- Email: [email protected]
Comparative efficacy of chlorpromazine and meperidine with dimenhydrinate in migraine headache
ORiGiNAL CONTRIBUTION 0hlorpromazine, migraine; meperidine, dimenhydrinate, migraine; migraine, chlorpromazine, meperidine and dimenhydrinate
Comparative Efficacy of Chlorpromazine and Meperidine With Dimenhydrinate in Migraine Headache Approximately 20% of the population suffers from migraine headache, and a significant number develop "'fixed" migraines, refractory to oral raedications. Of this group, many become habitual narcotic users. A previously published case series using IV chlorpromazine suggested efficacy, so a randomized, double-blind, controlled trial was conducted. The study compared IV chlorpromazine against IV meperidine with dimenhydrinate. Entry criteria were emergency department patients from 18 to 60 years of age with a clinical diagnosis of common or classic migraine headache. After informed consent was obtained, an IV line with normal saline was established, and a bolus of 5 mL/kg was administered. Patients were randomized into two groups: chlorpromazine and meperidine with dimenhydrinate. The chlorpromazine group received a bolus injection of 5 mL normal saline placebo followed by 0.4 mL/kg chlorpromazine solution (0.1 r~g/kg). The chlorpromazine was repeated every 15 minutes as needed up to a total of three doses. The meperidine with dimenhydrinate group received 5 mL dimenhydrinate solution (25 rag) followed by 0.04 mL/kg meperidine (0.4 mg/kg). Again, the meperidine solution was repeated in the same dosage every 15 minutes as needed up to a total of three doses. If response was inadequate 15 minutes after the third dose, the sequence was broken, and the other medication given. Blood pressure and response were assessed at 15-minute intervals for one hour. Pain was assessed by both visual and verbal analogue scales every 15 minutes. In all, 46 patients were entered in the study (24 chlorpromazine and 22 meperidine w~th dimenhydrinate). Both groups were comparable in terms of age, sex, type of migraine, duration of headache, prior medications, number of doses required, and adverse effects. No significant hypotensive or dystonic reactions were encountered.. Two of the 24 in the chlorpromazine group compared with Ii of the 22 in the meperidine with dimenhydrinate group experienced inadequate relief and required other medication (P < .01). Changes in both the visual and verbal analogue scales were significantly better in the Chlorpromazine group (P < .001). IV chlorpromazine appears to offer effective relief to ED patients with acute migraine headache while avoiding the potential for narcotic abuse and addiction. [Lane PL, McLellan BA, Baggoley CJ: Comparative efficacy of chlorpromazine and meperidine ~vith dimenhydrinate in migraine headache. Ann Emerg Med April I989;18:360-365.]
Peter L Lane, MD, FRCPC Barry A McLellan, MD, FRCPC Christopher J Baggoley, MD, FACEM Toronto, Ontario From the Department of Emergency Services, Sunnybrook Medical Centre, University of Toronto, Canada. Received for publication May 25, 1988. Revision received October 25, 1988. Accepted for publication December 2, 1988. Presented at the University Association for Emergency Medicine Annual Meeting in Cincinnati, May 1988. Address for reprints: Peter Lane, MD, FRCPC, Department of Emergency Medicine, Victoria Hospital, 375 South Street, London, Canada N6A 4G5.
INTRODUCTION Migraine headache is an extremely common condition, affecting about 20% of people. 1 Many of these patients present repeatedly to emergency departments with "fixed" migraines that are resistant to over-the-counter and prescribed medications taken at home. This entity has been referred to as "status migrainosus. ''z Common drug regimens for treatment of fixed migraine are unsatisfactory. Narcotic and ergot abuse is common among migraine sufferers and is one of the most common antecederfts to significant iatrogenic drug addiction. Recently, it has also been recognized that narcotic and ergot abuse are likely causes of the long-term daily migraine.2~4 A preliminary study 5 with IV chlorpromazine demonstrated considerable promise and therefore a double-blind, controlled study was carried out
18:4April 1989
Annals of Emergency Medicine
360/53
MIGRAINE HEADACHE Lane, McLellan & Baggoley
FIGURE 1. Visual analogue assessm e n t scale.
No Pain .
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Unbearable Pain .
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FIGURE 2. Verbal analogue scale. 10 cm
FIGURE 3. Pain assessment - visual analogue scale.
to demonstrate that IV chlorpromazine (Thorazine ®) was as effective as IV meperidine (Demerol ®) and dimenhydrinate (Dramamine ®) in providing pain relief to patients presenting to the ED with fixed migraine.
Question: How is .your pain now? The patient marks with a pen the point on the line that corresponds to the pain level.
METHODS The study was conducted in the S u n n y b r o o k Medical C e n t r e ED, University of Toronto, Canada. All patients presenting to the ED in w h o m a diagnosis of c o m m o n or classic migraine was made by the staff emergency physician were considered for entry into the study. The specific exclusion criteria for the study were first migraine; allergy to s t u d y drugs; c u r r e n t use of phenothiazines, monoamine oxidase inhibitors, isoniazid, or antidepressants; Parkinson's disease or history of dystonic reactions; seizure disorder; less than 18 or more than 60 years old; known or potential pregnancy; nursing mother; or no means of transport home. After informed consent was obtained, p a t i e n t s were assigned a study number. Study numbers were randomized into two groups: those receiving chlorpromazine and those receiving meperidine with dimenhydrinate. The study drugs were prepared by a nurse, labeled "syringe A" or "syringe B," and handed to the physician. The physician involved was blinded as to the actual contents of the syringes and gave these medications by volume in a blinded fashion. Syringe A contained either 10 mL normal saline or 50 mg dimenhydrinate diluted to 10 mL. Syringe B contained either 25 mg chlorpromazine diluted to 10 mL or 100 mg meperidine diluted to 10 mL. An IV line was established in all patients. Because a previous, uncontrolled case series 5 suggested the potential for significant orthostatic hypotension, a bolus of 5 mL/kg normal saline was administered before administration of any drug. Blood pressure and pain assessment measurements were taken by the physician before the administration of saline. 54/361
Intensity of Pain
[] [] [] []
None Mild Moderate Severe
Question: How is your pain now? (The patient checks off the appropriate box.) Change in Pain Intensity
[] [] [] [] []
Worse None Minimal improvement Good improvement Excellent improvement
Question: Do you feel any change after receiving the test solution? (The patient checks off the appropriate box.)
