What studies assess the safety of haloperidol administration by intravenous route?

Provide summary of studies assessing safety of haloperidol administration by intravenous route.

Comment by InpharmD Researcher

Intravenous (IV) haloperidol has been evaluated primarily in the settings of delirium and acute migraine, with oversedation and QTc prolongation being the most prominently reported safety events. However, a secondary analysis of a randomized clinical trial found no clinically significant risk of cardiac arrhythmias attributable to IV haloperidol use at a dose of 20 mg daily. While evidence suggesting a relationship between IV haloperidol and QTc prolongation or Torsades de Pointes is not robust, it is generally recommended that patients with a QTc >500 ms receive continuous monitoring and/or alternative agents.

Background

A 2020 systematic review of 77 studies evaluating side effects associated with intravenous (IV) haloperidol demonstrated no clinically significant QT prolongation. However, of the included clinical trials and case reports/series, three reports suggest that IV haloperidol could cause QT prolongation under certain circumstances. In the first report, 9 of 177 subjects had “marginal QT prolongation” of an undefined severity with no comparison to the control group. The second showed 34 patients treated with flunitrazepam followed by IV haloperidol to have longer QT by 9 ms compared to those receiving flunitrazepam alone, with two patients displaying an increase of >100 ms following a dose >25 mg, suggesting QT may be moderately correlated with the dose. Another retrospective found IV haloperidol to be associated with a higher rate of QT prolongation (>470 ms in men, >480 ms in women) than other antipsychotics (1.29 relative risk [RR]; 95% confidence interval [CI] 1.18 to 1.43). In general, QT prolongation was mostly of mild or unclear clinical significance within these reports. [1], [2], [3], [4]

Additionally, a commonly cited source for IV haloperidol association with QT interval prolongation was an unpublished 1995 observational study of 6 patients, which was never peer-reviewed. QT prolongation potential was concluded to be dose-related in a 2010 systematic review, where 80% of patients with QT prolongation or Torsades de Pointes (TdP) received >10 mg IV haloperidol. The vast majority of patients who develop TdP had other risk factors, such as critical illness, cardiac disease, or other QT-prolonging medications; 96% of patients with TdP had QTc >450 ms at the time of the event. It was concluded that the evidence suggesting a relationship between IV haloperidol, QT prolongation, and TdP is not robust. High-quality evidence from recent prospective studies shows that doses up to 20 mg daily do not appear to be associated with QT prolongation. However, no thorough clinical trial of QT changes has been conducted for IV haloperidol at the time of publication. Limitations of this review include the potential of selection bias for the case reports, due to them selecting more extreme cases, and the use of Bazett’s formulation as opposed to the recommended Framingham or Hodges formulas, causing a potential miscalculation of QT interval. For patients with QTc >500 ms or a total dose >100 mg, continuous monitoring through telemetry and/or alternative agents is recommended. If there is enough concern regarding QT prolongation to stop using IV haloperidol, a non-antipsychotic agent (i.e., valproate, benzodiazepine) is recommended, due to the lack of data presenting other antipsychotic alternatives to be safer. [1,5,6]

Relevant Prescribing Information

Warnings:
Cardiovascular Effects
Cases of sudden death, QTc interval-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol. Higher than recommended doses of any formulation and intravenous administration of haloperidol appear to be associated with a higher risk of QTc interval-prolongation and Torsades de Pointes. Also, a QTc interval that exceeds 500 msec is associated with an increased risk of Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QTc-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QTc, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). HALDOL DECANOATE MUST NOT BE ADMINISTERED INTRAVENOUSLY. [7]

Literature Review

A search of the published medical literature revealed 9 studies investigating the researchable question:

Provide summary of studies assessing safety of haloperidol administration by intravenous route.

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-9 for your response.

