ORIGINAL CONTRIBUTION dimenhydrinate; meperidine; methotrimeprazine; migraine
Methotrimeprazine Versus Meperidine and Dimenhydrinate in the Treatment of Severe Migraine: A Randomized, Controlled Trial Study objective: To compare the effectiveness of IM administration of methotrimeprazine, a non-narcotic, nonaddicting phenothiazine derivative, with that of a combination of rneperidine and dimenhydrinate in the treatment of severe migraine. Design: Double-blind, randomized, controlled trial. Setting: University hospital emergency department. Participants: Consecutive adult patients with migraine who met eligibility criteria. Interventions: Random allocation to receive IM injections of either 37.5 mg methotrimeprazine (Levoprorne ®, Nozinan ®) or 75 mg meperidine (Demerol ®) combined with 50 mg dimenhydrinate (Dramamine ®, Grnvol®). Measurements and main results: The 37 patients in each group who completed the study were similar in all demographic and clinical charncteristics. There were no statistical differences in pain intensity one hour after treatment, change in pain intensity, or pain relief as measured on a visual-analog scale; need for additional analgesia; persistence of nausea or vomiting; adverse effects; or follow-up status, except for prolonged drowsiness, in the group receiving methotrimeprazine. Conclusion: Methotrimeprazine is comparable to meperidine with dimenhydrinate for treating severe migraine and m a y be considered an effective, nonaddicting, IM alternative to narcotics for the management of this problem. [Stiell IG, Dufour DG, Moher D, Yen M, Beilby WJ, Smith NA: Methotrimeprazine versus rneperidine and dimenhydrinate in the treatment of severe migraine: A randomized, controlled trial. Ann Ernerg M e d November 1991;20:1201-1205.]
lan G Stiell, MD, FRCPC* Daniel G Dufour, MD* David Moher, MSct Margaret Yen, PharmD¢ William J Beilby, MD, FACEP* Norman A Smith, MD, FRCPC* Ottawa, Ontario, Canada From the Departments of Emergency Medicine,* Research,t and Pharmacy,¢ Ottawa Civic Hospital, University of Ottawa, Ottawa, Ontario, Canada. Received for publication December 4, 1990. Revision received March 19, 1991. Accepted for publication May 16, 1991. This study was supported by a grant from the Ottawa Civic Hospital Foundation. Address for reprints: lan G Stiell, MD, FRCPC, Department of Emergency Medicine, Ottawa Civic Hospital, 1053 Carling Avenue, Ottawa, Ontario, Canada K1Y 4E9.
INTRODUCTION Severe migraine is a common presenting problem in emergency departments and is frequently difficult to treat. Patients have usually suffered for many hours and tried oral medication before turning to the ED for help with their pain and nausea or vomiting. Physicians have traditionally used parenteral forms of narcotics, often combined with antiemetics, to treat such patients, Concerns about the effectiveness and potential for abuse of potent narcotics have led to consideration of other forms of treatment. Recent articles have addressed the use of phenothiazine derivatives as nonaddicting, non-narcotic therapy for severe migraine. Two studies have not provided convincing evidence of the effectiveness of chlorpromazine when given intramuscularly.I, ~ Other studies have shown chlorpromazine and prochlorperazine to be effective when given intravenously. 3-5 In a busy ED, starting an 1V line and administering repeated doses of medication are very time consuming. A medication that is effective for pain, relieves vomiting, is nonaddicting, and can be given efficiently by IM injection would seem ideal. Methotrimeprazine (MTZ), a phenothiazine with intrinsic analgesic properties, has been used successfully for many years in our ED to treat severe migraine. To date, there has been only one published study on the use of MTZ for migraine, a nonblinded trial that found MTZ to be very effective. 6 We thought that a randomized, double-blind, controlled trial comparing MTZ with a potent analgesic was warranted. Several studies assessing the effectiveness of phenothiazines in severe migraine haveused
20:11 November 1991
Annals of Emergency Medicine
1201/57
MIGRAINE Stiell et al
FIGURE 1. Eligibility criteria for enrollment in the migraine study. FIGURE 2. Exclusion criteria for patients in the migraine study. a placebo as a control. We believe that more information is gained by a comparison with c o m m o n l y used therapy such as the combination of a narcotic and an antiemetic/sedative. F u r t h e r m o r e , our research ethics committee considers the use of placebo tO be inappropriate for patients suffering severe pain when there is well-accepted alternate therapy. Our study compared the effects of IM MTZ with those of a combination of meperidine and dimenhydrinate (M/D). We assessed pain intensity and relief as the primary outcome measures as well as control of nausea or vomiting and incidence of adverse effects, both after one hour and by telephone follow-up.
