Sumatriptan in the treatment of acute migraine with aura
M Banerjee, LJ Findley
Department of Neurology, Regional Centre for Neurology and Neurosurgery, Oldchurch Hospital Romford, Essex, UK Cephalalgia
Banerjee M, Findley LJ. Sumatriptan in the treatment of acute migraine with aura. Cephalalgia 1992;12:39-44. Oslo. ISSN 0333-1024 The efficacy of the selective 5HT1-like agonist sumatriptan in acute treatment of classical migraine (i.e. migraine with aura) was assessed in a double-blind, placebo-controlled, parallel group randomized trial. An oral dose of 200 mg was chosen on the basis of the efficacy rates achieved (70-85%) with 70-280 mg in open studies (1, 2). The dose of 200 mg was also chosen for the study because preliminary data from an oral pilot study indicated that efficacy increased with increasing dose up to 200 mg. Each patient was treated for a maximum of three separate attacks of migraine with aura within a three months' period. Three attacks were treated so that we could examine consistency of response across more than one attack. For attack 1,200 mg sumatriptan was significantly more effective, safe and well tolerated than placebo at relieving headache 2 h after treatment was given (p = 0.023). In subsequent attacks, i.e. in attacks 2 and 3, there was no such significant effect of sumatriptan compared with placebo in relieving headache. This reduced efficacy of sumatriptan in the second and third attacks may be due to a high incidence of vomiting induced by the high dose of dispersible formulation and also by the bitter taste of the tablets. In addition, there was an increase in placebo response in attacks 2 and 3 compared to the first attack. • Migraine with aura, sumatriptan Mala Banerjee, Department of Neurology, Regional Centre for Neurology and Neurosurgery, Oldchurch Hospital Romford, Essex, UK. Received 30 September 1991, accepted 22 November 1991
Earlier investigations suggest that the two forms of migraine (i.e. migraine with aura and migraine without aura) are separate entities (3). They differ in that regional cerebral blood flow changes occur only in migraine with aura (4). This may reflect cortical arteriolar vasospasm with or without spreading depression of Leao. Owing to the relative infrequency of migraine with aura (10-15% of migraineurs), the availability of data from previous studies on the efficacy of sumatriptan on migraine with aura is limited. This inadequacy of data and knowledge about the role of sumatriptan in the treatment of migraine with aura prompted us to initiate a double-blind, placebo-controlled, parallel group clinical trial to assess the safety, efficacy and tolerability of sumatriptan (200 mg single dose dispersible tablets) in the acute treatment of classical migraine. The data were collected from diary booklets of the patients. Patients and methods
Patients A total number of 94 patients aged between 18 and 65 years (mean 35 years; 85% female) and experiencing one to three attacks per month were randomized to receive study medication. Eighteen of them did not treat any attacks with study medication; 39 patients treated a total of 101 attacks with placebo and 37 a total of 93 attacks with sumatriptan (GR43175C), (see Table 1 for details). All patients included were first diagnosed as having migraine with aura as defined by the Ad Hoc Committee of Table 1. Distribution of patients into two groups (placebo or 200 mg sumatriptan). Number of patients or attacks Placebo 200 mg sumatriptan Randomized patients 94 Patients treating an attack 39 37 Attacks treated 101 93 Patients evaluable for efficacy: Attack 1 37 34 Attack 2 33 28 Attack 3 27 22
the International Headache Society (5) with a history of at least one year, and had on average one to six attacks per month of severe to moderate in nature. They were also able to recognize early signs of migraine with aura and distinguish attacks from attacks of migraine without aura. Prophylactic medication was discontinued at least two weeks prior to entering the study. Exclusion criteria included the regular use or abuse of narcotics, ergotamines or other drugs, pregnancy or lactation, history of ischaemic heart diseases or psychiatric illness, and also hypertension, epilepsy or hepatic diseases. Study design
The investigation was based on a double-blind placebo-controlled randomized parallel group trial