Efficacy of Intravenous Haloperidol on the duration of Delirium and Coma in Critically Ill Patients (Hope-ICU): a Randomised, Placebo-Controlled Trial
Design	Prospective, randomized, double-blind, placebo-controlled trial N= 141
Objective	To establish whether early treatment with intravenous (IV) haloperidol would decrease the time that survivors of critical illness spent in delirium or coma
Study Groups	Haloperidol (n= 71) Placebo (n= 70)
Inclusion Criteria	Age > 18, needing mechanical ventilation within 72 hours of admission
Exclusion Criteria	Expected discharge/expected death within 48 hours, structural brain damage, haloperidol allergy, Parkinson's disease, QTc more than 500ms on electrocardiogram (ECG), already on antipsychotics
Methods	Patients irrespective of coma or delirium were randomized to receive haloperidol 2.5 mg IV Q8H or matching saline placebo within 72 hours of intensive care unit (ICU) admission at either 8 am, 4 pm, or midnight and continued until patients were delirium-free based on ICU discharge for two days or a maximum of 14 days of treatment. Delirium was measured using the confusion assessment method - for the ICU (CAM-ICU).
Duration	Maximum of 14 days
Outcome Measures	Primary: Delirium-free days and coma-free days up to day 14 Secondary: Delirium-free, ventilator-free, and coma-free days up to day 28, safety with prolonged QTc, length of hospital stay, and critical care stay
Baseline Characteristics		Haloperidol (n= 71)	Placebo (n= 70)
	Age, years	67.9 (16.5)	68.7 (14.9)
	Men	37 (52%)	45 (64%)
	Medical patient	42 (59%)	49 (70%)
	Surgical patient	29 (41%)	21 (30%)
	APACHE II score, points	19.8	19.7
	Time from ICU administration to randomization, days	0.9	0.88
	No major differences between groups for main diagnosis at ICU admission (sepsis/ARDS, pneumonia, acute coronary syndrome or cardiac failure, renal/hepatic failure, hemorrhage, COPD, drug overdose, other).
Results	Endpoint	Haloperidol (n= 71)	Placebo (n= 70)	Difference (95% CI)	p-value
	Alive, delirium-free, and coma-free days in first 14 days	5	6	-0.48 (-2.08 to 1.21)	0.53
	Alive, delirium-free, and coma-free days in first 28 days	19	19.5	-0.26 (-3.72 to 3.46)	0.57
	Ventilator-free days in first 28 days	21	17	0.25 (-3.26 to 4.16)	0.88
	Mortality at 28 days	20 (28.2%)	19 (27.1%)	1.04* (0.61 to 1.77)
	Length of ICU stay, days	9.5	9	-1.45 (-5.42 to 2.52)	0.47
	Length of hospital stay, days	18.5	26	-5.13 (-21.75 to 11.48)	0.54
	No differences found with regard to secondary outcomes at 28 days *Reported as risk ratio (RR)
Adverse Events	Common Adverse Events: oversedation, QTc prolongation, afib
Study Author Conclusions	These results do not support the hypothesis that haloperidol modifies the duration of delirium in critically ill patients. Although haloperidol can be used safely in this population of patients, the use of intravenous haloperidol should be reserved for short-term management of acute agitation.
InpharmD Researcher Critique	This study observed a lower dose of intravenous haloperidol based on information from Medsafe and PET scan studies that suggest higher doses greater than 10 mg/day may not provide further benefits. Patients were deemed delirium-free based on discharge from ICU which may not reflect results from instruments that measure delirium. However, as the drug appears to be safe from the results, the authors do advocate for short-term use which is reflected by the guidelines.

References:

Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial [published correction appears in Lancet Respir Med. 2013 Oct;1(8):592]. Lancet Respir Med. 2013;1(7):515-523. doi:10.1016/S2213-2600(13)70166-8

Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness
Design	Multicenter, randomized, double-blind, placebo-controlled, phase-3 trial N= 566
Objective	To examine the effects of haloperidol or ziprasidone on delirium during critical illness
Study Groups	Placebo (n= 184) Haloperidol (n= 192) Ziprasidone (n= 190)
Inclusion Criteria	Age ≥ 18 years old receiving treatment in a medical or surgical intensive care unit (ICU) with invasive or noninvasive positive pressure ventilation, vasopressors, or an intra-aortic balloon pump, presenting with delirium
Exclusion Criteria	Severe cognitive impairment as defined by the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), pregnancy, breastfeeding, history of torsades de pointes, QT prolongation, history of neuroleptic malignant syndrome, allergy to haloperidol or ziprasidone, ongiong treatment with antipsychotic medication, in a moribund state, rapidly resolving organ failure
Methods	Patients admitted to the ICU with acute respiratory failure or shock and hypoactive or hyperactive delirium were randomized to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. Before patients received the trial drug twice daily, QT interval was assessed using telemetry or 12-lead electrocardiography. Trained personnel assessed the patients twice daily using the Confusion Assessment Method for the ICU (CAM-ICU) for delirium.
Duration	Fourteen days of intervention
Outcome Measures	Primary Outcome: Number of days alive without delirium or coma during the 14-day intervention period Secondary Outcome: 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge Safety: Extrapyramidal symptoms and excessive sedation
Baseline Characteristics		Placebo (n= 184)	Haloperidol (n= 192)	Ziprasidone (n= 190)
	Median age, years	59	61	61
	Women	77 (42%)	84 (44%)	82 (43%)
	Race White Black Multiple/other	153 (83%) 26 (14%) 5 (3%)	163 (85%) 23 (12%) 6 (3%)	151 (79%) 27 (14%) 12 (6%)
	Median Charlson Comorbidity Index score	2	2	2
	Median The Acute Physiology and Chronic Health Evaluation (APACHE) II score	30	28.5	28
	Median Sequential Organ Failure Assessment (SOFA) score at randomization	11	11	10
	Hyperactive delirium at randomization	22 (12%)	19 (10%)	16 (8%)
	Hypoactive delirium at randomization	161 (88%)	172 (90%)	172 (91%)
Results	Endpoint	Placebo (n= 184)	Haloperidol (n= 192)	Ziprasidone (n= 190)
	Median days alive without delirium or coma Odds ratio (95% CI)	7 Reference	8 0.88 (0.64 to 1.21)	8 1.04 (0.73 to 1.48)
	Death at 90 days Hazard ratio (95% CI)	63 Reference	73 1.17 (0.99 to 1.40)	65 1.02 (0.79 to 1.30)
	Days to freedom of mechanical ventilation Hazard ratio (95% CI)	3 Reference	2 0.92 (0.71 to 1.19)	3 0.96 (0.74 to 1.25)
	Days to ICU discharge Hazard ratio (95% CI)	5 Reference	5 0.95 (0.81 to 1.12)	6 1.02 (0.88 to 1.17)
	Days to hospital discharge Hazard ratio	13 Reference	13 1.03 (0.85 to 1.23)	12 1.05 (0.88 to 1.25)
	Safety: There was no significant difference between groups for excessive sedation Extrapyramidal symptoms: One patient in each group had the respective medication withheld due to extrapyramidal symptoms and one patient in the haloperidol group developed dystonia leading to the trial drug being withheld.
Study Author Conclusions	The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium
InpharmD Researcher Critique	This trial shows that haloperidol was not greater than placebo in reducing various outcomes related to delirium and the ICU. While a similar safety endpoint observed with no significant risk on cardiovascular events, the applicability of haloperidol administered off-label intravenously for delirium remains suspect.

References:

Girard TD, Exline MC, Carson SS, et al. Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness. N Engl J Med. 2018;379(26):2506-2516. doi:10.1056/NEJMoa1808217

