ISSN 0017-8748 doi: 10.1111/head.12255 Published by Wiley Periodicals, Inc.
Headache © 2013 American Headache Society
Research Submission Chlorpromazine for the Treatment of Migraine in a Pediatric Emergency Department Jessica M. Kanis, MD; Nathan L. Timm, MD
Background.—Migraine headache is a common presenting condition to the pediatric emergency department (PED). Dopamine receptor antagonists, such as prochlorperazine and metoclopramide, serve as the primary treatment for migraine headache in many emergency departments; however, in 2012, our institution experienced a shortage of these drugs, resulting in the use of alternative medications. Chlorpromazine was included as an option for treatment at our institution during this shortage, although limited data exist on the effectiveness in children. Objective.—The objectives of this study were: (1) to compare the treatment failure rate of chlorpromazine in the treatment of migraine headache in youth presenting to the PED with those who received prochlorperazine; and (2) to identify the frequency and type of adverse events, and change in pain score. Methods.—We performed a retrospective cohort study of patients 12-21 years of age treated for migraine headache in our emergency department. Our treatment group received intravenous chlorpromazine between February and April 2012, while the comparison group consisted of children treated with intravenous prochlorperazine between February and April 2011. The outcomes of interest were: (1) treatment failure, defined as need for additional therapy, hospitalization or 48-hour return; (2) adverse reactions to drug therapy; and (3) change in pain score. Results.—This study yielded 75 patients in the treatment group and 274 in the comparison group. Forty percent (30/75) of the treatment group had treatment failure compared with 15% (41/274) of the comparison group. There was no difference in mean change in pain score between the groups. The most common adverse effects included hypotension in the treatment group (12%) and akathisia in the comparison group (12%). Conclusions.—This is the first study that has examined the use of chlorpromazine as a therapy in pediatric migraines. Abortive therapy for migraine headache in the PED with chlorpromazine is associated with greater need for rescue medication and hospitalization, and higher rates of hypotension. Key words: chlorpromazine, migraine, headache, prochlorperazine, pediatric emergency department Abbreviations: CCHMC Cincinnati Children’s Hospital Medical Center, EKG electrocardiogram, IHS International Headache Society, IV intravenous, NSAID non-steroidal anti-inflammatory drug, PED pediatric emergency department, VP ventriculoperitoneal (Headache 2014;54:335-342)
BACKGROUND Migraine headache in children and adolescents is a common problem that can lead to significant impairment in quality of life.1,2 Children with
From the Division of Emergency Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Address all correspondence to J. Kanis, Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA, email: [email protected]
Conflict of Interest: The authors have no conflicts of interest to disclose. Funding Source: This study received no financial support. Financial Disclosure: The authors have no financial relationships relevant to this article to disclose.
Accepted for publication August 22, 2013.
335
336 migraine headache frequently present to the pediatric emergency department (PED) when outpatient therapy has failed. Prevalence studies have shown that migraine headache accounts for 8-19% of all headaches in the PED.3,4 Despite the frequency of this complaint, there is significant practice variation with regard to route and class of medication used.5 Dopamine receptor antagonists, particularly prochlorperazine and metoclopramide, are most commonly used for both pediatric and adult migraine therapy.5 Although in the same class of medication, chlorpromazine has been shown to have limited effectiveness in adult migraine therapy, but there are no studies evaluating the effectiveness in the pediatric population. In recent years, medication shortages have affected availability of commonly used medications. Over the past 5-10 years, the number of drug shortages has increased annually and include many commonly used medications that significantly affect patient care, such as morphine, propofol, and furosemide.6 In 2010, the American Society of HealthSystem Pharmacists tracked a total of 211 drug shortages, the highest number to date in a single year.6,7 In 2012, our hospital was faced with a shortage of both prochlorperazine and metoclopramide. Our hospital developed a consensus guideline for alternative therapy for migraine headaches that included the use of chlorpromazine. Pediatric neurologists, pharmacists, and emergency medicine physicians participated in developing this guideline. The objective of this study was to compare the treatment failure rate of chlorpromazine in the treatment of migraine headache in youth presenting to the PED with those who received prochlorperazine. Secondary outcomes included determination of the change in pain score and identifying the frequency and type of adverse events that occurred with each medication.
MATERIALS AND METHODS Study Design.—We performed a retrospective cohort study of youth treated in our emergency department for migraine headache with either intravenous (IV) chlorpromazine or prochlorperazine.