with 200 mg sumatriptan. Patients were randomized equally to two groups (placebo and sumatriptan). Each patient treated up to three attacks with study medication within a period of three months. Each patient was supplied with three separate treatment packs, one for each of three migraine attacks. The patient was instructed to take the study medication as the first treatment as soon as s/he recognized an attack of migraine with aura. Moreover, the investigator had to be satisfied that the patient could recognize an attack with aura and also distinguish it from attacks without aura. The patient was asked to treat the second and third attacks, provided there was an interval of at least 48 h between each. The study procedures and parameters mentioned are shown in Fig. 1. Quality of migraine (aura, headache, nausea, vomiting) including headache severity (using a four-point scale, i.e. 0 = no headache, 1 = mild, 2 = moderate, 3 = severe) was assessed before and 2 h after the drug administration. The time to complete resolution of attack was also assessed (i.e. after 2 and 6 h of drug administration). Visit 1 - (pre-treatment) In this phase, patients who fulfilled the inclusion and exclusion criteria were informed about the study fully and consent was acquired. Those consenting
underwent a physical and neurological examination. A venous blood sample was taken for haematological and biochemical analysis. ECG, heart rate and blood pressure were recorded. Details of demography, migraine history, any other pertinent clinical history, any concurrent medical problem, concurrent medication, prophylactic medication and proposed rescue medication were also recorded. Prophylactic medication was discontinued at this point. Although the patient's quality of life was recorded in clinical record form, at both entry and follow-up visits, these data were not analysed statistically since there were some problems with the interpretation of the questions put to the patients by the investigators. Patients were then issued a practice diary card which they were asked to complete when next treating a migraine attack with their normal migraine therapy. Visit 2-issue of medication Two weeks later each patient received an appropriate supply of blinded study medication. This was supplied in the form of three separate treatment packs, one for each of three migraine attacks. The patient was instructed to take the study medication as soon as they recognized an attack with aura as the first treatment for a new migraine attack. Patients were issued with further diary cards on which to record the details of each attack treated, and were told to record their migraine symptoms before and after taking their study medication. Those patients showing inadequate symptom relief 2 h after taking the medication were able to take the rescue medication and were to record the result in the diary card. Patients were instructed to return to the clinic for monthly follow-up visits and to bring their study treatment packs with them. At each of these visits the treatment packs were checked as an assessment of compliance. Follow-up visit At clinic visit 1, two and three months following the issue of medication, the patients were asked about their intervening migraine attacks, response to study treatment and use of rescue medication. Quality of life was recorded again and adverse events were documented. Safety monitoring, such as heart rate, blood pressure, blood for haematological and biochemical analysis, was also carried out. At the final visit, unused medications was collected and the study summary in the clinical report form was completed. The data contained in the patients' diary booklets were processed and statistically analysed using the Mantel-Haenszel chi-square test with a 5% significance level. The efficacy of the drug was assessed on
the statistical variation of the following parameters: (i) headache relief at 2 h, (ii) requirement of rescue medication at 2 h, (iii) time to complete resolution of migraine attack, (iv) nausea and photophobia at 2 h, (v) percentage of patients vomiting. For all these parameters statistical significance was based on 'p' values, i.e. p < 0.05 is significant. Safety of the drug was also assessed as the percentage of patients with adverse effects. Results
Based on statistical analysis carried out on the data, the following results on the efficacy and safety of the drug were obtained (taking all three attacks into consideration). Comparison between sumatriptan and placebo was made using the Mantel-Haenszel chi-square test at the 5% significance level, i.e. with a statistical model of 95% confidence level. (i) Headache relief at two hours. For the patients with an initial headache severity grade of 2 or 3 at attack 1 (primary efficacy analysis was done), sumatriptan was significantly more effective than placebo (p = 0.023), with 63% of those treated with sumatriptan improving to grade 0 or 1 after 2 h compared with 33% of those receiving placebo. For attacks 2 and 3 (secondary analysis was done), there were no significant differences between sumatriptan and placebo with regard to the