journal of Internal Medicine 1992 : 231 : 551-554
Ketoprofen and ergotamine in acute migraine P. KANGASNIEMI & R. KAAJA* From the Department of Neurology. University Central Hospital of Turku. Turku. and the 'Medical Department. Rh6ne-Poulenc Rorer. Helsinki, Finland
Abstract. Kangasniemi P, Kaaja R (Department of Neurology, University Central Hospital of Turku, Turku, and Medical Department, Rhdne-Poulenc Rorer, Helsinki, Finland). Ketoprofen and ergotamine in acute migraine. journal of Internal Medicine 1992 : 231 : 5 5 1-5 54.
The objectives of this study were to evaluate and compare the efficacy and tolerability of ketoprofen and ergotamine in the treatment of acute migraine attacks without aura. The study design was a single-centre,double-blind,placebo-controlled,cross-over comparison of a single dose of ketoprofen (100 mg) and ergotamine (2 mg) suppositories in the treatment of acute migraine attacks. Fifty patients were included in the statistical evaluation. Ketoprofen was found to be more efficient than ergotamine and placebo in reducing the severity of pain. Ketoprofen was found to be more satisfactory than ergotamine and placebo with regard to influence on working ability, and better than placebo in global assessment. We conclude that ketoprofen (1 00 mg suppository) is superior to ergotamine ( 2 mg suppository) and placebo in the symptomatic treatment of acute migraine attacks, and has better tolerability. Keywords: ergotamine, ketoprofen, migraine.
Introduction Ketoprofen (OrudisB) is a non-steroidal antiinflammatory drug that has been widely used in the treatment of rheumatic disorders. In previous studies it has been tested in migraine prophylaxis and acute attacks [l-31. In one study [4], ketoprofen suppositories (100 mg) were compared with ergotamine suppositories ( 2 mg) and placebo. The study showed ketoprofen to be significantly more efficient than placebo. A similar difference could not be detected between ergotamine and placebo. This study sample consisted of relatively few patients ( 1 4 patients with common migraine). It was therefore of interest to verify the efficacy of ketoprofen suppositories (100 mg) compared to ergotamine suppositories (2 mg) and placebo in migraine without aura attacks in a larger study sample.
Patients and methods The study was conducted between January 1987 and January 1988 in the Department ofNeurology of Turku University, Finland. The trial plan was
approved by the local ethics committee. The patients gave their informed consent before the trial. Each patient was treated for six consecutive attacks with a single dose of either ketoprofen (100 mg), ergotamine suppositories ( 2 mg) or placebo, each treatment being given twice. The suppositories were identical in appearance. The drugs were randomized in blocks of three by use of 3 x 3 Latin Squares. Control visits by the investigator took place at monthly intervals until all six suppositories were used. Patients were of either sex, above the age of 18 years, suffering from migraine without aura with well-defined intermittent migraine attacks, and fulfilled at least four of the following criteria: heredity, pulsating headache, hemicrania. phono- and/or photophobia during the headache phase, gastrointestinal disturbances during the headache phase. Furthermore, all patients had had a history of migraine for at least 3 years, an attack duration of at least 1 h, and 3-10 migraine attacks per month. The exclusion criteria were as follows: severe cardiac, hepatic or renal disease, active gastroduodenal ulcer within the preceding 6 months, known
551
552
P . KANGASNIEMI & R . K A A J A
history of hypersensitivity or serious adverse reactions to test drugs, treatment with aspirin or other non-steroidal anti-inflammatory drugs which had provoked a n attack of asthma. Women who were pregnant or intended to become pregnant during the trial period as patients on prophylactic treatment of migraine were excluded from the study. Severity of pain and nausea were recorded by use of a Visual Analogue Scale (VAS).The questionnaire included other symptoms/side-effects, which were to be ticked off as present/not present, e.g. vomiting, sweating. Working ability was assessed by questioning the patient with regard to working capacity during the preceding attack, and was graded from 1 (able to work) to 4 (unable to work, confined to bed). During global assessment each patient was asked for his or her opinion of the drug. The global assessment was graded from 1 (very satisfied) to 4 (not satisfied at all). The assessments recorded are shown in Table 1. The regimens were compared in this study, and there were therefore three possible pairwise comparisons for each efficacy variable. In order to maintain the significance level for each comparison of the three regimens, the statistician decided to use the Bonferroni principle [ 3 ] . i.e. to divide the significance level (alpha) by 3, and use this constant (alpha/3) as the significance level for each pairwise comparison. For a pairwise comparison on a continuous or graded efficacy variable, a two-sided Wilcoxon signed mid-rank test was used. For a pairwise comparison on a binary variable, a two-sided sign test was used. The significance level was selected to be 5%. All the efficacy variables recorded in the study have been checked for carry-over effects, but no clear tendencies for carry-over effects were found.
