- Email: [email protected]
Prochlorperazine vs. Promethazine for Headache Treatment in the Emergency Department: A Randomized Controlled Trial
The Journal of Emergency Medicine, Vol. 35, No. 3, pp. 247–253, 2008 Published by Elsevier Inc. Printed in the USA 0736-4679/08 $–see front matter
doi:10.1016/j.jemermed.2007.09.047
Original Contributions
PROCHLORPERAZINE VS. PROMETHAZINE FOR HEADACHE TREATMENT IN THE EMERGENCY DEPARTMENT: A RANDOMIZED CONTROLLED TRIAL James E. Callan,
MD, LCDR, MC, USN,*
Mark A. Kostic, MD, and Thomas S. Rieg,
CDR, MC, USN,†
Ethan A. Bachrach,
MD,†
PhD‡
*Department of Emergency Medicine, Naval Hospital, Okinawa, Japan, †Department of Emergency Medicine, Naval Medical Center Portsmouth, Portsmouth, Virginia, and ‡Naval Medical Center Portsmouth, Portsmouth, Virginia Reprint Address: James E. Callan, MD, LCDR, MC, USN, Department of Emergency Medicine, Naval Hospital, Okinawa, Japan, PSC 482, Box 2544 FPO AP 96362; E-mail: [email protected]
e Abstract—Headache is a very common medical complaint. Four to six percent of the population will have a debilitating headache in their lifetime; and 1–2% of all Emergency Department (ED) visits involve patients with
headaches. Although promethazine is used frequently, it has never been studied as a single-agent treatment in undifferentiated headache. We hypothesized that promethazine would be superior to prochlorperazine in the treatment of headache. We conducted a prospective, double-blinded, randomized, controlled trial on patients presenting to our ED between May and August 2005 with a chief complaint of headache. Each subject was randomized to receive either intravenous promethazine 25 mg or prochlorperazine 10 mg, and graded the intensity of their headache on serial 100-mm visual analog scales (VAS). Patients with dystonic reactions or akathesia were treated with diphenhydramine. Adequate pain relief was defined as an absolute decrease in VAS score of 25 mm. After discharge from the ED, patients were queried regarding the recurrence of headache symptoms, the need for additional pain medications, and the occurrence of any side effects since discharge. Thirty-five patients were enrolled in each group. Both drugs were shown to be effective in treatment of headaches. Prochlorperazine provided a faster rate of pain resolution and less drowsiness when compared to promethazine. Both medications were individually effective as abortive therapy for headache. Prochlorperazine was superior to promethazine in the rate of headache reduction and rate of home drowsiness, with similar rates of akathesia, nausea resolution, patient satisfaction, and headache recurrence within 5 days of discharge. Published by Elsevier Inc.
This abstract was presented at the 2006 Society of Academic Emergency Medicine, resulting in the abstract being published in the May issue of the Journal of Emergency Medicine. It was also presented at the Naval Medical Center Portsmouth research competition in May 2006, and at the Government Services chapter meeting of the American College of Emergency Physicians in March 2006. The views expressed in this article are those of the author(s) and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. The Chief, Navy Bureau of Medicine and Surgery, Washington, DC, Clinical Investigation Program sponsored this study (CIP #P05-005). The local Institutional Review Board approved this study and written consent was obtained by all participants before being enrolled. I am a military service member (or employee of the U.S. Government). This work was prepared as part of my official duties. Title 17 U.S.C. 105 provides that ‘Copyright protection under this title is not available for any work of the United States Government.’ Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties.
RECEIVED: 24 February 2007; FINAL ACCEPTED: 13 September 2007
SUBMISSION RECEIVED:
e Keywords—headache; migraine; treatment; prochlorperazine; promethazine
1 September 2007; 247
248
J. E. Callan et al.
INTRODUCTION
MATERIALS AND METHODS
Background
Study Design
Headache is a very common medical complaint. Four to six percent of the population will have a debilitating headache in their lifetime, and 1–2% of all Emergency Department (ED) visits involve patients with headaches (1,2). Potentially devastating medical illness is present in only a minority of cases. Most headaches are of benign etiology, such as a migraine, tension, or cluster headache. Strategies to treat headache vary substantially between regions and even within individual EDs. Treatment options commonly available to emergency physicians include ergot derivatives, triptans, anti-psychotics, nonsteroidal anti-inflammatory drugs, steroids, anti-emetics, and opioids (3–13).
We conducted a prospective, double-blinded, randomized, controlled trial on consecutive patients presenting to our ED with the chief complaint of headache between May and August 2005. This study was in accord with the Standards of the Committee of Human Experimentation and was approved by the local Institutional Review Board.
Importance Multiple studies have addressed various treatment regimens for headache. In EDs, the most effective medications have been shown to be the ergot derivatives, the triptans, and the phenothiazines (12–23). Lacking the vasoconstrictive properties of ergots and triptans, phenothiazines have recently received more attention. Their mechanism of action includes blockade of the central dopamine receptors that mediate meningeal artery vasodilatation, specifically D2, and variably D1, D3, D4, and D5 (24,25). Additionally, phenothiazines have the added benefit of effectively treating the frequently associated symptoms of nausea and vomiting. Prochlorperazine (Compazine®, GlaxoSmithKline, Middlesex, UK) is the most commonly utilized and best-studied phenothiazine in headache abortive therapy. Promethazine (Phenergan®, Baxter, Deerfield, IL) gained popularity for headache treatment due to both a manufacturing shortage of prochlorperazine and the black box warning applied to droperidol. Because it is from the same class as prochlorperazine, it seemed logical that promethazine would be an effective therapy. Anecdotally this seemed to be true, yet no clinical trial has been performed to assess its efficacy as single-agent therapy.