February 2014 The Cincinnati Children’s Hospital Medical Center (CCHMC) Institutional Review Board approved the study. Setting.—CCHMC is a large, urban, tertiary care, pediatric teaching hospital, with a PED patient volume of nearly 130,000 visits per year and is an American College of Surgeons verified Level I Trauma Center. CCHMC serves the local pediatric needs of southwest Ohio, northern Kentucky, and southeast Indiana, and is the primary pediatric referral center for the greater Cincinnati area. Study Protocol.—In early 2012, our institution faced a national drug shortage of both prochlorperazine and metoclopramide. These were our firstline therapies in the PED for acute treatment of pediatric migraine. The existing protocol included prochlorperazine or metoclopramide with IV normal saline bolus (20 mL/kg) with/without ketorolac. An expert committee made up of CCHMC faculty from the Divisions of Pediatric Neurology, Emergency Medicine, and Pharmacy developed an alternative treatment strategy for use in the PED. The new protocol recommended an IV normal saline bolus (20 mL/kg up to 1 L), ketorolac if no non-steroidal anti-inflammatory drug (NSAID) was given prior to arrival (15 mg if weight 50 kg; 30 mg if weight ≥50 kg), and chlorpromazine (0.1 mg/kg).8 An electrocardiogram (EKG) was to be performed prior to administration of chlorpromazine to evaluate for prolonged QTc, as this is a contraindication to use. The rescue therapies available were the same as those prior to the drug shortage. These included IV dexamethasone, methylprednisolone, valproic acid, and dihydroergotamine. Participants.—Participants were determined by medication administration. The treatment group included children 12-21 years of age, who presented to the PED between February and April 2012, and received IV chlorpromazine for migraine headache as determined by the treating physician.The comparison group included patients ages 12-21 years who presented 1 year earlier to the PED between February and April 2011, and received IV prochlorperazine. Patients who met the International Headache Society (IHS) criteria for migraine were not determined from the chart; the diagnosis of migraine headache was
Headache determined clinically by the emergency medicine physician. We excluded patients who received chlorpromazine or prochlorperazine for headache due to other etiology, such as ventriculoperitoneal (VP) shunt, intracranial mass, hemorrhage, meningitis, trauma/concussion, or other illness. Patients who were non-verbal were also excluded as they were unable to give pain score. Record Review.—Data Collection.—All charts were identified through query of our electronic medical record, EPIC© (Epic Systems, Verona, WI, USA). We searched for the medication “chlorpromazine” administered between February 2012 and April 2012 to obtain the treatment group and “prochlorperazine” between February 2011 and April 2011 for the comparison group. Our primary outcome was treatment failure defined as administration of further rescue medication, hospitalization, or 48-hour return visit for symptom recurrence. Secondary outcomes included mean change in pain score and adverse events. Baseline patient demographics extracted electronically including age, race, and sex. Electronic query was also used to extract length of stay, all medications given, time of medication administration to determine initial therapy and rescue therapy, time to medication, documented pain scores, EKG obtained, diagnosis, disposition, time to disposition, and 48-hour return from PED visit. Charts were then reviewed by the principal investigator to determine prior diagnosis of migraine by patient or parent report, home medications given prior to arrival in PED, and adverse effects, such as akathisia, hypotension, dizziness, nausea, somnolence, dry mouth, or dystonic reactions. Home medications were classified into acetaminophen, NSAIDs, triptans or prophylactic medications (amitriptyline, valproic acid, and topiramate), or others. Rescue medications were medications given after prochlorperazine or chlorpromazine, fluids, and ketorolac, and included valproic acid, methylprednisilone, opiates, repeat dose of prochlorperazine or chlorpromazine, other anti-emetics, and dihydroergotamine. Akathisia was determined by documentation of agitation, irritability, or administration of diphenhydramine >30 minutes after administration of prochlorperazine or chlorpromazine. Patients were determined to have hypotension for a
337 blood pressure less than 90/50 as defined by the Pediatric Advanced Life Support for this age group.9 Pain scores were extracted prior to treatment, using the initial pain score upon arrival to the PED and final pain score after treatment. If rescue medication was given, we used the mean pain score prior to the administration of the additional medication. Our institution uses the numerical rating scale pain scale from 0 to 10 that is obtained by verbal assessment by the patient.10 Pain scores are documented by the nurse on initial assessment and after medication administration. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All data were entered into a REDCap database. Statistical analysis was performed using SAS v.9.3 (SAS Institute Inc, Cary, NC, USA). Sample Size.—From the literature using the same primary outcome measure, the failure rate of prochlorperazine is approximately 10%,11-14 and failure rate of chlorpromazine has range 10-50%.15-17 Assuming a 10% failure rate in the treatment group, we calculated a minimum sample size of 50 patients in each group to detect a difference of 15 percentage points with a power of 80%. We assumed an alpha = 0.05 and a two-sided test. Statistical Analysis.—Descriptive statistics including means, standard deviations, frequencies, and percentages were used to characterize the study population. Chi-square and Fisher’s exact tests were performed to assess for differences in proportions of the study demographics and the primary outcome, including overall treatment failure, hospital admission, rescue medication, and 48-hour return. Mean change in pain scores were derived using initial and final pain scores, substituting the pain score after initial therapy when the patient was given further rescue medication. Unpaired t-test was used to compare pain scores. Adverse events were characterized by frequencies and percentages.