Table 1 . Assessments of drug efficacy Just before insertion of suppository
Severity of pain Severity of nausea Questionnaire on symptoms/ side-effects
After 30 min
Severity of pain Severity of nausea
After 1 h
Severity of pain Severity of nausea Questionnaire on symptoms/ side-efiects
After 2 h
Table 2. Severity of pain before treatment (VAS. mm)
n Mean value 95% c.i.m. Median SD Min-Max P-value
A total of 52 patients were included in the study. Two of the patients did not complete at least one period with each regimen, leaving a total of 50 patients for statistical evaluation. Four of these 50 subjects completed at least three periods, but withdrew from the study before the regimen periods were completed. Reasons for withdrawal were pregnancy (1patient), lack of effect/burning sensation in rectum (1 patient), and unknown reason (4 patients). The 5 0 patients consisted of 44 women and 6 men, of mean age 39 years (range 19-60 years),
Ketoprofen
Ergotamine
Placebo
50 41 3347 40 22 3-9 1
50 43 37-49 44 20 11-81
50 44 38-50 43 21 4-90
-
= 0.40-P
-P
=
0 45-
I’ = 0.091
D
Table 3. Severity of pain: change (VAS. mm) from suppository intake to 2 h later Kctoprofen
n Mean value 95% c.i.m. Median SU Min-Max P-value
Results
Severity of pain Severity of nausea Working ability Global assessment
50
50 9 2-1 6 12 24 -43-55
17
12-22 15 19 - 24-52
-
-P
=
Ergotamine
0.40-P
Placebo 50 9 3-1 5
7 22 -29-76 = 0.85-
P = 0.004
D
mean weight 65 kg (range 47-90 kg), and mean height 166 cm (range 155-191 cm). All of the 50 patients included in the statistical analysis had migraine without aura. The main symptoms present during an attack were tiredness (90%),photophobia (70%) and vomiting (64%). Table 2 shows that severity of pain (VAS score, mm) at tablet intake was similar with ketoprofen, ergotamine and placebo. Two hours after the intake
KETOPROFEN AND ERGOTAMINE IN ACUTE MIGRAINE
The statistical analysis was based on data from the first three attacks in each patient (except for one patient, where the last three attacks were used).
