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Ketorolac versus meperidine-plus-promethazine treatment of migraine headache: Evaluations by patients
Ketorolac Versus Meperidine-Plus-Promethazine Treatment of Migraine Headache: Evaluations by Patients CHARLES P. DAVIS, MD, PHD, PAUL R. TORRE, MD, CHARLES WILLIAMS, MD, CHARLES GRAY, MPH, KEVIN BARRETT, MD, GUS KRUCKE, MD, DWIGHT PEAKE, MD, BILL BASS, JR, MD This study was designed to compare and contrast the speed and efficacy of meperidine (75 mg)/promethazine (25 mg) intramuscularly to ketorolac (60 mg) intramuscularly, in a double-blind study in reducing the symptoms of migraine headache. Forty-two patients who presented to the emergency department between July 1992 and February 1993, with previous diagnoses of migraine headache, were considered for this study. Patients subjectively evaluated parameters of their migraine headaches (eg, pain and nausea) using a numeric scale and were later asked to reevaluate these same parameters at 30, 60, and 360 minutes after a single intramuscular injection of either ketorolac (60 mg) or meperidine (75 mg)/promethazine (25 mg). Sixty-eight percent of patients given meperidine/promethazine responded whereas 55% of patients given ketorolac responded. The responder group showed a statistically significant reduction in headache within 30 minutes with both drug regimens. There was no statistically significant difference between the number of responders in either group. The responders from both groups had relief that lasted 6 hours alter injection. In the nonresponder groups, most of the patients withdrew within 1 hour after treatment. As determined by patient response to treatment of their migraine headaches, there was no statistically significant difference between the ketorolac and the meperidine/ promethazine groups. (Am J Emerg Med 1995;13:146-150. Copyright © 1995 by W.B. Saunders Company) Migraine headaches constitute a common disease in a large number of Americans. About 15% to 20% of Americans suffer from migraine headaches. Patients' perceptions of migraine headaches are severe; approximately 80% of patients report disability from their severe attacks, and about 44% of those suffering a moderate attack also report some level of disability. 1,2 Currently, emergency management of migraine headaches is based on rest and the administration of antiemetics, analgesics, vasoactive drugs, and serotonin antagonists. ~'3"4 Most patients that arrive in the emergency department (ED) require quick and effective relief from their symptoms. Despite the potential for abuse and addiction, narcotics have been a major therapeutic agent used in EDs for the treatment of these patients. Although the relationship From the Department of Surgery, Emergency Services, The University of Texas Medical Branch, Galveston, TX. Manuscript received November 9, 1993; accepted June 10, 1994. Address reprint requests to Dr Charles P. Davis, Department of Surgery (Emergency Services), J-73, The University of Texas Medical Branch, Galveston, TX 77555-1073. Supported by Hoffmann-LaRoche, Inc. Key Words: Migraine headache, patient evaluation, nausea, ketorolac, meperidine, promethazine. Copyright © 1995 by W.B. Saunders Company 0735-6757/95/1302-000655.00/0 146
between patient treatment in the ED and narcotic addiction is unclear, Langemark and Olsen 4 calculate that 13 individuals per one million people become dependent on narcotics secondary to the treatment of migraine headaches. Lack of understanding of the exact pathogenesis of migraine headaches explains the variety of treatment regimens cited recently in emergency medicine reports. Several recent studies have looked at ED treatment of migraine headache using ketorolac. Larken and Prescott 5 concluded that ketorolac was inferior to meperidine; however, the dose of ketorolac (30 mg) is less than the 60-mg initial dose normally recommended for the average adult. In addition, they did not mention whether their patients were taking other medications. Intravenous D H E and metoclopramide was compared with ketorolac by Klapper and Stanton. 6 This was a small study of nine patients in each study arm. They concluded that ketorolac was not as effective as D H E and metoclopramide. In contrast, a recent study by Duarte et al, 7 who used meperidine and hydroxyzine in comparison to a 60-mg dose of ketorolac, found that ketorolac was as effective as the combination of the two drugs. In another small study, Hardin et al 8 used a 60-mg dose of ketorolac and concluded that it was effective in reducing the pain of migraine headache. In a previous open study performed in our institution, we determined that a 60-mg dose of ketorolac was effective in reducing or eliminating migraine headache symptoms in approximately 75% of patients. 9 In addition, we showed that ketorolac was effective in reducing nausea, and determined that the length of relief from nausea in those patients that did respond to ketorolac was at least 6 hrs. The purpose of this study was to do a prospective doubleblind comparison of ketorolac (60 mg) intramuscularly to meperidine (75 mg), and promethazine (25 rag) intramuscularly, to determine the effectiveness of controlling pain, nausea, and other migraine symptoms for a period of at least 6 hours. MATERIALS AND METHODS The study was approved by the Institutional Review Board at The University of Texas Medical Branch (UTMB), Galveston, TX. Patients who presented to the ED between July 1992 and February 1993, with a prior diagnosis of migraine made by a physician (usually their family physician or neurologist), and were determined by an emergency physician to have acute migraine attacks (eg, history consistent with migraine headaches, current headache, no focal neurological findings, etc) were considered for entry into the study. Enrolled patients were given an "Informed Consent Form" to sign. Table 1 lists the inclusion and exclusion criteria. These criteria were
