Naproxen Sodium Versus Ergotamine Tartrate in the Treatment of Acute Migraine Attacks
T.A. Treves, M. Streiffler and A.D. Korczyn
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University Ramat Aviv 69978, Israel Reprint requests to: Professor A.D. Korczyn, M.D., M.Sc. Department of Physiology and Pharmacology, Sackler Faculty of Medicine, TeI-Aviv University Ramat Aviv 69978, Israel. Accepted for publication: March 21, 1992 SYNOPSIS
A double-blind parallel study compared the efficacy and safety of naproxen sodium (NPX) and ergotamine tartrate (ERG) as abortive therapy for acute headache in 79 patients with classical or common migraine. The design study was of the double-blind design. Forty-two patients completed the study. Discontinuation of treatment was generally due to lack of efficacy or adverse reactions. NPX was significantly better than ERG in the overall efficacy of treatment rated by the patients (p < 004). NPX was comparable to ERG in reducing the severity and duration of the headache and its associated symptoms. In classical migraine, NPX was better than ERG in alleviating the severity of headache. Patients in the NPX group tended to use less rescue medication. There was no significant difference in the frequency of side-effects reported by the patients under NPX or ERG. This study demonstrates that NPX is as safe as ERG, and somewhat more effective in acute migraine attacks (although the difference is not statistically significant) and that migrainous patients tend to prefer NPX to ERG in treating their acute migraine headaches. Key words: Headache, migraine, treatment, naproxen, ergotamine. Abbreviations:
NPX naproxen sodium, ERG ergotamine tartrate
(Headache 1992, 32:280-282) INTRODUCTION
The pathophysiology of migraine is not elucidated as yet. A neuronal theory1 and a vascular theory with "spreading oligemia''2 have been proposed, but how they are linked together is not known. Nevertheless, vasoactive substances and prostaglandins seem to play important roles in the mechanisms of migraine.3-5 Ergotamine compounds have been used for many years as standard agents in the symptomatic control of migraine; they probably alleviate migraine attacks by vasoconstricting extracerebral arteries.6 However, they are associated with side-effects that limit their use. NPX has been shown to inhibit platelet aggregation and prostaglandin synthesis7,8 and found to be a potent analgesic agent.8 It was also found to be effective in migraine attacks.9-14 The study was therefore undertaken to compare the relative efficacy and safety of Naproxen sodium (NPX) and ergotamine tartrate (ERG) in the treatment of acute migraine attacks. METHODS
The influence of the drugs was evaluated in a double-blind, randomized, parallel study. Patients suffering from classical or common migraine, as defined by the Ad Hoc Committee on Classification of Headache,15 were eligible if they met the following inclusion criteria: duration of migraine for at least one year prior to entry into the study and frequent migraine attacks (2 to 8 per month). Patients were excluded if they had cluster headache or complicated migraine, as well as those patients whose migraine was exacerbated by oral contraceptive therapy, and those with active peptic disease, disorders of the liver, kidney, hemopoietic or cardiovascular systems, and pregnant or breast-feeding women. Drugs were supplied as capsules containing NPX or ERG. At the first sign of an attack, patients had to take an initial dose of either NPX (750 mg) or ERG (2 mg). Thirty minutes after the first dose, if symptoms were still present, a second dose (NPX 500 mg or ERG 1 mg) was to be taken. One hour after the attack began, the patient was allowed to take a third dose (similar to the second) of the drug, if the symptoms improved but did not disappear, or a rescue analgesic (acetaminophen 1 g), if the symptoms were the same or worse. Patients were seen at monthly intervals for 6 months or until they had completed 6 treatments. Following each attack the patient graded the severity of the headache and of the accompanying symptoms (headache, photophobia, nausea, vomiting, light-headedness) as: none, mild, moderate or severe. Also, the duration of the attack and the use of rescue medication were recorded. After each attack, patients evaluated the effect of the drug on the severity and the duration of the symptoms. At the end of the study patients gave an overall rating of the effect of the drug on the treatment of migraine as: no effect, poor, fair, good, very good, or excellent. The comparability of the two treatment groups and the effect of the medications were analyzed using parametric (t-test) and nonparametric (Chi-square, Wilcoxon) tests. Analysis of the effect of the medication on symptoms of migraine attack was performed provided the patient was treated for at least two attacks. Individual migraine attacks were excluded from analyses if vomiting occurred within one hour after taking the first dose of test medication, if other drugs were taken within six hours of the onset of the migraine attack, or if data were incompletely recorded.