Table 4. Severity of nausea: change (VAS. mm) from suppository intake to 2 h later ~
Ketoprofen
n Mean value 95 % c.i.m. Median SD Min-Max P-value
Ergotamine
Placebo
50 - 1.9 - 6-2
50 1.8 - 4-8
0
0
21 - 53-66 = 0.076-P P = 0.70
13 -47-34
-P 4
50 -1 4 - 5-3 0 14 - 50-35 = 0.39b
Table 5. Working ability Ketoprofen
n Mean value 9 5 % c.i.m. SD Min-Max P-value
Ergotamine
50 50 1.9 2.2 1.7-2.1 2 .O-2.4 0.6 0.7 1-3.5 1-3.5 -p = 0.012-P 4 P = 0.031
Placebo
50 2.1 1.9-2.3 0.8 1 4 = 0.44-
*
Table 6. Global assessment of the drugs
n Mean value 9 5 % c.i.rn. SD Min-Max
Ketoprofen
Ergotamine
Placebo
50 2.6 2.4-2.8 0.9 1 4
50 2.9 2.7-3.1 0.8 1 4
50 3.1 2.9-3.3 0.9 1 4
553
of suppositories, ketoprofen was more efficient than ergotamine and placebo, and ergotamine and placebo were equally effective (Table 3) in reducing the severity of pain in acute migraine attacks. Ergotamine increased the severity of nausea compared to placebo, but ketoprofen did not increase the severity of nausea compared to placebo (Table 4). Ketoprofen was better than ergotamine and placebo, and ergotamine and placebo were similar with regard to their effect on working ability (Table 5). Ketoprofen was significantly better than placebo with regard to global assessment of the drugs ( P < 0.001) (Table 6). The difference between ketoprofen and ergotamine, and also between ergotamine and placebo, did not reach the level of statistical significance.
Discussion Ergotamine has been used in the treatment of migraine for more than 50 years. However, when used on a daily or almost daily basis, it can produce rebound and withdrawal symptoms [3]. Furthermore, its efficacy has been questioned in some studies, as in the present one, since no differences have been found between placebo and ergotamine [4]. It is well known that some patients do respond only to ergotamine, and non-steroidal anti-inflammatory drugs (NSAIDs) cannot be given to patients who have contraindication for NSAIDs (ulcus ventriculi and asthma). In practice, coffein is often added to ergotamine in order to improve absorption and thereby also the efficacy of the drug. Recently a trend has been developed towards the use of NSAIDs in various headache models, including migraine [13]. The NSAIDs have been shown to be as effective as ergotamine in treatment of migraine [4-81, particularly in menstrually related migraine [l.31. The results of our study are in close agreement with earlier reports where ketoprofen has been used to treat acute migraine [4]. The role of prostaglandins in the pathophysiology of migraine and therefore the beneficial effects observed with NSAIDs have been demonstrated in many studies [7, 9-14]. Prostaglandins are known to be potent vasodilators (PGA, PGE, PGE,), and they increase blood flow in the carotis externa and decrease blood flow in the carotis interna in animals [9]. A migraine-like headache can be induced after injection of prostaglandin E, to the carotis interna, or after infusion of prostacyclin (PGE,) [lo-1 21. Prostaglandins are released by serotonin, bradykinin, tissue hypoxia, and after thrombocyte aggregation, and these factors are also known to be associated with migraine. The prostaglandins are rapidly synthesized and metabolized, and could have a n important role in the pathophysiology of migraine, acting as modulators. There is no drug that could cure all patients with migraine attacks, i.e. there are responders and nonresponders to ergotamine and NSAIDs, demonstrating the complexity of the pathophysiology of this disease. It has been proposed that the use of NSAIDs could represent the treatment of choice in men-
554
P. KANGASNTEMI & R . K A A J A
strually related migraine [4]. Our study shows that ketoprofen could also be used instead of ergotamine in acute migraine attacks without aura.
8 9
10
References 1 Stensrud P. Sjaastad 0. Clinical trial of a new anti-bradykinin. anti-inflammatory drug, ketoprofen, in migraine prophylaxis. Headache 1974: 14: 96-100. 2 Pradalier A, Clapin A. Dry 1. Treatment review: non-steroid anti-inflammatory drugs in the treatment and long-term prevention of migraine attacks. Headache 1988: 28: 550-7. 3 Diamond S. Freitag FC. NSAlDs in migraine. Curr Ther 1989; 3 0 : 45-51 4 Kilpelainen H. Mahlamaki S. Riekkinen P. Ketoprofeeni migreenikohtausten hoidossa (ketoprofen in migraine attacks). Suomen Liiakiirilehti (Finnish Medicallournal) 1983 : 7: 567-70. 5 Ross-Lee L. Hazelwood V. Tyrer JH.Eadie MJ. Aspirin treatment of migraine attacks: plasma drug level data. Cephalalgia 1982: 2 : 9-1 4. 6 Peatfield RC. Petty RG, Rose FC. Double-blind comparison of mefenamic acid and acetaminophen (paracetamol) in migraine. Cephalalgia 1983 : 3: 129-34. 7 Hakkarainen H. Vapaatalo H. Gothoni G. Parantainen 1.
