A double-blind study of ibuprofen versus placebo in the treatment of acute migraine attacks
Reidar Kloster1 Knut Nestvold2, Steinar T Vilming3
Departments of Neurology of Vestfold Central Hospital Tønsberg, Norway1; Akershus Central Hospital, Nordbyhagen, Norway2; Ullevaal Hospital Oslo, Norway3 Cephalalgia
Kloster R, Nestvold K, Vilming ST. A double-blind study of ibuprofen versus placebo in the treatment of acute migraine attacks. Cephalalgia 1992;12:169-71. Oslo. ISSN 0333-1024 The efficacy of ibuprofen, a non-steroidal anti-inflammatory drug, was assessed in the acute treatment of migraine. Twenty-five patients completed a double-blind placebo-controlled multicrossover trial. The initial dose of ibuprofen was 1200 mg. Six migraine attacks were randomly treated in each patient, three with ibuprofen and three with placebo. The results indicated a statistically significant reduction in the duration of the migraine attacks and also a statistically significant reduction in the severity of headache and nausea in the ibuprofen-treated attacks. The use of additional medication was significantly reduced in the ibuprofen-treated attacks (25.6% vs 57.5%), No serious side effects were reported. Ibuprofen is valuable in the treatment of acute migraine attacks. • lbuprofen, migraine Reidar Kloster, Department of Neurology, Vestfold Central Hospital 3100 Tønsberg, Norway. Received 2 March 1992, accepted 3 March 1992
The pathogenesis of the migraine attack is still a matter for debate. A neurogenically induced sterile inflammation (1) in the wall of cerebral vessels may take place during an attack. Several groups of substances have been implicated with this, including prostaglandins (2). Some drugs which inhibit prostaglandin biosynthesis are found to be effective in the treatment of the acute migraine attack (3-7). Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) which inhibits prostaglandin biosynthesis. Therapeutic plasma concentration is reached 0.5-2 h after an oral dose, and thus has the potential to give rapid relief of a migraine attack. The plasma half-life (T 1/2) is 2 h. The aim of the present study was to compare ibuprofen and placebo in the treatment of the acute migraine attack. Material and methods
A double-blind, multicrossover trial investigating the efficacy of ibuprofen compared with placebo was carried out. Patients aged 18 to 70 years were included if they had migraine with or without aura for at least one year and in accordance with the criteria of the International Headache Society (8), and had two to eight attacks monthly. Patients with other kinds of headache were excluded, but patients with tension headache were included if they could clearly distinguish this headache from migraine. Pregnant women or those not using birth control methods, and patients with hepatic or renal dysfunction, obstructive pulmonary disease, heart disease, peptic ulcer or dyspepsia and known allergy to NSAIDs were excluded. The patients had not taken prophylactic migraine treatment within the previous month. The patient characteristics are summarized in Table 1. In a run-in period of one month,-the patients recorded the number of migraine attacks and completed a diary card for each attack. This was also a wash-out period and only paracetamol or a combination of paracetamol and codeine phosphate was allowed in this period. After the run-in period, the patients received ibuprofen or placebo for six migraine attacks in a multicrossover fashion. Three attacks were randomly treated with ibuprofen and three with placebo. Two of the first four attacks were treated with ibuprofen and two with placebo. Ibuprofen and placebo tablets were of identical size and shape. The initial dose of ibuprofen was 1200 mg (two tablets) taken as soon as the first symptom of an attack occurred. The patients were allowed to take an additional dose of 600 mg ibuprofen after 4 h and another 600 mg after 8 h if needed. If there was absolutely no effect after the first 4 h, the patient could take the rescue medicine (paracetamol or a combination of paracetamol and codeine phosphate) instead of the test medication. The patients completed a diary card for each attack, recording the timing and dosage of the test Table 1. Patient characteristics at inclusion (n = 36). Fulfilled the study Dropouts Total Females 19 8 27 Males 6 3 9 Age (years) Mean ± SD 39.9 ± 7.9 32.8 ± 9.0 37.8 ± 8.9 Range 24 - 56 23 - 53 23 - 56 Migraine without aura 20 9 29 Migraine with aura 5 2 7 and rescue medication, the duration of the attack, the severity of headache and nausea ( 0 = none, 1 = mild, 2 = moderate, 3 = severe), and the occurrence of vomiting, photophobia or dizziness. The maximal degree of headache during the attack was also recorded on a 10 cm visual analogue scale (VAS). The diary card was returned to the investigator after each attack. After each attack the patient was asked to evaluate whether the attack had been milder, the same or worse than the previous attack. To obtain an