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