11
12
13
14
Tolfenamic acid is as effective as ergotamine during migraine attacks. Irrncet 1979: 2: 326-7. Johnson ES, Ratcliffe DM, Wilkinson M. Naproxen sodium in the treatment of migraine. Cephalalgia 1985: 5 : 5-1 0. Welch KMA. Spira PJ, Knowles L. Lance JM. Effects of prostaglandins on the internal and external carotid blood flow in the monkey. Neurology 1974: 28: 705-10. Bergstrom S. Carlson LA, Ekelund L-G. Cardiovascular and metabolic response to infusions of prostaglandin E. and to simultaneous infusions of noradrenaline and prostaglandin E, in man. Acta Physiol Scand 1965: 6 4 : 332-9. Carlson LA, Fkelund L-G. Oro. L. Clinical and metabolic effects of different doses of prostaglandin E, in man. Acta Med Scand 1968: 1 8 3 : 423-30 Fuitzgerald GA. Friedman LA, Miyamori I. O'Grady 1. Lewis PJ. A double-blind placebo-controlled crossover study of prostaglandin in man. LiJe Sci 1979: 25: 665-72. Fozard JR. The animal pharmacology of drugs used in the Pharrn Pharmacol 1975; 27: treatment of migraine. 297-321. Hall DW. Migraine: mefenamic acid (Ponstan) in the treament ofattacks. / K Coll Gen Pract 1968: 1 5 : 3 2 1 4 .
Received 27 September 1991, accepted 5 December 1991 Correspondence: Pentti Kangasniemi. MD. Department of Neurology, University Central Hospital of Turku, SF-20520 Turku. Finland.
Ketoprofen and ergotamine in acute migraine P. KANGASNIEMI & R. KAAJA* From the Department of Neurology. University Central Hospital of Turku. Turku. and the 'Medical Department. Rh6ne-Poulenc Rorer. Helsinki, Finland
Abstract. Kangasniemi P, Kaaja R (Department of Neurology, University Central Hospital of Turku, Turku, and Medical Department, Rhdne-Poulenc Rorer, Helsinki, Finland). Ketoprofen and ergotamine in acute migraine. journal of Internal Medicine 1992 : 231 : 5 5 1-5 54.
The objectives of this study were to evaluate and compare the efficacy and tolerability of ketoprofen and ergotamine in the treatment of acute migraine attacks without aura. The study design was a single-centre,double-blind,placebo-controlled,cross-over comparison of a single dose of ketoprofen (100 mg) and ergotamine (2 mg) suppositories in the treatment of acute migraine attacks. Fifty patients were included in the statistical evaluation. Ketoprofen was found to be more efficient than ergotamine and placebo in reducing the severity of pain. Ketoprofen was found to be more satisfactory than ergotamine and placebo with regard to influence on working ability, and better than placebo in global assessment. We conclude that ketoprofen (1 00 mg suppository) is superior to ergotamine ( 2 mg suppository) and placebo in the symptomatic treatment of acute migraine attacks, and has better tolerability. Keywords: ergotamine, ketoprofen, migraine.
Introduction Ketoprofen (OrudisB) is a non-steroidal antiinflammatory drug that has been widely used in the treatment of rheumatic disorders. In previous studies it has been tested in migraine prophylaxis and acute attacks [l-31. In one study [4], ketoprofen suppositories (100 mg) were compared with ergotamine suppositories ( 2 mg) and placebo. The study showed ketoprofen to be significantly more efficient than placebo. A similar difference could not be detected between ergotamine and placebo. This study sample consisted of relatively few patients ( 1 4 patients with common migraine). It was therefore of interest to verify the efficacy of ketoprofen suppositories (100 mg) compared to ergotamine suppositories (2 mg) and placebo in migraine without aura attacks in a larger study sample.