overall impression of the severity of the migraine attacks we used a migraine index: the duration of the attack multiplied by the severity of the attack. Patients were considered as dropouts if they did not record at least four consecutive attacks. The average score for continuous and graded variables during the placebo-treated and ibuprofen-treated attacks was calculated for each patient. In order to judge whether a difference between treatments was statistically significant regarding these calculated scores, a one-sided Wilcoxon signed-rank test was applied, with a 5% significance level. For "yes/no" variables (e.g. use of additional medication during the attack) the following statistical method was applied: the frequency of attacks with "yes" was calculated for each patient during the placebo, and ibuprofen-treated attacks. These frequencies were then tabulated and the statistical significance of the differences calculated by means of a one-sided test with a 5% significance level (9). Results
Thirty-six patients were included in the trial. Eleven dropped out before they completed four treated attacks; six because they did not have a sufficient number of attacks, two did not want placebo because of severe attacks, one experienced no effect of treatment, one became pregnant and one suffered an acute infection. Twenty-five patients completed the study and were included in the statistical analysis. A total of 146 attacks were recorded (73 on ibuprofen and 73 on placebo). The main results of the study are presented in Table 2. The duration of the migraine attacks had a skewed distribution, so we calculated median duration instead of mean duration. The median duration of the migraine attacks treated with ibuprofen was 10.3 h and the duration of the placebo-treated attacks 15.7 h (p = 0.002). The average severity of headache and maximal degree of headache during the attack was significantly lower for the ibuprofen-treated attacks (p < 0.001). The severity of nausea was decreased during ibuprofen-treated attacks compared with placebo (p =0.010). The migraine index (duration x severity) was also significantly lower in the Table 2. Severity and duration of symptoms (n = 25). Ibuprofen Placebo Number of attacks 73 73 Duration of attacks Median ± SD (h) 10.3 ± 15 15.7 ± 12 Severity of headache Mean ± SD 1.78 ± 0.51 2.33 ± 0.52 Maximal degree of headache (VAS). Mean ± SD 5.4 ± 2.0 7.1 ± 1.9 Migraine index (duration X severity) Mean ± SD 25 ± 28 46 ± 27 Severity of nausea Mean ± SD 0.82 ± 0.59 1.22 ± 0.78
p-value
=0.002
Reidar Kloster1 Knut Nestvold2, Steinar T Vilming3
Departments of Neurology of Vestfold Central Hospital Tønsberg, Norway1; Akershus Central Hospital, Nordbyhagen, Norway2; Ullevaal Hospital Oslo, Norway3 Cephalalgia
Kloster R, Nestvold K, Vilming ST. A double-blind study of ibuprofen versus placebo in the treatment of acute migraine attacks. Cephalalgia 1992;12:169-71. Oslo. ISSN 0333-1024 The efficacy of ibuprofen, a non-steroidal anti-inflammatory drug, was assessed in the acute treatment of migraine. Twenty-five patients completed a double-blind placebo-controlled multicrossover trial. The initial dose of ibuprofen was 1200 mg. Six migraine attacks were randomly treated in each patient, three with ibuprofen and three with placebo. The results indicated a statistically significant reduction in the duration of the migraine attacks and also a statistically significant reduction in the severity of headache and nausea in the ibuprofen-treated attacks. The use of additional medication was significantly reduced in the ibuprofen-treated attacks (25.6% vs 57.5%), No serious side effects were reported. Ibuprofen is valuable in the treatment of acute migraine attacks. • lbuprofen, migraine Reidar Kloster, Department of Neurology, Vestfold Central Hospital 3100 Tønsberg, Norway. Received 2 March 1992, accepted 3 March 1992
The pathogenesis of the migraine attack is still a matter for debate. A neurogenically induced sterile inflammation (1) in the wall of cerebral vessels may take place during an attack. Several groups of substances have been implicated with this, including prostaglandins (2). Some drugs which inhibit prostaglandin biosynthesis are found to be effective in the treatment of the acute migraine attack (3-7). Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) which inhibits prostaglandin biosynthesis. Therapeutic plasma concentration is reached 0.5-2 h after an oral dose, and thus has the potential to give rapid relief of a migraine attack. The plasma half-life (T 1/2) is 2 h. The aim of the present study was to compare ibuprofen and placebo in the treatment of the acute migraine attack. Material and methods