improvement in headache severity to grade 0 or 1 with initial severity of grade 2 or 3. For attack 2, those treated with sumatriptan improved 50% compared with 52% treated with placebo. Similarly, in attack 3, improvement rate for those treated with sumatriptan was 47% compared with 38% of those treated with placebo (Fig. 2). (ii) Requirement for rescue medication at 2 h. For attack 1, significantly fewer patients (p = 0.004) on sumatriptan needed rescue medication: 27% compared with 62% of patients on placebo. For attacks 2 and 3, the need for rescue medication did not differ significantly between sumatriptan and placebo; the figures in attack 2 were 48% and 48% while in attack 3 they were 43% and 56% respectively (Fig. 3). (iii) Time to complete resolution of migraine attack. For attack 1, the time to complete resolution of the migraine was significantly less (0.034) for those patients receiving sumatriptan compared with those receiving placebo; 14% of patients treated with sumatriptan had resolution within 2 h compared with 3% in the placebo treatment group. Resolution of the migraine occurred within 6 h for 41% of patients treated with sumatriptan compared with 15% of placebo-treated patients. For attacks 2 and 3, there were no significant differences between the sumatrip
tan treated patient group and the placebo treated patient group, i.e. for attack 2 at 2 h and 6 h the figures for sumatriptan and placebo were 12% and 3%, 36% and 31%, respectively. Similarly, the figures
for attack 3 were 12% and 0%, 24% and 19%, respectively (Fig. 4). (iv) Nausea and photophobia. For attacks 1, 2 and 3, there were no significant differences between sumatriptan and placebo 2 h after the treatment (Fig. 5). (v) Percentage of patients vomiting. For the first attack, 9% of patients vomited post-treatment compared to 19% and 43% respectively for attacks 2 and 3. Vomiting is likely to have reduced absorption of sumatriptan. However, there was also a higher incidence of vomiting prior to treatment in the sumatriptan group than in the placebo group for attacks 2 and 3 respectively; 25% and 36% in the sumatriptan group compared with 10% and 22% in the placebo group (Fig. 6). (vi) Safety. One serious adverse event was reported in a patient receiving placebo. In addition, two patients on placebo and four patients on sumatriptan withdrew because of side effects (usually nausea, vomiting and unpleasant taste). Twenty-seven percent of attacks treated with sumatriptan were associated with adverse events compared with 6% of those treated with placebo but they were mild in nature (Table 2). There was no clinically significant change in pulse, blood pressure or haematology or biochemistry during the trial. Discussion
Sumatriptan is a 5HT1-like receptor agonist which probably reproduces the effect of 5HT in relieving headache. The effect in migraine may relate to the selective constriction part of the carotid artery circulation without affecting cerebral blood flow. Vasoconstrictive effects of sumatriptan are also expected to reduce the extravasation of protein associated with the putative pathological inflammatory response in intracranial vessels in migraine (6). A series of single dose, safety, tolerability and pharmacokinetic studies has been conducted with the intravenous, subcutaneous and oral administration of Table 2. Percentage of patients with adverse effects. Placebo Sumatriptan 200 mg Percentage of patients with: adverse effects 15 35 drug-related effects 10 35 moderate or severe effects 13 24 severe effects 8 16 gastrointestinal effects 8 24 nausea/vomiting 8 24
p-value
0.048 0.010 NS NS 0.048 0.048
sumatriptan in healthy subjects (7) and has proved to be well tolerated. Recently, it was observed in a study that a single 6 mg dose of sumatriptan given subcutaneously is a highly effective, rapidly acting and well-tolerated treatment for migraine attacks (8). The administration of a second dose 60 min later to patients not responding well to an initial dose affords little additional benefit. In a series of open, dose-ranging studies, oral doses of sumatriptan (70-280 mg) have produced complete or almost complete relief of migraine symptoms within 30-120 min (1, 2). The dose of 200 mg was chosen in this particular study based on preliminary data from an oral pilot study (an interim analysis carried out by Glaxo Research Laboratories), which indicated that efficacy increased with increasing dose up to 200 mg. However, no published literature appears to be available on this interim analysis of the pilot study to quote as a reference. Because of the relative infrequency of migraine with aura (only 10-15% of all migraineurs) only limited data from earlier studies on the efficacy of sumatriptan on migraine