Patients and methods The study was conducted between January 1987 and January 1988 in the Department ofNeurology of Turku University, Finland. The trial plan was
approved by the local ethics committee. The patients gave their informed consent before the trial. Each patient was treated for six consecutive attacks with a single dose of either ketoprofen (100 mg), ergotamine suppositories ( 2 mg) or placebo, each treatment being given twice. The suppositories were identical in appearance. The drugs were randomized in blocks of three by use of 3 x 3 Latin Squares. Control visits by the investigator took place at monthly intervals until all six suppositories were used. Patients were of either sex, above the age of 18 years, suffering from migraine without aura with well-defined intermittent migraine attacks, and fulfilled at least four of the following criteria: heredity, pulsating headache, hemicrania. phono- and/or photophobia during the headache phase, gastrointestinal disturbances during the headache phase. Furthermore, all patients had had a history of migraine for at least 3 years, an attack duration of at least 1 h, and 3-10 migraine attacks per month. The exclusion criteria were as follows: severe cardiac, hepatic or renal disease, active gastroduodenal ulcer within the preceding 6 months, known
551
552
P . KANGASNIEMI & R . K A A J A
history of hypersensitivity or serious adverse reactions to test drugs, treatment with aspirin or other non-steroidal anti-inflammatory drugs which had provoked a n attack of asthma. Women who were pregnant or intended to become pregnant during the trial period as patients on prophylactic treatment of migraine were excluded from the study. Severity of pain and nausea were recorded by use of a Visual Analogue Scale (VAS).The questionnaire included other symptoms/side-effects, which were to be ticked off as present/not present, e.g. vomiting, sweating. Working ability was assessed by questioning the patient with regard to working capacity during the preceding attack, and was graded from 1 (able to work) to 4 (unable to work, confined to bed). During global assessment each patient was asked for his or her opinion of the drug. The global assessment was graded from 1 (very satisfied) to 4 (not satisfied at all). The assessments recorded are shown in Table 1. The regimens were compared in this study, and there were therefore three possible pairwise comparisons for each efficacy variable. In order to maintain the significance level for each comparison of the three regimens, the statistician decided to use the Bonferroni principle [ 3 ] . i.e. to divide the significance level (alpha) by 3, and use this constant (alpha/3) as the significance level for each pairwise comparison. For a pairwise comparison on a continuous or graded efficacy variable, a two-sided Wilcoxon signed mid-rank test was used. For a pairwise comparison on a binary variable, a two-sided sign test was used. The significance level was selected to be 5%. All the efficacy variables recorded in the study have been checked for carry-over effects, but no clear tendencies for carry-over effects were found.
Table 1 . Assessments of drug efficacy Just before insertion of suppository
Severity of pain Severity of nausea Questionnaire on symptoms/ side-effects
After 30 min
Severity of pain Severity of nausea
After 1 h
Severity of pain Severity of nausea Questionnaire on symptoms/ side-efiects
After 2 h
Table 2. Severity of pain before treatment (VAS. mm)
n Mean value 95% c.i.m. Median SD Min-Max P-value
A total of 52 patients were included in the study. Two of the patients did not complete at least one period with each regimen, leaving a total of 50 patients for statistical evaluation. Four of these 50 subjects completed at least three periods, but withdrew from the study before the regimen periods were completed. Reasons for withdrawal were pregnancy (1patient), lack of effect/burning sensation in rectum (1 patient), and unknown reason (4 patients). The 5 0 patients consisted of 44 women and 6 men, of mean age 39 years (range 19-60 years),
Ketoprofen
Ergotamine
Placebo
50 41 3347 40 22 3-9 1
50 43 37-49 44 20 11-81
50 44 38-50 43 21 4-90
-
= 0.40-P
-P
=
0 45-
I’ = 0.091
D
Table 3. Severity of pain: change (VAS. mm) from suppository intake to 2 h later Kctoprofen
n Mean value 95% c.i.m. Median SU Min-Max P-value
Results
Severity of pain Severity of nausea Working ability Global assessment
50
50 9 2-1 6 12 24 -43-55
17
12-22 15 19 - 24-52
-
-P
=
Ergotamine
0.40-P
Placebo 50 9 3-1 5
7 22 -29-76 = 0.85-
P = 0.004
D
mean weight 65 kg (range 47-90 kg), and mean height 166 cm (range 155-191 cm). All of the 50 patients included in the statistical analysis had migraine without aura. The main symptoms present during an attack were tiredness (90%),photophobia (70%) and vomiting (64%). Table 2 shows that severity of pain (VAS score, mm) at tablet intake was similar with ketoprofen, ergotamine and placebo. Two hours after the intake
KETOPROFEN AND ERGOTAMINE IN ACUTE MIGRAINE
The statistical analysis was based on data from the first three attacks in each patient (except for one patient, where the last three attacks were used).