DAVIS ET AL • KETOROLAC VERSUS MEPERIDINE-PLUS-PROMETHAZINE
TABLE 1. Inclusion and Exclusion Criteria for Migraine Headache Patients
Inclusion Criteria Must be at least 18 years of age, but not older than 65 years Have the ability to give informed consent Must not be pregnant Exclusion Criteria Patient taking anti-inflammatory agents (NSAIDS) Patients taking salicylate, lithium, or methotrexate before or during the study period Patients allergic to meperidine or promethazine Patients with impaired hepatic or renal function Patients with a history of liver, kidney, or active ulcer disease Patients with allergies to aspirin or NSAIDS Patients with psychiatric disorders Patients with angioedema, nasal polyps, or bronchospastic disease
discussed with the patients; any patients undergoing current therapy for "minor" depression or anxiety were also excluded. Eligible patients were seen and examined by an attending physician who obtained a thorough headache history and a neurological examination. Patients symptoms were determined and subjectively quantified by the patient before drug administration. Patients were asked to rate their symptoms (Table 2) based on the psycho-physical scale developed by Borg.l° All patients were given the option to stop participation in the study at any time. After patients subjectively quantified their symptoms, they were given an intramuscular injection of either 60 mg of ketorolac or a combination drug consisting of 75 mg meperidine plus 25 mg of promethazine. Neither the patients nor their physicians or investigators involved in this study knew which drug was being administered. The UTMB pharmacy randomly assigned the drugs and placed them in identical containers of equal volume that were assigned code numbers. The code was not broken until the end of the study. Values for perceived reduction in headache pain and nausea were calculated for each of the various time interval observations (30 minutes, and 1 hour). None of the patients in either group remained in the ED for 360 minutes. All of the patients at discharge were clearly instructed not to take any other pain relief medications for at least 6 hours. Patients were given a stamped, addressed envelope with instructions to rate their headache according to severity (Table 2). The Borg scale value at that time was subtracted from the value at time zero; the greater the change in score, the greater the perceived relief. Relative efficacy of treatment was compared statistically by two procedures: (1) Because of the small sample size and TABLE 2.
Patient's Perceived Scale
Numerical Value
Description of Symptom
0 1 2 3 4 5 6 7 8 9 10
No symptoms Very very light Very light Light Fairly light Moderate Somewhat hard/somewhat intense Fairly hard/fairly intense Hard/intense Very hard/very intense Very very hard/very very intense
147
the fact that the subjective responses to the scale were not normally distributed, the data were analyzed using nonparametric procedures rather than only means and standard errors. Wilcoxon Rank Means were used to compare the relative efficacy of the two drug treatments over each time interval; (2) furthermore, at each posttreatment measurement, subjects were classified as responders or nonresponders with respect to reduction in headache pain and the two treatment groups were compared via chi-squared test to determine whether either treatment produced a statistically significant greater percentage of responders. A change of four or more units on the Borg pain scale was considered a positive response. This arbitrary decrease in pain by 4 or more units was chosen because, in general, patients who had a 4-unit drop could either go back to their normal activities or at least not require additional medication. As an additional test of relative efficacy, the responders and nonresponders were compared across treatment groups to determine whether there were differences in the subjective levels of relief obtained by members of the two groups. RESULTS
