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Acute Dystonic Reactions in Children Treated for Headache With Prochlorperazine or Metoclopramide
Journal Pre-proof Acute dystonic reactions in children treated for headache with prochlorperazine or metoclopramide Laura Kirkpatrick, MD, Yoshimi Sogawa, MD, MS, Catalina Cleves, MD PII:
S0887-8994(20)30039-4
DOI:
https://doi.org/10.1016/j.pediatrneurol.2020.01.013
Reference:
PNU 9720
To appear in:
Pediatric Neurology
Received Date: 9 December 2019 Revised Date:
23 January 2020
Accepted Date: 26 January 2020
Please cite this article as: Kirkpatrick L, Sogawa Y, Cleves C, Acute dystonic reactions in children treated for headache with prochlorperazine or metoclopramide, Pediatric Neurology (2020), doi: https:// doi.org/10.1016/j.pediatrneurol.2020.01.013. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
Complete title: Acute dystonic reactions in children treated for headache with prochlorperazine or metoclopramide Running title: dystonic reactions in children Laura Kirkpatrick MDa, Yoshimi Sogawa MD, MSa, Catalina Cleves MDa a=UPMC Children’s Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh PA 15225, [email protected], [email protected], [email protected]
Corresponding author: Laura Kirkpatrick MD 412-692-5520 [email protected] 4401 Penn Avenue, Pittsburgh PA, 15224
Word count: 599
Key words: dopamine receptor antagonists, extrapyramidal side effects, migraine cocktail
INTRODUCTION: Metoclopramide and prochlorperazine are dopamine receptor antagonists used to treat acute primary headaches [1]. Acute dystonic reactions are known adverse effects [2]. The incidences of dystonic reactions with these medications have not been definitively elucidated in children. The incidence of dystonic reactions in adults has been reported from 0.2% to 3% with metoclopramide, and up to 4% with prochlorperazine [3, 4, 5]. The goal of this study was to evaluate the incidence of acute dystonic reactions with metoclopramide and prochlorperazine in children treated for acute headache.
METHODS: We reviewed medical record data for patients who received prochlorperazine or metoclopramide for acute headache from 2014-2018 at one tertiary-care pediatric hospital. Patients were excluded if treated with other dopamine agonists or antagonists, or diagnosed with dystonia at baseline. Our primary endpoint was incidence of acute dystonic reactions with intravenous metoclopramide or prochlorperazine. These variables were also reviewed: age, gender, medication dose, number of doses, and pre-treatment with diphenhydramine. Categorical variables were compared by Fisher’s Exact Test or Chi Square. Continuous variables were compared by T test. This study was approved as exempt by the University of Pittsburgh Institutional Review Board.
RESULTS:
4590 encounters were identified with prochlorperazine and metoclopramide. Two patients were excluded due to baseline dystonia. Of 4588 remaining encounters, 2542 were with prochlorperazine and 2046 with metoclopramide. The overall incidence of dystonic reactions was 0.3% (12 patients). The incidence of dystonic reactions was 0.05% (1 patient) with metoclopramide and 0.4% (11 patients) with prochlorperazine. The relative risk of a dystonic reaction with prochlorperazine over metoclopramide was 8.85 (95% CI 1.15-68.5). The number needed to harm for use of prochlorperazine over metoclopramide was 260 (95% CI 146 to 1153). There were significant differences between groups of patients who received metoclopramide versus prochlorperazine (Table 1). In a logistic regression accounting for medication, gender, age, number of doses, and diphenhydramine administration, two variables remained associated with an acute dystonic reaction: administration of prochlorperazine over metoclopramide (p=0.019) and greater number of doses administered (p<0.001) (Table 2). Statistics were conducted in SPSS (IBM, Armonk, NY).
DISCUSSION: Our study is the first to evaluate rates of dystonic reactions with prochlorperazine and metoclopramide in children treated for acute headache. While the incidence of dystonic reactions was low with either medication, there was a greater chance of a dystonic reaction with prochlorperazine than metoclopramide. Our incidences are similar to or lower than have been reported in adults [3, 4, 5]. Administration of multiple doses of medication was associated with an increased likelihood of a dystonic reaction. This finding may be pertinent to decision-making regarding serial medication administration.