A double-blind, multicrossover trial investigating the efficacy of ibuprofen compared with placebo was carried out. Patients aged 18 to 70 years were included if they had migraine with or without aura for at least one year and in accordance with the criteria of the International Headache Society (8), and had two to eight attacks monthly. Patients with other kinds of headache were excluded, but patients with tension headache were included if they could clearly distinguish this headache from migraine. Pregnant women or those not using birth control methods, and patients with hepatic or renal dysfunction, obstructive pulmonary disease, heart disease, peptic ulcer or dyspepsia and known allergy to NSAIDs were excluded. The patients had not taken prophylactic migraine treatment within the previous month. The patient characteristics are summarized in Table 1. In a run-in period of one month,-the patients recorded the number of migraine attacks and completed a diary card for each attack. This was also a wash-out period and only paracetamol or a combination of paracetamol and codeine phosphate was allowed in this period. After the run-in period, the patients received ibuprofen or placebo for six migraine attacks in a multicrossover fashion. Three attacks were randomly treated with ibuprofen and three with placebo. Two of the first four attacks were treated with ibuprofen and two with placebo. Ibuprofen and placebo tablets were of identical size and shape. The initial dose of ibuprofen was 1200 mg (two tablets) taken as soon as the first symptom of an attack occurred. The patients were allowed to take an additional dose of 600 mg ibuprofen after 4 h and another 600 mg after 8 h if needed. If there was absolutely no effect after the first 4 h, the patient could take the rescue medicine (paracetamol or a combination of paracetamol and codeine phosphate) instead of the test medication. The patients completed a diary card for each attack, recording the timing and dosage of the test Table 1. Patient characteristics at inclusion (n = 36). Fulfilled the study Dropouts Total Females 19 8 27 Males 6 3 9 Age (years) Mean ± SD 39.9 ± 7.9 32.8 ± 9.0 37.8 ± 8.9 Range 24 - 56 23 - 53 23 - 56 Migraine without aura 20 9 29 Migraine with aura 5 2 7 and rescue medication, the duration of the attack, the severity of headache and nausea ( 0 = none, 1 = mild, 2 = moderate, 3 = severe), and the occurrence of vomiting, photophobia or dizziness. The maximal degree of headache during the attack was also recorded on a 10 cm visual analogue scale (VAS). The diary card was returned to the investigator after each attack. After each attack the patient was asked to evaluate whether the attack had been milder, the same or worse than the previous attack. To obtain an overall impression of the severity of the migraine attacks we used a migraine index: the duration of the attack multiplied by the severity of the attack. Patients were considered as dropouts if they did not record at least four consecutive attacks. The average score for continuous and graded variables during the placebo-treated and ibuprofen-treated attacks was calculated for each patient. In order to judge whether a difference between treatments was statistically significant regarding these calculated scores, a one-sided Wilcoxon signed-rank test was applied, with a 5% significance level. For "yes/no" variables (e.g. use of additional medication during the attack) the following statistical method was applied: the frequency of attacks with "yes" was calculated for each patient during the placebo, and ibuprofen-treated attacks. These frequencies were then tabulated and the statistical significance of the differences calculated by means of a one-sided test with a 5% significance level (9). Results
Thirty-six patients were included in the trial. Eleven dropped out before they completed four treated attacks; six because they did not have a sufficient number of attacks, two did not want placebo because of severe attacks, one experienced no effect of treatment, one became pregnant and one suffered an acute infection. Twenty-five patients completed the study and were included in the statistical analysis. A total of 146 attacks were recorded (73 on ibuprofen and 73 on placebo). The main results of the study are presented in Table 2. The duration of the migraine attacks had a skewed distribution, so we calculated median duration instead of mean duration. The median duration of the migraine attacks treated with ibuprofen was 10.3 h and the duration of the placebo-treated attacks 15.7 h (p = 0.002). The average severity of headache and maximal degree of headache during the attack was significantly lower for the ibuprofen-treated attacks (p < 0.001). The severity of nausea was decreased during ibuprofen-treated attacks compared with placebo (p =0.010). The migraine index (duration x severity) was also significantly lower in the Table 2. Severity and duration of symptoms (n = 25). Ibuprofen Placebo Number of attacks 73 73 Duration of attacks Median ± SD (h) 10.3 ± 15 15.7 ± 12 Severity of headache Mean ± SD 1.78 ± 0.51 2.33 ± 0.52 Maximal degree of headache (VAS). Mean ± SD 5.4 ± 2.0 7.1 ± 1.9 Migraine index (duration X severity) Mean ± SD 25 ± 28 46 ± 27 Severity of nausea Mean ± SD 0.82 ± 0.59 1.22 ± 0.78
p-value
=0.002