RESULTS
From 79 patients (NPX 38, ERG 41) who entered the study, 37 (NPX 17, ERG 20) terminated the trial prematurely. The reasons for interruptions are given in Table 1. Eight patients were excluded from the efficacy analysis: five were lost to follow-up (NPX 3, ERG 2), one had more than 8 attacks per month, and two (NPX 1, ERG 1) violated the protocol by taking additional medication. There were no significant differences between the two groups regarding patients' age, duration of disease, type of migraine, frequency and duration of attacks, or for the severity of the pain or symptoms. All patients had a history of either moderate or severe headaches. NPX was significantly better than ERG in the overall efficacy of treatment rated by the patients (Table 2). Patients in the NPX group used less rescue medication than those from the ERG group (23% and 29%, respectively), although this difference is not statistically significant. The effect of treatment on the severity of the individual symptoms was not statistically different between the two treatment groups although there was a trend in favor of NPX (Table 3). The duration of the symptoms was not significantly shorter in either group, nevertheless, headache tended to be of less duration in the NPX group (Table 4). On separate analysis, based on classification of migraine, NPX was found to afford more relief than ERG in the severity of pain in patients with classical migraine (p = 0.05). In the same group, a reduction in the duration of pain approached significance in favor of NPX. This difference was not observed for patients with common migraine. Table 1 Premature terminations of treatment Treatment Group Naproxen Ergotamine Presumed lack of efficacy 7 Reported adverse reactions 6 Lost to follow-up* 3 Protocol violations* 1 TotaI 17 * Patients withdrawn from efficacy analysis.
14 2 2 2 20
Total 21 8 5 3 37
Table 2 Overall efficacy rating to treatment Effect Naproxen Ergotamine (n = 34) (n = 37) None 6 (17.6%) 10 (27.0%) Poor 5 (14.7%) 9 (24.3%) Fair 5 (14.7%) 8 (21.6%) Good 6 (17.6%) 4 (10.8%) Very good 10 (29.4%) 6 (16.2%) Excellent 2 (5.9%) 0 (0.0%)
Wilcoxon rank sum test, p = 0.04 Adverse reactions were reported in 3 patients under ERG (nausea 2, dizziness 1) and in 8 patients under NPX (gastro-intestinal discomfort 7, generalized weakness 1). Because of these side-effects, 2 patients under ERG and 6 under NPX discontinued the medication (Table 5). The difference in the occurrence of side-effects was not statistically different among the two treatment groups. DISCUSSION
NPX has already been found to be effective in the prophylactic treatment of migraine.9-11 In acute migraine attacks, the drug, versus a placebo, has been shown to efficacious.12,13 However, NPX and ERG have been compared directly previously only to a limited extent.14 In this randomized, double-blind, parallel study, NPX was at least as efficacious as ERG in the treatTable 3 Effect of treatment on severity of symptoms* Symptom severity Naproxen Ergotamine p-value** Mean No Mean No Headache 2.35 34 2.10 37 0.17 Nausea 2.17 26 2.34 32 0.16 Vomiting 2.67 12 2.36 14 0.20 Photophobia 2.30 27 2.26 31 0.60 Lightheadedness 2.37 19 2.06 17 0.20 * Improvement scale: 5 = abolished completely, 4 = substantially better, 3 = slightly better, 2 = usual severity, 1 = worse. ** Two-tailed Wilcoxon rank sum test.
Table 4 Effect of treatment on duration of symptoms* Symptom duration
Naproxen Ergotamine Mean No Mean No Headache 2.62 34 2.28 37 Nausea 2.42 26 2.48 32 Vomiting 2.73 12 2.64 14 Photophobia 2.61 27 2.39 31 Lightheadedness 2.61 19 2.15 17 * Improvement scale: 5 = abolished completely, 4 = substantially shorter, 3 2 = usual duration, 1 = longer than usual. ** Two-tailed Wilcoxon rank sum test.