Our findings also raise questions about diphenhydramine. All patients who experienced dystonic reactions received diphenhydramine pre-treatment. Yet, no patients who did not receive diphenhydramine experienced a dystonic reaction. Previous questions have been raised about the utility of diphenhydramine in preventing dystonic reactions, as in a previous randomized controlled trial wherein patients received metoclopramide with or without diphenhydramine, there was no difference in extrapyramidal side effects between groups [6]. Limitations of the study include that it is a single-center retrospective observational study. There may have been confounding variables that we did not consider. Future studies should assess for the impact of the time between doses. Overall, our characterization of the incidence of acute dystonic reactions in children makes a contribution to the literature on extrapyramidal side effects of dopamine antagonists. The findings of our study are likely generalizable to other large centers treating a high volume of pediatric headache patients. More research is needed to explore the risks and benefits of dopamine antagonist therapy for headache in the pediatric population.
Declarations of interest: none. This research did not receive any specific grant from funding agencies in the public, commercial, or non-for-profit sectors.
References: [1] Orr S, Friedman B, Christie S, et al. Management of adults with acute migraine in the Emergency Department: The American Headache Society evidence assessment of parenteral pharmacotherapies. Headache. 2016; 56: 911-40.
[2] Wijemanne S, Jankovic J, Evans RW. Movement disorders from the use of metoclopramide and other antiemetics in the treatment of migraine. Headache. 2016; 56: 153-161. [3] Cete Y, Dora B, Ertan C, et al. A randomized prospective placebo‐controlled study of intravenous magnesium sulphate vs. metoclopramide in the management of acute migraine attacks in the emergency department. Cephalalgia. 2005; 25: 199–204. [4] Yis U, Ozdemir D, Murat D, et al. Metoclopramide induced dystonia in children: two case reports. Eur J Emerg Med. 2005; 12(3): 117-119. [5] Olsen J, Keng J, Clark J. Frequency of adverse reactions to prochlorperazine in the Emergency Department. Am J Emerg Med, 2000; 18: 609-11. [6] Friedman BW, Cabral L, Adewunmi V, et al. Diphenhydramine as adjuvant therapy for acute migraine: an emergency department-based randomized clinical trial. Ann Emerg Med. 2016; 67: 32-39. Table 1: Demographics Treatment with Metoclopramide
Treatment with Prochlorperazine
Overall
P value
Gender
1323 female (65%) 723 male (35%)
1705 female (67%) 837 male (33%)
3028 female (66%) 1560 male (34%)
0.09#
Age (years)
13.3 +/- 4.7
14.6 +/- 3.7
14.0 +/- 4.2
<0.001*^
Dose (mg/kg)
0.13 +/- 0.1
0.13 +/- 0.8
0.13 +/- 0.9
0.85^
Average number of doses per headache
2.6 +/- 1.6
2.5 +/- 1.1
2.5 +/- 1.3
<0.001*^
Concurrent treatment with diphenhydramine
1395 (68%)
2359 (92%)
3718 (81%)
<0.001*#
* denotes significance # denotes analyzed by Chi Square
^ denotes analyzed by two-tailed T test
Table 2: Variables associated with dystonic reactions in binary logistic regression Variable
Dystonic Reactions
Odds Ratio
P value
Gender
5/3028 female (0.2%)
0.30 (95% CI 0.09-1.02)
0.054
0.97 (95% CI 0.83-1.14)
0.735
0.082 (95% CI 0.0100.66)
0.019*
1.92 (95% CI 1.41-2.61)
<0.001*
0.000 (95% CI 0.000 – 0.000)
0.992
7/1560 male (0.4%) Age (years)
Average with dystonic reaction: 13.9 +/ 2.8 Average without dystonic reaction: 14.0 +/- 4.2
Medication
11/2542 with prochlorperazine 1/2046 with metoclopramide
Number of doses
Average with dystonic reaction: 4 +/- 1.7 Average without dystonic reaction: 2.5 +/1.3
Concurrent treatment with diphenhydramine
12/3754 with diphenhydramine 0/834 without diphenhydramine
*denotes significance
S0887-8994(20)30039-4
DOI:
https://doi.org/10.1016/j.pediatrneurol.2020.01.013
Reference:
PNU 9720
To appear in:
Pediatric Neurology
Received Date: 9 December 2019 Revised Date:
23 January 2020