Selection of Participants In our young population, many patients claim they have “migraine” headaches without any formal diagnoses or without meeting the strict International Headache Society guidelines that require five prior episodes. In our experience, many of these patients had resolution of their headaches with phenothiazines. Therefore, we decided this study would include all patients between the ages of 18 and 65 years who did not meet the exclusion criteria and who presented with a benign headache. All enrolling providers were told that a benign headache consisted of either a headache that was similar to prior headaches, a headache with gradual increase in intensity of pain, a headache without neurologic deficits, a headache not described as the “worst headache of their lives,” or a headache without thunderclap onset. Thus, the study would potentially include those patients with undiagnosed migraine, tension, or cluster headaches. Patients were excluded if they had prior involvement in this study, were pregnant, had a temperature ⬎ 38.5°C (100.5°F), had a diastolic blood pressure ⬎ 104 mm Hg, had a history of non-skin cancer, described their current headache as atypical in character or location from their usual headaches, had altered mental status, had the “worst headache of their life,” had neurological symptoms, had a history of trauma, had thunderclap onset, had meningeal signs, or had a headache post lumbar puncture. Additionally, patients were excluded if they had a known allergy to the study drugs, or reported use of ergot amines, anti-emetics, anti-psychotics, or sedatives in the previous 24 h.
Goals of this Investigation Interventions In our experience, promethazine seemed to be superior to prochlorperazine in the treatment of headache and its associated symptoms. Therefore, we hypothesized that promethazine would be superior to prochlorperazine in both side-effect profile and efficacy in patients presenting to the ED with a primary benign headache.
A study investigator obtained informed consent from each patient. To maintain blinding, a standardized order sheet was utilized to prevent foreknowledge or the ability to alter subject assignment. Vital signs were monitored on a routine basis per standard ED protocols. Each pa-
Prochlorperazine vs. Promethazine for Headache in the ED
249
tient had an intravenous catheter placed, received the study medication, and a 500-mL normal saline bolus. On the basis of a computer-generated random numbers table, each subject was randomized to receive a 2-mL solution containing either promethazine (25 mg) or prochlorperazine (10 mg) intravenously, over a 2-min period, followed by a 10-mL flush of normal saline. Drug preparation and subject randomization were performed by a research pharmacist before patient enrollment. The study medication doses were chosen to reflect the most common doses used in emergency medicine practice. Study results reflect only these dosages.
groups, measured both as the absolute difference between the means at 30 and 60 min, as well as the difference between the rates of decline. Secondary outcome measures were the rates of akathesia, the need for rescue medications (other pain medications or diphenhydramine), nausea resolution in the department, recurrence of headache within 5 days of discharge, drowsiness within 1 day of discharge, and total patient satisfaction with the study drug.
Methods of Measurement Patients graded the intensity of their headache on separate 100-mm non-hatched visual analog scales at 0, 15, 30, 45, and 60 min. Time zero began immediately after administration of the study drug (26,27). At these same intervals, patients also completed a questionnaire regarding symptoms of nausea, anxiety, or jitteriness. If the provider felt the patient was having akathesia or a dystonic reaction, diphenhydramine 25 mg was given intravenously (28). Diphenhydramine administration was treated as a rescue medication and no further VAS scores were recorded. A similar prior study used a 25-mm difference in mean VAS score reduction between groups to show a clinical benefit (2). Based on this study, we defined adequate pain relief as an absolute decrease in the mean VAS score of 25 mm. If this reduction in pain was not achieved after 30 min, the treating physician had the option of providing a rescue medication and terminating the study. Two separate analyses were performed, one at 30 min and one at 60 min. The primary analysis was at 60 min, and all patient number calculations were based on that time interval. This analysis included only those patients who did not receive a rescue medication or diphenhydramine before 60 min. Because 34% of patients received either a rescue medication or diphenhydramine at 30 min, a separate analysis was performed at 30 min that included all patients. Only the VAS scores recorded up to the point of rescue therapy were included. After discharge from the ED, patients were contacted and asked a standard set of questions regarding the recurrence of headache symptoms, satisfaction with medication, and the occurrence of drowsiness or agitation.
Outcome Measures The primary outcome measure was the difference in pain scores between the prochlorperazine and promethazine
Primary Data Analysis Thirty-two patients were needed in each group to find a 25-mm difference between the group mean on the VAS at 60 min, with a power of 0.80 and an alpha of 0.05. Expecting a 10% dropout rate, 35 subjects were enrolled in each group. The groups were compared using a t-test on gender, race, and age; and a chi (with Yates correction)squared test on severity of presenting headache, to determine if they were similar. The individual VAS measurements were compared using a repeated measures analysis of variance (ANOVA) test.
RESULTS A total of 887 patients presented during the enrollment time frame with a chief complaint of headache. All patients were screened by departmental researchers. There were 753 patients who met at least one of the exclusion criteria. The vast majority of excluded patients described a headache that differed from prior headaches in either location or character. On chart review, most of these patients had a discharge diagnosis of benign headache, but at the time of initial evaluation were excluded from the study. Eighteen patients refused to be in the study and 32 patients were missed. Another 14 patients were not enrolled because one of the attending physicians declined to participate in the study. Seventy patients were enrolled in the study, with 35 receiving prochlorperazine and 35 receiving promethazine (Figure 1). An intention-to-treat analysis was performed, including 3 subjects who dropped out before study completion, and another subject that was subsequently diagnosed with aseptic meningitis the following day. Using t-tests and chi (with Yates correction)-squared tests, it was established that the groups did not differ statistically in age, race, sex, or severity of presenting headache (Table 1). Those patients lost to follow-up were distributed evenly between both groups and included in the Table 1 analysis. For patients lost to follow-up, the secondary outcomes that could not be
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J. E. Callan et al.