8.31
Severity of Pain (Visual Analogue Scale)
5
~
~
~ ~
m~,~ ~
m
CPZ
m m ~
D/M
~,
3.44 1.25 0 Pre
Post Time of Measurement
Pain assessments performed at this time and later in the protocol used b o t h visual and verbal analogue scales (Figures 1 and 2). Patients were given 5.0 mL of syringe A (normal saline or 25 mg d i m e n h y d r i n a t e ) Annals of Emergency Medicine
through a proximal port in the I\ line. Subsequently, patients wet( given 0.04 mL/kg of either chlor promazine (0.1 mg/kg) or meperidinl (0.4 mg/kg). Pain, blood pressure, anl adverse effects a s s e s s m e n t s wer~ 18:4 April 1989
TABLE 1. Demographic characteristics
Chloropramazine
Dimenhydrinate With Meperidine
3 21
4 18
31.00 (21 to 47)
31.09 (19 to 48)
54.6 (2 to 336)
41.8 (2 to 216)
9 15 24
9 13 22
Sex Male Female
Age (yr) Duration of headache (hr) Type of headache Classic Common
Total group
TABLE 2. Drugs taken before arrival
Chlorpromazine
Dimenhydrinate With Meperidine
Total
13
8
21
3
0
3
6 12 3 0 0 1
7 8 3 2 3 1
13 20 6 2 3 2
0 1
0 4
0 5
Acetaminophen Nonsteroidal antiinflammatory drug Aspirin, butalbital, codeine Narcotic, codeine Narcotic, other Ergot Antiemetic Beta-blocker Calcium channel blockers Other
then conducted at 15, 30, and 45 minutes. A final assessment was done at time of discharge. Up to two repeat doses of the second solution ( c h l o r p r o m a z i n e or meperidine) were given as needed as judged by the patient at 15-minute intervals. If the response was inadequate as judged by the patient at 45 minutes, the sequence was broken and the patient was given the other drug. Patients were required to remain in the ED for monitoring for a period of one hour after the last dose of medication. All patient data were collected and recorded by the physician, who was blinded to the medication given. Statistical analysis was performed on two outcome measures, the pro18:4April 1989
portion of patients experiencing inadequate relief and requiring another drug and the subjective ratings of the visual analogue scale pain assessments. Fisher's exact probability test was used to compare the proportion of inadequate relief results for both drug treatments. An analysis of varia n c e w i t h drug as a t w o - l e v e l , between-subjects factor and with.the "pro" and "post" measurements as a repeated measure within subject factor was used on the visual analogue ratings. RESULTS Forty-six patients were entered into the study. Of these, 22 were randomized to the meperidine with dimenhydrinate group (group 1} and 24
Annals of EmergencyMedicine
to the chlorpromazine group (group 2). Characteristics of this study population can be seen (Tables t and 2). A number of patients experienced adverse side effects (Table 3). It is difficult to determine which were due to the headache and which were due to the medications administered. No incident of clinically significant orthostatic hypotension (change in systolic blood pressure of more than 10 m m Hg) were reported for either group at any time. Two of the patients in group 2 experienced inadequate relief and were given meperidine, whereas ten of the group 1 patients required the administration of chlorpromazine (Fisher's exact test, P < .01, two-tailed). The number of doses given of each drug are listed (Table 4). Ten of the 13 group i patients requiring three doses went on to receive chlorpromazine because of inadequate relief. Pain assessments were performed by both verbal and visual analogue scales. The changes noted according to the verbal scale are outlined (Table 5). The difference on the visual analogue scale between beginning time and final time was taken as t = discharge for those with a satisfactory result and t = 45 for those requiring another medication (Table 6 and Figure 3). The decrease in pain intensity after t r e a t m e n t was s i g n i f i c a n t l y larger for group 2 than for group 1 (F (1.44) = 13.54, P < .001). The correlation between response and diagnosis (common versus classic) and d u r a t i o n was a t t e m p t e d . In both cases, however, differences did not reach statistical significance because of sample size. DISCUSSION Migraine headache has been defined by The Research Group on Headache and Migraine, World Federation of Neurology, as a "familial disorder characterized by recurrent attacks of headache, widely variable in intensity, frequency and duration. Attacks are c o m m o n l y unilateral, and are usually associated with anorexia, nausea and vomiting. In some cases, they are preceded by or associated with neurological and mood disturbances. All of these characteristics are not necessarily present in each attack."6 The pathophysiology of migraine has been and will be debated for many years, with current theories 362/55
MIGRAINE HEADACHE Lane, McLellan & Baggoley