with aura are available. Thus it would seem important to assess the efficacy of sumatriptan in the acute treatment of migraine with aura. This investigation was undertaken to fulfil these objectives. In this study of the first attack treatment, 200 mg sumatriptan was significantly more effective than placebo. More patients on sumatriptan than on placebo experienced headache relief at 2 h after treatment, while fewer patients required rescue medication at 2 h. The time to complete resolution of the attack was shorter for patients on sumatriptan. The response rate (63% at 2 h) to 200 mg sumatriptan was similar to that observed in a large, placebo-controlled study of orally administered sumatriptan (75%) where the majority of patients had migraine without aura (9). These results were not repeated for attacks 2 and 3. An increased response to placebo (particularly in attack 2) and a decreased response to sumatriptan resulted in there being no significant difference in headache relief between the two treatments. The reduced efficacy of sumatriptan in these attacks was probably due to the high incidence of vomiting, both before and after treatment, in patients on sumatriptan compared with those on placebo and reducing absorption. In addition, the bitter taste of the dispersible tablet formulation of sumatriptan is likely to have induced further vomiting in patients who were vomiting before treatment. In a large, placebo-controlled study of orally administered sumatriptan (10), where 100 mg, 200 mg and 300 mg doses were compared, 100 mg had a comparable efficacy profile to higher doses but had a better tolerability profile and is now the recommended oral dose. The high dose of sumatriptan
used in the present study may have contributed to the high incidence of post-treatment patients vomiting, leading to decreased efficacy of all but first attack. In addition, the dispersible tablet formulation of sumatriptan has been replaced with a tasteless, film-coated, conventional tablet, which should lead to a reduced incidence of vomiting and has been adopted for all further clinical use. Sumatriptan was generally well tolerated in this study. Although significantly more patients on sumatriptan reported adverse effects, the excess was made up of effects of mild to moderate severity. There were no clinically relevant chages in haematological and biochemical parameters, heart rate or blood pressure following treatment with sumatriptan. Conclusion
Sumatriptan (200 mg) was effective and generally well tolerated in the treatment of the first attack of migraine with aura. The reduced efficacy in later attacks was probably due to a high incidence of vomiting induced by the high dose of the dispersible formulation. Subsequently, 100 mg has been chosen as optimum oral dose for use in migraine and has been shown in a large dose-ranging study to be equally effective in migraine without aura (9). A new film-coated tablet which does not have the unpleasant taste of the dispersible formulation has been developed. This new formulation is definitely not
associated with the provocation of nausea and vomiting and has been ultimately adopted for further clinical use (9). Acknowledgements.-The authors are greatful to Glaxo Group Research Ltd, UK for providing a grant which made this work possible. The investigation was carried out at the Regional Centre for Neurology and Neurosurgery, Oldchurch Hospital, Romford, Essex, UK. Thanks are also due to Drs A. Abbas and Evelyn Bayliss for their assistance in the study. References
1.
Perrin VL, Farkkila M, Goasguen J, Doenicke A, Tfelt-Hansen P. Overview of initial clinical studies with intravenous and oral GR43175 in acute migraine. Cephalalgia 1989;9(suppl):63-72
2.
Doenicke A, Elchart D, Bayliss EM. Effective improvement of symptoms in patients with acute migraine by GR43175 administered in dispersible tablets. Cephalalgia 1989;9 (suppl):89-92
3.
Manzoni GC, Farina S, Granella F, Alfiere M, Bisi M. Classical and common migraine: suggestive of clinical evidence of two separate entities. Functional Neurology 1986;1:112-22
4.
Lauritzen M, Olesen J. Regional cerebral blood flow during migraine attacks by xenon-133 inhalation and emission tomography. Brain 1984;107:447-61
5.
Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. I. Migraine. Cephalalgia 1988;8(suppl 7):19-28
6.
Humphrey PPA. Mechanism of antimigraine action of Sumatriptan. The Fifth International Headache Congress, Washington, DC, 1991
7.
Fowler PA, Thomas M, Lacey LF, Andrew P, Dallas FAA. Early studies with the novel 5HT1-like agonist GR43175 in healthy volunteers. Cephalalgia 1989;9(suppl 9):56-62
8.
The Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with Sumatriptan. N Engl J Med 1991;325:316-21
9.