O v e r an approximate 8-month period, 48 patients w e r e enrolled in our study. F i v e patients (after enrollment) failed either follow-up or appropriate data collection during the E D stay or after discharge. One patient was inappropriately enrolled in the study. T h e s e patients were e x c l u d e d from the statistical analysis of the data. C o n s e q u e n t l y , 42 patients were considered for the statistical analysis. The patients were almost equally grouped into k e t o r o l a c recipients (20 patients) or m e p e r i d i n e / p r o m e t h a z i n e r e c i p i e n t s (22 patients). Patient characteristics are listed in Table 3. The patient characteristics are grouped in terms of the ketorolac patients and meperidine/promethazine patients. As s h o w n in Table 3, characteristics of all of the groups of patients, including responders and nonresponders, are similar in terms of m e a n age and weight e x c e p t for the two y o u n g e r males in the meperidine/promethazine r e s p o n d e r group. The predominance of females (81%) in our patient population has b e e n seen in similar analyses of migraine h e a d a c h e patients in many different studies. 2'7 Additionally, not e v e r y patient was weighed in our study, and as a c o n s e q u e n c e the average weights shown for the responders and n o n r e s p o n d e r s in the two drug treatment groups are averages of those weights that we had recorded. A total of six patients w e r e not weighed. This is d o c u m e n t e d in the patient characteristics (Table 3). Populations of the two t r e a t m e n t groups w e r e statistically indistinguishable in p r e t r e a t m e n t level o f h e a d a c h e pain and nausea. 11 M e a n rank scores on the Borg scale for h e a d a c h e w e r e 21.38 f o r k e t o r o l a c a n d 21.61 f o r m e p e r i d i n e / promethazine (z = .0517, P = .9588); for nausea the m e a n ranks w e r e 23.73 and 19.48, respectively (z = 1.1187, P = .2633). A t no time after t r e a t m e n t w e r e there any statistically significant differences b e t w e e n the two groups regarding change in p e r c e i v e d h e a d a c h e pain or change in nausea. Thirty minutes after treatment, m e a n rank scores for change in h e a d a c h e pain were 22.25 for ketorolac and 20.82 for meperidine/promethazine (z = .3706, P = .7109); for change in nausea rank means w e r e 22.50 and 20.59 (z = .5070, P = .6122). Sixty minutes after treatment, m e a n ranks for headache change w e r e 21.85 and 21.29 (z = .1654, P = .8686); means for nausea change w e r e 23.48 and 19.70, r e s p e c t i v e l y for ketorolac and m e p e r i d i n e / p r o m e t h a z i n e (z = .9943, P = .3201). Six hours after treatment, change in m e a n h e a d a c h e
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TABLE 3.
Patient Characteristics Mean Age (yr)
Mean Weight (kg)
F (13) M (2) F (4) M (3) F (17) M (5)
36.8 25.0 42.7 38.3 38.2 30.0
71.7 (12/12):~ 83,9 (2/2) 76.7 (3/4) 76.2 (3/3) 72.6 (15/17) 79.4 (5/5)
F (11)
32.7
73.9 (8/11)
Sex Meperidine (75 mg)/ Promethazine (25 mg) Responders* (15)t Nonresponders§ (7) Total average for patients receiving meperidine (75 mg)/promethazine (25 rag) Ketorolac (60 mg) Responders (11)
M (0) N o n r e s p o n d e r s (9)
Total average for patients receiving ketorolac (60 mg) Total averages for all patients
--
--
F (6) M (6) F (17) M (3)
35.3 37.6 33.6 37.6
59.9 95.3 68.5 95.3
(5/6) (3/3) (13/17) (3/3)
F (34) M (8)
35.9 32.8
70.8 (28/34) 85.3 (8/8)
* Refers to patients who reported a reduction in symptoms to a level four or more on a perceived intensity scale (Table 2). 1" Single numbers within brackets refer to the number of human patients in each related category. These numbers within the brackets refer to those patients out of the total number of patients in each category whose weights were known and were used to calculate the mean weight in each category. § Refers to patients who reported a reduction in symptoms to a level <4 on a perceived intensity scale. rank were 21.50 for ketorolac and 21.50 for meperidine/ promethazine (z = .3705, P = .7110). At 30 minutes after treatment, eight and nine patients were classified as responders among the ketorolac and meperidine/promethazine groups, respectively. These represent 40.0% and 40.9% of their respective groups; these percentages were not statistically different (chi-square = .004, P = .952). At 60 minutes after treatment, 10 ketorolac and 14 meperidine/promethazine subjects were classified as responders (50.0% and 63.6%, respectively). Again, this difference was not statistically significant (chi-square = .795, P = .372). After 360 minutes, 12 of 22 treated patients (54.6%) r e s p o n d e d to the m e p e r i d i n e / p r o m e t h a z i n e t r e a t m e n t whereas 10 of 20 (50%) responded to ketorolac in terms of headache reduction (Table 3; Figure 1). There was no statistically significant difference between the numbers of responders in each group (chi-square = .087, P = .7768). Figures 1 and 2 exhibit the means and standard errors of headache pain for those patients classified as responders and nonresponders (respectively). As described earlier; these figures, as well as Figures 3 and 4 (which represent ratings of nausea), depict patient symptom evaluations on the 10-point Borg scale. There were no significant differences between Wilcoxon scores for headache relief at any time period among those who responded to treatment for headache pain (change in Borg score I>4). At 30 minutes after treatment, the nine me-
|
Pretreate(:l
FIGURE 1. methazine.
30 min.
60 rain.
360 min.