Haloperidol Versus Ondansetron for Treatment of Established Nausea and Vomiting Following General Anesthesia: A Randomized Clinical Trial
Design	Prospective, randomized, double-blinded study N= 112
Objective	To test whether haloperidol 1 mg intravenous (IV) is noninferior to ondansetron 4 mg (the “gold standard” compared with other antiemetics), in the early treatment of established postoperative nausea and vomiting (PONV) in patients undergoing surgery under general anesthesia
Study Groups	Haloperidol (n= 59) Ondansetron (n= 53)
Inclusion Criteria	Age 18 to 80 years, American Society of Anesthesiologists (ASA) class I to III, undergoing elective surgery under general anesthesia
Exclusion Criteria	History of arrhythmias, QTc prolongation, or allergies to the study drugs
Methods	Patients experiencing PONV were randomized to receive haloperidol 1 mg IV or ondansetron 4 mg IV. Additional rescue antiemetics were available if study drug failed within 30 minutes or earlier based on patient request. Noninferiority was defined as a percent difference between groups of less than 15%. An electrocardiogram was obtained 5 minutes after drug administration.
Duration	Enrollment period: September 2008 to June 2013 Study duration: 24 hours
Outcome Measures	Primary: Patients free from PONV for 4 hours Secondary: Free from PONV for 6 and 24 hours, QT_c before and after treatment
Baseline Characteristics		Haloperidol (n= 59)	Ondansetron (n= 53)
	Age, years	48	45
	Female/Male, n	42/17	39/14
	Weight, kg	77	74
	Height, cm	167	167
	American Society of Anesthesiology (ASA) status I II III	27 30 2	30 19 4
	Smoking status, yes/no	22/37	17/36
	Surgery time, min	93	98
	Anesthesia time, min	119	123
	Patients with nausea Nausea score	59 (100%) 3	53 (100%) 3
	Patients with vomiting Patients with retching	22 (37%) 28 (47%)	28 (53%) 28 (53%)
	Single drug prophylaxis with dexamethasone Single drug prophylaxis with ondansetron Both dexamethasone and ondansetron	20 7 8	38 1 3
Results	Endpoint	Haloperidol (n= 59)	Ondansetron (n= 53)	Difference	95% CI
	Patients free from PONV for 4 hours	35 (59%)	29 (55%)	5%	-13% to 22%
	Patients free from PONV for 6 hours	33 (56%)	28 (53%)	3%	-15% to 21%
	Patients free from PONV for 24 hours	31 (53%)	26 (49%)	4%	-15% to 21%
	QT_c before treatment, ms QT_cafter treatment, ms	430.4 446.8	421.4 441.7	9 5.1	-2.9 to 18.9 -5.3 to 19.5
	Only the per-protocol analysis was documented in this table to observe the safety and efficacy trend of patients who have completed the trial. Intention-to-treat analysis of all patients also reported non-significant differences. CI, confidence interval
Adverse Events	Sedation (more frequent in haloperidol group)
Study Author Conclusions	Our study showed that haloperidol is at worst 13% and 8% less effective than ondansetron as for the complete response during the first 4 hours (primary outcome) by the per-protocol analysis and by the intention-to-treat analysis, respectively. Therefore, haloperidol is noninferior to ondansetron in patients with established PONV but is associated with more sedation. However, both drugs had a failure rate of 50% over the 24-hour period and additional studies are required with other drugs or combinations for satisfactory clinical use.
InpharmD Researcher Critique	This study showed that haloperidol administered off-label intravenously may display similar efficacy to an atypical antipsychotic with more frequent sedative effects but suffers from multiple uncontrolled variables. There was no placebo for comparison and the type of surgery and opioid post-op were uncontrolled, which may have affected results. Patients also received other prophylactic antiemetics based on the discretion of the anesthesiologist.

References:

Yazbeck-Karam VG, Siddik-Sayyid SM, Barakat HB, Korjian S, Aouad MT. Haloperidol Versus Ondansetron for Treatment of Established Nausea and Vomiting Following General Anesthesia: A Randomized Clinical Trial. Anesth Analg. 2017;124(2):438-444. doi:10.1213/ANE.0000000000001723