The Oral Sumatriptan International Multiple-Dose Study Group. Evaluation of a multiple-dose regimen of oral Sumatriptan for the acute treatment of migraine. Eur Neurol 1991;31:306-13
10.
The Oral Sumatriptan Dose Defining Study Group. Sumatriptan-an oral dose-defining study. Eur Neurol 1991;31: 300-5
M Banerjee, LJ Findley
Department of Neurology, Regional Centre for Neurology and Neurosurgery, Oldchurch Hospital Romford, Essex, UK Cephalalgia
Banerjee M, Findley LJ. Sumatriptan in the treatment of acute migraine with aura. Cephalalgia 1992;12:39-44. Oslo. ISSN 0333-1024 The efficacy of the selective 5HT1-like agonist sumatriptan in acute treatment of classical migraine (i.e. migraine with aura) was assessed in a double-blind, placebo-controlled, parallel group randomized trial. An oral dose of 200 mg was chosen on the basis of the efficacy rates achieved (70-85%) with 70-280 mg in open studies (1, 2). The dose of 200 mg was also chosen for the study because preliminary data from an oral pilot study indicated that efficacy increased with increasing dose up to 200 mg. Each patient was treated for a maximum of three separate attacks of migraine with aura within a three months' period. Three attacks were treated so that we could examine consistency of response across more than one attack. For attack 1,200 mg sumatriptan was significantly more effective, safe and well tolerated than placebo at relieving headache 2 h after treatment was given (p = 0.023). In subsequent attacks, i.e. in attacks 2 and 3, there was no such significant effect of sumatriptan compared with placebo in relieving headache. This reduced efficacy of sumatriptan in the second and third attacks may be due to a high incidence of vomiting induced by the high dose of dispersible formulation and also by the bitter taste of the tablets. In addition, there was an increase in placebo response in attacks 2 and 3 compared to the first attack. • Migraine with aura, sumatriptan Mala Banerjee, Department of Neurology, Regional Centre for Neurology and Neurosurgery, Oldchurch Hospital Romford, Essex, UK. Received 30 September 1991, accepted 22 November 1991
Earlier investigations suggest that the two forms of migraine (i.e. migraine with aura and migraine without aura) are separate entities (3). They differ in that regional cerebral blood flow changes occur only in migraine with aura (4). This may reflect cortical arteriolar vasospasm with or without spreading depression of Leao. Owing to the relative infrequency of migraine with aura (10-15% of migraineurs), the availability of data from previous studies on the efficacy of sumatriptan on migraine with aura is limited. This inadequacy of data and knowledge about the role of sumatriptan in the treatment of migraine with aura prompted us to initiate a double-blind, placebo-controlled, parallel group clinical trial to assess the safety, efficacy and tolerability of sumatriptan (200 mg single dose dispersible tablets) in the acute treatment of classical migraine. The data were collected from diary booklets of the patients. Patients and methods
Patients A total number of 94 patients aged between 18 and 65 years (mean 35 years; 85% female) and experiencing one to three attacks per month were randomized to receive study medication. Eighteen of them did not treat any attacks with study medication; 39 patients treated a total of 101 attacks with placebo and 37 a total of 93 attacks with sumatriptan (GR43175C), (see Table 1 for details). All patients included were first diagnosed as having migraine with aura as defined by the Ad Hoc Committee of Table 1. Distribution of patients into two groups (placebo or 200 mg sumatriptan). Number of patients or attacks Placebo 200 mg sumatriptan Randomized patients 94 Patients treating an attack 39 37 Attacks treated 101 93 Patients evaluable for efficacy: Attack 1 37 34 Attack 2 33 28 Attack 3 27 22
the International Headache Society (5) with a history of at least one year, and had on average one to six attacks per month of severe to moderate in nature. They were also able to recognize early signs of migraine with aura and distinguish attacks from attacks of migraine without aura. Prophylactic medication was discontinued at least two weeks prior to entering the study. Exclusion criteria included the regular use or abuse of narcotics, ergotamines or other drugs, pregnancy or lactation, history of ischaemic heart diseases or psychiatric illness, and also hypertension, epilepsy or hepatic diseases. Study design
The investigation was based on a double-blind placebo-controlled randomized parallel group trial