Responders to ketorolac and meperidine/pro-
peridine/promethazine patients had a mean rank score of 6.33 whereas the eight ketorolac patients scored 12.00 (z = 2.3810, P = .0173). Although this comparison might suggest that ketorolac represents a slight improvement over the combination drug therapy, the difference is insignificant after Bonferroni correction for multiple analyses. After 60 minutes, the mean rank scores were 10.64 and 15.10 respectively for 15 meperidine/promethazine subjects and 10 ketorolac subjects (z = 1.5302, P = .1260). After 6 hours, the scores for the 14 meperidine/promethazine patients who had positive responses at that time exhibited a mean of 10.00 and those of 10 ketorolac patients exhibited a mean of 13.30 (z = 1.1774, P = .2390). For nausea, results were comparable. At no time after treatment did those who had been labeled as responders for headache pain show any significant differences across treatment groups for relief of nausea. After 30 minutes, Wilcoxon scores were statistically indistinguishable between change scores of the two groups (meperidine/promethazine mean of scores = 8.22, ketorolac mean of scores = 9.88, z = .6321, P = .5273). Nor were there any significant differences at 60 minutes (meperidine/promethazine mean of scores = 10.71, ketorolac mean of scores = 15.00, z = 1.4418, P = . 1494) or 6 hours (meperidine/promethazine mean of scores = 10.29, ketorolac mean of scores = 12.95, z = .9300, P = .3529). For those patients who were classified as nonresponders,
7-"
J
6-J 5-"
J
4 - ~
3.11 2.~
Pretreazeo
30 min.
60 min.
360 min.
FIGURE 2. Responders/nausea.
DAVIS ET AL • KETOROLAC VERSUS MEPERIDINE-PLUS-PROMETHAZINE
10" 9" 8"
/
sometimes limit the willingness of a patient to accept a particular therapy. The purpose of our study was to compare the effectiveness of ketorolac treatment with a combination of meperidine/promethazine treatment. This was done because meperidine/promethazine treatment is frequently used in the management of migraine headaches in EDs throughout the United States. Consequently, because ketorolac offered fewer adverse side effects than sedatives, narcotics, or antiemetics, 12'14 and has not been shown to have physiological addictive potential," the drug seems to be a good choice for patients who present with migraine headaches, especially when considering the danger of sending these patients home alone after giving them strong sedative drugs. In our double-blind study, we showed that ketorolac treatment versus meperidine/promethazine treatment was essentially the same in terms of patients' perceived scales of pain reduction for headache. This was also the case with reduction of nausea. Interestingly, both drugs produced approximately the same response over the 6-hour period that the patients were required to report their perceived headache and nausea symptoms. In this double-blind study, both drug treatment protocols resulted in patients that either responded or did not respond. Again both drug regimens in terms of the nonresponders showed about the same results over the 6-hour time period. We believe that our data strongly support the conclusion that a 60-mg injection of ketorolac is about as likely to produce a reduction in migraine headaches as a 75-mg dose of meperidine in conjunction with 25 mg promethazine. However, to show a small 20% difference between the two treatment protocols, we project that over 200 patients may need to be prospectively studied. Nonetheless, our data suggest that those individuals who will respond to either treatment will do so in a similar fashion with the maximum headache reduction occurring between 30 to 60 minutes, and within 30 minutes, there is likely to be a significant reduction in headaches and nausea. F o r both groups, our data suggest that if the patient's headache pain is reduced within 30 to 60 minutes, the patient can be given relatively good assurance that the migraine headache will continue to be suppressed for hours. Conversely, the data suggest that for both drug regimens, if the response is poor within 30 to 60 minutes, then other agents can and probably should be administered for headache and nausea reduction. In addition, the data support that both drug regimens are effective in a significant number of patients for at least 6 hours.
rle (25 mg) 1
/ /
~ 7. / .
/
~ 6 .
•
,
~ 4'~. •m ,-
. ~ 3-
2-'~ 0
Pretreated
30
rain.
60 min.
FIGURE 3. Nonresponders/headache.
results were similar. After 30 minutes, meperidine/promethazine subjects had a headache mean score of 13.54, whereas ketorolac patients had a mean of 12.42 (z = .3742, P -.7083). Nausea means of scores were 12.88 and 13.13, respectively (z = .0588, P = .9531). After 60 minutes, headache meperidine/promethazine mean of scores was 8.13 and headache ketorolac mean of scores was 10.60 (z = 1.0093, P = .3128), and nausea means of scores were 9.13 and 9.80, respectively (z --- .2330, P = .8158). After 6 hours, headache means of scores averaged 11.30 and 9.70 (z = .5966, P = .5508), and nausea means of scores were 11.15 and 9.85 for meperidine/promethazine and ketorolac, respectively (z = .4980, P = .6185). None of these values were statistically significant. DISCUSSION
We believe that a reduction in the patient's headache pain is usually the best indicator of a successful drug treatment. 9 There are many drugs available for migraine therapy, but none uniformly reduce migraine headache pain. 1'3-9"~2"13 Drugs used to treat migraine headache pain are limited by frequent and multiple side effects, and these side effects
mg,
5 rag) / Promethazine (25 rag) ,r of the Mean
Q
Pretreated
30 min,
60 min.