Examination of Baseline Risk Factors for QTc Interval Prolongation in Patients Prescribed Intravenous Haloperidol
Design	Retrospective cohort study N= 175
Objective	To determine the prevalence of baseline risk factors for QTc prolongation and TdP in hospitalized medical inpatients prescribed intravenous haloperidol
Study Groups	Study patients (N= 175)
Inclusion Criteria	Patients aged ≥ 18 years who received intravenous haloperidol while hospitalized in one of two 32-bed standard-care medical units
Exclusion Criteria	Patients prescribed but did not receive intravenous haloperidol; patients who received intramuscular haloperidol
Methods	Data was collected from medical records of two standard-care medical units. Haloperidol was administered via intravenous injection. The study did not require a baseline limit of QTc-prolongation and could include patients with QTc > 500 ms.
Duration	Data collection: June 30, 2007 to January 1, 2010 Follow-up: 24 hours post-haloperidol injection
Outcome Measures	Prevalence of baseline risk factors for QTc prolongation and TdP
Baseline Characteristics		Study patients (N= 175)
	Age, years; mean	62.9
	Female	48.6%
	Patients with ≥ 1 risk factor 1 risk factor ≥ 2 to < 5 risk factors ≥ 5 risk factors	85.7% 36.0% 58.0% 6.0%
	Patients with ≥ 1 cardiovascular risk factor Left ventricular dysfunction Left ventricular hypertrophy Ischemia Slow heart rate < 60 bpm Past history of syncope Family history of sudden death (age < 40 years)	80 29 65 14 10 9 1
	Patients with ≥1 non-cardiovascular risk factor Alcohol dependence Liver disease Diabetes Hypothyroidism Overdose Pituitary insufficiency Obesity CNS trauma/infection Stroke	124 34 30 43 19 4 0 48 4 16
	Length of hospital stay, days; mean	16.3
Results	Endpoint	Study patients (N= 175)
	QTC Baseline Patients with ≥ 500 ms	457 ± 40.8 16 (12.2%)
	Follow-up ECG within 24 hours	82 (46.9%)
	Pre-intravenous haloperidol potassium value available	163 (93.1%)
	Mean potassium level, mmol/L	3.7 ± 0.5
	Subnormal potassium values	50 (30.7%)
	Potassium <3, mmol/L	11 (6.7%)
	Magnesium value available	110 (62.9%)
	Mean magnesium level, mg/dL	1.9 ± 0.3
	Subnormal magnesium values	29 (26.4%)
	Magnesium <1.6, mg/dL	12 (10.9%)
	Concomitant QTc-prolonging medication	76 (43.4%)
Adverse Events	No deaths were reported during the index hospitalization
Study Author Conclusions	Patients prescribed intravenous haloperidol had multiple risk factors for QTc prolongation and TdP. Modifiable risk factors should be targeted for interventions to optimize safety, while non-modifiable risk factors warrant closer scrutiny and consideration of alternative therapies and continuous monitoring.
InpharmD Researcher Critique	There was limited discussion regarding clinical outcomes of patients, especially those who received haloperidol with QTc above 500 ms. However, the study demonstrates the potential of administering haloperidol despite elevated OTc if patients are accompanied by monitoring of safety parameters and ECG.

References:

Muzyk AJ, Rayfield A, Revollo JY, Heinz H, Gagliardi JP. Examination of baseline risk factors for QTc interval prolongation in patients prescribed intravenous haloperidol. Drug Saf. 2012;35(7):547-553. doi:10.2165/11599960-000000000-00000

Antipsychotics and the QTc Interval During Delirium in the Intensive Care Unit: A Secondary Analysis of a Randomized Clinical Trial
Design	A priori analysis of a randomized clinical trial N= 566
Objective	To determine whether antipsychotics increase the QTc interval in patients with delirium in the ICU
Study Groups	Placebo (n= 184) Haloperidol (n= 192) Ziprasidone (n= 190)
Inclusion Criteria	Adults with delirium in the ICU with baseline QTc interval less than 550 ms
Exclusion Criteria	Baseline QTc interval ≥ 550 ms, reversible causes of QTc prolongation not corrected within 5 days
Methods	Patients were randomized 1:1:1 to intravenous haloperidol (max 20 mg/d), ziprasidone (max 40 mg/d), or saline placebo, administered twice daily until resolution of delirium, ICU discharge, or 14 days. QTc measured using 12-lead ECG and telemetry.
Duration	14 days or until ICU discharge or resolution of delirium
Outcome Measures	Primary: Median change in QTc interval between day 1 and day 2 Secondary: Effect on postrandomization day 2 maximum predose QTc interval, correlation between telemetry and ECG measurements, association of sex with QTc interval on day 2, incidence of ventricular arrhythmias
Baseline Characteristics		Placebo (n= 184)	Haloperidol (n= 192)	Ziprasidone (n= 190)
	Age, years	59.2	60.5	60.5
	Female	42%	44%	43%
	Race and ethnicity American Indian or Alaska Native Asian Black White	2% 0 14% 83%	2% 1% 12% 85%	0% 2% 14% 79%
	Charlson Comorbidity Index score	2.0	2.0	2.0
	APACHE II score at ICU admission	30.0	28.5	28.0
	SOFA score at randomization	10.0	9.0	9.0
	Median baseline/pre-randomization QTc interval (interquartile range [IQR])	452.0 (431.8 to 472.2)	457.5 (432.0 to 479.0)	451.0) 424.2 to 472.0)
	Study drug ever held for QTc-interval prolongation during intervention period	5%	7%	11%
	Median of average predose QTc interval for all days during intervention period (interquartile range [IQR])	442.5 (421.4 to 469.4)	444.0 (420.5 to 470.0)	445.0 (419.5 to 465.0)
Results	Endpoint	Placebo (n= 184)	Haloperidol (n= 192)	Ziprasidone (n= 190)
Results	QTc interval change, ms (IQR) day 1 to day 2	-3.5 (-24.8 to 17.0)	-1.0 (-28.0 to 15.0)	0 (-23.0 to 23.0)
Adverse Events	Two occurrences of nonfatal torsade de pointes in the haloperidol group, not associated with study drug administration. Ventricular tachycardia occurred in 5 patients (2 haloperidol, 3 ziprasidone) the same day as receiving study drug, and in 1 patient (haloperidol) 1 day after study drug receipt.
Study Author Conclusions	The findings of this trial suggest that haloperidol and ziprasidone do not cause clinically significant QTc interval prolongation or ventricular arrhythmias and that daily QTc interval monitoring during antipsychotic use may have limited value in patients in the ICU with normal baseline QTc and few risk factors for QTc prolongation.
InpharmD Researcher Critique	While it was possible that patients with baseline QTc > 500 ms were included and given haloperidol, the characteristics and outcomes of these patients were not reported within the study.