MATERIALS A N D METHODS All adults 18 to 60 years old With migraine who presented to the ED of the Ottawa Civic Hospital, a large urban/suburban university hospital, between February and September 1990 were eligible for enrollment in this study. Eligibility definition and exclusion criteria are listed (Figures 1 and 2).7 The study protocol was reviewed and approved by the hospital research ethics committee, and written informed consent was obtained from all participating patients. Baseline assessments were made by the ED staff and included clinical examination, measurement of supine and sitting blood pressures, a brief questionnaire, and administration of a 10-cm visual-analog scale for pain intensity, s-10 The visual2analog scale measured pain intensity from "no pain" at 0 cm to "unbearable pain" at 10 cm. Patients were randomly allocated to the MTZ group or the M/D group with the use of a random-number table prepared by the pharmacy department. All medications were prepared under nitrogen to ensure maximum stability and provided in a blinded fashion in packages containing two vials labeled " A " and "B." In the package intended for the MTZ group, vial A contained 37.5 mg (25 mg/mL) MTZ (Levoprome®, Nozinan®), and vial B contained 1 mL normal saline. 58/1202
Mandatory for all patients 1. Well-defined headache attacks separated by headache-free intervals At least one of the following mandatory 2. Anorexia, nausea, or vomiting 3. Photophobia If only one of nos. 2 and 3 is present, one of the following required 4. Unilateral pain during initial phase of headache 5. Throbbing or pulsating pain 6. For women, relief during pregnancy and/ or exacerbation with menses and/or oral contraceptives 7. Family history of intermittent headaches associated with gastrointestinal upset and/or neurologic prodrome For classic migraine diagnosis 8. Discrete neurologic event (scotoma, hemianopsia, paresthesia of a limb, motor weakness) preceding or accompanying the headache
In the M/D group package, vial A c o n t a i n e d 75 m g (50 m g / m L ) meperidine (Demerol®), and vial B contained 50 mg (50 mg/mL) dimenhydrinate (Dramamine ®, Gravol®). The nurse combined the contents of the two vials and administered a single IM injection, after which patients lay in a darkened room for one hour. The emergency physician assessed outcome measures after one hour. Patients were asked to mark a repeat visual-analog scale for pain intensity and another visual-analog scale for pain relief (from "no relief" at 0 cm to "complete relief" at 10 cm). They were asked about nausea or vomiting, drowsiness, dizziness, and any other complaints and had their blood pressure measured in both supine and sitting positions. After these assessments and at the discretion of the treating physician, additional unblinded analgesics were given before discharge. Attempts were made to telephone all patients after 24 to 48 hours to determine the patient's status and the incidence of adverse effects. The daily computerized patient visit log was scanned to determine if patients returned to the hospital. All assessments (at baseline, one hour, and f o l l o w - u p ) were c o m p l e t e l y blinded as to the intervention. Statistical analyses were done using spssPc v3.1 and SAS statistical software packages. The primary outcomes were the change in scores for pain intensity after one hour (ie, iniAnnals of Emergency Medicine
2
Age less than 18 or more than 60 years Known allergy to phenothiazines, meperidine, or dimenhydrinate Current use of phenothiazines, monoamine oxidase inhibitors, isozianid, or antihypertensive medications (except propranolol) Proven or potential pregnancy History of dystonie reaction or Parkinson's disease History of cardiovascular disease, hepatic disease, or epilepsy First episode of migraine New neurologic signs on physical examination Physician believes that episode not severe enough to warrant parenteral medication Return for treatment of the same migraine episode
tial pain intensity score minus repeat pain intensity score) and the scores for pain relief. Differences between the means of the two groups were analyzed for significance with a twotailed unpaired Student's t test. For the visual analog scales for pain, we chose a parametric analysis, an approach that has generated controversy in the past but has recently been validated.11-13 Differences between the frequencies of findings in the groups were analyzed with the X2 test. To assess potential confounding of the results resulting from differences in the two populations, a multivariate analysis was p e r f o r m e d using logistic regression.
RESULTS During the study period, 75 patients in 82 separate visits satisfied the eligibility criteria, consented to participate, and were enrolled in the study (Table 1). Of these, eight cases were excluded from the final analysis for the reasons indicated (Table 1). Thus, 74 cases, including five patients who were enrolled for two separate migraine episodes, were incorporated into the final analysis. It was demonstrated that the patients randomized to the two treatment groups were similar in all respects (Table 2). Slight differences in sex distribution were not statistically significant. The initial pain intensity scores were virtually identical. The primary outcomes were the pain improvement assessments as outlined (Table 3). There were no dif20:11 November 1991
MIGRAINE Stiell et al
TABLE 1. Accounting of patients in the migraine study Patient Accounting
N
Patient visits that met inclusion criteria Patient visits with exclusion criteria Age less than 18 or more than 60 years Allergy to study medications Current use of contraindicated medication Pregnanuy History of cardiovascular disease or epilepsy First episode of migraine New neurolegic signs Physician believes that episode is not severe Return for same headache Refused to participate Randomized to study Excluded from analysis Left before reassessment Uncooperative with pain scale Study sheet lost Exclusion criteria (return for same headache) Patients included in analysis
252 84 4 26 12 3 8 10 1 5 15 86 82 8 4 2 1 1 74
TABLE 2. Initial patient characteristics Palient Characteristic Age (yr)t Female (%) Weight (kg) initial systolic blood pressure (mm Hg) Supine Duration of headache (hr) Nausea or vomiting (%) Type of migraine (%) Common Classic Medications taken before visit (%) None Aspirin or acetaminophen Codeine preparation Meperidine or oxycodone Antiemetie Ergot preparation Other Initial pain intensity score (cm)
M/D Group* (N = 37) 32.5 _+ 8.9 83.8 64.8 _+ 12.4
MTZ Group (N = 37) 30.9 + 7.3 67.6 66.7 ÷ 11.1
P .43 .18 .51
123.5 _+ 15.7
127.5 _+ 20.8
.35
23.9 _+ 27.9 94.6
27.2 _+ 32.6 94.6
.65
81.1 18.9
91.9 8.1
.31
18.9 27.0 43.2 8.1 13.5 8.1 10.8 7.92 _+ 1.50
29.7 24.3 40.5 5.4 10.8 10.8 8.1 7.94 + 1.57
.42 1.0 1.0 1.0 1.0 1.0 1.0 .95
1.0
*M/D, meperidine/dimenhydrinate; MTZ, methotrimeprazine. tPlus-minus values are given as mean -+ SD.