FIGURE 4. Nonresponders/nausea.
149
L
REFERENCES
1. Waters, WE: Headache, Clinical Epidemiology, vol 2. Littleton, MA, PSG 1986, pp 37-39 2. Stewart WF, Lipton RB, Celentano DD, et ah Prevalence of migraine headache in the United States. JAMA 1992;267:64-69 3. Ferrari MP, Melamed E, Garvel MJ, et al: Treatment of migraine attacks with Sumatriptan. New Eng J Med 325:316-321, 1991 4. Langemark M, Olesen J: Drug abuse in migraine patients. Pain 1984;19:81-86 5. Larkin LL, 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;21:37-42 6. Klapper J, Stanton J: Ketorolac versus DHE and metoclo-
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AMERICAN JOURNAL OF EMERGENCY MEDICINE • Volume 13, Number 2 • March 1995
pramide in the treatment of migraine headaches. Headache 1991 ;31:523-524 7. Duarte L, Dunaway F, Turner L, et al: Ketorolac versus meperidine and hydroxyzine in the treatment of acute migraine headache: A randomized, prospective, double-blind trial. Ann Emerg Med 1992;21:1116-1121 8. Harden RN, Carter TD, Gilman CS, et al: Ketorolac in acute headache management. Headache 1991 ;311:463-464 9. Davis CP, Torre PR, Schafer NC, et al: Ketorolac as a rapid and effective treatment of migraine headache: Evaluations by patients. Am J Emerg Med 1993;11:573-575 10. Borg C: The perception of physical performance. In Shep-
hard RJ (ed): Frontiers of Fitness. Springfield, IL, Thomas, 1971, pp 280-294 11. Zar J: Biostatistical Analysis. Englewood Cliffs, NJ, Prentice-Hall, 1974, pp 101-120 12. Lane PL, McLellan, Baggoley CJ: Comparative efficacy of chlorpromazine and meperidine with dimenhydrate in migraine headache. Ann Emerg Med 1989;18:360-365 13. Tek DS, McClellan DS, Olshaker JS, et al: A prospective, double-blind study of metoclopramide hydrochlorate for the control of migraine in the emergency department. Ann Emerg Med 1990;19:1083-1087. 14. Abramowica M: Ketorolac tromethamine. Med Lett 1990; 32:79-81
between patient treatment in the ED and narcotic addiction is unclear, Langemark and Olsen 4 calculate that 13 individuals per one million people become dependent on narcotics secondary to the treatment of migraine headaches. Lack of understanding of the exact pathogenesis of migraine headaches explains the variety of treatment regimens cited recently in emergency medicine reports. Several recent studies have looked at ED treatment of migraine headache using ketorolac. Larken and Prescott 5 concluded that ketorolac was inferior to meperidine; however, the dose of ketorolac (30 mg) is less than the 60-mg initial dose normally recommended for the average adult. In addition, they did not mention whether their patients were taking other medications. Intravenous D H E and metoclopramide was compared with ketorolac by Klapper and Stanton. 6 This was a small study of nine patients in each study arm. They concluded that ketorolac was not as effective as D H E and metoclopramide. In contrast, a recent study by Duarte et al, 7 who used meperidine and hydroxyzine in comparison to a 60-mg dose of ketorolac, found that ketorolac was as effective as the combination of the two drugs. In another small study, Hardin et al 8 used a 60-mg dose of ketorolac and concluded that it was effective in reducing the pain of migraine headache. In a previous open study performed in our institution, we determined that a 60-mg dose of ketorolac was effective in reducing or eliminating migraine headache symptoms in approximately 75% of patients. 9 In addition, we showed that ketorolac was effective in reducing nausea, and determined that the length of relief from nausea in those patients that did respond to ketorolac was at least 6 hrs. The purpose of this study was to do a prospective doubleblind comparison of ketorolac (60 mg) intramuscularly to meperidine (75 mg), and promethazine (25 rag) intramuscularly, to determine the effectiveness of controlling pain, nausea, and other migraine symptoms for a period of at least 6 hours. MATERIALS AND METHODS The study was approved by the Institutional Review Board at The University of Texas Medical Branch (UTMB), Galveston, TX. Patients who presented to the ED between July 1992 and February 1993, with a prior diagnosis of migraine made by a physician (usually their family physician or neurologist), and were determined by an emergency physician to have acute migraine attacks (eg, history consistent with migraine headaches, current headache, no focal neurological findings, etc) were considered for entry into the study. Enrolled patients were given an "Informed Consent Form" to sign. Table 1 lists the inclusion and exclusion criteria. These criteria were
DAVIS ET AL • KETOROLAC VERSUS MEPERIDINE-PLUS-PROMETHAZINE
TABLE 1. Inclusion and Exclusion Criteria for Migraine Headache Patients
Inclusion Criteria Must be at least 18 years of age, but not older than 65 years Have the ability to give informed consent Must not be pregnant Exclusion Criteria Patient taking anti-inflammatory agents (NSAIDS) Patients taking salicylate, lithium, or methotrexate before or during the study period Patients allergic to meperidine or promethazine Patients with impaired hepatic or renal function Patients with a history of liver, kidney, or active ulcer disease Patients with allergies to aspirin or NSAIDS Patients with psychiatric disorders Patients with angioedema, nasal polyps, or bronchospastic disease