RESULTS From February 2012 to April 2012, 83 patients received chlorpromazine. Among these patients, 1 patient received chlorpromazine for hiccups and 7 for
338
February 2014 Table 1.—Patient Demographics
Mean age (SD) in years Male Race Caucasian African American Other† Prior migraine*‡ Medications given prior to arrival None Acetaminophen NSAID Triptans Prophylaxis*§ Others¶
Total N = 349 (%)
Chlorpromazine N = 75 (%)
Prochlorperazine N = 274 (%)
15.1 (2.1) 91 (26%)
15.1 (2.2) 21 (28%)
15.3 (1.9) 70 (26%)
256 (73%) 69 (20%) 24 (7%) 209 (60%)
56 (75%) 15 (20%) 4 (5%) 60 (80%)
200 (73%) 54 (20%) 20 (7%) 149 (54%)
101 (29%) 64 (18%) 168 (48%) 58 (17%) 61 (17%) 47 (13%)
20 (27%) 14 (19%) 36 (48%) 11 (15%) 21 (28%) 12 (16%)
81 (30%) 50 (18%) 132 (48%) 47 (17%) 40 (15%) 35 (13%)
*Denotes statically significant difference for P value
Headache © 2013 American Headache Society
Research Submission Chlorpromazine for the Treatment of Migraine in a Pediatric Emergency Department Jessica M. Kanis, MD; Nathan L. Timm, MD
Background.—Migraine headache is a common presenting condition to the pediatric emergency department (PED). Dopamine receptor antagonists, such as prochlorperazine and metoclopramide, serve as the primary treatment for migraine headache in many emergency departments; however, in 2012, our institution experienced a shortage of these drugs, resulting in the use of alternative medications. Chlorpromazine was included as an option for treatment at our institution during this shortage, although limited data exist on the effectiveness in children. Objective.—The objectives of this study were: (1) to compare the treatment failure rate of chlorpromazine in the treatment of migraine headache in youth presenting to the PED with those who received prochlorperazine; and (2) to identify the frequency and type of adverse events, and change in pain score. Methods.—We performed a retrospective cohort study of patients 12-21 years of age treated for migraine headache in our emergency department. Our treatment group received intravenous chlorpromazine between February and April 2012, while the comparison group consisted of children treated with intravenous prochlorperazine between February and April 2011. The outcomes of interest were: (1) treatment failure, defined as need for additional therapy, hospitalization or 48-hour return; (2) adverse reactions to drug therapy; and (3) change in pain score. Results.—This study yielded 75 patients in the treatment group and 274 in the comparison group. Forty percent (30/75) of the treatment group had treatment failure compared with 15% (41/274) of the comparison group. There was no difference in mean change in pain score between the groups. The most common adverse effects included hypotension in the treatment group (12%) and akathisia in the comparison group (12%). Conclusions.—This is the first study that has examined the use of chlorpromazine as a therapy in pediatric migraines. Abortive therapy for migraine headache in the PED with chlorpromazine is associated with greater need for rescue medication and hospitalization, and higher rates of hypotension. Key words: chlorpromazine, migraine, headache, prochlorperazine, pediatric emergency department Abbreviations: CCHMC Cincinnati Children’s Hospital Medical Center, EKG electrocardiogram, IHS International Headache Society, IV intravenous, NSAID non-steroidal anti-inflammatory drug, PED pediatric emergency department, VP ventriculoperitoneal (Headache 2014;54:335-342)
BACKGROUND Migraine headache in children and adolescents is a common problem that can lead to significant impairment in quality of life.1,2 Children with
From the Division of Emergency Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Address all correspondence to J. Kanis, Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA, email: [email protected]
Conflict of Interest: The authors have no conflicts of interest to disclose. Funding Source: This study received no financial support. Financial Disclosure: The authors have no financial relationships relevant to this article to disclose.