Table 4. Severity of nausea: change (VAS. mm) from suppository intake to 2 h later ~
Ketoprofen
n Mean value 95 % c.i.m. Median SD Min-Max P-value
Ergotamine
Placebo
50 - 1.9 - 6-2
50 1.8 - 4-8
0
0
21 - 53-66 = 0.076-P P = 0.70
13 -47-34
-P 4
50 -1 4 - 5-3 0 14 - 50-35 = 0.39b
Table 5. Working ability Ketoprofen
n Mean value 9 5 % c.i.m. SD Min-Max P-value
Ergotamine
50 50 1.9 2.2 1.7-2.1 2 .O-2.4 0.6 0.7 1-3.5 1-3.5 -p = 0.012-P 4 P = 0.031
Placebo
50 2.1 1.9-2.3 0.8 1 4 = 0.44-
*
Table 6. Global assessment of the drugs
n Mean value 9 5 % c.i.rn. SD Min-Max
Ketoprofen
Ergotamine
Placebo
50 2.6 2.4-2.8 0.9 1 4
50 2.9 2.7-3.1 0.8 1 4
50 3.1 2.9-3.3 0.9 1 4
553
of suppositories, ketoprofen was more efficient than ergotamine and placebo, and ergotamine and placebo were equally effective (Table 3) in reducing the severity of pain in acute migraine attacks. Ergotamine increased the severity of nausea compared to placebo, but ketoprofen did not increase the severity of nausea compared to placebo (Table 4). Ketoprofen was better than ergotamine and placebo, and ergotamine and placebo were similar with regard to their effect on working ability (Table 5). Ketoprofen was significantly better than placebo with regard to global assessment of the drugs ( P < 0.001) (Table 6). The difference between ketoprofen and ergotamine, and also between ergotamine and placebo, did not reach the level of statistical significance.
Discussion Ergotamine has been used in the treatment of migraine for more than 50 years. However, when used on a daily or almost daily basis, it can produce rebound and withdrawal symptoms [3]. Furthermore, its efficacy has been questioned in some studies, as in the present one, since no differences have been found between placebo and ergotamine [4]. It is well known that some patients do respond only to ergotamine, and non-steroidal anti-inflammatory drugs (NSAIDs) cannot be given to patients who have contraindication for NSAIDs (ulcus ventriculi and asthma). In practice, coffein is often added to ergotamine in order to improve absorption and thereby also the efficacy of the drug. Recently a trend has been developed towards the use of NSAIDs in various headache models, including migraine [13]. The NSAIDs have been shown to be as effective as ergotamine in treatment of migraine [4-81, particularly in menstrually related migraine [l.31. The results of our study are in close agreement with earlier reports where ketoprofen has been used to treat acute migraine [4]. The role of prostaglandins in the pathophysiology of migraine and therefore the beneficial effects observed with NSAIDs have been demonstrated in many studies [7, 9-14]. Prostaglandins are known to be potent vasodilators (PGA, PGE, PGE,), and they increase blood flow in the carotis externa and decrease blood flow in the carotis interna in animals [9]. A migraine-like headache can be induced after injection of prostaglandin E, to the carotis interna, or after infusion of prostacyclin (PGE,) [lo-1 21. Prostaglandins are released by serotonin, bradykinin, tissue hypoxia, and after thrombocyte aggregation, and these factors are also known to be associated with migraine. The prostaglandins are rapidly synthesized and metabolized, and could have a n important role in the pathophysiology of migraine, acting as modulators. There is no drug that could cure all patients with migraine attacks, i.e. there are responders and nonresponders to ergotamine and NSAIDs, demonstrating the complexity of the pathophysiology of this disease. It has been proposed that the use of NSAIDs could represent the treatment of choice in men-
554
P. KANGASNTEMI & R . K A A J A
strually related migraine [4]. Our study shows that ketoprofen could also be used instead of ergotamine in acute migraine attacks without aura.