discussed with the patients; any patients undergoing current therapy for "minor" depression or anxiety were also excluded. Eligible patients were seen and examined by an attending physician who obtained a thorough headache history and a neurological examination. Patients symptoms were determined and subjectively quantified by the patient before drug administration. Patients were asked to rate their symptoms (Table 2) based on the psycho-physical scale developed by Borg.l° All patients were given the option to stop participation in the study at any time. After patients subjectively quantified their symptoms, they were given an intramuscular injection of either 60 mg of ketorolac or a combination drug consisting of 75 mg meperidine plus 25 mg of promethazine. Neither the patients nor their physicians or investigators involved in this study knew which drug was being administered. The UTMB pharmacy randomly assigned the drugs and placed them in identical containers of equal volume that were assigned code numbers. The code was not broken until the end of the study. Values for perceived reduction in headache pain and nausea were calculated for each of the various time interval observations (30 minutes, and 1 hour). None of the patients in either group remained in the ED for 360 minutes. All of the patients at discharge were clearly instructed not to take any other pain relief medications for at least 6 hours. Patients were given a stamped, addressed envelope with instructions to rate their headache according to severity (Table 2). The Borg scale value at that time was subtracted from the value at time zero; the greater the change in score, the greater the perceived relief. Relative efficacy of treatment was compared statistically by two procedures: (1) Because of the small sample size and TABLE 2.
Patient's Perceived Scale
Numerical Value
Description of Symptom
0 1 2 3 4 5 6 7 8 9 10
No symptoms Very very light Very light Light Fairly light Moderate Somewhat hard/somewhat intense Fairly hard/fairly intense Hard/intense Very hard/very intense Very very hard/very very intense
147
the fact that the subjective responses to the scale were not normally distributed, the data were analyzed using nonparametric procedures rather than only means and standard errors. Wilcoxon Rank Means were used to compare the relative efficacy of the two drug treatments over each time interval; (2) furthermore, at each posttreatment measurement, subjects were classified as responders or nonresponders with respect to reduction in headache pain and the two treatment groups were compared via chi-squared test to determine whether either treatment produced a statistically significant greater percentage of responders. A change of four or more units on the Borg pain scale was considered a positive response. This arbitrary decrease in pain by 4 or more units was chosen because, in general, patients who had a 4-unit drop could either go back to their normal activities or at least not require additional medication. As an additional test of relative efficacy, the responders and nonresponders were compared across treatment groups to determine whether there were differences in the subjective levels of relief obtained by members of the two groups. RESULTS
O v e r an approximate 8-month period, 48 patients w e r e enrolled in our study. F i v e patients (after enrollment) failed either follow-up or appropriate data collection during the E D stay or after discharge. One patient was inappropriately enrolled in the study. T h e s e patients were e x c l u d e d from the statistical analysis of the data. C o n s e q u e n t l y , 42 patients were considered for the statistical analysis. The patients were almost equally grouped into k e t o r o l a c recipients (20 patients) or m e p e r i d i n e / p r o m e t h a z i n e r e c i p i e n t s (22 patients). Patient characteristics are listed in Table 3. The patient characteristics are grouped in terms of the ketorolac patients and meperidine/promethazine patients. As s h o w n in Table 3, characteristics of all of the groups of patients, including responders and nonresponders, are similar in terms of m e a n age and weight e x c e p t for the two y o u n g e r males in the meperidine/promethazine r e s p o n d e r group. The predominance of females (81%) in our patient population has b e e n seen in similar analyses of migraine h e a d a c h e patients in many different studies. 2'7 Additionally, not e v e r y patient was weighed in our study, and as a c o n s e q u e n c e the average weights shown for the responders and n o n r e s p o n d e r s in the two drug treatment groups are averages of those weights that we had recorded. A total of six patients w e r e not weighed. This is d o c u m e n t e d in the patient characteristics (Table 3). Populations of the two t r e a t m e n t groups w e r e statistically indistinguishable in p r e t r e a t m e n t level o f h e a d a c h e pain and nausea. 11 M e a n rank scores on the Borg scale for h e a d a c h e w e r e 21.38 f o r k e t o r o l a c a n d 21.61 f o r m e p e r i d i n e / promethazine (z = .0517, P = .9588); for nausea the m e a n ranks w e r e 23.73 and 19.48, respectively (z = 1.1187, P = .2633). A t no time after t r e a t m e n t w e r e there any statistically significant differences b e t w e e n the two groups regarding change in p e r c e i v e d h e a d a c h e pain or change in nausea. Thirty minutes after treatment, m e a n rank scores for change in h e a d a c h e pain were 22.25 for ketorolac and 20.82 for meperidine/promethazine (z = .3706, P = .7109); for change in nausea rank means w e r e 22.50 and 20.59 (z = .5070, P = .6122). Sixty minutes after treatment, m e a n ranks for headache change w e r e 21.85 and 21.29 (z = .1654, P = .8686); means for nausea change w e r e 23.48 and 19.70, r e s p e c t i v e l y for ketorolac and m e p e r i d i n e / p r o m e t h a z i n e (z = .9943, P = .3201). Six hours after treatment, change in m e a n h e a d a c h e
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AMERICAN JOURNAL OF EMERGENCY MEDICINE • Volume 13, Number 2 • March 1995
TABLE 3.