Accepted Date: 26 January 2020
Please cite this article as: Kirkpatrick L, Sogawa Y, Cleves C, Acute dystonic reactions in children treated for headache with prochlorperazine or metoclopramide, Pediatric Neurology (2020), doi: https:// doi.org/10.1016/j.pediatrneurol.2020.01.013. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
Complete title: Acute dystonic reactions in children treated for headache with prochlorperazine or metoclopramide Running title: dystonic reactions in children Laura Kirkpatrick MDa, Yoshimi Sogawa MD, MSa, Catalina Cleves MDa a=UPMC Children’s Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh PA 15225, [email protected], [email protected], [email protected]
Corresponding author: Laura Kirkpatrick MD 412-692-5520 [email protected] 4401 Penn Avenue, Pittsburgh PA, 15224
Word count: 599
Key words: dopamine receptor antagonists, extrapyramidal side effects, migraine cocktail
INTRODUCTION: Metoclopramide and prochlorperazine are dopamine receptor antagonists used to treat acute primary headaches [1]. Acute dystonic reactions are known adverse effects [2]. The incidences of dystonic reactions with these medications have not been definitively elucidated in children. The incidence of dystonic reactions in adults has been reported from 0.2% to 3% with metoclopramide, and up to 4% with prochlorperazine [3, 4, 5]. The goal of this study was to evaluate the incidence of acute dystonic reactions with metoclopramide and prochlorperazine in children treated for acute headache.
METHODS: We reviewed medical record data for patients who received prochlorperazine or metoclopramide for acute headache from 2014-2018 at one tertiary-care pediatric hospital. Patients were excluded if treated with other dopamine agonists or antagonists, or diagnosed with dystonia at baseline. Our primary endpoint was incidence of acute dystonic reactions with intravenous metoclopramide or prochlorperazine. These variables were also reviewed: age, gender, medication dose, number of doses, and pre-treatment with diphenhydramine. Categorical variables were compared by Fisher’s Exact Test or Chi Square. Continuous variables were compared by T test. This study was approved as exempt by the University of Pittsburgh Institutional Review Board.
RESULTS:
4590 encounters were identified with prochlorperazine and metoclopramide. Two patients were excluded due to baseline dystonia. Of 4588 remaining encounters, 2542 were with prochlorperazine and 2046 with metoclopramide. The overall incidence of dystonic reactions was 0.3% (12 patients). The incidence of dystonic reactions was 0.05% (1 patient) with metoclopramide and 0.4% (11 patients) with prochlorperazine. The relative risk of a dystonic reaction with prochlorperazine over metoclopramide was 8.85 (95% CI 1.15-68.5). The number needed to harm for use of prochlorperazine over metoclopramide was 260 (95% CI 146 to 1153). There were significant differences between groups of patients who received metoclopramide versus prochlorperazine (Table 1). In a logistic regression accounting for medication, gender, age, number of doses, and diphenhydramine administration, two variables remained associated with an acute dystonic reaction: administration of prochlorperazine over metoclopramide (p=0.019) and greater number of doses administered (p<0.001) (Table 2). Statistics were conducted in SPSS (IBM, Armonk, NY).
DISCUSSION: Our study is the first to evaluate rates of dystonic reactions with prochlorperazine and metoclopramide in children treated for acute headache. While the incidence of dystonic reactions was low with either medication, there was a greater chance of a dystonic reaction with prochlorperazine than metoclopramide. Our incidences are similar to or lower than have been reported in adults [3, 4, 5]. Administration of multiple doses of medication was associated with an increased likelihood of a dystonic reaction. This finding may be pertinent to decision-making regarding serial medication administration.