Patients with Headache 887
# Enrolled
# Excluded
# Missed/Refused
70
753
64
# Missed 46
# Refused 18
Figure 1. Flow chart of patients.
established before discharge were not used in the analysis for Table 2. At 30 min, 69% (20/29) in the prochlorperazine group and 39% (n ⫽ 33) in the promethazine group had a reduction in VAS ⬎ 25 mm (p ⫽ 0.006), which was statistically significant (Table 2). For these patients, a repeated measures ANOVA showed that the 13.5-mm difference between the mean VAS scores for each group was not significant (p ⫽ 0.581). However, the rates of decline of the VAS scores were significantly greater in the prochlorperazine group (p ⫽ 0.013), signifying that this group of patients had resolution of their headaches faster than the promethazine group (Figure 2). At 60 min, 91% (21/23) in the prochlorperazine group and 47% (16/23) in the promethazine group had a VAS reduction of ⬎ 25 mm (p ⫽ 0.133), which failed to reach statistical significance (Table 2). The absolute mean reduction in VAS score was 19 mm greater in the prochlorperazine group. Although statistical significance for this difference was not achieved (p ⫽ 0.439), there was a significant difference between the groups in the rate at which the VAS scores declined over 60 min (p ⫽ 0.028) (Figure 3). Headache recurrence, rates of akathesia, need for rescue medications in the ED, patient satisfaction, nausea
Table 1. Mean and 95% Confidence Intervals for Subject Variables for the Two Study Groups Variable
Prochlorperazine n ⫽ 35
Promethazine n ⫽ 35
p-Value
Mean age (years) Female % Caucasian % VAS time 0
28.3 77 54 75.2
29.5 85 42 70.7
0.550 0.356 0.537 0.340
VAS ⫽ visual analog scale.
resolution, and rates of agitation were all similar between the groups. All patients with akathesia were successfully treated with diphenhydramine. The rate of drowsiness after discharge from the ED was greater in the promethazine group (p ⫽ 0.002) (Table 2). Eighty-five percent of patients were successfully contacted for follow-up questioning post-discharge. DISCUSSION Both prochlorperazine and promethazine effectively treated headache in the ED, but the rate by which prochlorperazine diminished headache was superior. At 30 min, significantly more patients in the prochlorperazine group had a reduction in their headache ⱖ 25 mm. By 60 min, there was no statistically significant difference. It is possible that this was due to an inadequate number of patients reaching 60 min without rescue drugs. Thirtyfour percent of patients in each group required a rescue medication or diphenhydramine by the 60-min mark. Previous studies following a single drug over time showed that a change of 13 mm is clinically significant. Eighty percent of the prochlorperazine group and 71% of the promethazine group met this mark (26,27,29). Because these studies did not address what would be a clinically significant change between groups, we used a similar headache study and set a difference of 25 mm between the mean VAS scores as our threshold for clinical significance. The 19.5-mm difference found in our study did not reach this previously set threshold (2). Prochlorperazine also produced less home drowsiness, but was similar in rates of akathesia, nausea resolution, and patient satisfaction. The akathesia rate reported in this study (27%) was much higher than reported in previous studies (10%) (14). This rate may be elevated due to the study defini-
Prochlorperazine vs. Promethazine for Headache in the ED
251
Table 2. Descriptive and Inferential Statistics Comparing the Two Study Drugs for Each Recorded Measure Characteristic
Prochlorperazine (n ⫽ 35)
Promethazine (n ⫽ 35)
p-Value
VAS reduction at 30 min (mm) VAS reduction at 60 min (mm) 30 min VAS reduction ⬎ 25 mm 60 min VAS reduction ⬎ 25 mm Headache within 5 days (%) Akathesia in ED (%) Rescue medication in ED (%) Patient satisfaction (%) Home drowsiness (1 day) (%) Home agitation (%) Nausea resolution in ED (%)
36.43 64.27 *n ⫽ 29 20 (69%) *n ⫽ 23 21 (91%) 15 (45%) 10 (28.6%) 12 (34%) 19 (54.3%) 14 (40%) 13 (37%) †n ⫽ 17 16 (94%)
23.66 45.22 *n ⫽ 33 13 (39%) *n ⫽ 23 16 (47.9%) 21 (39%) 9 (25.7%) 12 (34%) 19 (54.3%) 25 (71.4%) 8 (22.9%) †n ⫽ 20 14 (70.0%)
0.581 0.439 0.006 0.133 0.444 0.779 0.423 0.499 0.002 0.284 0.587
* Patients not receiving rescue medication/diphenhydramine before specified time. † Number of patients presenting with nausea.
tion of akathesia, which included patient-reported jitteriness. Upon reviewing the treating physicians’ notes, akathesia was reported in 18.5% of patients. Although the rate remained higher than expected, it was more in line with the higher estimates (as high as 15%) seen in other studies (30). It is conceivable that prior studies underestimated true akathesia rates because a patient feels the symptoms of akathesia long before the outward appearance that would normally trigger therapy. Diphenhydramine was required in 7 patients in the prochlorperazine group and 6 patients in the promethazine group. It has been well documented that diphenhy-
dramine can cause drowsiness, but because both groups had similar usage of diphenhydramine, patients that received diphenhydramine were not excluded from any of the secondary outcome analyses, including home drowsiness. Excluding these patients would likely decrease the total percentage of drowsiness in each group, but would not likely change the ratio difference between the groups. The mechanism of action employed by phenothiazines in treating headache, specifically migraine, has not been fully elucidated, but is thought to be related to dopamine blockade. It has also been hypothesized that the propensity of phenothiazines to cause sedation may
100
90
80
Mean (95% CI) VAS Score
70
60 Prochlorperazine Promethazine
50
40
30
20
10
0 0
15
30
Time (minutes)
Figure 2. The comparison of mean VAS scores over time for all subjects at 30 min (n ⴝ 70).
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J. E. Callan et al. 100
90
80
Mean (95% CI) VAS Scores
70
60 Prochlorperazine Promethazine
50
40
30
20
10
0 0
15
30
45
60
Time (minutes)
Figure 3. The comparison of mean VAS scores over time for those subjects who reached 60 min (n ⴝ 46).
also be a factor. In this study, the drug that was more sedating was found to be less effective in headache treatment. Future studies could be designed to collect data on all patients for at least 60 min and standardize rescue and discharge medication regimes.