References:

Stollings JL, Boncyk CS, Birdrow CI, et al. Antipsychotics and the QTc Interval During Delirium in the Intensive Care Unit: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2024;7(1):e2352034. Published 2024 Jan 2. doi:10.1001/jamanetworkopen.2023.52034

Haloperidol in the acute treatment of migraine: a randomized, double-blind, placebo-controlled study
Design	Randomized, double-blinded, placebo-controlled trial N=47
Objective	To assess the efficacy and safety of IV haloperidol in treatment of acute migraine headache
Study Groups	Haloperidol (n=20) Placebo (n=20) Open-label haloperidol (n=24)
Inclusion criteria	Sent to an acute care unit due to acute or prolonged migraine attack
Exclusion criteria	long QT-interval, usage of drugs prolonging QT-interval, hepatic disease, epilepsy or history of seizures, parkinsonism, chronic psychiatric disease, other neuroleptic medications
Methods	Participants were randomized to receive either haloperidol 5 mg in 500 mL of normal saline or 500 mL of normal saline alone as a 20 to 30-minute infusion. Seven patients who did not consent to participation in the double-blinded study and 17 patients who did not respond to placebo were given haloperidol in an open-label fashion.
Duration	Pain assessment 3 hours after infusion
Outcome Measures	Pain via the visual analog scale (VAS), patient-reported pain relief
Baseline Characteristics		Total study population (n=47)
	Age, years	36
	Female	41 (85%)
	Duration of headache <72 hours >72 hours	32 (68%) 15 (32%)
	Any previous medication administration Triptan NSAID Acetaminophen Tramadol Other	43 (91%) 27 (57%) 24 (51%) 13 (28%) 3 (6%) 8 (17%)
	Previously tried more than one medication type	23 (49%)
Results		Haloperidol (n=20)	Placebo (n=20)	Open-label haloperidol (n=24)
	VAS score Baseline After treatment	7.7 2.3	7.2 6.3	6.6 2.3
	Marked pain relief	16 (80%)	3 (15%)	19 (79%)
Adverse Events	Haloperidol: motor agitation (53%), sedation (53%)
Study Author Conclusions	This study shows that IV haloperidol is very effective in relieving migraine-associated pain. Because the majority of the patients had taken other medication without response, haloperidol appears to be an effective rescue medication even when other types of treatment have failed. Relapses are rare, but side effects are common, limiting the use of haloperidol in some patients.
InpharmD Researcher Critique	Electrocardiography was not checked for patients prior to infusion. Some of the adverse events were considered intolerable, which may further limit haloperidol use.

References:

Honkaniemi J, Liimatainen S, Rainesalo S, Sulavuori S. Haloperidol in the acute treatment of migraine: a randomized, double-blind, placebo-controlled study. Headache. 2006;46(5):781-7.