T A B L E 3. Pain assessments one hour after medicatio~ Assessment Pain intensity score at one hour (cm)t Change in pain intensity score (cm) Pain relief score (cm) Patients requiring additional analgesic before discharge (%)
M/D Group* (N = 37)
MTZ Group (N = 37)
P
3.26 ± 2.93 4.66 _+ 2.58 6.63 + 3.43
3.91 -,- 2.55 4.03 _+ 2.27 5.84 _+ 2.90
.31 .27 29
27.0
29.7
*M/D, meperidine/dimenhydrinate; MTZ, methotrimeprazine. tPlus-minus values are given as mean -+ SO.
20:11 November 1991
Annals of Emergency Medicine
1.0
ferences between the M/D and MTZ groups for change in pain intensity (4.66 vs 4.03, P = .27) or pain relief (6.63 vs 5.84, P = .27). The sample size of 74 cases allowed 80% statistical power to demonstrate a 2.0-crn difference in scores for pain relief. Equal proportions in each group required administration of additional analgesic before discharge. M u l t i v a r i a t e analysis was performed using the proportion of patients with relief of 7.0 cm or more on the visual analog scale as the dependent variable. The cutoff point chosen was 7.0 cm because it was thought to be clinically significant and because it was the median value for relief. The potential confounders entered as i n d e p e n d e n t variables were age, sex, weight, type of migraine, duration of migraine, initial pain intensity score, and drug type. The difference b e t w e e n the two groups remained insignificant after adjusting for potential confounders (P = .26). There were too few patients with classic migraine to allow separate analysis of groups with common and classic migraine. Other outcome assessments (Table 4) showed that there was no difference between the M/D and MTZ groups for residual nausea or vomiting (27.0% and 21.6%, P = .79), dizziness (29.7% and 33.3%, P = .94), or drowsiness (64.9% and 83.8%, P = .11). Although not statistically significant, the following adverse effects were seen only in the MTZ group: postural hypotension of 20 m m Hg or more (five), syncope (three), and muscle "twitching" (three). One patient, a 57-year-old man who had received MTZ, required IV fluids for symptomatic hypotension. He responded quickly to fluids and was discharged home after three hours. Another patient in the MTZ group fainted at home after inappropriately receiving a second 37.5-mg dose of MTZ before discharge. None of the patients with syncope was inconvenienced beyond requiring several hours of bedrest. The telephone follow-up reached 79.7% of the patients in the study (Table 5). A similar proportion in each group reported feeling better (M/D group, 76.7%; MTZ group, 82.1%; P = .85}. Significantly more patients in the MTZ group reported prolonged drowsiness (MTZ group, 51.7%; M/D group, 16.7%; P = .01). However, more patients in the M/D 1203/59
MIGRAINE Stiell et al
group returned to the hospital or required admission for further treatment of the same migraine episode (M/D group, 24.3%; MTZ group, 8.1%; P = .11). Miscellaneous complaints were more c o m m o n in the MTZ group: three patients noticed nasal congestion, one mentioned restlessness, and one complained of severe agitation. Several in this group reported prolonged lethargy or drowsiness. Review of the five patients who enrolled twice was not helpful: only two received different medications, and both patients were unavailable for follow-up.
TABLE 4. Adverse effects one hour after medication Adverse Effects (%)
60/1204
MTZ Group (N = 37)
P
27,0 29,7 64,9 0,0 0.0
21.6 33,3 83.8 8.1 8.1
.79 .94 ,11 .25 ,24
0.0
13.9
.08
3.0
5.6
Continued nausea or vomiting Dizziness Drowsiness Muscle "twitching" Syncope Postural hypotension (20 mm or more supine to sitting) Relative hypotension (20 mm or more baseline to repeat)
1.0
*M/D, meperidine/dimenhydrinatelMTZ, methotrimeprazine.
TABLE 5. Follow-up status (by telephone)
DISCUSSION This study demonstrated that the effects of IM MTZ M/D are similar for relief of pain and nausea or vomiting in acute migraine. The incidence of side effects is similar in the two treatment regimens except for increased drowsiness in the MTZ group, which may be desirable for patients with severe migraine. This may also be related to the trend toward more frequent return visits to the hospital for the M/D group. Although not statistically significant, syncope and postural hypotension were more c o m m o n in the MTZ group, a finding that has been well documented.~4 This study provided a valid and unbiased assessment of the relative merits of MTZ and M/D in the treatment of acute migraine. The sample was relatively small, but we estimate that unreasonably large numbers of patients would be required to show a 0.5-cm (1,268 patients) or 1.0-cm (318 patients) difference in the pain relief scores. Excluding 10% of patients from the analysis was unavoidable, given the nature of the clinical problem and the hectic conditions of ED practice. An interesting trend toward fewer return visits by patients in the MTZ group was unanticipated and could be assessed m o r e s y s t e m atically in a future study. The few other studies that have assessed the e f f e c t i v e n e s s of phen o t h i a z i n e s for the t r e a t m e n t of acute m i g r a i n e have had m e t h odological or clinical drawbacks. The only other study that evaluated MTZ was unblinded and had a smaller sample size. 6 An early study of IM chlorpromazine was uncontrolled and had no clearly defined, objective
M/D Group* (N = 37)
Follow-up Status (%) Successfully contacted Returned to hospital or required admission for same migraine episode Prolonged drowsiness Felt better
M/D Group* (N = 37)
MTZ Group (N ~ 37)
P
81.1
78.4
1.0
24.3 16.7 (N = 30) 76.7 (N = 30)
8.1 51.7 (N = 29) 82.1 (N = 29)
.11 .01 .85
*M/D, meperidine/dimenhydrinate;MTZ, methotrimeprazine.