Limitations Patients with undifferentiated primary headaches were enrolled, as opposed to only enrolling those that met the strict definition of migraine. Although this may have affected the results, we felt that this was more consistent with the patient population that a typical emergency physician encounters on a daily basis. Greater power would have been achieved to detect a difference in the mean VAS score reductions at 60 min if all subjects remained in the ED for the collection of all five data points. We did not wish to inconvenience our patients in this way. However, it is reasonable to conclude that there is a clinical difference between these medications based upon the significantly greater rate of VAS reduction in the prochlorperazine group. We decided to use a patient-based diagnosis of akathesia, rather than a provider-based diagnosis of akathesia. We feel that this more closely approximated true akathesia because patients feel jittery before outward clinical signs that providers would use for diagnosis. In summary, although both medications were effective in treating headache in the ED, prochlorperazine was
superior to promethazine, with less drowsiness and similar rates of akathesia.
Acknowledgments—We would like to thank Mr. Timothy Gendron and the pharmacy staff for preparing the medications. We would especially like to thank the nurses, doctors, and staff for their outstanding support of this project.
REFERENCES 1. Lake AE, Saper JR. Chronic headache: new advances in treatment strategies. Neurology 2002;59(5 Suppl 2):S8 –13. 2. Tanen DA, Miller S, French T, Riffenburgh RH. Intravenous sodium valproate versus prochlorperazine for the emergency department treatment of acute migraine headaches: a prospective, randomized, double-blind trial. Ann Emerg Med 2003;41:847–53. 3. Vinson DR. Treatment patterns of isolated benign headache in US emergency departments. Ann Emerg Med 2002;39:215–22. 4. Dib MM, Massiou H, Weber M, Henry P, Garcia-Acosta S, Bousser MG; Bi-Profenid Migraine Study Group. Efficacy of oral ketoprofen in acute migraine: a double blind randomized clinical trial. Neurology 2002;58:1660 –5. 5. Larkin GL, Prescott JE. A randomized, double blind, comparative study of the efficacy of Ketorolac tromethamine versus meperidine in the treatment of severe migraine. Ann Emerg Med 1992;21: 919 –24. 6. Kumar KL. Recent advances in the acute management of migraine and cluster headaches. J Gen Intern Med 1994;9:339 – 48. 7. Dahlof C. Clinical applications of new therapeutic deliveries in migraine. Neurology 2003;61(8 Suppl 4):S31– 4. 8. Ashkenazi A, Silberstein SD. The evolving management of migraine. Curr Opin Neurol 2003;16:341–5. 9. Raskin NH. Modern pharmacotherapy of migraine. Neurol Clin 1990;8:857– 65.
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10. Ellis GL, Delaney J, DeHart DA, Owens A. The efficacy of metoclopramide in the treatment of migraine headache. Ann Emerg Med 1993;22:191–5. 11. Tek DS. A prospective, double-blind study of metoclopramide hydrochloride for the control of migraine in the emergency department. Ann Emerg Med 1991;20:711–2. 12. DiMonda V. Efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine versus sumatriptan in acute treatment of multiple migraine attacks: a multicenter, randomized, crossover trial. Headache 2003;43:835– 44. 13. Cameron JD, Lane PL, Speechley M. Intravenous chlorpromazine vs. intravenous metoclopramide in acute migraine headache. Acad Emerg Med 1995;2:597– 602. 14. Coppola M, Yealy DM, Leibold RA. Randomized, placebocontrolled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache. Ann Emerg Med 1995;26:541–50. 15. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology 1986;36:995–7. 16. Gallagher RM. Acute treatment of migraine with dihydroergotamine nasal spray. Dihydroergotamine Working Group. Arch Neurol 1996;53:1285–91. 17. Singh SM, Hayes MJ. Ketorolac vs. chlorpromazine in the treatment of acute migraine without aura. A prospective randomized, double-blind trial. Arch Intern Med 1996;156:1725– 8. 18. Kwiatkowski T, Alagappan K. Headache. In: Marx JA, Hockberger RS, Walls RM, eds. Rosen’s emergency medicine: concepts and clinical practice, 5th edn. St. Louis, MO: C.V. Mosby; 2002: 1456 – 60. 19. Davis CP, Torre PR, Williams C, et al. Ketorolac versus meperidine-plus-promethazine treatment of migraine headache: evaluations by patients. Am J Emerg Med 1995;13:146 –50.
20. Kabbouche MA, Vockell AL, LeCates SL, Powers SW, Hershey AD. Tolerability and effectiveness of prochlorperazine for intractable migraine in children. Pediatrics 2001;107:E62. 21. Sharma S, Prasad A, Nehru R, et al. Efficacy and tolerability of prochlorperazine buccal tablets in treatment of acute migraine. Headache 2002;42:896 –902. 22. Seim MB, March JA, Dunn KA. Intravenous ketorolac vs. intravenous prochlorperazine for the treatment of migraine headaches. Acad Emerg Med 1998;5:573– 6. 23. Jones J, Pack S, Chun E. Intramuscular prochlorperazine versus metoclopramide as single-agent therapy for the treatment of acute migraine headache. Am J Emerg Med 1996;14:262– 4. 24. Lavonas EJ, Ford MD. Antipsychotics. In: Marx JA, Hockberger RS, Walls RM, eds. Rosen’s emergency medicine: concepts and clinical practice, 5th edn. St. Louis, MO: C.V. Mosby; 2002:2174 –5. 25. Peroutka SJ, Jones WT. Clinical susceptibility to migraine with aura is modified by dopamine D2 receptor (DRD2) Ncol alleles. Neurology 1997;49:201– 6. 26. Gallagher EJ, Liebman M, Bijur PE. Prospective validation of clinically important changes in pain severity measured on a visual analog scale. Ann Emerg Med 2001;38:633– 8. 27. Bijur PE, Latimer CT, Gallagher EJ. Validation of a verbally administered numerical rating scale of acute pain for use in the emergency department. Acad Emerg Med 2003;10:390 –2. 28. Vinson DR. Diphenhydramine for the prevention of akathisia induced by prochlorperazine: a randomized, controlled trial. Ann Emerg Med 2001;37:125–31. 29. Todd KH, Funk KG, Funk JP, Bonacci R. Clinical significance of reported changes in pain severity. Ann Emerg Med 1996;27:485–9. 30. Weaver CS, Jones JB, Chisholm CD. Droperidol vs. prochlorperazine for the treatment of acute headache. J Emerg Med 2004;26: 145–50.