with 200 mg sumatriptan. Patients were randomized equally to two groups (placebo and sumatriptan). Each patient treated up to three attacks with study medication within a period of three months. Each patient was supplied with three separate treatment packs, one for each of three migraine attacks. The patient was instructed to take the study medication as the first treatment as soon as s/he recognized an attack of migraine with aura. Moreover, the investigator had to be satisfied that the patient could recognize an attack with aura and also distinguish it from attacks without aura. The patient was asked to treat the second and third attacks, provided there was an interval of at least 48 h between each. The study procedures and parameters mentioned are shown in Fig. 1. Quality of migraine (aura, headache, nausea, vomiting) including headache severity (using a four-point scale, i.e. 0 = no headache, 1 = mild, 2 = moderate, 3 = severe) was assessed before and 2 h after the drug administration. The time to complete resolution of attack was also assessed (i.e. after 2 and 6 h of drug administration). Visit 1 - (pre-treatment) In this phase, patients who fulfilled the inclusion and exclusion criteria were informed about the study fully and consent was acquired. Those consenting
underwent a physical and neurological examination. A venous blood sample was taken for haematological and biochemical analysis. ECG, heart rate and blood pressure were recorded. Details of demography, migraine history, any other pertinent clinical history, any concurrent medical problem, concurrent medication, prophylactic medication and proposed rescue medication were also recorded. Prophylactic medication was discontinued at this point. Although the patient's quality of life was recorded in clinical record form, at both entry and follow-up visits, these data were not analysed statistically since there were some problems with the interpretation of the questions put to the patients by the investigators. Patients were then issued a practice diary card which they were asked to complete when next treating a migraine attack with their normal migraine therapy. Visit 2-issue of medication Two weeks later each patient received an appropriate supply of blinded study medication. This was supplied in the form of three separate treatment packs, one for each of three migraine attacks. The patient was instructed to take the study medication as soon as they recognized an attack with aura as the first treatment for a new migraine attack. Patients were issued with further diary cards on which to record the details of each attack treated, and were told to record their migraine symptoms before and after taking their study medication. Those patients showing inadequate symptom relief 2 h after taking the medication were able to take the rescue medication and were to record the result in the diary card. Patients were instructed to return to the clinic for monthly follow-up visits and to bring their study treatment packs with them. At each of these visits the treatment packs were checked as an assessment of compliance. Follow-up visit At clinic visit 1, two and three months following the issue of medication, the patients were asked about their intervening migraine attacks, response to study treatment and use of rescue medication. Quality of life was recorded again and adverse events were documented. Safety monitoring, such as heart rate, blood pressure, blood for haematological and biochemical analysis, was also carried out. At the final visit, unused medications was collected and the study summary in the clinical report form was completed. The data contained in the patients' diary booklets were processed and statistically analysed using the Mantel-Haenszel chi-square test with a 5% significance level. The efficacy of the drug was assessed on
the statistical variation of the following parameters: (i) headache relief at 2 h, (ii) requirement of rescue medication at 2 h, (iii) time to complete resolution of migraine attack, (iv) nausea and photophobia at 2 h, (v) percentage of patients vomiting. For all these parameters statistical significance was based on 'p' values, i.e. p < 0.05 is significant. Safety of the drug was also assessed as the percentage of patients with adverse effects. Results