focusing on serotonin release and release of vasoactive substances by platelets. 7ql Patients presenting to the ED with fixed migraine represent a therapeutic dilemma to the emergency physician. Narcotic preparations, orally or parenterally, are frequently used12A3 with the knowledge that this is one of the most common antecedents to significant iatrogenic drug addiction. 14 Because of the side effects of narcotics, their addictive potential, and the relative lack of other therapeutic modalities, an alternative is sought. An uncontrolled trial of IV chlorpromazine for acute migraine was previously conducted, s This therapy was found to be completely effective on 38 of 52 occasions, left very mild residual pain on 11 of the 52 occasions, and provided only minor relief on the other three. Adverse effects were minimal, with most patients reporting only some mild drowsiness. This uncontrolled study suggested that IV chlorpromazine may be superior to the alternative methods of therapy available but pointed out the need for a controlled trial. Chlorpromazine is the prototype phenothiazine, a neuroleptic agent that was first developed in 1950 for use as a preanesthetic medication, is In the central nervous system, chlorpromazine acts on postsynaptic cells as a dopamine antagonist, particularly in the limbic system and the basal ganglia. 7 It also has a particular effect in the chemoreceptor trigger zone of the reticular formation and, hence, is a p o w e r f u l a n t i e m e t i c agent.TA 5 It was initially termed a neuroleptic because it induced "an indifference to pain." Chlorpromazine has important effects outside of the central nervous s y s t e m . It is a p o w e r f u l alphaadrenergic antagonist with some anticholinergic properties. 15 As a result, it causes an alpha blockade and orthostatic hypotension, and a myocardial depressant effect has been noted. It also acts as a weak diuretic.~S,16 As with other antimigraine therapy, the precise mechanism of action of chlorpromazine in acute migraine headache is not clear. The alpha blockade may be of benefit in reducing tension on the walls of extracranial arteries. The central antiemetic effect of chlorpromazine is
56/363
TABLE 3. Adverse effects reported
Chlorpromazine
Dimenhydrinate With Meperidine
Total
Drowsiness Nausea, vomiting
5 2
4 2
9 4
Dizziness Postural hypotension
2 0
1 0
3 0
Burning at IV site
3
0
Dry mouth Nasal congestion
1 2
0 0
3 1
Total No. of patients suffering adverse effects
15
7
22
11 of 24
6 of 22
17 of 46
2
TABLE 4. Number of doses of test drug given
Chlorpromazine
Dimenhydrinate With Meperidine
6
8
1 dose
2 doses 9 3 doses 9 Second medication 2 of 24 Fisher's exact test, P < .01, two-tailed.
clearly of value. Chlorpromazine also m a y alter serotonin levels. 15 The neuroleptic effect itself may also be of value. Reports of the use of chlorpromazine for migraine are few. Caviness and O'Brien 16 reported a short series of 13 patients with cluster headaches who benefited from oral chlorpromazine as prophylaxis. Iserson 1~ reported good success with intramuscularly administered chlorpromazine for acute migraine. However, doses were much larger than those used in the present study, and time to relief of symptoms was m u c h longer (55 minutes compared with five to ten minutes in the present study). Experience at this c e n t e r w i t h intramuscular administration demonstrated a m u c h lower rate of efficacy. 17 McEwen et al is demonstrated simi l a r l y u n i m p r e s s i v e r e s u l t s in a double-blind, controlled trial comparing intramuscular chlorpromazine with placebo, although verbal descriptors alone were used to assess
Annals of EmergencyMedicine
1 13 11 of 22
pain relief. Hoag and Mortimer, 19 in another randomized trial, used a vi. sual analogue scale and compared i n t r a m u s c u l a r methotrimeprazine against meperidine with dimenhydrinate. They were able to show improved results with this phenothiazine, although study size was too small to reach significance. Our study was a controlled, randomized, double-blind study of the therapeutic effectiveness of chlorpromazine as compared with standard therapy (meperidine with dimenhydrinate) for migraine headache. A crossover design was initially considered but abandoned because of the possible "carryover" effect. A controlled, randomized, double-blind study against placebo was abandoned because of ethical considerations. Standard therapy in most North A m e r i c a n EDs has been an intram u s c u l a r injection of meperidine with an antiemetic, frequently dimenhydrinate. There is, however, no published evidence to suggest the efficacy of this approach. Gallagher 2° 18:4 April 1989
TABLE 5. Pain a s s e s s m e n t -- verbal analogue scale Time (min) 15 Headache Description
30
45 Group 1
Group 2
Final Group 1 Group 2
Group 1
Group 2
Group 1
Group 2
Worse
0
0
0
0
0
0
0
0
No better
7
5
2
1
4
0
1
0
Minimal improvement
6
7
8
5
3
2
0
1
Good improvement
8
11
6
15
8
9
12
8
Excellent improvement
1
1
5
3
7
13
9
15
TABLE 6. Pain a s s e s s m e n t - visual analogue scale Chlorpromazine N
=
24
Variable
Minimum
t=O
4.50
Maximum 10.00
Mean
SD
8.31
1.54
t = final
0.00
7.10
1.25
1.70
Change
- 10.00
-2.30
-7.06
2.18
Meperidine With Dimenhydrinate N = 22
Mean
SD
t=0
Variable
5.50
10.00
7.89
1.45
t = final
0.00
10.00
3.44
3.34
9.10
0.00
-4.45
2.62
Change
Minimum
-
Maximum
F (1.44) = 13.54. P < .001.