doi:10.1016/j.jemermed.2007.09.047
Original Contributions
PROCHLORPERAZINE VS. PROMETHAZINE FOR HEADACHE TREATMENT IN THE EMERGENCY DEPARTMENT: A RANDOMIZED CONTROLLED TRIAL James E. Callan,
MD, LCDR, MC, USN,*
Mark A. Kostic, MD, and Thomas S. Rieg,
CDR, MC, USN,†
Ethan A. Bachrach,
MD,†
PhD‡
*Department of Emergency Medicine, Naval Hospital, Okinawa, Japan, †Department of Emergency Medicine, Naval Medical Center Portsmouth, Portsmouth, Virginia, and ‡Naval Medical Center Portsmouth, Portsmouth, Virginia Reprint Address: James E. Callan, MD, LCDR, MC, USN, Department of Emergency Medicine, Naval Hospital, Okinawa, Japan, PSC 482, Box 2544 FPO AP 96362; E-mail: [email protected]
e Abstract—Headache is a very common medical complaint. Four to six percent of the population will have a debilitating headache in their lifetime; and 1–2% of all Emergency Department (ED) visits involve patients with
headaches. Although promethazine is used frequently, it has never been studied as a single-agent treatment in undifferentiated headache. We hypothesized that promethazine would be superior to prochlorperazine in the treatment of headache. We conducted a prospective, double-blinded, randomized, controlled trial on patients presenting to our ED between May and August 2005 with a chief complaint of headache. Each subject was randomized to receive either intravenous promethazine 25 mg or prochlorperazine 10 mg, and graded the intensity of their headache on serial 100-mm visual analog scales (VAS). Patients with dystonic reactions or akathesia were treated with diphenhydramine. Adequate pain relief was defined as an absolute decrease in VAS score of 25 mm. After discharge from the ED, patients were queried regarding the recurrence of headache symptoms, the need for additional pain medications, and the occurrence of any side effects since discharge. Thirty-five patients were enrolled in each group. Both drugs were shown to be effective in treatment of headaches. Prochlorperazine provided a faster rate of pain resolution and less drowsiness when compared to promethazine. Both medications were individually effective as abortive therapy for headache. Prochlorperazine was superior to promethazine in the rate of headache reduction and rate of home drowsiness, with similar rates of akathesia, nausea resolution, patient satisfaction, and headache recurrence within 5 days of discharge. Published by Elsevier Inc.
This abstract was presented at the 2006 Society of Academic Emergency Medicine, resulting in the abstract being published in the May issue of the Journal of Emergency Medicine. It was also presented at the Naval Medical Center Portsmouth research competition in May 2006, and at the Government Services chapter meeting of the American College of Emergency Physicians in March 2006. The views expressed in this article are those of the author(s) and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. The Chief, Navy Bureau of Medicine and Surgery, Washington, DC, Clinical Investigation Program sponsored this study (CIP #P05-005). The local Institutional Review Board approved this study and written consent was obtained by all participants before being enrolled. I am a military service member (or employee of the U.S. Government). This work was prepared as part of my official duties. Title 17 U.S.C. 105 provides that ‘Copyright protection under this title is not available for any work of the United States Government.’ Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties.
RECEIVED: 24 February 2007; FINAL ACCEPTED: 13 September 2007
SUBMISSION RECEIVED:
e Keywords—headache; migraine; treatment; prochlorperazine; promethazine
1 September 2007; 247
248
J. E. Callan et al.
INTRODUCTION
MATERIALS AND METHODS
Background
Study Design
Headache is a very common medical complaint. Four to six percent of the population will have a debilitating headache in their lifetime, and 1–2% of all Emergency Department (ED) visits involve patients with headaches (1,2). Potentially devastating medical illness is present in only a minority of cases. Most headaches are of benign etiology, such as a migraine, tension, or cluster headache. Strategies to treat headache vary substantially between regions and even within individual EDs. Treatment options commonly available to emergency physicians include ergot derivatives, triptans, anti-psychotics, nonsteroidal anti-inflammatory drugs, steroids, anti-emetics, and opioids (3–13).
We conducted a prospective, double-blinded, randomized, controlled trial on consecutive patients presenting to our ED with the chief complaint of headache between May and August 2005. This study was in accord with the Standards of the Committee of Human Experimentation and was approved by the local Institutional Review Board.
Importance Multiple studies have addressed various treatment regimens for headache. In EDs, the most effective medications have been shown to be the ergot derivatives, the triptans, and the phenothiazines (12–23). Lacking the vasoconstrictive properties of ergots and triptans, phenothiazines have recently received more attention. Their mechanism of action includes blockade of the central dopamine receptors that mediate meningeal artery vasodilatation, specifically D2, and variably D1, D3, D4, and D5 (24,25). Additionally, phenothiazines have the added benefit of effectively treating the frequently associated symptoms of nausea and vomiting. Prochlorperazine (Compazine®, GlaxoSmithKline, Middlesex, UK) is the most commonly utilized and best-studied phenothiazine in headache abortive therapy. Promethazine (Phenergan®, Baxter, Deerfield, IL) gained popularity for headache treatment due to both a manufacturing shortage of prochlorperazine and the black box warning applied to droperidol. Because it is from the same class as prochlorperazine, it seemed logical that promethazine would be an effective therapy. Anecdotally this seemed to be true, yet no clinical trial has been performed to assess its efficacy as single-agent therapy.