outcome measures. 1 Another study had a small sample size and compared IM chlorpromazine with placebo, finding no difference in the major outcome of "successful" headache relief. 2 Hence, there is no strong evidence of the effectiveness of chlorpromazine given by the IM route. Recent reports of promising results with chlorpromazine or prochlorperazine require establishment of an IV line and, in some cases, repeated boluses of medication. 35 The IV administration of medication to treat migraine patients in a busy ED can be time consuming and may not be acceptable to some nursing and medical staff. MTZ is a phenothiazine derivative that shares m a n y properties with chlorpromazine. Unlike chlorpromazine, however, MTZ has intrinsic analgesic qualities. MTZ has never been reported to cause psychological or p h y s i c a l d e p e n d e n c e or withdrawal s y m p t o m s . Studies have shown MTZ to be an effective analgesic and antiemetic, especially for surgical and obstetric pain, but it has not been more widely embraced because of its sedating properties. 14-1s Because of the tendency of MTZ to cause orthostatic hypotension, it Annals of Emergency Medicine
should be avoided in the elderly, cardiac patients, and those receiving antihypertensive medication. Patients should be accompanied home and advised to remain in bed for six to 12 hours after receiving MTZ. Other contraindications to MTZ include age less than 12 years, early pregnancy, allergy to phenothiazines, history of severe renal or heptic disease, and epilepsy. We believe that MTZ is an attractive alternative to narcotics in the treatment of severe migraine. MTZ is effective for pain and nausea, is nonaddicting, and can be administered quickly by the IM route. Patients frequently experience marked sedation and must be prepared to go home to bed for six to 12 hours. Sedation may be a desirable property for these patients who have been suffering severe migraine for an average of 24 hours. MTZ may be equally effective at the smaller dose of 25 mg, as demonstrated by Hoag and Mortimer. 6 We have been using MTZ, without problems, in the dose of 25 to 50 mg for acute migraine for ten years in our own department. Doses recommended for pain by the pharmacy literature vary from 10 to 20 mg 14 to 25 to 100 mg. 19 The dosage and the ap20:11 November 1991
MIGRAINE Stiell et al
parent decrease in return visits to the hospital must be evaluated by further study. CONCLUSION This study demonstrates that MTZ is as effective as M/D in the treatment of severe migraine. Improvement in pain intensity and relief of nausea or vomiting are equivalent with the two treatments. The drug is associated w i t h slight increase in such adverse effects as prolonged drowsiness, syncope, and postural hypotension, and patients should be advised to rest in bed for six to 12 hours. MTZ, a nonaddicting phenothiazine derivative, is an effective ahemative to narcotics for the treatment of severe migraine by intramuscular injection. The authors thank Margaret Trbovich, RN, for her assistance in collecting data and following up patients. We are also indebted to the typists, nurses, and physicians of the ED for their assistance
20:11 November 1991
throughout the study. Thanks also go to Ron Donnelly of the pharmacy department for preparing and blinding the medications and to Irene Harris for her expert help with the manuscript.
pron. Pain 1976;2:175-184.
REFERENCES I. Iserson KV: Parenteral chlorpremazine treatment of migraine. Ann Emerg Med 1983;12:756-758.
12. Carlsson AM: Assessment of chronic pain: I. Aspects of the reliability and validity of the visual analog scale. Pain 1983;16:87-101.
2. McEwen JI, O'Connor HM, Dinsdale FIB: Treatment of migraine with intramuscular chlorpromazine. A n n Emerg Med 1987;16:758-763.
13. Price DD, Harkins SW, Baker C: Sensory affective relationships among different types of clinical and experimental pain. Pain 1987;28:297-307.
3. Lane PL, McLellan BA, Baggoley CJ: Comparative efficacy of chlorpromazine and meperidine with dimenhydrinate in m i g r a i n e headache. A n n Emerg M e d 1989;18:360-365.
14. McEvoy GK (ed}: American Hospital Formulary Service. Bethesda, Maryland, American Society of Hospital Pharmacists, 1990, pp 1289-1291.
4. Jones J, Sklar D, Dougherty J, et ah Randomized double-blind trial of intravenous prochlorperazine for the treatment of acute headache. JAMA 1989;261:1174-1176.
10. McDowell I, Newell C: Measuring Health: A Guide to Rating Scales and Questionnaires. Oxford, Oxford University Press, 1987, p 235-239. 11. Price DD, McGrath PA, Rafii A, et ah The validation of visual analog scales as ratio scale measures for chronic and experimental pain. Pain 1983;17:45-56.
15. Lasagna L~ DeKornfeld J: Methotrimeprazine: A new phenothiazine derivative with analgesic properties. JAMA 1961;178:887-890.
8. Bell R, Montoya D, Shuaib A, et ah A comparative trial of three agents in the treatment of acute migraine headache. Ann Emerg ivied 1990;19:1079-i082.
16. Beaver WT, Wallenstein SL, Houde RW, et ah A comparison of the analgesic effects of methotrimeprazine and morphine in patients with cancer. Clin Pharmacol Ther 1966;7:436-446.
6. Hoag R, Mortimer L: Methotrimeprazine compared to meperidine and dimenhydrinate in the treatment of migraine headache. CAEP Rev 1986;7:29-31.
17. 8tirman JA: A comparison of methotrimeprazine and meperidine as analgesic agents. Anesth Anulg 1967;46:176-180.
7. Diamond 8, Solomon GD~ Freitag FG, et ah Selection of patients-critical aspects. Methodological problems in migraine trials. Neuroepidemiol 1987;6:172-177.
18. Minuck M: Postoperative analgesia-Comparison of methotrimeprazine {Nozinan e] and meperidine (Demerol ®) as postoperative analgesia agents. Can Anaesth Soc J 1972;19:87-96.
8. Huskisson EC: Measurement of pain. Lancet 1974; 2:1127-113L 9. Scott J, Huskisson BC: Graphic representation of
Annals of Emergency Medicine
19. Krogh CME (ed}: Compendium of Pharmaceuticals and Specialties. Ottawa, Canadian Pharmaceutical Association, 1990, p 752-753.