reported results of nonblinded trial involving meperidine in combination with a variety of other medications - an antiemetic, an ergot preparation, and a steroid. In that study, a dose of 75 to 100 mg meperidine IM was used. Both Mather et a121 and Austin et a122 reported wide variability in absorption, peak concentration, and the plasma concentrationtime profile after intramuscular injection. As a result, the IV route of administration of meperidine was elected for our study. The work of Mather and his colleagues2u23 has suggested that pain relief is best achieved by IV infusion to maintain plasma concentrations between 0.5 and 0.7 m g / L . Mather and Meffin 23 suggested that levels greater than this result from injections of 50-mg boluses and may result in unpleasant side effects, including v o m i t i n g and r e s p i r a t o r y depression. T h e y r e c o m m e n d an infusion of 25 mg/hr IV after an initial bolus injection of 50 mg over 45 18:4April 1989
minutes. This r e c o m m e n d a t i o n is supported by Edwards et a124 based on more recent data regarding clearance estimates. In the present study, therefore, a substantially higher initial dose was used in that up to three bolus injections (0.4 m g / k g each) were given within 30 minutes for a total of 84 mg IV for a 70-kg patient. Because of the reassessments at 15 and 30 minutes before a repeat injection, if unpleasant side effects occurred or sufficient pain relief was achieved, the subsequent bolus could be avoided. In the preliminary study, s a significant number of adverse effects w~re noted, particularly pastural hypotension. Further experience with the medication resulted in the protocol used in this study (ie, establishment of an IV line and administration of a 5-mL/kg bolus normal saline before the use of the drug and the administration of bolus doses of 0.1 mg/kg IV at 15-minute intervals). The dosages required in this study were signifiAnnals of Emergency Medicine
cantly less than those in the preliminary study. No incident of clinically significant pastural hypotension was encountered with this regimen. Also, no incident of dystonic reaction or significant allergy was encountered. This is likely because of the very small doses of chlorpromazine being used, although a much larger experience is necessary before that conclusion can be drawn. CONCLUSION Our study suggests that IV chlorpromazine is an effective remedy in the ED for fixed migraine headache. It is associated with an acceptable incidence of m i n o r side effects and avoids the important potential problems of narcotic addiction and substance abuse associated with the use of parenteral narcotics. The future challenge will be to identify medications that are equally effective as IV chlorpromazine but can be administered either orally or through subcutaneous or intramuscular routes. 364/57
MIGRAINE HEADACHE Lane, McLellan & Baggoley
The authors gratefully acknowledge the s u p p o r t p r o v i d e d by t h e S u n n y b r o o k T r u s t Fund, t h e D e p a r t m e n t of R e s e a r c h D e s i g n a n d B i o s t a t i s t i c s for t h e i r g e n erous a s s i s t a n c e in a n a l y s i s of o u r results, M s M a r t h a Flavelle for h e r clerical support t h r o u g h o u t t h e study, a n d t h e p h y s i cians and n u r s e s of S u n n y b r o o k M e d i c a l C e n t r e for t h e i r p a t i e n t s a n d t h e i r patience.
REFERENCES 1. Waters WE: Headache IClinical Epidemiology Series vol 2). Littleton, Massachusetts, John Wright - PSG, 1986, p 37-39. 2. Edmeads J: Migraine. Can Med Assoc J 1988;138:107-113. 3. Kudrow L: Paradoxical effects of frequent analgesic use, in Critchley M (ed): Advances in Neurology, vol 33. New York, Raven Press, 1982, p 335-341. 4. Mathew NT, Reuveni U, Perez F: Transformed or evolutive migraine. Headache 1987; 27:102-106. 5. Lane PL, Ross R: Intravenous chlorpromaz i n e - Preliminary results in acute migraine. Headache 1985;25:302-304. 6. The Research Group on Headache and Migraine of the World Federation of Neurologists,
58/365
Cochrane AL (ed}: The Background of Migraine. London, Heinemann, 1970, p 181-182.
Response to chlorpromazine. Headache 1980 20:128-131.
7. O'Brien MD: Central blood flow changes in migraine. Headache 1971;10:134-143.
17. Lane PL: Intramuscular chlorpromazine fo~ acute migraine [unpublished report, 1981).
8. Skinhoj E: Hemodynamic studies with the brain during migraine. Arch Neurol 1973; 29:95-98.
18. McEwen JI, O'Connor HM, Dinsdale I-I~: The treatment of migraine with intramuscula~ chlorpromazine. Ann Emerg Med 1987;16: 758-763.
9. Edmeads J: Cerebral blood flow in migraine. Headache 1977;17:148-152. 10. Ruskin NH: Pharmacology of migraine. Annu Rev Pharmacol Toxicol 1981;21:463-478. 11. Saxena PR: The effects of antimigrainous drugs on vascular responses by 5-HT and other related biogenic substances on the external carotid bed of dogs: Possible pharmacological implications to their antimigraine actions. Headache 1972;12:44-54. 12. Iserson KV: Parenteral chlorpromazine in the t r e a t m e n t of migraine. Ann Emerg Med 1983;12:756-758. 13. Saper JR: Migraine: II. Treatment. JAMA 1978;239:2480-2484. 14. Caviness V8, O'Brien MD: Headache. N Engl J Med 1980;302:446-449. 15. 8eeman P, Sellers EM, Roschlan WHE: Principles of Medical Pharmacology, ed 3. Toronto, Canada, University of Toronto Press, 1980. 16. Caviness VSA, O'Brien P: Cluster headache:
Annals of Emergency Medicine
19. Hoag R, Mortimer L: Methotrimeprazin¢ compared to meperidine and dimenhydrinate in the treatment of migraine headache. CAEP Re. view 1986;7:29-31. 20. Gallagher RM: Emergency treatment of intractable migraine. Headache 1986;26:74-75. 21. Mather LE, Tucker GT, Pflug AE, et al: Meperidine kinetics in man: Intravenous injec. tions in surgical patients and volunteers. Clin Pharmacol Ther 1975;17:21-30. 22. Austin KL, 8tapleton JV, Mather LE: Multi. ple intramuscular injections: A major source 0t variability in analgesic response to meperidine. Pain 1980;8:47-62. 23. M a t h e r LE, Meffin PJ: C l i n i c a l phar. macokinetics of pethidine. Clin Pharmacokinei 1978;3:352-368. 24. Edwards DJ, Srenson CK, Visco JP, et al: Clinical pharmacokinetics of pethidine: 1982 Clin Pharmacokinet 1982;7:421-433.