Selection of Participants In our young population, many patients claim they have “migraine” headaches without any formal diagnoses or without meeting the strict International Headache Society guidelines that require five prior episodes. In our experience, many of these patients had resolution of their headaches with phenothiazines. Therefore, we decided this study would include all patients between the ages of 18 and 65 years who did not meet the exclusion criteria and who presented with a benign headache. All enrolling providers were told that a benign headache consisted of either a headache that was similar to prior headaches, a headache with gradual increase in intensity of pain, a headache without neurologic deficits, a headache not described as the “worst headache of their lives,” or a headache without thunderclap onset. Thus, the study would potentially include those patients with undiagnosed migraine, tension, or cluster headaches. Patients were excluded if they had prior involvement in this study, were pregnant, had a temperature ⬎ 38.5°C (100.5°F), had a diastolic blood pressure ⬎ 104 mm Hg, had a history of non-skin cancer, described their current headache as atypical in character or location from their usual headaches, had altered mental status, had the “worst headache of their life,” had neurological symptoms, had a history of trauma, had thunderclap onset, had meningeal signs, or had a headache post lumbar puncture. Additionally, patients were excluded if they had a known allergy to the study drugs, or reported use of ergot amines, anti-emetics, anti-psychotics, or sedatives in the previous 24 h.
Goals of this Investigation Interventions In our experience, promethazine seemed to be superior to prochlorperazine in the treatment of headache and its associated symptoms. Therefore, we hypothesized that promethazine would be superior to prochlorperazine in both side-effect profile and efficacy in patients presenting to the ED with a primary benign headache.
A study investigator obtained informed consent from each patient. To maintain blinding, a standardized order sheet was utilized to prevent foreknowledge or the ability to alter subject assignment. Vital signs were monitored on a routine basis per standard ED protocols. Each pa-
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tient had an intravenous catheter placed, received the study medication, and a 500-mL normal saline bolus. On the basis of a computer-generated random numbers table, each subject was randomized to receive a 2-mL solution containing either promethazine (25 mg) or prochlorperazine (10 mg) intravenously, over a 2-min period, followed by a 10-mL flush of normal saline. Drug preparation and subject randomization were performed by a research pharmacist before patient enrollment. The study medication doses were chosen to reflect the most common doses used in emergency medicine practice. Study results reflect only these dosages.
groups, measured both as the absolute difference between the means at 30 and 60 min, as well as the difference between the rates of decline. Secondary outcome measures were the rates of akathesia, the need for rescue medications (other pain medications or diphenhydramine), nausea resolution in the department, recurrence of headache within 5 days of discharge, drowsiness within 1 day of discharge, and total patient satisfaction with the study drug.
Methods of Measurement Patients graded the intensity of their headache on separate 100-mm non-hatched visual analog scales at 0, 15, 30, 45, and 60 min. Time zero began immediately after administration of the study drug (26,27). At these same intervals, patients also completed a questionnaire regarding symptoms of nausea, anxiety, or jitteriness. If the provider felt the patient was having akathesia or a dystonic reaction, diphenhydramine 25 mg was given intravenously (28). Diphenhydramine administration was treated as a rescue medication and no further VAS scores were recorded. A similar prior study used a 25-mm difference in mean VAS score reduction between groups to show a clinical benefit (2). Based on this study, we defined adequate pain relief as an absolute decrease in the mean VAS score of 25 mm. If this reduction in pain was not achieved after 30 min, the treating physician had the option of providing a rescue medication and terminating the study. Two separate analyses were performed, one at 30 min and one at 60 min. The primary analysis was at 60 min, and all patient number calculations were based on that time interval. This analysis included only those patients who did not receive a rescue medication or diphenhydramine before 60 min. Because 34% of patients received either a rescue medication or diphenhydramine at 30 min, a separate analysis was performed at 30 min that included all patients. Only the VAS scores recorded up to the point of rescue therapy were included. After discharge from the ED, patients were contacted and asked a standard set of questions regarding the recurrence of headache symptoms, satisfaction with medication, and the occurrence of drowsiness or agitation.
Outcome Measures The primary outcome measure was the difference in pain scores between the prochlorperazine and promethazine
Primary Data Analysis Thirty-two patients were needed in each group to find a 25-mm difference between the group mean on the VAS at 60 min, with a power of 0.80 and an alpha of 0.05. Expecting a 10% dropout rate, 35 subjects were enrolled in each group. The groups were compared using a t-test on gender, race, and age; and a chi (with Yates correction)squared test on severity of presenting headache, to determine if they were similar. The individual VAS measurements were compared using a repeated measures analysis of variance (ANOVA) test.
RESULTS A total of 887 patients presented during the enrollment time frame with a chief complaint of headache. All patients were screened by departmental researchers. There were 753 patients who met at least one of the exclusion criteria. The vast majority of excluded patients described a headache that differed from prior headaches in either location or character. On chart review, most of these patients had a discharge diagnosis of benign headache, but at the time of initial evaluation were excluded from the study. Eighteen patients refused to be in the study and 32 patients were missed. Another 14 patients were not enrolled because one of the attending physicians declined to participate in the study. Seventy patients were enrolled in the study, with 35 receiving prochlorperazine and 35 receiving promethazine (Figure 1). An intention-to-treat analysis was performed, including 3 subjects who dropped out before study completion, and another subject that was subsequently diagnosed with aseptic meningitis the following day. Using t-tests and chi (with Yates correction)-squared tests, it was established that the groups did not differ statistically in age, race, sex, or severity of presenting headache (Table 1). Those patients lost to follow-up were distributed evenly between both groups and included in the Table 1 analysis. For patients lost to follow-up, the secondary outcomes that could not be
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Patients with Headache 887
# Enrolled
# Excluded
# Missed/Refused
70
753
64
# Missed 46
# Refused 18
Figure 1. Flow chart of patients.