1205/61
Methotrimeprazine Versus Meperidine and Dimenhydrinate in the Treatment of Severe Migraine: A Randomized, Controlled Trial Study objective: To compare the effectiveness of IM administration of methotrimeprazine, a non-narcotic, nonaddicting phenothiazine derivative, with that of a combination of rneperidine and dimenhydrinate in the treatment of severe migraine. Design: Double-blind, randomized, controlled trial. Setting: University hospital emergency department. Participants: Consecutive adult patients with migraine who met eligibility criteria. Interventions: Random allocation to receive IM injections of either 37.5 mg methotrimeprazine (Levoprorne ®, Nozinan ®) or 75 mg meperidine (Demerol ®) combined with 50 mg dimenhydrinate (Dramamine ®, Grnvol®). Measurements and main results: The 37 patients in each group who completed the study were similar in all demographic and clinical charncteristics. There were no statistical differences in pain intensity one hour after treatment, change in pain intensity, or pain relief as measured on a visual-analog scale; need for additional analgesia; persistence of nausea or vomiting; adverse effects; or follow-up status, except for prolonged drowsiness, in the group receiving methotrimeprazine. Conclusion: Methotrimeprazine is comparable to meperidine with dimenhydrinate for treating severe migraine and m a y be considered an effective, nonaddicting, IM alternative to narcotics for the management of this problem. [Stiell IG, Dufour DG, Moher D, Yen M, Beilby WJ, Smith NA: Methotrimeprazine versus rneperidine and dimenhydrinate in the treatment of severe migraine: A randomized, controlled trial. Ann Ernerg M e d November 1991;20:1201-1205.]
lan G Stiell, MD, FRCPC* Daniel G Dufour, MD* David Moher, MSct Margaret Yen, PharmD¢ William J Beilby, MD, FACEP* Norman A Smith, MD, FRCPC* Ottawa, Ontario, Canada From the Departments of Emergency Medicine,* Research,t and Pharmacy,¢ Ottawa Civic Hospital, University of Ottawa, Ottawa, Ontario, Canada. Received for publication December 4, 1990. Revision received March 19, 1991. Accepted for publication May 16, 1991. This study was supported by a grant from the Ottawa Civic Hospital Foundation. Address for reprints: lan G Stiell, MD, FRCPC, Department of Emergency Medicine, Ottawa Civic Hospital, 1053 Carling Avenue, Ottawa, Ontario, Canada K1Y 4E9.
INTRODUCTION Severe migraine is a common presenting problem in emergency departments and is frequently difficult to treat. Patients have usually suffered for many hours and tried oral medication before turning to the ED for help with their pain and nausea or vomiting. Physicians have traditionally used parenteral forms of narcotics, often combined with antiemetics, to treat such patients, Concerns about the effectiveness and potential for abuse of potent narcotics have led to consideration of other forms of treatment. Recent articles have addressed the use of phenothiazine derivatives as nonaddicting, non-narcotic therapy for severe migraine. Two studies have not provided convincing evidence of the effectiveness of chlorpromazine when given intramuscularly.I, ~ Other studies have shown chlorpromazine and prochlorperazine to be effective when given intravenously. 3-5 In a busy ED, starting an 1V line and administering repeated doses of medication are very time consuming. A medication that is effective for pain, relieves vomiting, is nonaddicting, and can be given efficiently by IM injection would seem ideal. Methotrimeprazine (MTZ), a phenothiazine with intrinsic analgesic properties, has been used successfully for many years in our ED to treat severe migraine. To date, there has been only one published study on the use of MTZ for migraine, a nonblinded trial that found MTZ to be very effective. 6 We thought that a randomized, double-blind, controlled trial comparing MTZ with a potent analgesic was warranted. Several studies assessing the effectiveness of phenothiazines in severe migraine haveused
20:11 November 1991
Annals of Emergency Medicine
1201/57
MIGRAINE Stiell et al
FIGURE 1. Eligibility criteria for enrollment in the migraine study. FIGURE 2. Exclusion criteria for patients in the migraine study. a placebo as a control. We believe that more information is gained by a comparison with c o m m o n l y used therapy such as the combination of a narcotic and an antiemetic/sedative. F u r t h e r m o r e , our research ethics committee considers the use of placebo tO be inappropriate for patients suffering severe pain when there is well-accepted alternate therapy. Our study compared the effects of IM MTZ with those of a combination of meperidine and dimenhydrinate (M/D). We assessed pain intensity and relief as the primary outcome measures as well as control of nausea or vomiting and incidence of adverse effects, both after one hour and by telephone follow-up.