Patient Characteristics Mean Age (yr)
Mean Weight (kg)
F (13) M (2) F (4) M (3) F (17) M (5)
36.8 25.0 42.7 38.3 38.2 30.0
71.7 (12/12):~ 83,9 (2/2) 76.7 (3/4) 76.2 (3/3) 72.6 (15/17) 79.4 (5/5)
F (11)
32.7
73.9 (8/11)
Sex Meperidine (75 mg)/ Promethazine (25 mg) Responders* (15)t Nonresponders§ (7) Total average for patients receiving meperidine (75 mg)/promethazine (25 rag) Ketorolac (60 mg) Responders (11)
M (0) N o n r e s p o n d e r s (9)
Total average for patients receiving ketorolac (60 mg) Total averages for all patients
--
--
F (6) M (6) F (17) M (3)
35.3 37.6 33.6 37.6
59.9 95.3 68.5 95.3
(5/6) (3/3) (13/17) (3/3)
F (34) M (8)
35.9 32.8
70.8 (28/34) 85.3 (8/8)
* Refers to patients who reported a reduction in symptoms to a level four or more on a perceived intensity scale (Table 2). 1" Single numbers within brackets refer to the number of human patients in each related category. These numbers within the brackets refer to those patients out of the total number of patients in each category whose weights were known and were used to calculate the mean weight in each category. § Refers to patients who reported a reduction in symptoms to a level <4 on a perceived intensity scale. rank were 21.50 for ketorolac and 21.50 for meperidine/ promethazine (z = .3705, P = .7110). At 30 minutes after treatment, eight and nine patients were classified as responders among the ketorolac and meperidine/promethazine groups, respectively. These represent 40.0% and 40.9% of their respective groups; these percentages were not statistically different (chi-square = .004, P = .952). At 60 minutes after treatment, 10 ketorolac and 14 meperidine/promethazine subjects were classified as responders (50.0% and 63.6%, respectively). Again, this difference was not statistically significant (chi-square = .795, P = .372). After 360 minutes, 12 of 22 treated patients (54.6%) r e s p o n d e d to the m e p e r i d i n e / p r o m e t h a z i n e t r e a t m e n t whereas 10 of 20 (50%) responded to ketorolac in terms of headache reduction (Table 3; Figure 1). There was no statistically significant difference between the numbers of responders in each group (chi-square = .087, P = .7768). Figures 1 and 2 exhibit the means and standard errors of headache pain for those patients classified as responders and nonresponders (respectively). As described earlier; these figures, as well as Figures 3 and 4 (which represent ratings of nausea), depict patient symptom evaluations on the 10-point Borg scale. There were no significant differences between Wilcoxon scores for headache relief at any time period among those who responded to treatment for headache pain (change in Borg score I>4). At 30 minutes after treatment, the nine me-
|
Pretreate(:l
FIGURE 1. methazine.
30 min.
60 rain.
360 min.