established before discharge were not used in the analysis for Table 2. At 30 min, 69% (20/29) in the prochlorperazine group and 39% (n ⫽ 33) in the promethazine group had a reduction in VAS ⬎ 25 mm (p ⫽ 0.006), which was statistically significant (Table 2). For these patients, a repeated measures ANOVA showed that the 13.5-mm difference between the mean VAS scores for each group was not significant (p ⫽ 0.581). However, the rates of decline of the VAS scores were significantly greater in the prochlorperazine group (p ⫽ 0.013), signifying that this group of patients had resolution of their headaches faster than the promethazine group (Figure 2). At 60 min, 91% (21/23) in the prochlorperazine group and 47% (16/23) in the promethazine group had a VAS reduction of ⬎ 25 mm (p ⫽ 0.133), which failed to reach statistical significance (Table 2). The absolute mean reduction in VAS score was 19 mm greater in the prochlorperazine group. Although statistical significance for this difference was not achieved (p ⫽ 0.439), there was a significant difference between the groups in the rate at which the VAS scores declined over 60 min (p ⫽ 0.028) (Figure 3). Headache recurrence, rates of akathesia, need for rescue medications in the ED, patient satisfaction, nausea
Table 1. Mean and 95% Confidence Intervals for Subject Variables for the Two Study Groups Variable
Prochlorperazine n ⫽ 35
Promethazine n ⫽ 35
p-Value
Mean age (years) Female % Caucasian % VAS time 0
28.3 77 54 75.2
29.5 85 42 70.7
0.550 0.356 0.537 0.340
VAS ⫽ visual analog scale.
resolution, and rates of agitation were all similar between the groups. All patients with akathesia were successfully treated with diphenhydramine. The rate of drowsiness after discharge from the ED was greater in the promethazine group (p ⫽ 0.002) (Table 2). Eighty-five percent of patients were successfully contacted for follow-up questioning post-discharge. DISCUSSION Both prochlorperazine and promethazine effectively treated headache in the ED, but the rate by which prochlorperazine diminished headache was superior. At 30 min, significantly more patients in the prochlorperazine group had a reduction in their headache ⱖ 25 mm. By 60 min, there was no statistically significant difference. It is possible that this was due to an inadequate number of patients reaching 60 min without rescue drugs. Thirtyfour percent of patients in each group required a rescue medication or diphenhydramine by the 60-min mark. Previous studies following a single drug over time showed that a change of 13 mm is clinically significant. Eighty percent of the prochlorperazine group and 71% of the promethazine group met this mark (26,27,29). Because these studies did not address what would be a clinically significant change between groups, we used a similar headache study and set a difference of 25 mm between the mean VAS scores as our threshold for clinical significance. The 19.5-mm difference found in our study did not reach this previously set threshold (2). Prochlorperazine also produced less home drowsiness, but was similar in rates of akathesia, nausea resolution, and patient satisfaction. The akathesia rate reported in this study (27%) was much higher than reported in previous studies (10%) (14). This rate may be elevated due to the study defini-
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Table 2. Descriptive and Inferential Statistics Comparing the Two Study Drugs for Each Recorded Measure Characteristic
Prochlorperazine (n ⫽ 35)
Promethazine (n ⫽ 35)
p-Value
VAS reduction at 30 min (mm) VAS reduction at 60 min (mm) 30 min VAS reduction ⬎ 25 mm 60 min VAS reduction ⬎ 25 mm Headache within 5 days (%) Akathesia in ED (%) Rescue medication in ED (%) Patient satisfaction (%) Home drowsiness (1 day) (%) Home agitation (%) Nausea resolution in ED (%)
36.43 64.27 *n ⫽ 29 20 (69%) *n ⫽ 23 21 (91%) 15 (45%) 10 (28.6%) 12 (34%) 19 (54.3%) 14 (40%) 13 (37%) †n ⫽ 17 16 (94%)
23.66 45.22 *n ⫽ 33 13 (39%) *n ⫽ 23 16 (47.9%) 21 (39%) 9 (25.7%) 12 (34%) 19 (54.3%) 25 (71.4%) 8 (22.9%) †n ⫽ 20 14 (70.0%)
0.581 0.439 0.006 0.133 0.444 0.779 0.423 0.499 0.002 0.284 0.587
* Patients not receiving rescue medication/diphenhydramine before specified time. † Number of patients presenting with nausea.
tion of akathesia, which included patient-reported jitteriness. Upon reviewing the treating physicians’ notes, akathesia was reported in 18.5% of patients. Although the rate remained higher than expected, it was more in line with the higher estimates (as high as 15%) seen in other studies (30). It is conceivable that prior studies underestimated true akathesia rates because a patient feels the symptoms of akathesia long before the outward appearance that would normally trigger therapy. Diphenhydramine was required in 7 patients in the prochlorperazine group and 6 patients in the promethazine group. It has been well documented that diphenhy-
dramine can cause drowsiness, but because both groups had similar usage of diphenhydramine, patients that received diphenhydramine were not excluded from any of the secondary outcome analyses, including home drowsiness. Excluding these patients would likely decrease the total percentage of drowsiness in each group, but would not likely change the ratio difference between the groups. The mechanism of action employed by phenothiazines in treating headache, specifically migraine, has not been fully elucidated, but is thought to be related to dopamine blockade. It has also been hypothesized that the propensity of phenothiazines to cause sedation may
100
90
80
Mean (95% CI) VAS Score
70
60 Prochlorperazine Promethazine
50
40
30
20
10
0 0
15
30
Time (minutes)
Figure 2. The comparison of mean VAS scores over time for all subjects at 30 min (n ⴝ 70).
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90
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Mean (95% CI) VAS Scores
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60 Prochlorperazine Promethazine
50
40
30
20
10
0 0
15
30
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Time (minutes)
Figure 3. The comparison of mean VAS scores over time for those subjects who reached 60 min (n ⴝ 46).
also be a factor. In this study, the drug that was more sedating was found to be less effective in headache treatment. Future studies could be designed to collect data on all patients for at least 60 min and standardize rescue and discharge medication regimes.
Limitations Patients with undifferentiated primary headaches were enrolled, as opposed to only enrolling those that met the strict definition of migraine. Although this may have affected the results, we felt that this was more consistent with the patient population that a typical emergency physician encounters on a daily basis. Greater power would have been achieved to detect a difference in the mean VAS score reductions at 60 min if all subjects remained in the ED for the collection of all five data points. We did not wish to inconvenience our patients in this way. However, it is reasonable to conclude that there is a clinical difference between these medications based upon the significantly greater rate of VAS reduction in the prochlorperazine group. We decided to use a patient-based diagnosis of akathesia, rather than a provider-based diagnosis of akathesia. We feel that this more closely approximated true akathesia because patients feel jittery before outward clinical signs that providers would use for diagnosis. In summary, although both medications were effective in treating headache in the ED, prochlorperazine was
superior to promethazine, with less drowsiness and similar rates of akathesia.