MATERIALS A N D METHODS All adults 18 to 60 years old With migraine who presented to the ED of the Ottawa Civic Hospital, a large urban/suburban university hospital, between February and September 1990 were eligible for enrollment in this study. Eligibility definition and exclusion criteria are listed (Figures 1 and 2).7 The study protocol was reviewed and approved by the hospital research ethics committee, and written informed consent was obtained from all participating patients. Baseline assessments were made by the ED staff and included clinical examination, measurement of supine and sitting blood pressures, a brief questionnaire, and administration of a 10-cm visual-analog scale for pain intensity, s-10 The visual2analog scale measured pain intensity from "no pain" at 0 cm to "unbearable pain" at 10 cm. Patients were randomly allocated to the MTZ group or the M/D group with the use of a random-number table prepared by the pharmacy department. All medications were prepared under nitrogen to ensure maximum stability and provided in a blinded fashion in packages containing two vials labeled " A " and "B." In the package intended for the MTZ group, vial A contained 37.5 mg (25 mg/mL) MTZ (Levoprome®, Nozinan®), and vial B contained 1 mL normal saline. 58/1202
Mandatory for all patients 1. Well-defined headache attacks separated by headache-free intervals At least one of the following mandatory 2. Anorexia, nausea, or vomiting 3. Photophobia If only one of nos. 2 and 3 is present, one of the following required 4. Unilateral pain during initial phase of headache 5. Throbbing or pulsating pain 6. For women, relief during pregnancy and/ or exacerbation with menses and/or oral contraceptives 7. Family history of intermittent headaches associated with gastrointestinal upset and/or neurologic prodrome For classic migraine diagnosis 8. Discrete neurologic event (scotoma, hemianopsia, paresthesia of a limb, motor weakness) preceding or accompanying the headache
In the M/D group package, vial A c o n t a i n e d 75 m g (50 m g / m L ) meperidine (Demerol®), and vial B contained 50 mg (50 mg/mL) dimenhydrinate (Dramamine ®, Gravol®). The nurse combined the contents of the two vials and administered a single IM injection, after which patients lay in a darkened room for one hour. The emergency physician assessed outcome measures after one hour. Patients were asked to mark a repeat visual-analog scale for pain intensity and another visual-analog scale for pain relief (from "no relief" at 0 cm to "complete relief" at 10 cm). They were asked about nausea or vomiting, drowsiness, dizziness, and any other complaints and had their blood pressure measured in both supine and sitting positions. After these assessments and at the discretion of the treating physician, additional unblinded analgesics were given before discharge. Attempts were made to telephone all patients after 24 to 48 hours to determine the patient's status and the incidence of adverse effects. The daily computerized patient visit log was scanned to determine if patients returned to the hospital. All assessments (at baseline, one hour, and f o l l o w - u p ) were c o m p l e t e l y blinded as to the intervention. Statistical analyses were done using spssPc v3.1 and SAS statistical software packages. The primary outcomes were the change in scores for pain intensity after one hour (ie, iniAnnals of Emergency Medicine
2
Age less than 18 or more than 60 years Known allergy to phenothiazines, meperidine, or dimenhydrinate Current use of phenothiazines, monoamine oxidase inhibitors, isozianid, or antihypertensive medications (except propranolol) Proven or potential pregnancy History of dystonie reaction or Parkinson's disease History of cardiovascular disease, hepatic disease, or epilepsy First episode of migraine New neurologic signs on physical examination Physician believes that episode not severe enough to warrant parenteral medication Return for treatment of the same migraine episode
tial pain intensity score minus repeat pain intensity score) and the scores for pain relief. Differences between the means of the two groups were analyzed for significance with a twotailed unpaired Student's t test. For the visual analog scales for pain, we chose a parametric analysis, an approach that has generated controversy in the past but has recently been validated.11-13 Differences between the frequencies of findings in the groups were analyzed with the X2 test. To assess potential confounding of the results resulting from differences in the two populations, a multivariate analysis was p e r f o r m e d using logistic regression.
RESULTS During the study period, 75 patients in 82 separate visits satisfied the eligibility criteria, consented to participate, and were enrolled in the study (Table 1). Of these, eight cases were excluded from the final analysis for the reasons indicated (Table 1). Thus, 74 cases, including five patients who were enrolled for two separate migraine episodes, were incorporated into the final analysis. It was demonstrated that the patients randomized to the two treatment groups were similar in all respects (Table 2). Slight differences in sex distribution were not statistically significant. The initial pain intensity scores were virtually identical. The primary outcomes were the pain improvement assessments as outlined (Table 3). There were no dif20:11 November 1991
MIGRAINE Stiell et al
TABLE 1. Accounting of patients in the migraine study Patient Accounting
N
Patient visits that met inclusion criteria Patient visits with exclusion criteria Age less than 18 or more than 60 years Allergy to study medications Current use of contraindicated medication Pregnanuy History of cardiovascular disease or epilepsy First episode of migraine New neurolegic signs Physician believes that episode is not severe Return for same headache Refused to participate Randomized to study Excluded from analysis Left before reassessment Uncooperative with pain scale Study sheet lost Exclusion criteria (return for same headache) Patients included in analysis
252 84 4 26 12 3 8 10 1 5 15 86 82 8 4 2 1 1 74
TABLE 2. Initial patient characteristics Palient Characteristic Age (yr)t Female (%) Weight (kg) initial systolic blood pressure (mm Hg) Supine Duration of headache (hr) Nausea or vomiting (%) Type of migraine (%) Common Classic Medications taken before visit (%) None Aspirin or acetaminophen Codeine preparation Meperidine or oxycodone Antiemetie Ergot preparation Other Initial pain intensity score (cm)
M/D Group* (N = 37) 32.5 _+ 8.9 83.8 64.8 _+ 12.4
MTZ Group (N = 37) 30.9 + 7.3 67.6 66.7 ÷ 11.1
P .43 .18 .51
123.5 _+ 15.7
127.5 _+ 20.8
.35
23.9 _+ 27.9 94.6
27.2 _+ 32.6 94.6
.65
81.1 18.9
91.9 8.1
.31
18.9 27.0 43.2 8.1 13.5 8.1 10.8 7.92 _+ 1.50
29.7 24.3 40.5 5.4 10.8 10.8 8.1 7.94 + 1.57
.42 1.0 1.0 1.0 1.0 1.0 1.0 .95
1.0
*M/D, meperidine/dimenhydrinate; MTZ, methotrimeprazine. tPlus-minus values are given as mean -+ SD.
T A B L E 3. Pain assessments one hour after medicatio~ Assessment Pain intensity score at one hour (cm)t Change in pain intensity score (cm) Pain relief score (cm) Patients requiring additional analgesic before discharge (%)
M/D Group* (N = 37)
MTZ Group (N = 37)
P
3.26 ± 2.93 4.66 _+ 2.58 6.63 + 3.43
3.91 -,- 2.55 4.03 _+ 2.27 5.84 _+ 2.90
.31 .27 29
27.0
29.7
*M/D, meperidine/dimenhydrinate; MTZ, methotrimeprazine. tPlus-minus values are given as mean -+ SO.