Based on statistical analysis carried out on the data, the following results on the efficacy and safety of the drug were obtained (taking all three attacks into consideration). Comparison between sumatriptan and placebo was made using the Mantel-Haenszel chi-square test at the 5% significance level, i.e. with a statistical model of 95% confidence level. (i) Headache relief at two hours. For the patients with an initial headache severity grade of 2 or 3 at attack 1 (primary efficacy analysis was done), sumatriptan was significantly more effective than placebo (p = 0.023), with 63% of those treated with sumatriptan improving to grade 0 or 1 after 2 h compared with 33% of those receiving placebo. For attacks 2 and 3 (secondary analysis was done), there were no significant differences between sumatriptan and placebo with regard to the improvement in headache severity to grade 0 or 1 with initial severity of grade 2 or 3. For attack 2, those treated with sumatriptan improved 50% compared with 52% treated with placebo. Similarly, in attack 3, improvement rate for those treated with sumatriptan was 47% compared with 38% of those treated with placebo (Fig. 2). (ii) Requirement for rescue medication at 2 h. For attack 1, significantly fewer patients (p = 0.004) on sumatriptan needed rescue medication: 27% compared with 62% of patients on placebo. For attacks 2 and 3, the need for rescue medication did not differ significantly between sumatriptan and placebo; the figures in attack 2 were 48% and 48% while in attack 3 they were 43% and 56% respectively (Fig. 3). (iii) Time to complete resolution of migraine attack. For attack 1, the time to complete resolution of the migraine was significantly less (0.034) for those patients receiving sumatriptan compared with those receiving placebo; 14% of patients treated with sumatriptan had resolution within 2 h compared with 3% in the placebo treatment group. Resolution of the migraine occurred within 6 h for 41% of patients treated with sumatriptan compared with 15% of placebo-treated patients. For attacks 2 and 3, there were no significant differences between the sumatrip
tan treated patient group and the placebo treated patient group, i.e. for attack 2 at 2 h and 6 h the figures for sumatriptan and placebo were 12% and 3%, 36% and 31%, respectively. Similarly, the figures
for attack 3 were 12% and 0%, 24% and 19%, respectively (Fig. 4). (iv) Nausea and photophobia. For attacks 1, 2 and 3, there were no significant differences between sumatriptan and placebo 2 h after the treatment (Fig. 5). (v) Percentage of patients vomiting. For the first attack, 9% of patients vomited post-treatment compared to 19% and 43% respectively for attacks 2 and 3. Vomiting is likely to have reduced absorption of sumatriptan. However, there was also a higher incidence of vomiting prior to treatment in the sumatriptan group than in the placebo group for attacks 2 and 3 respectively; 25% and 36% in the sumatriptan group compared with 10% and 22% in the placebo group (Fig. 6). (vi) Safety. One serious adverse event was reported in a patient receiving placebo. In addition, two patients on placebo and four patients on sumatriptan withdrew because of side effects (usually nausea, vomiting and unpleasant taste). Twenty-seven percent of attacks treated with sumatriptan were associated with adverse events compared with 6% of those treated with placebo but they were mild in nature (Table 2). There was no clinically significant change in pulse, blood pressure or haematology or biochemistry during the trial. Discussion
Sumatriptan is a 5HT1-like receptor agonist which probably reproduces the effect of 5HT in relieving headache. The effect in migraine may relate to the selective constriction part of the carotid artery circulation without affecting cerebral blood flow. Vasoconstrictive effects of sumatriptan are also expected to reduce the extravasation of protein associated with the putative pathological inflammatory response in intracranial vessels in migraine (6). A series of single dose, safety, tolerability and pharmacokinetic studies has been conducted with the intravenous, subcutaneous and oral administration of Table 2. Percentage of patients with adverse effects. Placebo Sumatriptan 200 mg Percentage of patients with: adverse effects 15 35 drug-related effects 10 35 moderate or severe effects 13 24 severe effects 8 16 gastrointestinal effects 8 24 nausea/vomiting 8 24
p-value
0.048 0.010 NS NS 0.048 0.048
sumatriptan in healthy subjects (7) and has proved to be well tolerated. Recently, it was observed in a study that a single 6 mg dose of sumatriptan given subcutaneously is a highly effective, rapidly acting and well-tolerated treatment for migraine attacks (8). The administration of a second dose 60 min later to patients not responding well to an initial dose affords little additional benefit. In a series of open, dose-ranging studies, oral doses of sumatriptan (70-280 mg) have produced complete or almost complete relief of migraine symptoms within 30-120 min (1, 2). The dose of 200 mg was chosen in this particular study based on preliminary data from an oral pilot study (an interim analysis carried out by Glaxo Research Laboratories), which indicated that efficacy increased with increasing dose up to 200 mg. However, no published literature appears to be available on this interim