18:4 April 1989
Comparative Efficacy of Chlorpromazine and Meperidine With Dimenhydrinate in Migraine Headache Approximately 20% of the population suffers from migraine headache, and a significant number develop "'fixed" migraines, refractory to oral raedications. Of this group, many become habitual narcotic users. A previously published case series using IV chlorpromazine suggested efficacy, so a randomized, double-blind, controlled trial was conducted. The study compared IV chlorpromazine against IV meperidine with dimenhydrinate. Entry criteria were emergency department patients from 18 to 60 years of age with a clinical diagnosis of common or classic migraine headache. After informed consent was obtained, an IV line with normal saline was established, and a bolus of 5 mL/kg was administered. Patients were randomized into two groups: chlorpromazine and meperidine with dimenhydrinate. The chlorpromazine group received a bolus injection of 5 mL normal saline placebo followed by 0.4 mL/kg chlorpromazine solution (0.1 r~g/kg). The chlorpromazine was repeated every 15 minutes as needed up to a total of three doses. The meperidine with dimenhydrinate group received 5 mL dimenhydrinate solution (25 rag) followed by 0.04 mL/kg meperidine (0.4 mg/kg). Again, the meperidine solution was repeated in the same dosage every 15 minutes as needed up to a total of three doses. If response was inadequate 15 minutes after the third dose, the sequence was broken, and the other medication given. Blood pressure and response were assessed at 15-minute intervals for one hour. Pain was assessed by both visual and verbal analogue scales every 15 minutes. In all, 46 patients were entered in the study (24 chlorpromazine and 22 meperidine w~th dimenhydrinate). Both groups were comparable in terms of age, sex, type of migraine, duration of headache, prior medications, number of doses required, and adverse effects. No significant hypotensive or dystonic reactions were encountered.. Two of the 24 in the chlorpromazine group compared with Ii of the 22 in the meperidine with dimenhydrinate group experienced inadequate relief and required other medication (P < .01). Changes in both the visual and verbal analogue scales were significantly better in the Chlorpromazine group (P < .001). IV chlorpromazine appears to offer effective relief to ED patients with acute migraine headache while avoiding the potential for narcotic abuse and addiction. [Lane PL, McLellan BA, Baggoley CJ: Comparative efficacy of chlorpromazine and meperidine ~vith dimenhydrinate in migraine headache. Ann Emerg Med April I989;18:360-365.]
Peter L Lane, MD, FRCPC Barry A McLellan, MD, FRCPC Christopher J Baggoley, MD, FACEM Toronto, Ontario From the Department of Emergency Services, Sunnybrook Medical Centre, University of Toronto, Canada. Received for publication May 25, 1988. Revision received October 25, 1988. Accepted for publication December 2, 1988. Presented at the University Association for Emergency Medicine Annual Meeting in Cincinnati, May 1988. Address for reprints: Peter Lane, MD, FRCPC, Department of Emergency Medicine, Victoria Hospital, 375 South Street, London, Canada N6A 4G5.
INTRODUCTION Migraine headache is an extremely common condition, affecting about 20% of people. 1 Many of these patients present repeatedly to emergency departments with "fixed" migraines that are resistant to over-the-counter and prescribed medications taken at home. This entity has been referred to as "status migrainosus. ''z Common drug regimens for treatment of fixed migraine are unsatisfactory. Narcotic and ergot abuse is common among migraine sufferers and is one of the most common antecederfts to significant iatrogenic drug addiction. Recently, it has also been recognized that narcotic and ergot abuse are likely causes of the long-term daily migraine.2~4 A preliminary study 5 with IV chlorpromazine demonstrated considerable promise and therefore a double-blind, controlled study was carried out
18:4April 1989
Annals of Emergency Medicine
360/53
MIGRAINE HEADACHE Lane, McLellan & Baggoley
FIGURE 1. Visual analogue assessm e n t scale.
No Pain .
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Unbearable Pain .
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FIGURE 2. Verbal analogue scale. 10 cm
FIGURE 3. Pain assessment - visual analogue scale.
to demonstrate that IV chlorpromazine (Thorazine ®) was as effective as IV meperidine (Demerol ®) and dimenhydrinate (Dramamine ®) in providing pain relief to patients presenting to the ED with fixed migraine.
Question: How is .your pain now? The patient marks with a pen the point on the line that corresponds to the pain level.
