Is it safe to administer Benadryl (Diphenhydramine), Haldol (Haloperidol), and Lorazepam together?

From the Guidelines

The combination of Benadryl (diphenhydramine), Haldol (haloperidol), and Lorazepam can be administered together in specific clinical situations, but this should only be done under direct medical supervision. This combination is typically used for severe agitation or delirium in hospital settings, particularly in emergency departments or intensive care units. The standard doses are typically diphenhydramine 25-50mg, haloperidol 2-5mg, and lorazepam 1-2mg, though these vary based on patient factors, as seen in studies such as 1 which suggests haloperidol 0.5-1 mg orally at night and every 2 hours when required. Each medication works differently: diphenhydramine is an antihistamine with sedative properties, haloperidol is an antipsychotic that helps control psychosis and agitation, and lorazepam is a benzodiazepine that reduces anxiety and causes sedation.

The main concerns with this combination include potential for excessive sedation, respiratory depression, QT interval prolongation (heart rhythm issues), and anticholinergic effects, as noted in 1 which highlights the risk of QTc prolongation with antipsychotics. Patients receiving this combination require close monitoring of vital signs, cardiac rhythm, and mental status.

• Key considerations for administration include:
  • Close clinical observation
  • Cardiorespiratory monitoring
  • Pulse oximetry
  • Electrocardiogram monitoring when possible
• The combination should be used with caution, especially in patients with risk factors for QT prolongation, such as those taking other QT-interval-prolonging medications, as listed in 1.

This combination is not appropriate for outpatient use or self-administration and should only be used in controlled medical environments where emergency support is available. The most recent and highest quality study, 1, supports the use of haloperidol and lorazepam in specific clinical situations, but emphasizes the need for careful dosing and monitoring. Therefore, the administration of Benadryl, Haldol, and Lorazepam together should be approached with caution and only considered under the guidance of a healthcare professional.

From the FDA Drug Label

Apnea, coma, bradycardia, arrhythmia, heart arrest, and death have been reported with the concomitant use of haloperidol and lorazepam The administration of Benadryl (Diphenhydramine), Haldol (Haloperidol), and Lorazepam together is not safe due to the potential for severe adverse reactions, including respiratory depression, sedation, and even death, as reported with the concomitant use of haloperidol and lorazepam 2.

• Key risks include:
  • Respiratory depression
  • Sedation
  • Coma
  • Bradycardia
  • Arrhythmia
  • Heart arrest
  • Death It is essential to exercise caution and avoid concomitant administration of these drugs unless absolutely necessary and under close monitoring. 2

From the Research

Safety of Administering Benadryl, Haldol, and Lorazepam Together

• The combination of Benadryl (Diphenhydramine), Haldol (Haloperidol), and Lorazepam is not directly studied in the provided evidence.
• However, a study on the visual compatibility and particle counter evaluations of syringes of intramuscular psychotropic coadministered solutions 3 found that the triple combination of lorazepam and haloperidol with diphenhydramine was physically compatible.
• Another study compared the combination of intramuscular droperidol and midazolam to haloperidol and lorazepam for acute agitation management in the emergency department 4, but did not include diphenhydramine in the combination.
• A prospective study compared the combination of intramuscular haloperidol and lorazepam to droperidol and midazolam for the treatment of acute agitation in the emergency department 5, and found that both combinations were effective, but did not include diphenhydramine.
• A multicenter, prospective, double-blind, emergency department study compared haloperidol, lorazepam, or both for psychotic agitation 6, but did not include diphenhydramine in the study.
• A systematic review of prospective interventional studies on the effectiveness and safety of intravenous medications for the management of acute disturbance 7 did not find eligible data on the use of IV diphenhydramine, but found mixed but positive results for the effectiveness of IV lorazepam and haloperidol.

Potential Risks and Benefits

• The combination of Benadryl, Haldol, and Lorazepam may be beneficial for the management of acute agitation, but the potential risks and benefits are not well studied.
• The physical compatibility of the combination has been established 3, but the clinical efficacy and safety of the combination are not well understood.
• The use of multiple psychotropic medications in a single syringe can be beneficial to both the patient and healthcare professionals, but the potential risks of adverse events and interactions must be carefully considered.