20:11 November 1991
Annals of Emergency Medicine
1.0
ferences between the M/D and MTZ groups for change in pain intensity (4.66 vs 4.03, P = .27) or pain relief (6.63 vs 5.84, P = .27). The sample size of 74 cases allowed 80% statistical power to demonstrate a 2.0-crn difference in scores for pain relief. Equal proportions in each group required administration of additional analgesic before discharge. M u l t i v a r i a t e analysis was performed using the proportion of patients with relief of 7.0 cm or more on the visual analog scale as the dependent variable. The cutoff point chosen was 7.0 cm because it was thought to be clinically significant and because it was the median value for relief. The potential confounders entered as i n d e p e n d e n t variables were age, sex, weight, type of migraine, duration of migraine, initial pain intensity score, and drug type. The difference b e t w e e n the two groups remained insignificant after adjusting for potential confounders (P = .26). There were too few patients with classic migraine to allow separate analysis of groups with common and classic migraine. Other outcome assessments (Table 4) showed that there was no difference between the M/D and MTZ groups for residual nausea or vomiting (27.0% and 21.6%, P = .79), dizziness (29.7% and 33.3%, P = .94), or drowsiness (64.9% and 83.8%, P = .11). Although not statistically significant, the following adverse effects were seen only in the MTZ group: postural hypotension of 20 m m Hg or more (five), syncope (three), and muscle "twitching" (three). One patient, a 57-year-old man who had received MTZ, required IV fluids for symptomatic hypotension. He responded quickly to fluids and was discharged home after three hours. Another patient in the MTZ group fainted at home after inappropriately receiving a second 37.5-mg dose of MTZ before discharge. None of the patients with syncope was inconvenienced beyond requiring several hours of bedrest. The telephone follow-up reached 79.7% of the patients in the study (Table 5). A similar proportion in each group reported feeling better (M/D group, 76.7%; MTZ group, 82.1%; P = .85}. Significantly more patients in the MTZ group reported prolonged drowsiness (MTZ group, 51.7%; M/D group, 16.7%; P = .01). However, more patients in the M/D 1203/59
MIGRAINE Stiell et al
group returned to the hospital or required admission for further treatment of the same migraine episode (M/D group, 24.3%; MTZ group, 8.1%; P = .11). Miscellaneous complaints were more c o m m o n in the MTZ group: three patients noticed nasal congestion, one mentioned restlessness, and one complained of severe agitation. Several in this group reported prolonged lethargy or drowsiness. Review of the five patients who enrolled twice was not helpful: only two received different medications, and both patients were unavailable for follow-up.
TABLE 4. Adverse effects one hour after medication Adverse Effects (%)
60/1204
MTZ Group (N = 37)
P
27,0 29,7 64,9 0,0 0.0
21.6 33,3 83.8 8.1 8.1
.79 .94 ,11 .25 ,24
0.0
13.9
.08
3.0
5.6
Continued nausea or vomiting Dizziness Drowsiness Muscle "twitching" Syncope Postural hypotension (20 mm or more supine to sitting) Relative hypotension (20 mm or more baseline to repeat)
1.0
*M/D, meperidine/dimenhydrinatelMTZ, methotrimeprazine.
TABLE 5. Follow-up status (by telephone)
DISCUSSION This study demonstrated that the effects of IM MTZ M/D are similar for relief of pain and nausea or vomiting in acute migraine. The incidence of side effects is similar in the two treatment regimens except for increased drowsiness in the MTZ group, which may be desirable for patients with severe migraine. This may also be related to the trend toward more frequent return visits to the hospital for the M/D group. Although not statistically significant, syncope and postural hypotension were more c o m m o n in the MTZ group, a finding that has been well documented.~4 This study provided a valid and unbiased assessment of the relative merits of MTZ and M/D in the treatment of acute migraine. The sample was relatively small, but we estimate that unreasonably large numbers of patients would be required to show a 0.5-cm (1,268 patients) or 1.0-cm (318 patients) difference in the pain relief scores. Excluding 10% of patients from the analysis was unavoidable, given the nature of the clinical problem and the hectic conditions of ED practice. An interesting trend toward fewer return visits by patients in the MTZ group was unanticipated and could be assessed m o r e s y s t e m atically in a future study. The few other studies that have assessed the e f f e c t i v e n e s s of phen o t h i a z i n e s for the t r e a t m e n t of acute m i g r a i n e have had m e t h odological or clinical drawbacks. The only other study that evaluated MTZ was unblinded and had a smaller sample size. 6 An early study of IM chlorpromazine was uncontrolled and had no clearly defined, objective
M/D Group* (N = 37)
Follow-up Status (%) Successfully contacted Returned to hospital or required admission for same migraine episode Prolonged drowsiness Felt better
M/D Group* (N = 37)
MTZ Group (N ~ 37)
P
81.1
78.4
1.0
24.3 16.7 (N = 30) 76.7 (N = 30)
8.1 51.7 (N = 29) 82.1 (N = 29)
.11 .01 .85
*M/D, meperidine/dimenhydrinate;MTZ, methotrimeprazine.