METHODS The study was conducted in the S u n n y b r o o k Medical C e n t r e ED, University of Toronto, Canada. All patients presenting to the ED in w h o m a diagnosis of c o m m o n or classic migraine was made by the staff emergency physician were considered for entry into the study. The specific exclusion criteria for the study were first migraine; allergy to s t u d y drugs; c u r r e n t use of phenothiazines, monoamine oxidase inhibitors, isoniazid, or antidepressants; Parkinson's disease or history of dystonic reactions; seizure disorder; less than 18 or more than 60 years old; known or potential pregnancy; nursing mother; or no means of transport home. After informed consent was obtained, p a t i e n t s were assigned a study number. Study numbers were randomized into two groups: those receiving chlorpromazine and those receiving meperidine with dimenhydrinate. The study drugs were prepared by a nurse, labeled "syringe A" or "syringe B," and handed to the physician. The physician involved was blinded as to the actual contents of the syringes and gave these medications by volume in a blinded fashion. Syringe A contained either 10 mL normal saline or 50 mg dimenhydrinate diluted to 10 mL. Syringe B contained either 25 mg chlorpromazine diluted to 10 mL or 100 mg meperidine diluted to 10 mL. An IV line was established in all patients. Because a previous, uncontrolled case series 5 suggested the potential for significant orthostatic hypotension, a bolus of 5 mL/kg normal saline was administered before administration of any drug. Blood pressure and pain assessment measurements were taken by the physician before the administration of saline. 54/361
Intensity of Pain
[] [] [] []
None Mild Moderate Severe
Question: How is your pain now? (The patient checks off the appropriate box.) Change in Pain Intensity
[] [] [] [] []
Worse None Minimal improvement Good improvement Excellent improvement
Question: Do you feel any change after receiving the test solution? (The patient checks off the appropriate box.)
8.31
Severity of Pain (Visual Analogue Scale)
5
~
~
~ ~
m~,~ ~
m
CPZ
m m ~
D/M
~,
3.44 1.25 0 Pre
Post Time of Measurement
Pain assessments performed at this time and later in the protocol used b o t h visual and verbal analogue scales (Figures 1 and 2). Patients were given 5.0 mL of syringe A (normal saline or 25 mg d i m e n h y d r i n a t e ) Annals of Emergency Medicine
through a proximal port in the I\ line. Subsequently, patients wet( given 0.04 mL/kg of either chlor promazine (0.1 mg/kg) or meperidinl (0.4 mg/kg). Pain, blood pressure, anl adverse effects a s s e s s m e n t s wer~ 18:4 April 1989
TABLE 1. Demographic characteristics
Chloropramazine
Dimenhydrinate With Meperidine
3 21
4 18
31.00 (21 to 47)
31.09 (19 to 48)
54.6 (2 to 336)
41.8 (2 to 216)
9 15 24
9 13 22
Sex Male Female
Age (yr) Duration of headache (hr) Type of headache Classic Common
Total group
TABLE 2. Drugs taken before arrival
Chlorpromazine
Dimenhydrinate With Meperidine
Total
13
8
21
3
0
3
6 12 3 0 0 1
7 8 3 2 3 1
13 20 6 2 3 2
0 1
0 4
0 5
Acetaminophen Nonsteroidal antiinflammatory drug Aspirin, butalbital, codeine Narcotic, codeine Narcotic, other Ergot Antiemetic Beta-blocker Calcium channel blockers Other
then conducted at 15, 30, and 45 minutes. A final assessment was done at time of discharge. Up to two repeat doses of the second solution ( c h l o r p r o m a z i n e or meperidine) were given as needed as judged by the patient at 15-minute intervals. If the response was inadequate as judged by the patient at 45 minutes, the sequence was broken and the patient was given the other drug. Patients were required to remain in the ED for monitoring for a period of one hour after the last dose of medication. All patient data were collected and recorded by the physician, who was blinded to the medication given. Statistical analysis was performed on two outcome measures, the pro18:4April 1989
portion of patients experiencing inadequate relief and requiring another drug and the subjective ratings of the visual analogue scale pain assessments. Fisher's exact probability test was used to compare the proportion of inadequate relief results for both drug treatments. An analysis of varia n c e w i t h drug as a t w o - l e v e l , between-subjects factor and with.the "pro" and "post" measurements as a repeated measure within subject factor was used on the visual analogue ratings. RESULTS Forty-six patients were entered into the study. Of these, 22 were randomized to the meperidine with dimenhydrinate group (group 1} and 24
Annals of EmergencyMedicine
to the chlorpromazine group (group 2). Characteristics of this study population can be seen (Tables t and 2). A number of patients experienced adverse side effects (Table 3). It is difficult to determine which were due to the headache and which were due to the medications administered. No incident of clinically significant orthostatic hypotension (change in systolic blood pressure of more than 10 m m Hg) were reported for either group at any time. Two of the patients in group 2 experienced inadequate relief and were given meperidine, whereas ten of the group 1 patients required the administration of chlorpromazine (Fisher's exact test, P < .01, two-tailed). The number of doses given of each drug are listed (Table 4). Ten of the 13 group i patients requiring three doses went on to receive chlorpromazine because of inadequate relief. Pain assessments were performed by both verbal and visual analogue scales. The changes noted according to the verbal scale are outlined (Table 5). The difference on the visual analogue scale between beginning time and final time was taken as t = discharge for those with a satisfactory result and t = 45 for those requiring another medication (Table 6 and Figure 3). The decrease in pain intensity after t r e a t m e n t was s i g n i f i c a n t l y larger for group 2 than for group 1 (F (1.44) = 13.54, P < .001). The correlation between response and diagnosis (common versus classic) and d u r a t i o n was a t t e m p t e d . In both cases, however, differences did not reach statistical significance because of sample size. DISCUSSION Migraine headache has been defined by The Research Group on Headache and Migraine, World Federation of Neurology, as a "familial disorder characterized by recurrent attacks of headache, widely variable in intensity, frequency and duration. Attacks are c o m m o n l y unilateral, and are usually associated with anorexia, nausea and vomiting. In some cases, they are preceded by or associated with neurological and mood disturbances. All of these characteristics are not necessarily present in each attack."6 The pathophysiology of migraine has been and will be debated for many years, with current theories 362/55