A New Approach to Emergency Department Therapy of Migraine Headache with Intravenous Haloperidol: A Case Series
Design	Case series N=6
Objective	To determine how efficacious intravenous haloperidol is for migraines in the emergency department
Study Groups	Haloperidol (n=6)
Methods	All patients had a long-standing history of migraine headache with unremarkable past histories and presented with their typical headache. One liter of normal saline bolus was administered intravenously, followed by haloperidol 5 mg in a minibag over 2-3 minutes. Patients were monitored every 15 minutes.
Duration	Patients were monitored for about an hour after drug administration in the emergency department
Outcome Measures	Pain severity (scale of 1-10)
Baseline Characteristics		Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6
	Age, years	33	22	30	26	40	34
	Sex	Female	Female	Female	Female	Female	Male
	Duration of headache prior to presentation, hours	48	24	7	72	336	2
	Aura	Yes	No	No	No	No	No
Results		Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6
	Pain severity Pre-treatment Post-treatment	8.5 "severe" 2 "much better"	8 1	"usual" "totally gone"	10 0	"severe" "gone"	8 2
	Time until pain relief/discharge, minutes	47	25	35	65	65	66
Adverse Events	Only one patient (patient number one) reported an adverse event of feeling anxious after the haloperidol infusion, which subsided a few minutes later
Study Author Conclusions	Haloperidol is a commonly used butyrophenone as it is a potent antiemetic by its action on central chemoreceptors, which can be effective in migraine therapy. In this case series, all of the patients treated with intravenous haloperidol had significant or complete relief within approximately one hour. Haloperidol was found to be efficacious in this study with a low rate or return visits for treatment of migraines. None of the patients returned to the institution with a migraine or for any reason in the following 3 weeks, although some returned after intervals of 6 months of longer for treatment of migraine headache.
InpharmD Researcher Critique	A limitation is that only a small patient population was included and there were no standardized criteria to be included in the study, even though they tried to only treat patients with a longstanding and preferably well-documented history of migraines. Another limitation is that there was no telephone follow-up with these patients afterward to assess if they returned to any other institution because of a migraine.

References:

Fisher H. A new approach to emergency department therapy of migraine headache with intravenous haloperidol: a case series. J Emerg Med. 1995;13(1):119-22.

A Randomized Controlled Trial of Intravenous Haloperidol vs. Intravenous Metoclopramide for Acute Migraine Therapy in the Emergency Department

Design

Prospective, double-blinded, randomized control trial

N=64

Objective

To compare the efficacy of intravenous haloperidol with intravenous metoclopramide (both in combination with diphenhydramine) for the treatment of acute migraine headache in the emergency department (ED).

Study Groups

Haloperidol (n=31)

Metoclopramide (n=33)

Inclusion criteria

18-50 years old presenting with their typical migraine headache, no recognized risks for QT-prolongation

Exclusion criteria

History of heart disease, electrolyte abnormalities, prolonged QT interval, hypothyroidism, use of an ergotamine derivative within the past 24 hours, use of an MAOI inhibitor within the past two weeks

Methods

Patients were randomized to receive either haloperidol 5 mg or metoclopramide 10 mg intravenously over two minutes after diphenhydramine 25 mg.

Visual analog scale (VAS) measured pain, nausea, restlessness, and sedation at baseline and every 20 minutes, to a maximum of 80 minutes

Duration

Patients were monitored for 80 minutes in the ED

Follow-up calls after 48 hours assessed satisfaction and recurrent or persistent symptoms

Outcome Measures

Visual analog scale (VAS) score out of 100 measuring pain, nausea, restlessness, and sedation

Baseline Characteristics

Haloperidol (n=31)

Metoclopramide (n=33)

Mean age, years

Women

27 (87%)

25 (76%)

Results

The VAS pain scores for the haloperidol and metoclopramide groups did not differ at baseline, at the last recorded measurement, or in the magnitude of pre-post treatment change (p<0.01 for each comparison compared to baseline). The two regimen were also equivalent in the time to achieve maximum pain relief: 55 minutes for metoclopramide, and 56 minutes for haloperidol (p>0.05).

Both agents were effective at treating nausea, when present. There were no differences between the two groups in reported nausea either prior to or after treatment. Neither agents produced a statistically significant change in restlessness.

Patients in both groups recorded a baseline level of sedation that did not change statistically after treatment, and did not differ at baseline or study completion between groups.

Eight of the 33 patients (24%) in the metoclopramide group were given resuce medications, whereas only one of the 31 patients (3%) in the haloperidol group received rescue medications.

After the ED stay, 92% of the 24 responding patients in the haloperidol group and 75% of the 28 responding patients in the metoclopramide group stated that they would want the same medication again.

