Is promethazine or olanzapine safer for an agitated patient?

Olanzapine is Safer for Agitated Patients

For acute agitation in undifferentiated patients, intramuscular olanzapine (10 mg) is safer than promethazine because olanzapine provides effective rapid tranquilization with a superior adverse effect profile, while promethazine lacks evidence as monotherapy for agitation and is primarily used only in combination with haloperidol. 1

Evidence Supporting Olanzapine

Efficacy in Acute Agitation

• Intramuscular olanzapine 10 mg effectively sedates 78.9% of acutely agitated patients within 20 minutes, with the remaining patients responding to a repeat dose within 25 minutes. 2

• Olanzapine demonstrates superior efficacy compared to haloperidol in agitation secondary to organic medical conditions (79.1% vs 25% sedated within 20 minutes), and is equally effective as haloperidol plus lorazepam for psychiatric agitation (90% vs 94.1% sedated within 20 minutes). 2

• In a large meta-analysis of 13 randomized controlled trials involving over 2,700 patients, olanzapine outperformed haloperidol on the Agitation-Calmness Evaluation Scale at 2 hours and demonstrated comparable efficacy on symptom reduction scales. 3

• In a prospective study of 737 patients, olanzapine resulted in a greater proportion of adequately sedated patients at 15 minutes compared to haloperidol 5 mg (difference 20%) and haloperidol 10 mg (difference 18%). 4

Safety Profile Advantages

• Olanzapine is associated with significantly fewer extrapyramidal symptoms, akathisia, dystonia, and anticholinergic medication requirements compared to haloperidol. 3

• Adverse events with olanzapine are uncommon, with rates of hypotension (0.5%), hypoxemia (1%), and extrapyramidal effects (0.3%) comparable to other agents, and no increased risk of cardiac arrest or intubation. 4

• Olanzapine demonstrates marginally less QT prolongation compared to haloperidol, an important safety consideration in agitated patients with unknown cardiac history. 3

Why Promethazine Alone is Not Recommended

Lack of Monotherapy Evidence

• Promethazine is classified as a "less commonly used drug" for agitation management and has been less well studied than benzodiazepines or antipsychotics. 5

• The pediatric emergency medicine literature describes promethazine only as an antihistamine with sedative effects, primarily used as a nighttime sleep aid for insomnia rather than acute agitation. 5

• No controlled trials support promethazine monotherapy for acute agitation; it appears in the literature only as an adjunct to haloperidol in combination therapy. 5, 6

Combination Therapy Context

• When promethazine is used clinically, it is administered as intramuscular haloperidol plus promethazine combination, not as monotherapy. 6

• In a randomized trial comparing olanzapine to haloperidol plus promethazine, both treatments achieved similar tranquilization rates (87% vs 91% at 15 minutes), but the combination required fewer additional interventions over 4 hours. 6

• However, olanzapine monotherapy required additional drugs in 43% of cases versus 21% for the haloperidol-promethazine combination, suggesting the combination may be more effective but at the cost of polypharmacy. 6

Clinical Algorithm for Drug Selection

First-Line: Intramuscular Olanzapine 10 mg

• Use for undifferentiated acute agitation when rapid tranquilization is needed and the patient cannot take oral medications. 2, 4

• Particularly effective for agitation secondary to organic medical conditions and psychiatric illness. 2

• Reassess at 15-20 minutes; if inadequate response, repeat olanzapine 10 mg IM. 2

Alternative: Haloperidol Plus Promethazine

• Consider only when olanzapine is unavailable or contraindicated, as this combination requires two injections and increases medication burden. 6

• May be slightly more effective in alcohol intoxication and traumatic brain injury, though differences are not statistically significant. 2

What to Avoid

• Do not use promethazine as monotherapy for acute agitation, as there is no evidence supporting this approach. 5

• Avoid benzodiazepines as first-line for undifferentiated agitation unless alcohol or benzodiazepine withdrawal is suspected, as they increase delirium risk in elderly patients and cause paradoxical agitation in 10% of cases. 1

Important Safety Considerations

Monitoring Requirements

• Assess vital signs and sedation level every 5-15 minutes during the first hour after medication administration. 7

• Monitor for hypotension, respiratory depression, and extrapyramidal symptoms, though these are uncommon with olanzapine. 4

Special Populations

• In elderly patients over 75 years, olanzapine is less effective and carries increased mortality risk; use the lowest effective dose (2.5 mg) with extreme caution. 1

• Avoid combining olanzapine with benzodiazepines due to risk of fatal respiratory depression and oversedation. 1

• In patients with known cardiac disease or QT prolongation, olanzapine may be preferable to haloperidol due to lower QT prolongation risk. 3

Common Pitfalls

• Do not assume promethazine alone will control agitation—it lacks evidence as monotherapy and should only be considered as part of combination therapy with haloperidol. 5, 6

• Do not delay treatment while attempting to determine the exact etiology of agitation; olanzapine is effective across multiple causes including psychiatric illness, organic medical conditions, and undifferentiated presentations. 2

• Do not use excessive doses—olanzapine 10 mg IM is the standard effective dose, and higher doses provide no additional benefit while increasing adverse effects. 2, 4