Our findings also raise questions about diphenhydramine. All patients who experienced dystonic reactions received diphenhydramine pre-treatment. Yet, no patients who did not receive diphenhydramine experienced a dystonic reaction. Previous questions have been raised about the utility of diphenhydramine in preventing dystonic reactions, as in a previous randomized controlled trial wherein patients received metoclopramide with or without diphenhydramine, there was no difference in extrapyramidal side effects between groups [6]. Limitations of the study include that it is a single-center retrospective observational study. There may have been confounding variables that we did not consider. Future studies should assess for the impact of the time between doses. Overall, our characterization of the incidence of acute dystonic reactions in children makes a contribution to the literature on extrapyramidal side effects of dopamine antagonists. The findings of our study are likely generalizable to other large centers treating a high volume of pediatric headache patients. More research is needed to explore the risks and benefits of dopamine antagonist therapy for headache in the pediatric population.
Declarations of interest: none. This research did not receive any specific grant from funding agencies in the public, commercial, or non-for-profit sectors.
References: [1] Orr S, Friedman B, Christie S, et al. Management of adults with acute migraine in the Emergency Department: The American Headache Society evidence assessment of parenteral pharmacotherapies. Headache. 2016; 56: 911-40.
[2] Wijemanne S, Jankovic J, Evans RW. Movement disorders from the use of metoclopramide and other antiemetics in the treatment of migraine. Headache. 2016; 56: 153-161. [3] Cete Y, Dora B, Ertan C, et al. A randomized prospective placebo‐controlled study of intravenous magnesium sulphate vs. metoclopramide in the management of acute migraine attacks in the emergency department. Cephalalgia. 2005; 25: 199–204. [4] Yis U, Ozdemir D, Murat D, et al. Metoclopramide induced dystonia in children: two case reports. Eur J Emerg Med. 2005; 12(3): 117-119. [5] Olsen J, Keng J, Clark J. Frequency of adverse reactions to prochlorperazine in the Emergency Department. Am J Emerg Med, 2000; 18: 609-11. [6] Friedman BW, Cabral L, Adewunmi V, et al. Diphenhydramine as adjuvant therapy for acute migraine: an emergency department-based randomized clinical trial. Ann Emerg Med. 2016; 67: 32-39. Table 1: Demographics Treatment with Metoclopramide
Treatment with Prochlorperazine
Overall
P value
Gender
1323 female (65%) 723 male (35%)
1705 female (67%) 837 male (33%)
3028 female (66%) 1560 male (34%)
0.09#
Age (years)
13.3 +/- 4.7
14.6 +/- 3.7
14.0 +/- 4.2
<0.001*^
Dose (mg/kg)
0.13 +/- 0.1
0.13 +/- 0.8
0.13 +/- 0.9
0.85^
Average number of doses per headache
2.6 +/- 1.6
2.5 +/- 1.1
2.5 +/- 1.3
<0.001*^
Concurrent treatment with diphenhydramine
1395 (68%)
2359 (92%)
3718 (81%)
<0.001*#
* denotes significance # denotes analyzed by Chi Square
^ denotes analyzed by two-tailed T test
Table 2: Variables associated with dystonic reactions in binary logistic regression Variable
Dystonic Reactions
Odds Ratio
P value
Gender
5/3028 female (0.2%)
0.30 (95% CI 0.09-1.02)
0.054
0.97 (95% CI 0.83-1.14)
0.735
0.082 (95% CI 0.0100.66)
0.019*
1.92 (95% CI 1.41-2.61)
<0.001*
0.000 (95% CI 0.000 – 0.000)
0.992
7/1560 male (0.4%) Age (years)
Average with dystonic reaction: 13.9 +/ 2.8 Average without dystonic reaction: 14.0 +/- 4.2
Medication
11/2542 with prochlorperazine 1/2046 with metoclopramide
Number of doses
Average with dystonic reaction: 4 +/- 1.7 Average without dystonic reaction: 2.5 +/1.3
Concurrent treatment with diphenhydramine
12/3754 with diphenhydramine 0/834 without diphenhydramine
*denotes significance