a b s t r a c t

Study objective: To compare the efficacy and frequency of akathisia and dystonia between the dopamine antago- nist headache medications olanzapine, metoclopramide and prochlorperazine.

Methods: This was a retrospective observational cohort study of patients presenting to a large urban level one trauma center between 2010 and 2018. Inclusion criteria was age >= 18 who presented to the emergency depart- ment with a chief complaint of headache who received either olanzapine, metoclopramide or prochlorperazine. The primary outcome was need for rescue medication. Secondary outcomes were receiving medication for either akathisia or dystonia. Logistic regression was used to identify differences between the three cohorts up to 72 h from initial presentation.

Results: There were 5643 patients who met inclusion criteria. Olanzapine was the most commonly used drug (n = 2994, 53%) followed by prochlorperazine (n = 2100, 37%) and metoclopramide (n = 549, 10%). After adjusting for age and gender, there were no differences in risk for receiving Rescue therapy or developing akathisia or dystonia.

Conclusion: During initial ED visit and up to 72 h after receiving olanzapine, metoclopramide or prochlorperazine, we found no difference in risk for requiring rescue medication or developing akathisia or dystonia.

(C) 2022 Published by Elsevier Inc.

1. Introduction

Headache is the fifth most common reason for an Emergency De- partment (ED) visit with over 4 million annual ED encounters, or 2.8% of overall ED visits [1]. migraine headaches have an estimated $13-17 billion annual cost due to Healthcare costs, reduced quality of life and lost productivity in the workplace [2,3]. primary headaches therefore constitute a significant public health burden and should be managed with rapid, effective pain relief that minimizes side effects.

The precise underlying pathophysiology of primary headaches is un- certain, but there are several classes of medications that are effective ther- apies including nonsteroidal anti-inflammatories (NSAIDs), selective serotonin agonists (triptans), dopamine antagonists (eg, metoclopramide, prochlorperazine), and antipsychotics (eg, droperidol, haloperidol, and

* Corresponding author at: Hennepin County Medical Center, Dept of Emergency Medicine, 701 Park Ave, Minneapolis, MN 55415, United States of America.

E-mail address: drchinn@gmail.com (E. Chinn).

olanzapine). In the emergency department, expert recommendations sug- gest first-line therapy should be dopamine antagonists [4]. The use of antidopaminergic therapy has been well-described for headache treat- ment, but there are varying levels of evidence comparing the effectiveness and safety of unique dopamine antagonist therapies. The antiemetics prochlorperazine, droperidol, metoclopramide provide effective migraine pain relief compared to placebo, however overall strength of evidence is low [5]. While some studies suggest there is no difference in the efficacy of metoclopramide versus prochlorperazine, a recent meta-analysis sug- gests that prochlorperazine is the more effective medication for migraine [6,7]. Other randomized trials in the ED have shown droperidol to be supe- rior to the more commonly used metoclopramide and prochlorperazine [8,9], however until recently droperidol was on a prolonged shortage in the US [10]. One randomized trial showed olanzapine to be equivalent to droperidol for acute primary headache in the ED while causing fewer adverse events; as such, the use of olanzapine for headache in the ED has become a local standard practice [11]. In addition, both intramuscular and intravenous olanzapine has been shown to be a safe and effective

https://doi.org/10.1016/j.ajem.2022.12.039 0735-6757/(C) 2022 Published by Elsevier Inc.

therapy for a variety of conditions in both pediatric and adult populations in the emergency department [12-14].

Given the evolution of our local practice and limited evidence for olanzapine use versus other primary headache therapies we sought to

Table 1

Demographics.

Characteristic Olanzapine,

N = 2,994¹

Metoclopramide, N = 549¹

Prochlorperazine, N = 2,100¹

compare olanzapine to metoclopramide and prochlorperazine, the other commonly used dopamine antagonists in our ED. The primary ob- jective was to evaluate how often patients required additional rescue medication, a clinically relevant outcome that accurately reflects whether the headache resolved after the administration of initial ther-

Age 37 (28, 48) 34 (26, 46) 35 (26, 46)

Female 2031 (68%) 416 (76%) 1403 (67%)

Race

Unknown 63 (2.1%) 10 (1.8%) 48 (2.3%)

American Indian (Native American) or Alaskan

apy. To assess safety and risk of adverse events, secondary outcomes	Native	117 (3.9%)	17 (3.1%)	86 (4.1%)
of interest were rates of dystonia and akathisia, the most common	Asian	51 (1.7%)	13 (2.4%)	37 (1.8%)

extrapyramidal side effects associated with dopamine antagonism, in addition to return visits for either recurring headache, akathisia, and dystonia within 72 h after initial ED visit.

1. Methods
   1. Study design & setting

This was a retrospective observational study conducted by medical record review at an urban Level 1 trauma center that sees 110,000 pa- tients annually. Inclusion criteria was defined as adult patients >=18 years old who were evaluated with a chief complaint of headache from 2010 to 2018 and received olanzapine, metoclopramide, or prochlorperazine by any route. We did not include droperidol because it was unavailable at our institution for the majority of the study period [15].