Acknowledgments—We would like to thank Mr. Timothy Gendron and the pharmacy staff for preparing the medications. We would especially like to thank the nurses, doctors, and staff for their outstanding support of this project.
REFERENCES 1. Lake AE, Saper JR. Chronic headache: new advances in treatment strategies. Neurology 2002;59(5 Suppl 2):S8 –13. 2. Tanen DA, Miller S, French T, Riffenburgh RH. Intravenous sodium valproate versus prochlorperazine for the emergency department treatment of acute migraine headaches: a prospective, randomized, double-blind trial. Ann Emerg Med 2003;41:847–53. 3. Vinson DR. Treatment patterns of isolated benign headache in US emergency departments. Ann Emerg Med 2002;39:215–22. 4. Dib MM, Massiou H, Weber M, Henry P, Garcia-Acosta S, Bousser MG; Bi-Profenid Migraine Study Group. Efficacy of oral ketoprofen in acute migraine: a double blind randomized clinical trial. Neurology 2002;58:1660 –5. 5. Larkin GL, Prescott JE. A randomized, double blind, comparative study of the efficacy of Ketorolac tromethamine versus meperidine in the treatment of severe migraine. Ann Emerg Med 1992;21: 919 –24. 6. Kumar KL. Recent advances in the acute management of migraine and cluster headaches. J Gen Intern Med 1994;9:339 – 48. 7. Dahlof C. Clinical applications of new therapeutic deliveries in migraine. Neurology 2003;61(8 Suppl 4):S31– 4. 8. Ashkenazi A, Silberstein SD. The evolving management of migraine. Curr Opin Neurol 2003;16:341–5. 9. Raskin NH. Modern pharmacotherapy of migraine. Neurol Clin 1990;8:857– 65.
Prochlorperazine vs. Promethazine for Headache in the ED
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10. Ellis GL, Delaney J, DeHart DA, Owens A. The efficacy of metoclopramide in the treatment of migraine headache. Ann Emerg Med 1993;22:191–5. 11. Tek DS. A prospective, double-blind study of metoclopramide hydrochloride for the control of migraine in the emergency department. Ann Emerg Med 1991;20:711–2. 12. DiMonda V. Efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine versus sumatriptan in acute treatment of multiple migraine attacks: a multicenter, randomized, crossover trial. Headache 2003;43:835– 44. 13. Cameron JD, Lane PL, Speechley M. Intravenous chlorpromazine vs. intravenous metoclopramide in acute migraine headache. Acad Emerg Med 1995;2:597– 602. 14. Coppola M, Yealy DM, Leibold RA. Randomized, placebocontrolled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache. Ann Emerg Med 1995;26:541–50. 15. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology 1986;36:995–7. 16. Gallagher RM. Acute treatment of migraine with dihydroergotamine nasal spray. Dihydroergotamine Working Group. Arch Neurol 1996;53:1285–91. 17. Singh SM, Hayes MJ. Ketorolac vs. chlorpromazine in the treatment of acute migraine without aura. A prospective randomized, double-blind trial. Arch Intern Med 1996;156:1725– 8. 18. Kwiatkowski T, Alagappan K. Headache. In: Marx JA, Hockberger RS, Walls RM, eds. Rosen’s emergency medicine: concepts and clinical practice, 5th edn. St. Louis, MO: C.V. Mosby; 2002: 1456 – 60. 19. Davis CP, Torre PR, Williams C, et al. Ketorolac versus meperidine-plus-promethazine treatment of migraine headache: evaluations by patients. Am J Emerg Med 1995;13:146 –50.
20. Kabbouche MA, Vockell AL, LeCates SL, Powers SW, Hershey AD. Tolerability and effectiveness of prochlorperazine for intractable migraine in children. Pediatrics 2001;107:E62. 21. Sharma S, Prasad A, Nehru R, et al. Efficacy and tolerability of prochlorperazine buccal tablets in treatment of acute migraine. Headache 2002;42:896 –902. 22. Seim MB, March JA, Dunn KA. Intravenous ketorolac vs. intravenous prochlorperazine for the treatment of migraine headaches. Acad Emerg Med 1998;5:573– 6. 23. Jones J, Pack S, Chun E. Intramuscular prochlorperazine versus metoclopramide as single-agent therapy for the treatment of acute migraine headache. Am J Emerg Med 1996;14:262– 4. 24. Lavonas EJ, Ford MD. Antipsychotics. In: Marx JA, Hockberger RS, Walls RM, eds. Rosen’s emergency medicine: concepts and clinical practice, 5th edn. St. Louis, MO: C.V. Mosby; 2002:2174 –5. 25. Peroutka SJ, Jones WT. Clinical susceptibility to migraine with aura is modified by dopamine D2 receptor (DRD2) Ncol alleles. Neurology 1997;49:201– 6. 26. Gallagher EJ, Liebman M, Bijur PE. Prospective validation of clinically important changes in pain severity measured on a visual analog scale. Ann Emerg Med 2001;38:633– 8. 27. Bijur PE, Latimer CT, Gallagher EJ. Validation of a verbally administered numerical rating scale of acute pain for use in the emergency department. Acad Emerg Med 2003;10:390 –2. 28. Vinson DR. Diphenhydramine for the prevention of akathisia induced by prochlorperazine: a randomized, controlled trial. Ann Emerg Med 2001;37:125–31. 29. Todd KH, Funk KG, Funk JP, Bonacci R. Clinical significance of reported changes in pain severity. Ann Emerg Med 1996;27:485–9. 30. Weaver CS, Jones JB, Chisholm CD. Droperidol vs. prochlorperazine for the treatment of acute headache. J Emerg Med 2004;26: 145–50.