Accepted for publication August 22, 2013.
335
336 migraine headache frequently present to the pediatric emergency department (PED) when outpatient therapy has failed. Prevalence studies have shown that migraine headache accounts for 8-19% of all headaches in the PED.3,4 Despite the frequency of this complaint, there is significant practice variation with regard to route and class of medication used.5 Dopamine receptor antagonists, particularly prochlorperazine and metoclopramide, are most commonly used for both pediatric and adult migraine therapy.5 Although in the same class of medication, chlorpromazine has been shown to have limited effectiveness in adult migraine therapy, but there are no studies evaluating the effectiveness in the pediatric population. In recent years, medication shortages have affected availability of commonly used medications. Over the past 5-10 years, the number of drug shortages has increased annually and include many commonly used medications that significantly affect patient care, such as morphine, propofol, and furosemide.6 In 2010, the American Society of HealthSystem Pharmacists tracked a total of 211 drug shortages, the highest number to date in a single year.6,7 In 2012, our hospital was faced with a shortage of both prochlorperazine and metoclopramide. Our hospital developed a consensus guideline for alternative therapy for migraine headaches that included the use of chlorpromazine. Pediatric neurologists, pharmacists, and emergency medicine physicians participated in developing this guideline. The objective of this study was to compare the treatment failure rate of chlorpromazine in the treatment of migraine headache in youth presenting to the PED with those who received prochlorperazine. Secondary outcomes included determination of the change in pain score and identifying the frequency and type of adverse events that occurred with each medication.
MATERIALS AND METHODS Study Design.—We performed a retrospective cohort study of youth treated in our emergency department for migraine headache with either intravenous (IV) chlorpromazine or prochlorperazine.
February 2014 The Cincinnati Children’s Hospital Medical Center (CCHMC) Institutional Review Board approved the study. Setting.—CCHMC is a large, urban, tertiary care, pediatric teaching hospital, with a PED patient volume of nearly 130,000 visits per year and is an American College of Surgeons verified Level I Trauma Center. CCHMC serves the local pediatric needs of southwest Ohio, northern Kentucky, and southeast Indiana, and is the primary pediatric referral center for the greater Cincinnati area. Study Protocol.—In early 2012, our institution faced a national drug shortage of both prochlorperazine and metoclopramide. These were our firstline therapies in the PED for acute treatment of pediatric migraine. The existing protocol included prochlorperazine or metoclopramide with IV normal saline bolus (20 mL/kg) with/without ketorolac. An expert committee made up of CCHMC faculty from the Divisions of Pediatric Neurology, Emergency Medicine, and Pharmacy developed an alternative treatment strategy for use in the PED. The new protocol recommended an IV normal saline bolus (20 mL/kg up to 1 L), ketorolac if no non-steroidal anti-inflammatory drug (NSAID) was given prior to arrival (15 mg if weight 50 kg; 30 mg if weight ≥50 kg), and chlorpromazine (0.1 mg/kg).8 An electrocardiogram (EKG) was to be performed prior to administration of chlorpromazine to evaluate for prolonged QTc, as this is a contraindication to use. The rescue therapies available were the same as those prior to the drug shortage. These included IV dexamethasone, methylprednisolone, valproic acid, and dihydroergotamine. Participants.—Participants were determined by medication administration. The treatment group included children 12-21 years of age, who presented to the PED between February and April 2012, and received IV chlorpromazine for migraine headache as determined by the treating physician.The comparison group included patients ages 12-21 years who presented 1 year earlier to the PED between February and April 2011, and received IV prochlorperazine. Patients who met the International Headache Society (IHS) criteria for migraine were not determined from the chart; the diagnosis of migraine headache was