Adverse Events

	Haloperidol (n=31)		Metoclopramide (n=33)
Side effect	Baseline	Developed after haloperidol	Baseline	Developed after metoclopramide
Sleepiness	25 (81%)	5 (16%)	17 (52%)	9 (27%)
Nausea	22 (71%)	0 (0%)	20 (61%)	1 (3%)
Restlessness	10 (32%)	10 (32%)	13 (39%)	4 (12%)
Chest Pain	0 (0%)	2 (6%)	2 (6%)	0 (0%)

Study Author Conclusions

Intravenous haloperidol is as safe and effective as metoclopramide for the ED treatment of migraine headahces, with less frequent need for rescue medications.

InpharmD Researcher Critique

This study included a small sample size with females as the majority of the participants. Another limitation is that it is unknown whether the adverse event, sleepiness, was due to the administration of diphenhydramine prior to receiving the study drug or a result of the combination of the two medications.

References:

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;49(3):326-34.

Treatment of Headache in the Emergency Department: Haloperidol in the Acute Setting (THE-HA Study): A Randomized Clinical Trial
Design	A randomized, double-blind, placebo-controlled trial; N= (118)
Objective	Our aim was to evaluate the efficacy and safety of 2.5 mg i.v. haloperidol in the treatment of severe benign headache in the ED.
Study Groups	Haloperidol (n=58) Placebo (n=60)
Inclusion Criteria	Patients 13-55 years old presenting to the ED w/ the chief complaint of headache or migraine
Exclusion Criteria	Patients with abnormal BP, sudden/rapid onset, fever, acute trauma, history of brain mass or stroke, QT > 450 ms, altered mental status, etc
Methods	Patients received haloperidol 2.5 mg diluted to a final concentration of 5 mL with 0.9% sodium chloride or 5 mL of 0.9% sodium chloride. Nurses were instructed to push the medication slowly over 1 to 2 min. After drug administration, vital signs, pain score, and side effects were documented at 0, 30, 60, and 90 min, and at discharge. If the patient did not have at least a 50% reduction in VAS at the 60-min assessment, ketorolac i.v. was offered for rescue medication, with 30 mg i.v. in adults and 15 mg i.v. in patients aged 13 to 17 years or weighing < 50 kg. In patients with an allergy to ketorolac, metoclopramide 10 mg i.v. was offered as rescue medication. Patients who required rescue medication were observed an additional 60 min prior to discharge, and repeat VAS and vital signs were recorded at 120 min. Headache resolution was defined as a VAS pain score of 0 or 1 at 30, 60, or 90 min, or at discharge.
Duration	October 2015 to June 2016
Outcome Measures	The primary outcome measure was pain reduction at 60 min. Secondary outcomes: Evaluation of the effectiveness in patients 13-17 years old, time of VAS change, side effect profile, and the safety of IV haloperidol at a lower dosing regimen.
Baseline Characteristics		Haloperidol (n=58)	Control (n=60)	P value
	Age, years, median	32.5	29.5	0.53
	White, n (%)	43 (74.1)	38 (63.3)
	Sex, female, n (%)	37 (63.8)	49 (81.7)
	History of Migraines	38	32	0.73
	History of migraines, n (%)	38 (65.5)	32 (53.3)	0.82
	There were 5 participants within the range of 12-17 years old in the haloperidol group and 4 in the control group.
Results	Endpoint	Haloperidol (n=58)	Control (n=60)	p-Value
	Mean pain reduction from baseline at 60 min	4.77 units	1.87 units
	Average VAS at 60 minutes	3.5	6.5	<0.0001
	Number of patients that received rescue medication at 60 min	18 (31%)	47 (78.3%)
Adverse Events	Patients with anxiety or restlessness were treated with diphenhydramine in 7 patients and lorazepam in 2 patients at 30 min, with complete resolution of side effects in 8 of 9 patients (89%). Overall, the most common adverse event was nausea/vomiting.
Study Author Conclusions	This study suggests that 2.5 mg i.v. haloperidol is a rapid and effective treatment for acute, severe, benign headache in ED patients aged 18 to 55 years. Further study is warranted to confirm these results in adolescents.
InpharmD Researcher Critique	The type of benign headaches were not defined in the study which may have led to misclassification of serious headaches in this study. The small sample size of the pediatric population limits the conclusions that can be drawn on efficacy of haloperidol in this group.

References:

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;59(1):12-20. doi:10.1016/j.jemermed.2020.04.018