MIGRAINE HEADACHE Lane, McLellan & Baggoley
focusing on serotonin release and release of vasoactive substances by platelets. 7ql Patients presenting to the ED with fixed migraine represent a therapeutic dilemma to the emergency physician. Narcotic preparations, orally or parenterally, are frequently used12A3 with the knowledge that this is one of the most common antecedents to significant iatrogenic drug addiction. 14 Because of the side effects of narcotics, their addictive potential, and the relative lack of other therapeutic modalities, an alternative is sought. An uncontrolled trial of IV chlorpromazine for acute migraine was previously conducted, s This therapy was found to be completely effective on 38 of 52 occasions, left very mild residual pain on 11 of the 52 occasions, and provided only minor relief on the other three. Adverse effects were minimal, with most patients reporting only some mild drowsiness. This uncontrolled study suggested that IV chlorpromazine may be superior to the alternative methods of therapy available but pointed out the need for a controlled trial. Chlorpromazine is the prototype phenothiazine, a neuroleptic agent that was first developed in 1950 for use as a preanesthetic medication, is In the central nervous system, chlorpromazine acts on postsynaptic cells as a dopamine antagonist, particularly in the limbic system and the basal ganglia. 7 It also has a particular effect in the chemoreceptor trigger zone of the reticular formation and, hence, is a p o w e r f u l a n t i e m e t i c agent.TA 5 It was initially termed a neuroleptic because it induced "an indifference to pain." Chlorpromazine has important effects outside of the central nervous s y s t e m . It is a p o w e r f u l alphaadrenergic antagonist with some anticholinergic properties. 15 As a result, it causes an alpha blockade and orthostatic hypotension, and a myocardial depressant effect has been noted. It also acts as a weak diuretic.~S,16 As with other antimigraine therapy, the precise mechanism of action of chlorpromazine in acute migraine headache is not clear. The alpha blockade may be of benefit in reducing tension on the walls of extracranial arteries. The central antiemetic effect of chlorpromazine is
56/363
TABLE 3. Adverse effects reported
Chlorpromazine
Dimenhydrinate With Meperidine
Total
Drowsiness Nausea, vomiting
5 2
4 2
9 4
Dizziness Postural hypotension
2 0
1 0
3 0
Burning at IV site
3
0
Dry mouth Nasal congestion
1 2
0 0
3 1
Total No. of patients suffering adverse effects
15
7
22
11 of 24
6 of 22
17 of 46
2
TABLE 4. Number of doses of test drug given
Chlorpromazine
Dimenhydrinate With Meperidine
6
8
1 dose
2 doses 9 3 doses 9 Second medication 2 of 24 Fisher's exact test, P < .01, two-tailed.
clearly of value. Chlorpromazine also m a y alter serotonin levels. 15 The neuroleptic effect itself may also be of value. Reports of the use of chlorpromazine for migraine are few. Caviness and O'Brien 16 reported a short series of 13 patients with cluster headaches who benefited from oral chlorpromazine as prophylaxis. Iserson 1~ reported good success with intramuscularly administered chlorpromazine for acute migraine. However, doses were much larger than those used in the present study, and time to relief of symptoms was m u c h longer (55 minutes compared with five to ten minutes in the present study). Experience at this c e n t e r w i t h intramuscular administration demonstrated a m u c h lower rate of efficacy. 17 McEwen et al is demonstrated simi l a r l y u n i m p r e s s i v e r e s u l t s in a double-blind, controlled trial comparing intramuscular chlorpromazine with placebo, although verbal descriptors alone were used to assess
Annals of EmergencyMedicine
1 13 11 of 22
pain relief. Hoag and Mortimer, 19 in another randomized trial, used a vi. sual analogue scale and compared i n t r a m u s c u l a r methotrimeprazine against meperidine with dimenhydrinate. They were able to show improved results with this phenothiazine, although study size was too small to reach significance. Our study was a controlled, randomized, double-blind study of the therapeutic effectiveness of chlorpromazine as compared with standard therapy (meperidine with dimenhydrinate) for migraine headache. A crossover design was initially considered but abandoned because of the possible "carryover" effect. A controlled, randomized, double-blind study against placebo was abandoned because of ethical considerations. Standard therapy in most North A m e r i c a n EDs has been an intram u s c u l a r injection of meperidine with an antiemetic, frequently dimenhydrinate. There is, however, no published evidence to suggest the efficacy of this approach. Gallagher 2° 18:4 April 1989
TABLE 5. Pain a s s e s s m e n t -- verbal analogue scale Time (min) 15 Headache Description
30
45 Group 1
Group 2
Final Group 1 Group 2
Group 1
Group 2
Group 1
Group 2
Worse
0
0
0
0
0
0
0
0
No better
7
5
2
1
4
0
1
0
Minimal improvement
6
7
8
5
3
2
0
1
Good improvement
8
11
6
15
8
9
12
8
Excellent improvement
1
1
5
3
7
13
9
15
TABLE 6. Pain a s s e s s m e n t - visual analogue scale Chlorpromazine N
=
24
Variable
Minimum
t=O
4.50
Maximum 10.00
Mean
SD
8.31
1.54
t = final
0.00
7.10
1.25
1.70
Change
- 10.00
-2.30
-7.06
2.18
Meperidine With Dimenhydrinate N = 22
Mean
SD
t=0
Variable
5.50
10.00
7.89
1.45
t = final
0.00
10.00
3.44
3.34
9.10
0.00
-4.45
2.62
Change
Minimum
-
Maximum
F (1.44) = 13.54. P < .001.