8 9
10
References 1 Stensrud P. Sjaastad 0. Clinical trial of a new anti-bradykinin. anti-inflammatory drug, ketoprofen, in migraine prophylaxis. Headache 1974: 14: 96-100. 2 Pradalier A, Clapin A. Dry 1. Treatment review: non-steroid anti-inflammatory drugs in the treatment and long-term prevention of migraine attacks. Headache 1988: 28: 550-7. 3 Diamond S. Freitag FC. NSAlDs in migraine. Curr Ther 1989; 3 0 : 45-51 4 Kilpelainen H. Mahlamaki S. Riekkinen P. Ketoprofeeni migreenikohtausten hoidossa (ketoprofen in migraine attacks). Suomen Liiakiirilehti (Finnish Medicallournal) 1983 : 7: 567-70. 5 Ross-Lee L. Hazelwood V. Tyrer JH.Eadie MJ. Aspirin treatment of migraine attacks: plasma drug level data. Cephalalgia 1982: 2 : 9-1 4. 6 Peatfield RC. Petty RG, Rose FC. Double-blind comparison of mefenamic acid and acetaminophen (paracetamol) in migraine. Cephalalgia 1983 : 3: 129-34. 7 Hakkarainen H. Vapaatalo H. Gothoni G. Parantainen 1.
11
12
13
14
Tolfenamic acid is as effective as ergotamine during migraine attacks. Irrncet 1979: 2: 326-7. Johnson ES, Ratcliffe DM, Wilkinson M. Naproxen sodium in the treatment of migraine. Cephalalgia 1985: 5 : 5-1 0. Welch KMA. Spira PJ, Knowles L. Lance JM. Effects of prostaglandins on the internal and external carotid blood flow in the monkey. Neurology 1974: 28: 705-10. Bergstrom S. Carlson LA, Ekelund L-G. Cardiovascular and metabolic response to infusions of prostaglandin E. and to simultaneous infusions of noradrenaline and prostaglandin E, in man. Acta Physiol Scand 1965: 6 4 : 332-9. Carlson LA, Fkelund L-G. Oro. L. Clinical and metabolic effects of different doses of prostaglandin E, in man. Acta Med Scand 1968: 1 8 3 : 423-30 Fuitzgerald GA. Friedman LA, Miyamori I. O'Grady 1. Lewis PJ. A double-blind placebo-controlled crossover study of prostaglandin in man. LiJe Sci 1979: 25: 665-72. Fozard JR. The animal pharmacology of drugs used in the Pharrn Pharmacol 1975; 27: treatment of migraine. 297-321. Hall DW. Migraine: mefenamic acid (Ponstan) in the treament ofattacks. / K Coll Gen Pract 1968: 1 5 : 3 2 1 4 .
Received 27 September 1991, accepted 5 December 1991 Correspondence: Pentti Kangasniemi. MD. Department of Neurology, University Central Hospital of Turku, SF-20520 Turku. Finland.