Headache determined clinically by the emergency medicine physician. We excluded patients who received chlorpromazine or prochlorperazine for headache due to other etiology, such as ventriculoperitoneal (VP) shunt, intracranial mass, hemorrhage, meningitis, trauma/concussion, or other illness. Patients who were non-verbal were also excluded as they were unable to give pain score. Record Review.—Data Collection.—All charts were identified through query of our electronic medical record, EPIC© (Epic Systems, Verona, WI, USA). We searched for the medication “chlorpromazine” administered between February 2012 and April 2012 to obtain the treatment group and “prochlorperazine” between February 2011 and April 2011 for the comparison group. Our primary outcome was treatment failure defined as administration of further rescue medication, hospitalization, or 48-hour return visit for symptom recurrence. Secondary outcomes included mean change in pain score and adverse events. Baseline patient demographics extracted electronically including age, race, and sex. Electronic query was also used to extract length of stay, all medications given, time of medication administration to determine initial therapy and rescue therapy, time to medication, documented pain scores, EKG obtained, diagnosis, disposition, time to disposition, and 48-hour return from PED visit. Charts were then reviewed by the principal investigator to determine prior diagnosis of migraine by patient or parent report, home medications given prior to arrival in PED, and adverse effects, such as akathisia, hypotension, dizziness, nausea, somnolence, dry mouth, or dystonic reactions. Home medications were classified into acetaminophen, NSAIDs, triptans or prophylactic medications (amitriptyline, valproic acid, and topiramate), or others. Rescue medications were medications given after prochlorperazine or chlorpromazine, fluids, and ketorolac, and included valproic acid, methylprednisilone, opiates, repeat dose of prochlorperazine or chlorpromazine, other anti-emetics, and dihydroergotamine. Akathisia was determined by documentation of agitation, irritability, or administration of diphenhydramine >30 minutes after administration of prochlorperazine or chlorpromazine. Patients were determined to have hypotension for a
337 blood pressure less than 90/50 as defined by the Pediatric Advanced Life Support for this age group.9 Pain scores were extracted prior to treatment, using the initial pain score upon arrival to the PED and final pain score after treatment. If rescue medication was given, we used the mean pain score prior to the administration of the additional medication. Our institution uses the numerical rating scale pain scale from 0 to 10 that is obtained by verbal assessment by the patient.10 Pain scores are documented by the nurse on initial assessment and after medication administration. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All data were entered into a REDCap database. Statistical analysis was performed using SAS v.9.3 (SAS Institute Inc, Cary, NC, USA). Sample Size.—From the literature using the same primary outcome measure, the failure rate of prochlorperazine is approximately 10%,11-14 and failure rate of chlorpromazine has range 10-50%.15-17 Assuming a 10% failure rate in the treatment group, we calculated a minimum sample size of 50 patients in each group to detect a difference of 15 percentage points with a power of 80%. We assumed an alpha = 0.05 and a two-sided test. Statistical Analysis.—Descriptive statistics including means, standard deviations, frequencies, and percentages were used to characterize the study population. Chi-square and Fisher’s exact tests were performed to assess for differences in proportions of the study demographics and the primary outcome, including overall treatment failure, hospital admission, rescue medication, and 48-hour return. Mean change in pain scores were derived using initial and final pain scores, substituting the pain score after initial therapy when the patient was given further rescue medication. Unpaired t-test was used to compare pain scores. Adverse events were characterized by frequencies and percentages.
RESULTS From February 2012 to April 2012, 83 patients received chlorpromazine. Among these patients, 1 patient received chlorpromazine for hiccups and 7 for
338
February 2014 Table 1.—Patient Demographics
Mean age (SD) in years Male Race Caucasian African American Other† Prior migraine*‡ Medications given prior to arrival None Acetaminophen NSAID Triptans Prophylaxis*§ Others¶
Total N = 349 (%)
Chlorpromazine N = 75 (%)
Prochlorperazine N = 274 (%)
15.1 (2.1) 91 (26%)
15.1 (2.2) 21 (28%)
15.3 (1.9) 70 (26%)
256 (73%) 69 (20%) 24 (7%) 209 (60%)
56 (75%) 15 (20%) 4 (5%) 60 (80%)
200 (73%) 54 (20%) 20 (7%) 149 (54%)
101 (29%) 64 (18%) 168 (48%) 58 (17%) 61 (17%) 47 (13%)
20 (27%) 14 (19%) 36 (48%) 11 (15%) 21 (28%) 12 (16%)
81 (30%) 50 (18%) 132 (48%) 47 (17%) 40 (15%) 35 (13%)
*Denotes statically significant difference for P value
