Brief Communication
A double-blind controlled study of nifedipine as an abortive treatment in acute attacks of migraine with aura
Marvin J Hoffert, Mary J Scholz, Roy Kanter
John R Graham Headache Centre, Boston, MA, USA Cephalalgia
Hoffert MJ, Scholz MJ, Kanter R. A double-blind controlled study of nifedipine as an abortive treatment in acute attacks of migraine with aura. Cephalalgia 1992;12:323-4. Oslo. ISSN 0333-1024 Patients with migraine with aura treated each of six acute attacks with either nifedipine or vehicle administered in double-blind, randomized form. Two modes of administration were studied. Both increased the intensity of headaches compared to vehicle. We conclude that nifedipine is not useful as an abortive treatment of migraine with aura. Abortive treatment of migraine, migraine with aura, nifedipine Marvin Jay Hoffert, John R. Graham Headache Centre, 1153 Centre Street, Boston, MA 02130, USA. Received 24 March 1992, accepted 11 June 1992
Nifedipine as a prophylactic treatment of migraine is supported by some (1) and rejected by others (2). As a separate issue, various clinicians have reported the successful abortive treatment of migraine with aura with sublingual nifedipine (3). We studied the usefulness of nifedipine as an abortive treatment of acute attacks of migraine with aura in a double-blind, controlled, randomized, crossover format. Methods
This work was done at the Headache Clinic, University of Wisconsin Clinical Science Center, Madison, Wisconsin. Patients were recruited into the study with informed consent if they met the following criteria: age 18 or older; subject to a unilateral throbbing head pain preceded by 5-60 min of focal neurologic dysfunction such as flickering lights, visual scotomata, paresthesias or pareses (classic migraine) (in 1986, when this study was completed, the IHS diagnostic criteria (4) for migraine with aura were not available to us); a history of at least two such headaches per month in the recent past; without exposure to prophylactic migraine medications in the previous two weeks; and without contraindication to nifedipine use. Electrocardiograms, SMA12's (a general blood chemistry screen), complete blood counts, urinalysis, pregnancy screening and physical examination were normal. Patients were taught a 0-10 scale anchored by the words "no pain" at the 0 point and "worst headache ever" at the 10 point to rate the intensity of their headache. They were asked to measure their headache in hours, and note any side effects from the study medication. They were provided with a headache diary designed to facilitate recording of these observations for each headache studied. A drug titration was performed (while patients were headache-free) in which patients were given nifedipine in the study format (see below) while blood pressure, pulse, and side effects, were monitored. Patients who developed symptomatic orthostatic hypotension or headache with three nifedipine capsules were advised to limit their maximum dose to two. Patients returned home with the headache diary and a bottle with three capsules to treat their next appropriate headache. Patients were instructed to take one capsule in the format described below at the onset of their next recognizable aura. If the aura persisted they were allowed to repeat that dose every 20 min to the maximum determined by drug titration. Patients recorded the intensity and duration of the subsequent headache and possible drug side effects in their diary. Patients then returned to the Headache Clinic for review of their diary and return of their medication bottle. At that time, they were given the next medication bottle and asked to repeat the protocol for a total of six headaches. Of the six bottles of medication provided per patient, three contained nifedipine capsules (20 mg per capsule) and three contained capsules filled with a vehicle which provided identical taste and viscosity characteristics to the nifedipine capsules. Nifedipine and vehicle containing bottles were randomly ordered in a sequence that was unknown both to the investigators and to the patients. There were two phases to this study. In the first phase, patients were instructed to bite the capsule open and swallow the liquid contents (to obtain the fastest absorption and highest plasma concentration for the first hour (5)). After the negative results reported below were obtained we revised our protocol to use the more standard method of sticking a
pinhole in the capsule, leaving it under the tongue for 5 min and then spitting it out (hoping to imitate the clinical success reported by exactly imitating the technique). Statistical significance was assessed using Student's t-test. Results
Patient demographics and usual headache characteristics are presented in Table 1. Two patients in Phase II were limited to two treatment capsules after the nifedipine titration was performed. There was no overlap in patient population for the two phases. Several patients treated fewer than six headaches within the time frame of the study, but their treated headaches were included in the data. Hence the discrepancy between the number of headaches studied and the 102 headaches that could have been studied. No clinically significant side effects were reported. Headache intensity and duration of treated headaches are tabulated in Table 2. The intensity of Table 1. Patient demographics and usual headache characteristics. Phase I Phase II Number Age (years) Age of onset of headaches Usual frequency (per month) Usual duration (hours) Usual intensity
Female Male mean range mean range mean range mean range
4 2 33 23 - 46 19 8-30 5 2-9 28 2 - 48 moderatesevere
7 4 37 18 - 59 15 6-28 10 1.5-30 17 3 - 39 moderatesevere
Table 2. Intensity and duration of treated headaches in phases I and If. Intensity Duration (0-10 ± SD) (hours ± SD) Phase I Nifedipine (n = 14) 6.9* ± 3.0 11.9 ± 10.5 Vehicle (n = 13) 4.2 ± 3.3 3.3 ± 3.5 Phase II Nifedipine (n = 23) 6.4* ± 2.1 10.2 ±13.7 Vehicle (n = 23) 4.3 ± 1.8 6.7 ± 12.0 *
p < .05, significant from vehicle.