outcome measures. 1 Another study had a small sample size and compared IM chlorpromazine with placebo, finding no difference in the major outcome of "successful" headache relief. 2 Hence, there is no strong evidence of the effectiveness of chlorpromazine given by the IM route. Recent reports of promising results with chlorpromazine or prochlorperazine require establishment of an IV line and, in some cases, repeated boluses of medication. 35 The IV administration of medication to treat migraine patients in a busy ED can be time consuming and may not be acceptable to some nursing and medical staff. MTZ is a phenothiazine derivative that shares m a n y properties with chlorpromazine. Unlike chlorpromazine, however, MTZ has intrinsic analgesic qualities. MTZ has never been reported to cause psychological or p h y s i c a l d e p e n d e n c e or withdrawal s y m p t o m s . Studies have shown MTZ to be an effective analgesic and antiemetic, especially for surgical and obstetric pain, but it has not been more widely embraced because of its sedating properties. 14-1s Because of the tendency of MTZ to cause orthostatic hypotension, it Annals of Emergency Medicine
should be avoided in the elderly, cardiac patients, and those receiving antihypertensive medication. Patients should be accompanied home and advised to remain in bed for six to 12 hours after receiving MTZ. Other contraindications to MTZ include age less than 12 years, early pregnancy, allergy to phenothiazines, history of severe renal or heptic disease, and epilepsy. We believe that MTZ is an attractive alternative to narcotics in the treatment of severe migraine. MTZ is effective for pain and nausea, is nonaddicting, and can be administered quickly by the IM route. Patients frequently experience marked sedation and must be prepared to go home to bed for six to 12 hours. Sedation may be a desirable property for these patients who have been suffering severe migraine for an average of 24 hours. MTZ may be equally effective at the smaller dose of 25 mg, as demonstrated by Hoag and Mortimer. 6 We have been using MTZ, without problems, in the dose of 25 to 50 mg for acute migraine for ten years in our own department. Doses recommended for pain by the pharmacy literature vary from 10 to 20 mg 14 to 25 to 100 mg. 19 The dosage and the ap20:11 November 1991
MIGRAINE Stiell et al
parent decrease in return visits to the hospital must be evaluated by further study. CONCLUSION This study demonstrates that MTZ is as effective as M/D in the treatment of severe migraine. Improvement in pain intensity and relief of nausea or vomiting are equivalent with the two treatments. The drug is associated w i t h slight increase in such adverse effects as prolonged drowsiness, syncope, and postural hypotension, and patients should be advised to rest in bed for six to 12 hours. MTZ, a nonaddicting phenothiazine derivative, is an effective ahemative to narcotics for the treatment of severe migraine by intramuscular injection. The authors thank Margaret Trbovich, RN, for her assistance in collecting data and following up patients. We are also indebted to the typists, nurses, and physicians of the ED for their assistance
20:11 November 1991
throughout the study. Thanks also go to Ron Donnelly of the pharmacy department for preparing and blinding the medications and to Irene Harris for her expert help with the manuscript.
pron. Pain 1976;2:175-184.
REFERENCES I. Iserson KV: Parenteral chlorpremazine treatment of migraine. Ann Emerg Med 1983;12:756-758.
12. Carlsson AM: Assessment of chronic pain: I. Aspects of the reliability and validity of the visual analog scale. Pain 1983;16:87-101.
2. McEwen JI, O'Connor HM, Dinsdale FIB: Treatment of migraine with intramuscular chlorpromazine. A n n Emerg Med 1987;16:758-763.
13. Price DD, Harkins SW, Baker C: Sensory affective relationships among different types of clinical and experimental pain. Pain 1987;28:297-307.
3. Lane PL, McLellan BA, Baggoley CJ: Comparative efficacy of chlorpromazine and meperidine with dimenhydrinate in m i g r a i n e headache. A n n Emerg M e d 1989;18:360-365.
14. McEvoy GK (ed}: American Hospital Formulary Service. Bethesda, Maryland, American Society of Hospital Pharmacists, 1990, pp 1289-1291.
4. Jones J, Sklar D, Dougherty J, et ah Randomized double-blind trial of intravenous prochlorperazine for the treatment of acute headache. JAMA 1989;261:1174-1176.
10. McDowell I, Newell C: Measuring Health: A Guide to Rating Scales and Questionnaires. Oxford, Oxford University Press, 1987, p 235-239. 11. Price DD, McGrath PA, Rafii A, et ah The validation of visual analog scales as ratio scale measures for chronic and experimental pain. Pain 1983;17:45-56.
15. Lasagna L~ DeKornfeld J: Methotrimeprazine: A new phenothiazine derivative with analgesic properties. JAMA 1961;178:887-890.
8. Bell R, Montoya D, Shuaib A, et ah A comparative trial of three agents in the treatment of acute migraine headache. Ann Emerg ivied 1990;19:1079-i082.
16. Beaver WT, Wallenstein SL, Houde RW, et ah A comparison of the analgesic effects of methotrimeprazine and morphine in patients with cancer. Clin Pharmacol Ther 1966;7:436-446.
6. Hoag R, Mortimer L: Methotrimeprazine compared to meperidine and dimenhydrinate in the treatment of migraine headache. CAEP Rev 1986;7:29-31.
17. 8tirman JA: A comparison of methotrimeprazine and meperidine as analgesic agents. Anesth Anulg 1967;46:176-180.
7. Diamond 8, Solomon GD~ Freitag FG, et ah Selection of patients-critical aspects. Methodological problems in migraine trials. Neuroepidemiol 1987;6:172-177.
18. Minuck M: Postoperative analgesia-Comparison of methotrimeprazine {Nozinan e] and meperidine (Demerol ®) as postoperative analgesia agents. Can Anaesth Soc J 1972;19:87-96.
8. Huskisson EC: Measurement of pain. Lancet 1974; 2:1127-113L 9. Scott J, Huskisson BC: Graphic representation of
Annals of Emergency Medicine
19. Krogh CME (ed}: Compendium of Pharmaceuticals and Specialties. Ottawa, Canadian Pharmaceutical Association, 1990, p 752-753.
1205/61