analysis of the pilot study to quote as a reference. Because of the relative infrequency of migraine with aura (only 10-15% of all migraineurs) only limited data from earlier studies on the efficacy of sumatriptan on migraine with aura are available. Thus it would seem important to assess the efficacy of sumatriptan in the acute treatment of migraine with aura. This investigation was undertaken to fulfil these objectives. In this study of the first attack treatment, 200 mg sumatriptan was significantly more effective than placebo. More patients on sumatriptan than on placebo experienced headache relief at 2 h after treatment, while fewer patients required rescue medication at 2 h. The time to complete resolution of the attack was shorter for patients on sumatriptan. The response rate (63% at 2 h) to 200 mg sumatriptan was similar to that observed in a large, placebo-controlled study of orally administered sumatriptan (75%) where the majority of patients had migraine without aura (9). These results were not repeated for attacks 2 and 3. An increased response to placebo (particularly in attack 2) and a decreased response to sumatriptan resulted in there being no significant difference in headache relief between the two treatments. The reduced efficacy of sumatriptan in these attacks was probably due to the high incidence of vomiting, both before and after treatment, in patients on sumatriptan compared with those on placebo and reducing absorption. In addition, the bitter taste of the dispersible tablet formulation of sumatriptan is likely to have induced further vomiting in patients who were vomiting before treatment. In a large, placebo-controlled study of orally administered sumatriptan (10), where 100 mg, 200 mg and 300 mg doses were compared, 100 mg had a comparable efficacy profile to higher doses but had a better tolerability profile and is now the recommended oral dose. The high dose of sumatriptan
used in the present study may have contributed to the high incidence of post-treatment patients vomiting, leading to decreased efficacy of all but first attack. In addition, the dispersible tablet formulation of sumatriptan has been replaced with a tasteless, film-coated, conventional tablet, which should lead to a reduced incidence of vomiting and has been adopted for all further clinical use. Sumatriptan was generally well tolerated in this study. Although significantly more patients on sumatriptan reported adverse effects, the excess was made up of effects of mild to moderate severity. There were no clinically relevant chages in haematological and biochemical parameters, heart rate or blood pressure following treatment with sumatriptan. Conclusion
Sumatriptan (200 mg) was effective and generally well tolerated in the treatment of the first attack of migraine with aura. The reduced efficacy in later attacks was probably due to a high incidence of vomiting induced by the high dose of the dispersible formulation. Subsequently, 100 mg has been chosen as optimum oral dose for use in migraine and has been shown in a large dose-ranging study to be equally effective in migraine without aura (9). A new film-coated tablet which does not have the unpleasant taste of the dispersible formulation has been developed. This new formulation is definitely not
associated with the provocation of nausea and vomiting and has been ultimately adopted for further clinical use (9). Acknowledgements.-The authors are greatful to Glaxo Group Research Ltd, UK for providing a grant which made this work possible. The investigation was carried out at the Regional Centre for Neurology and Neurosurgery, Oldchurch Hospital, Romford, Essex, UK. Thanks are also due to Drs A. Abbas and Evelyn Bayliss for their assistance in the study. References
1.
Perrin VL, Farkkila M, Goasguen J, Doenicke A, Tfelt-Hansen P. Overview of initial clinical studies with intravenous and oral GR43175 in acute migraine. Cephalalgia 1989;9(suppl):63-72
2.
Doenicke A, Elchart D, Bayliss EM. Effective improvement of symptoms in patients with acute migraine by GR43175 administered in dispersible tablets. Cephalalgia 1989;9 (suppl):89-92
3.
Manzoni GC, Farina S, Granella F, Alfiere M, Bisi M. Classical and common migraine: suggestive of clinical evidence of two separate entities. Functional Neurology 1986;1:112-22
4.
Lauritzen M, Olesen J. Regional cerebral blood flow during migraine attacks by xenon-133 inhalation and emission tomography. Brain 1984;107:447-61
5.
Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. I. Migraine. Cephalalgia 1988;8(suppl 7):19-28
6.
Humphrey PPA. Mechanism of antimigraine action of Sumatriptan. The Fifth International Headache Congress, Washington, DC, 1991
7.
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