Study #1: Single center, prospective, randomized, placebo controlled, double blinded study comparing 2.5 mg haloperidol diluted in 5ml saline vs 5 ml saline as placebo.  Vital signs, pain, and side effects were documented at 0, 30, 60, 90 minutes, and at discharge.  QT intervals were measured at medication administration and discharge.  If at 60 minutes a patient did not have 50% reduction in pain, rescue medication (ketorolac) was given.  118 patients were randomized to 58 in the haloperidol group and 60 to placebo. Exclusion criteria included blood pressure >200/100, sudden/rapid onset headache, fever, trauma, history of brain mass, stroke, or intracranial abnormality, QT >450ms, GCS <15, allergy to haloperidol, neurological abnormality on exam, any concerns requiring CT, pregnancy, or prisoner. There was a statistically significant reduction in pain in the haloperidol group at 4.77 units on VAS vs 1.87 in placebo, with more in placebo requiring rescue medication (78.3% vs 31%).  At 60 minutes, 64.9% in the haloperidol group reported >50% reduction in pain vs 21.7% in the placebo group. Follow up done at 24 hours found that 14.6% of patients reported side effects in haloperidol (restlessness and anxiety) vs 7% in placebo.  75.9% of the haloperidol group requested the medication in the future vs 35% in placebo.  32.7% of patients in haloperidol experienced return of symptoms vs 50.9% in placebo. 7.3% in haloperidol returned for additional care vs 17.5% in control.  Differences in side effects were not significant between the groups with benadryl and ativan given to patients for restlessness or anxiety.  No significant difference was seen in QT intervals pre-post medication in either group.

Weakness: Females are the majority in each group especially in control. Convenience sampling done at this hospital. Unsure of overall demographics of this specific hospital, as it was done at one center.  Initial power calculated 80% with 71 per group to establish the difference in VAS change of 2 units as significant.  Interim analysis found that 118 patients that were enrolled were enough. 9 pediatric patients were done, 5 of which received haloperidol , which is not significant enough to stand alone in data. Types of headache were not differentiated, possible that more ‘migraines’ went to one group and ‘primary headache’ to another skewing data. Not sure if medications are more effective in one type of a headache than another

Study #2: Single center, prospective, double-blinded, randomized, controlled trial on convenience sample of patients. Each patient received 1000mL of NS and a BMP, placed on a monitor with ECG done.  Diphenyhydramine 25 mg IV was given before either 10mg metoclopramide or 5mg haloperidol , both IV.  Groups were assigned based on random-numbers table generated. Patients excluded were those with an allergy to medications given, history of heart disease, electrolyte abnormalities, on any prodysrhythmic, MAO inhibitors, or ergot derivatives, history of neurologic disorders, hepatic impairment, cancer, pregnant breastfeeding, febrile, or requiring CT/lumbar puncture.  Vitals were taken at triage and were, along with another ECG, repeated prior to discharge. The visual analog scale (100-mm nonhatched) along with side effects were assessed at 20 minute intervals until 80 minutes. Rescue medications were given at the discretion of the physician.  64 patients were enrolled with 31 to receive haloperidol and 33 receiving metoclopramide. The mean reduction for pain in the haloperidol group was 57 mm and 49mm for metoclopramide (p<0.01) in each with the magnitude compared to each other, no significant difference was found (p>0.05).  They were equivalent in time to maximum pain relief with 55 minutes for metoclopramide and 56 minutes for haloperidol (p>0.05).  Both agents helped with nausea 31 mm for haloperidol and 25 for metoclopramide (p<0.01 each), neither produced restlessness that was significant (p>0.05) and no statistically significant change in level of sedation in either group occurred (p>0.05).  33 (25%) of the metoclopramide group were given rescue medication whereas 1 (3%) in the haloperidol group did. There was no difference in subjects requesting early discharge prior to 80 minutes (35% in haloperidol and 21% in metoclopramide, p>0.05).  Patient follows showed that more in the haloperidol group reported restlessness (43% v 10%). 

Weakness: Larger sample size might be helpful, as well as more detail in terms of demographic distribution of the subjects.  Furthermore, 28% of patients left early, unsure of how that affects data.  They also premedicated with benadryl in both groups. I don’t know if this creates some sort of additive or synergistic effect when combined with haloperidol or metoclopramide.  It is therefore unknown if these results would be valid if haloperidol or metoclopramide are given alone, and if these drugs should be routinely given with diphenhydramine, as this is not commented on.  They also noted inconsistencies in ECG monitoring.  This study also does not elaborate on the definition of “migraine” or whether this was a formal prior diagnosis or a generalized term for headache.

Conclusion: 

• Stimulation at dopamine receptors thought to cause pain, nausea, anxiety, and hemodynamic response in acute headache
• Thought is that haloperidol works at these receptors (antagonist) and also affects serotonin and alpha 1 adrenergic receptors 
• Studies using 2.5mg of haloperidol compared better than placebo
• 5mg haloperidol was equal to metoclopramide for for treatment of headache in the ED
• Watch out for side effects (anxiety, restlessness, nausea, vomiting)
• Potential risk of QT prolongation

References:

#1 McCoy JJ, Aldy K, Arnall E, Petersen J. Treatment of Headache in the Emergency Department: Haloperidol in the Acute Setting (THE-HA Study): A Randomized Clinical Trial. J Emerg Med. 2020 Jul;59(1):12-20. doi: 10.1016/j.jemermed.2020.04.018. Epub 2020 May 10. PMID: 32402480.

#2 Gaffigan ME, Bruner DI, Wason C, Pritchard A, Frumkin K. A Randomized Controlled Trial of Intravenous Haloperidol vs. Intravenous Metoclopramide for Acute Migraine Therapy in the Emergency Department. J Emerg Med. 2015 Sep;49(3):326-34. doi: 10.1016/j.jemermed.2015.03.023. Epub 2015 Jun 2. PMID: 26048068.