Responders to ketorolac and meperidine/pro-
peridine/promethazine patients had a mean rank score of 6.33 whereas the eight ketorolac patients scored 12.00 (z = 2.3810, P = .0173). Although this comparison might suggest that ketorolac represents a slight improvement over the combination drug therapy, the difference is insignificant after Bonferroni correction for multiple analyses. After 60 minutes, the mean rank scores were 10.64 and 15.10 respectively for 15 meperidine/promethazine subjects and 10 ketorolac subjects (z = 1.5302, P = .1260). After 6 hours, the scores for the 14 meperidine/promethazine patients who had positive responses at that time exhibited a mean of 10.00 and those of 10 ketorolac patients exhibited a mean of 13.30 (z = 1.1774, P = .2390). For nausea, results were comparable. At no time after treatment did those who had been labeled as responders for headache pain show any significant differences across treatment groups for relief of nausea. After 30 minutes, Wilcoxon scores were statistically indistinguishable between change scores of the two groups (meperidine/promethazine mean of scores = 8.22, ketorolac mean of scores = 9.88, z = .6321, P = .5273). Nor were there any significant differences at 60 minutes (meperidine/promethazine mean of scores = 10.71, ketorolac mean of scores = 15.00, z = 1.4418, P = . 1494) or 6 hours (meperidine/promethazine mean of scores = 10.29, ketorolac mean of scores = 12.95, z = .9300, P = .3529). For those patients who were classified as nonresponders,
7-"
J
6-J 5-"
J
4 - ~
3.11 2.~
Pretreazeo
30 min.
60 min.
360 min.
FIGURE 2. Responders/nausea.
DAVIS ET AL • KETOROLAC VERSUS MEPERIDINE-PLUS-PROMETHAZINE
10" 9" 8"
/
sometimes limit the willingness of a patient to accept a particular therapy. The purpose of our study was to compare the effectiveness of ketorolac treatment with a combination of meperidine/promethazine treatment. This was done because meperidine/promethazine treatment is frequently used in the management of migraine headaches in EDs throughout the United States. Consequently, because ketorolac offered fewer adverse side effects than sedatives, narcotics, or antiemetics, 12'14 and has not been shown to have physiological addictive potential," the drug seems to be a good choice for patients who present with migraine headaches, especially when considering the danger of sending these patients home alone after giving them strong sedative drugs. In our double-blind study, we showed that ketorolac treatment versus meperidine/promethazine treatment was essentially the same in terms of patients' perceived scales of pain reduction for headache. This was also the case with reduction of nausea. Interestingly, both drugs produced approximately the same response over the 6-hour period that the patients were required to report their perceived headache and nausea symptoms. In this double-blind study, both drug treatment protocols resulted in patients that either responded or did not respond. Again both drug regimens in terms of the nonresponders showed about the same results over the 6-hour time period. We believe that our data strongly support the conclusion that a 60-mg injection of ketorolac is about as likely to produce a reduction in migraine headaches as a 75-mg dose of meperidine in conjunction with 25 mg promethazine. However, to show a small 20% difference between the two treatment protocols, we project that over 200 patients may need to be prospectively studied. Nonetheless, our data suggest that those individuals who will respond to either treatment will do so in a similar fashion with the maximum headache reduction occurring between 30 to 60 minutes, and within 30 minutes, there is likely to be a significant reduction in headaches and nausea. F o r both groups, our data suggest that if the patient's headache pain is reduced within 30 to 60 minutes, the patient can be given relatively good assurance that the migraine headache will continue to be suppressed for hours. Conversely, the data suggest that for both drug regimens, if the response is poor within 30 to 60 minutes, then other agents can and probably should be administered for headache and nausea reduction. In addition, the data support that both drug regimens are effective in a significant number of patients for at least 6 hours.
rle (25 mg) 1
/ /
~ 7. / .
/
~ 6 .
•
,
~ 4'~. •m ,-
. ~ 3-
2-'~ 0
Pretreated
30
rain.
60 min.
FIGURE 3. Nonresponders/headache.
results were similar. After 30 minutes, meperidine/promethazine subjects had a headache mean score of 13.54, whereas ketorolac patients had a mean of 12.42 (z = .3742, P -.7083). Nausea means of scores were 12.88 and 13.13, respectively (z = .0588, P = .9531). After 60 minutes, headache meperidine/promethazine mean of scores was 8.13 and headache ketorolac mean of scores was 10.60 (z = 1.0093, P = .3128), and nausea means of scores were 9.13 and 9.80, respectively (z --- .2330, P = .8158). After 6 hours, headache means of scores averaged 11.30 and 9.70 (z = .5966, P = .5508), and nausea means of scores were 11.15 and 9.85 for meperidine/promethazine and ketorolac, respectively (z = .4980, P = .6185). None of these values were statistically significant. DISCUSSION
We believe that a reduction in the patient's headache pain is usually the best indicator of a successful drug treatment. 9 There are many drugs available for migraine therapy, but none uniformly reduce migraine headache pain. 1'3-9"~2"13 Drugs used to treat migraine headache pain are limited by frequent and multiple side effects, and these side effects
mg,
5 rag) / Promethazine (25 rag) ,r of the Mean
Q
Pretreated
30 min,
60 min.
FIGURE 4. Nonresponders/nausea.
149
L
REFERENCES
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