• 1. Study protocol, variables, and outcomes

The electronic medical record (Epic, Verona, WI) was queried for ED encounters that fit the study criteria. A blinded analyst extracted data directly from the electronic medical record. Patients were categorized by the initial drug they received – prochlorperazine, metoclopramide, or olanzapine. Other extracted variables included gender, age, race, the presence of dystonia or akathisia in the ED, and return visits within 72 h for either headache, dystonia, or akathisia. We determined who re- ceived rescue therapy, our primary outcome, which was defined as the administration of more than one total dose of any of the drugs of inter- est (eg, one dose of olanzapine and one dose of prochlorperazine). A trained abstractor reviewed charts to determine if patients had akathisia or dystonia for secondary outcome analysis in patients receiv- ing either diphenhydramine, benztropine, or lorazepam. 10% of charts were reviewed to calculate inter-rater reliability (IRR).

Black (African American

or African) 1453 (49%) 279 (51%) 1093 (52%)

Hispanic (Latinx) 522 (17%) 112 (20%) 371 (18%)

Multi-racial 0 (0%) 1 (0.2%) 1 (<0.1%) Native Hawaiian or

Pacific Islander 3 (0.1%) 0 (0%) 5 (0.2%) White (Caucasian,

Non-Hispanic) 785 (26%) 117 (21%) 459 (22%)

¹ Median (IQR); n (%).

exception of a higher proportion of female patients receiving metoclopramide (Table 1). Olanzapine (n = 2994, 53%) was the most prescribed medication followed by prochlorperazine (n = 2100, 37%) and metoclopramide (n = 549, 10%). Study population demographics are summarized in Table 1.

The proportion of patients who received rescue therapy was 14.9% (95% CI 12-18) after metoclopramide; 16.5% (95% CI 15-18) for

prochlorperazine; and 18.2% (95% CI 17-20) for olanzapine (Table 2). Metoclopramide had 0 cases of dystonia while prochlorperazine had

4 (0.2%) and olanzapine had 2 (0.1%). Additionally, rates of akathisia

were 8 (1.5%) for metoclopramide, 28 (1.3%) for prochlorperazine, and 35 (1.2%) for olanzapine. IRR was 94% for akathisia in the ED and while there was 100% agreement in the 10% sample, we could not calcu- late IRR for the other variables because there were no instances of dys- tonia in the ED or within 72 h and no akathisia at 72 h.

In the unadjusted model, there was no difference in need for rescue medication for either metoclopramide (0.79, 95% CI 0.61-1) or

prochlorperazine (0.88, 95% CI 0.76-1) compared to olanzapine (Table 3). In the model that adjusted for age and gender, there was also no significant difference in rescue therapy between the medica- tions of interest. Increasing age (1.01, 95% CI 1-1.02) and Female gender

Table 2

Frequencies of Primary and Secondary Outcomes in the ED.

• 1. Statistical methods

Characteristic Olanzapine, N = 2,994¹

Metoclopramide, N = 549¹

Prochlorperazine,

N = 2,100¹

Continuous elements were summarized with medians and inter- quartile ranges while categorical features were summarized with fre-	Rescue Male	546 (18.2%) 163 (29.9%)	82 (14.9%) 19 (23.2%)	346 (16.5%) 104 (30.1%)
quency counts and percentages. Statistical analyses were performed in	Female	383 (70.1%)	63 (76.8%)	242 (69.9%)
RStudio [16], including multivariable logistic regression for primary and secondary outcomes. Given olanzapine is a more novel migraine medication, we used it as the reference drug for calculating odds ratios	Dystonia Male Female Akathisia	2 (0.1%) 1 (50%) 1 (50%) 35 (1.2%)	0 (0%) 0 (0%) 0 (0%) 8 (1.5%)	4 (0.2%) 3 (75%) 1 (25%) 28 (1.3%)
(OR) in both unadjusted and adjusted models. Adjusted models were	Male	9 (25.7%)	0 (0%)	10 (35.7%)
constructed a priori based on available covariates that could influence	Female	26 (74.3%)	8 (100%)	18 (64.3%)
the need for administration of a second dose for headache relief. Age was included in our model as older adults tend to be on more medications, increasing the likelihood of adverse reactions. Gender	1 n (%).

was included in the model as female patients suffer from migraines at a higher rate than males. r² was calculated for adjusted models to mea- sure goodness of fit.

1. Result

Table 3

Rescue Medication.

Olanzapine

Unadjusted (OR, 95% C.I.) Adjusted (OR, 95% C.I.)

A total of 5643 patients fit the inclusion criteria. There were no major differences in demographics between the three groups with the

Metoclopramide 0.79 (0.61-1.01) 0.79 (0.61-1.01)

Prochlorperazine 0.88 (0.76-1.02) 0.9 (0.77-1.04) r2 for age and gender = 0.004.