headaches after treatment with nifedipine was greater than of those after treatment with vehicle in phases I and II. There was a trend for the duration of headaches to be greater but large variability precluded statistical significance. The apparent difference in duration of vehicle-treated headaches between phases I and II (3.3 h vs 6.7 h) was not statistically significant. Discussion
Nifedipine was not useful in the abortive treatment of migraine with aura but made headaches more intense. The data obtained in the two phases of the study were virtually identical, indicating that the lower dose of nifedipine obtained by the pinhole and sublingual delivery (3) was adequate for the full clinical effect. This is consistent with the clinical use of nifedipine in other acute settings such as the treatment of malignant hypertension, where the pinhole and sublingual delivery seems to produce a robust clinical response (6). The intensity and duration of vehicle-treated headaches in our study were less than anticipated. In fact, the average duration of vehicle-treated headaches in phase I was less than the IHS criteria for migraine without aura and in phase II was just above the lower limit. (There are no IHS duration criteria for migraine with aura). This may be due to a placebo effect (7). Acknowledgements.-Pfizer Laboratories, New York, provided placebo capsules and generously funded this study. References
1.
Meyer JS, Hardenberg I. Clinical effectiveness of calcium entry blockers in prophylactic treatment of migraine and cluster headache. Headache 1983;23:266-77
2.
McArthur JC, Marek K, Pestronk A, McArthur J, Peroutka SJ. Nifedipine in the prophylaxis of classic migraine: a crossover, double-masked, placebo-controlled study of headache frequency and side effects. Neurology 1989;39:284-6
3.
Golder JA, Levitt LP. Treatment of complicated migraine with sublingual nifedipine. Headache 1987;27:484-6
4.
Headache classification committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8( suppl 7):1-96
5.
McAllister RG, Jr. Kinetics and dynamics of nifedipine after oral and sublingual doses. AJM 1986;81:2-5
6.
Opie LH, Jennings AA. Rote of calcium channel blockade in chronic hypertension following successful management of hypertensive emergency. AJM 1986;81:35-42
7.
Couch JR. Placebo effect and clinical trials in migraine treatment. J Neuroepidemiology 1987;6:178-85
A double-blind controlled study of nifedipine as an abortive treatment in acute attacks of migraine with aura
Marvin J Hoffert, Mary J Scholz, Roy Kanter
John R Graham Headache Centre, Boston, MA, USA Cephalalgia
Hoffert MJ, Scholz MJ, Kanter R. A double-blind controlled study of nifedipine as an abortive treatment in acute attacks of migraine with aura. Cephalalgia 1992;12:323-4. Oslo. ISSN 0333-1024 Patients with migraine with aura treated each of six acute attacks with either nifedipine or vehicle administered in double-blind, randomized form. Two modes of administration were studied. Both increased the intensity of headaches compared to vehicle. We conclude that nifedipine is not useful as an abortive treatment of migraine with aura. Abortive treatment of migraine, migraine with aura, nifedipine Marvin Jay Hoffert, John R. Graham Headache Centre, 1153 Centre Street, Boston, MA 02130, USA. Received 24 March 1992, accepted 11 June 1992
Nifedipine as a prophylactic treatment of migraine is supported by some (1) and rejected by others (2). As a separate issue, various clinicians have reported the successful abortive treatment of migraine with aura with sublingual nifedipine (3). We studied the usefulness of nifedipine as an abortive treatment of acute attacks of migraine with aura in a double-blind, controlled, randomized, crossover format. Methods
This work was done at the Headache Clinic, University of Wisconsin Clinical Science Center, Madison, Wisconsin. Patients were recruited into the study with informed consent if they met the following criteria: age 18 or older; subject to a unilateral throbbing head pain preceded by 5-60 min of focal neurologic dysfunction such as flickering lights, visual scotomata, paresthesias or pareses (classic migraine) (in 1986, when this study was completed, the IHS diagnostic criteria (4) for migraine with aura were not available to us); a history of at least two such headaches per month in the recent past; without exposure to prophylactic migraine medications in the previous two weeks; and without contraindication to nifedipine use. Electrocardiograms, SMA12's (a general blood chemistry screen), complete blood counts, urinalysis, pregnancy screening and physical examination were normal. Patients were taught a 0-10 scale anchored by the words "no pain" at the 0 point and "worst headache ever" at the 10 point to rate the intensity of their headache. They were asked to measure their headache in hours, and note any side effects from the study medication. They were provided with a headache diary designed to facilitate recording of these observations for each headache studied. A drug titration was performed (while patients were headache-free) in which patients were given nifedipine in the study format (see below) while blood pressure, pulse, and side effects, were monitored. Patients who developed symptomatic orthostatic hypotension or headache with three nifedipine capsules were advised to limit their maximum dose to two. Patients returned home