reported results of nonblinded trial involving meperidine in combination with a variety of other medications - an antiemetic, an ergot preparation, and a steroid. In that study, a dose of 75 to 100 mg meperidine IM was used. Both Mather et a121 and Austin et a122 reported wide variability in absorption, peak concentration, and the plasma concentrationtime profile after intramuscular injection. As a result, the IV route of administration of meperidine was elected for our study. The work of Mather and his colleagues2u23 has suggested that pain relief is best achieved by IV infusion to maintain plasma concentrations between 0.5 and 0.7 m g / L . Mather and Meffin 23 suggested that levels greater than this result from injections of 50-mg boluses and may result in unpleasant side effects, including v o m i t i n g and r e s p i r a t o r y depression. T h e y r e c o m m e n d an infusion of 25 mg/hr IV after an initial bolus injection of 50 mg over 45 18:4April 1989
minutes. This r e c o m m e n d a t i o n is supported by Edwards et a124 based on more recent data regarding clearance estimates. In the present study, therefore, a substantially higher initial dose was used in that up to three bolus injections (0.4 m g / k g each) were given within 30 minutes for a total of 84 mg IV for a 70-kg patient. Because of the reassessments at 15 and 30 minutes before a repeat injection, if unpleasant side effects occurred or sufficient pain relief was achieved, the subsequent bolus could be avoided. In the preliminary study, s a significant number of adverse effects w~re noted, particularly pastural hypotension. Further experience with the medication resulted in the protocol used in this study (ie, establishment of an IV line and administration of a 5-mL/kg bolus normal saline before the use of the drug and the administration of bolus doses of 0.1 mg/kg IV at 15-minute intervals). The dosages required in this study were signifiAnnals of Emergency Medicine
cantly less than those in the preliminary study. No incident of clinically significant pastural hypotension was encountered with this regimen. Also, no incident of dystonic reaction or significant allergy was encountered. This is likely because of the very small doses of chlorpromazine being used, although a much larger experience is necessary before that conclusion can be drawn. CONCLUSION Our study suggests that IV chlorpromazine is an effective remedy in the ED for fixed migraine headache. It is associated with an acceptable incidence of m i n o r side effects and avoids the important potential problems of narcotic addiction and substance abuse associated with the use of parenteral narcotics. The future challenge will be to identify medications that are equally effective as IV chlorpromazine but can be administered either orally or through subcutaneous or intramuscular routes. 364/57
MIGRAINE HEADACHE Lane, McLellan & Baggoley
The authors gratefully acknowledge the s u p p o r t p r o v i d e d by t h e S u n n y b r o o k T r u s t Fund, t h e D e p a r t m e n t of R e s e a r c h D e s i g n a n d B i o s t a t i s t i c s for t h e i r g e n erous a s s i s t a n c e in a n a l y s i s of o u r results, M s M a r t h a Flavelle for h e r clerical support t h r o u g h o u t t h e study, a n d t h e p h y s i cians and n u r s e s of S u n n y b r o o k M e d i c a l C e n t r e for t h e i r p a t i e n t s a n d t h e i r patience.
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18. McEwen JI, O'Connor HM, Dinsdale I-I~: The treatment of migraine with intramuscula~ chlorpromazine. Ann Emerg Med 1987;16: 758-763.
9. Edmeads J: Cerebral blood flow in migraine. Headache 1977;17:148-152. 10. Ruskin NH: Pharmacology of migraine. Annu Rev Pharmacol Toxicol 1981;21:463-478. 11. Saxena PR: The effects of antimigrainous drugs on vascular responses by 5-HT and other related biogenic substances on the external carotid bed of dogs: Possible pharmacological implications to their antimigraine actions. Headache 1972;12:44-54. 12. Iserson KV: Parenteral chlorpromazine in the t r e a t m e n t of migraine. Ann Emerg Med 1983;12:756-758. 13. Saper JR: Migraine: II. Treatment. JAMA 1978;239:2480-2484. 14. Caviness V8, O'Brien MD: Headache. N Engl J Med 1980;302:446-449. 15. 8eeman P, Sellers EM, Roschlan WHE: Principles of Medical Pharmacology, ed 3. Toronto, Canada, University of Toronto Press, 1980. 16. Caviness VSA, O'Brien P: Cluster headache:
Annals of Emergency Medicine
19. Hoag R, Mortimer L: Methotrimeprazin¢ compared to meperidine and dimenhydrinate in the treatment of migraine headache. CAEP Re. view 1986;7:29-31. 20. Gallagher RM: Emergency treatment of intractable migraine. Headache 1986;26:74-75. 21. Mather LE, Tucker GT, Pflug AE, et al: Meperidine kinetics in man: Intravenous injec. tions in surgical patients and volunteers. Clin Pharmacol Ther 1975;17:21-30. 22. Austin KL, 8tapleton JV, Mather LE: Multi. ple intramuscular injections: A major source 0t variability in analgesic response to meperidine. Pain 1980;8:47-62. 23. M a t h e r LE, Meffin PJ: C l i n i c a l phar. macokinetics of pethidine. Clin Pharmacokinei 1978;3:352-368. 24. Edwards DJ, Srenson CK, Visco JP, et al: Clinical pharmacokinetics of pethidine: 1982 Clin Pharmacokinet 1982;7:421-433.
18:4 April 1989