Table 4 Secondary Outcomes in ED.
	Dystonia			Akathisia
	Unadjusted	Adjusted		Unadjusted	Adjusted
Olanzapine
Metoclopramide Prochlorperazine	na 4.76 (0.92-34.6)	0.79 (0.61-1.01) 0.90 (0.77-1.04)		2.19 (0.89-4.9) 2.05 (1.19-3.5)	0.79 (0.61-1.01) 0.90 (0.77-1.04)

r2 for age and gender = 0.004.

Table 5

Secondary Outcomes at 72 Hours.

		Headache			Dystonia			Akathisia
		Unadjusted	Adjusted		Unadjusted	Adjusted		Unadjusted	Adjusted
	Olanzapine
	Metoclopramide	0.77 (0.41-1.34)	0.76 (0.4-1.32)		*	*		5.46 (0.22-138.25)	5.3 (0.21-135.4)
	Prochlorperazine	0.86 (0.61-1.2)	0.84 (0.6-1.18)		*	*		1.43 (0.06-36.07)	1.32 (0.05-33.97)

* Zero cases of dystonia at 72 h. r2 for age and gender = 0.004.

(1.18, 95% CI 1.02-1.38) were associated with an increased need for res- cue medication, however the r² was 0.004 meaning this model accounts for 0.4% of the variability between the data and the model which is rather weak.

For dystonic reactions, there was no difference between the three drugs in unadjusted and adjusted models (Table 4). Similar to need for rescue medication, age (1.01, 95% CI 1-1.02) and female gender (1.18, 95% CI 1.02-1.38) predicted an increased odds of having a dys- tonic reaction.

In the unadjusted model, prochlorperazine was significantly more likely to be associated with akathisia compared to olanzapine (2.05, 95% CI 1.19-3.5) whereas metoclopramide was not (2.19, 95% CI 0.89-4.9), however after adjusting for age and gender, there was no dif- ference between all three drugs in causing akathisia (Table 4).

At 72 h, there were no differences in return visits for recurring mi- graine, dystonia, or akathisia in either unadjusted or adjusted models (Table 5). Most returned for headache (N = 159) followed by akathisia (N = 3). None returned for dystonia.

1. Discussion

For adult patients with a chief complaint of headache in the emergency department, patients who received olanzapine, metoclopramide, and prochlorperazine had no significant differ- ence in the need for rescue medication. Metoclopramide and prochlorperazine are commonly used for primary headache phar- macotherapy and can provide effective headache relief [4-6]. This study reinforces prior studies that suggest olanzapine may also be a suitable therapy for primary headache management in the ED, as most patients who received olanzapine obtained adequate head- ache relief without the need for rescue medication.

Additionally, there was no difference in the rates of dystonia or akathisia for any of the medications after adjusting for age and gender. Both conclusions are consistent with previous studies examining the use and safety of olanzapine therapy [9,10]. Choosing the most appro- priate primary headache pharmacotherapy requires the consideration of many factors, including diagnosis, patient preference, previous ther- apy effectiveness, cost, contraindications, and side effect profile. It is thus beneficial for physicians to have access to a broad range of potential therapeutic options.

Controlling for age and gender also demonstrated no difference in the need for rescue medication or frequency of adverse events for any of the medications, both in the ED and within 72 h after initial visit.

1. Limitations

There were several limitations identified in this study. First, this study was retrospective and depended upon accurate data documenta- tion within the medical record. With a large enough sample size this ef- fect should be minimal. Adverse events may also be underreported, leading to underestimating dystonia and akathisia. Additionally, this study did not compare medications with a placebo and can only provide comparative analysis. Further, this study focused on single visits and did not explore long-term sequelae or the rates of Headache recurrence re- quiring additional visits and therapy beyond 72 h from initial presenta- tion. Finally, while this chart review study found no difference in efficacy or adverse events between olanzapine, metoclopramide, and prochlorperazine for acute primary headache, additional randomized controlled trials with standardized dosing, indications, and documenta- tion practices may be warranted to limit bias and confounding effects.

1. Conclusion

The results of this study ultimately suggest that olanzapine should be considered as a potential alternative pharmacotherapy option for primary headache in the emergency department. Olanzapine provided adequate pain relief as measured by use of rescue medication and was similarly effective and safe in comparison to other anti-dopaminergic therapies such as prochlorperazine and metoclopramide.

External funding

None.

CRediT authorship contribution statement

Elliott Chinn: Writing – review & editing, Supervision, Formal anal- ysis. Nicholas D. Brunette: Writing – original draft. Brian E. Driver: Writing – review & editing, Supervision, Project administration, Con- ceptualization. Lauren R. Klein: Validation, Methodology, Investigation,

Conceptualization. Jamie L. Stang: Data curation. Paige DeVries: Data curation. Erika Mojica: Data curation. Abagail Raiter: Data curation. James R. Miner: Writing – review & editing. Jon B. Cole: Writing – review & editing, Supervision, Conceptualization.

Declaration of Competing Interest

There are no conflicts of interest to disclose for this publication.

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