with the headache diary and a bottle with three capsules to treat their next appropriate headache. Patients were instructed to take one capsule in the format described below at the onset of their next recognizable aura. If the aura persisted they were allowed to repeat that dose every 20 min to the maximum determined by drug titration. Patients recorded the intensity and duration of the subsequent headache and possible drug side effects in their diary. Patients then returned to the Headache Clinic for review of their diary and return of their medication bottle. At that time, they were given the next medication bottle and asked to repeat the protocol for a total of six headaches. Of the six bottles of medication provided per patient, three contained nifedipine capsules (20 mg per capsule) and three contained capsules filled with a vehicle which provided identical taste and viscosity characteristics to the nifedipine capsules. Nifedipine and vehicle containing bottles were randomly ordered in a sequence that was unknown both to the investigators and to the patients. There were two phases to this study. In the first phase, patients were instructed to bite the capsule open and swallow the liquid contents (to obtain the fastest absorption and highest plasma concentration for the first hour (5)). After the negative results reported below were obtained we revised our protocol to use the more standard method of sticking a
pinhole in the capsule, leaving it under the tongue for 5 min and then spitting it out (hoping to imitate the clinical success reported by exactly imitating the technique). Statistical significance was assessed using Student's t-test. Results
Patient demographics and usual headache characteristics are presented in Table 1. Two patients in Phase II were limited to two treatment capsules after the nifedipine titration was performed. There was no overlap in patient population for the two phases. Several patients treated fewer than six headaches within the time frame of the study, but their treated headaches were included in the data. Hence the discrepancy between the number of headaches studied and the 102 headaches that could have been studied. No clinically significant side effects were reported. Headache intensity and duration of treated headaches are tabulated in Table 2. The intensity of Table 1. Patient demographics and usual headache characteristics. Phase I Phase II Number Age (years) Age of onset of headaches Usual frequency (per month) Usual duration (hours) Usual intensity
Female Male mean range mean range mean range mean range
4 2 33 23 - 46 19 8-30 5 2-9 28 2 - 48 moderatesevere
7 4 37 18 - 59 15 6-28 10 1.5-30 17 3 - 39 moderatesevere
Table 2. Intensity and duration of treated headaches in phases I and If. Intensity Duration (0-10 ± SD) (hours ± SD) Phase I Nifedipine (n = 14) 6.9* ± 3.0 11.9 ± 10.5 Vehicle (n = 13) 4.2 ± 3.3 3.3 ± 3.5 Phase II Nifedipine (n = 23) 6.4* ± 2.1 10.2 ±13.7 Vehicle (n = 23) 4.3 ± 1.8 6.7 ± 12.0 *
p < .05, significant from vehicle.
headaches after treatment with nifedipine was greater than of those after treatment with vehicle in phases I and II. There was a trend for the duration of headaches to be greater but large variability precluded statistical significance. The apparent difference in duration of vehicle-treated headaches between phases I and II (3.3 h vs 6.7 h) was not statistically significant. Discussion
Nifedipine was not useful in the abortive treatment of migraine with aura but made headaches more intense. The data obtained in the two phases of the study were virtually identical, indicating that the lower dose of nifedipine obtained by the pinhole and sublingual delivery (3) was adequate for the full clinical effect. This is consistent with the clinical use of nifedipine in other acute settings such as the treatment of malignant hypertension, where the pinhole and sublingual delivery seems to produce a robust clinical response (6). The intensity and duration of vehicle-treated headaches in our study were less than anticipated. In fact, the average duration of vehicle-treated headaches in phase I was less than the IHS criteria for migraine without aura and in phase II was just above the lower limit. (There are no IHS duration criteria for migraine with aura). This may be due to a placebo effect (7). Acknowledgements.-Pfizer Laboratories, New York, provided placebo capsules and generously funded this study. References
1.
Meyer JS, Hardenberg I. Clinical effectiveness of calcium entry blockers in prophylactic treatment of migraine and cluster headache. Headache 1983;23:266-77
2.
McArthur JC, Marek K, Pestronk A, McArthur J, Peroutka SJ. Nifedipine in the prophylaxis of classic migraine: a crossover, double-masked, placebo-controlled study of headache frequency and side effects. Neurology 1989;39:284-6
3.
Golder JA, Levitt LP. Treatment of complicated migraine with sublingual nifedipine. Headache 1987;27:484-6
4.
Headache classification committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8( suppl 7):1-96
5.
McAllister RG, Jr. Kinetics and dynamics of nifedipine after oral and sublingual doses. AJM 1986;81:2-5
6.
Opie LH, Jennings AA. Rote of calcium channel blockade in chronic hypertension following successful management of hypertensive emergency. AJM 1986;81:35-42
7.
Couch JR. Placebo effect and clinical trials in migraine treatment. J Neuroepidemiology 1987;6:178-85