Table 5 Adverse reactions Treatment group Naproxen Ergotamine Gastro-intestinal 7 (6) 2 (1) GeneraI weakness 1 Lightheadedness 1 (1) Total 8 (6) 3 (2) Number of patients who discontinued the medication due to the adverse experience is given in brackets.
p-value** 0.08 0.97 0.71 0.16 0.10 = slightly shorter,
ment of acute migraine attacks (Tables 2-4). It was significantly superior on global assessment. Analyzing the effect on individual symptoms, NPX tended to be more effective on the duration than on the severity of the headache. This finding differs from Pradalier et al.'s results,14 who, in a study similar to ours, observed better effect of NPX than of ERG on the severity of the pain, although overall efficacy assessments were similar. The benefit of NPX was found to be more salient on classical than common migraine, no previous similar analysis was conducted for comparison of NPX and ERG. Our results show that side-effects were reported in both treatments (Table 5). Nevertheless, we have to keep in mind that the more severe side-effects of ERG may appear only at high doses.16 In the setting of an experimental study, patients are not expected to exceed the recommended dose. On free medication, severe toxic effects could more likely occur with ERG than with NPX. In addition, it will be helpful to find out whether patients who have not responded to one of the drugs may respond to the other. This question was not addressed in the present study and could only be answered by a crossover design. REFERENCES
1.
Pearce JMS: Is migraine explained by Leão's spreading depression? Lancet 1985; 2(8458):763-766.
2.
Lauritzen M, Olsen ST, Lassen NA, and Paulson OB: Regulation of regional cerebral blood flow during and between migraine attacks. Ann Neurol 1983; 14:569-572.
3.
Harrobin DF. Prostglandins and migraine. Headache 1977; 17:113-117.
4.
Dvilansky A, Rishpon S, Nathan I, Zolotow Z, and Korczyn AD: Release of platelet 5-hydroxytryptamine by plasma taken from patients during and between migraine attacks. Pain 1976; 2:315-318.
5.
Kruglak L, Nathan I, Korczyn AD, Berginer V, and Dvilansky A: Platelet aggregability, disaggregability and serotonin uptake in migraine. Cephalalgia 1984; 4:221-225.
6.
Fanchamps A: Pharmacodynamic principles and anti-migraine therapy. Headache 1975; 15:79-90.
7.
Tomlinson RV, Ringold H, Quereshi MC, and Forchielli E: Relationship between inhibition of prostaglandin synthesis and drug efficacy: support for the current theory on mode of action of aspirin-like drugs. Biochem Biophys Res Comm 1972; 45:552-559.
8.
Nadell J, Bruno J, Varady J, Segre EJ: Effect of naproxen and of aspirin on bleeding time and platelet aggregation. J Clin Pharmacol 1974; 14:176-182.
9.
Lindegaard KF, Ovrelid L, and Sjaastad O: Naproxen in the prevention of migraine attacks. A double-blind placebo-controlled cross-over study. Headache 1980; 20:96-98.
10.
Welch KMA, Ellis DJ, Keenan PA: Successful migraine phophylaxis with Naproxen sodium. Neurology 1985: 35:1304-1310.
11.
Ziegler DK, and Ellis DJ: Naproxen in prophylaxis of migraine. Arch Neurol 1985; 42:582-584.
12.
Johnson ES, Ratcliffe DM, and Wilkinson M: Naproxen sodium in the treatment of migraine. Cephalalgia 1985; 5:5-10.
13.
Nestvold K, Kloster R, Partinen M, and Sulkava R: Treatment of acute migraine attack: Naproxen and placebo compared. Cephalalgia 1985; 5:115-119.
14.
Pradalier A, Rancurel G, Dordain G, Verdure L, Rascol A, and Dry J: Acute migraine attack therapy: comparison of Naproxen sodium and an ergotamine tartrate compound. Cephalalgia 1985; 5:107-113.
15.
Ad Hoc Committee on Classification of Headache: Classification of headache. JAMA 1962; 179:717-718.
16.
Rall TW, Schleifer LS: Oxytocin, prostaglandins, ergot alkaloids, and other drugs; tocolytic agents. In: Goodman Gilman A, Goodman LS, Rail TW, Murad F (eds). The Pharmacological Basis of Therapeutics, seventh edition. New York: Macmillan Publishing Co., 1985:926-945.
T.A. Treves, M. Streiffler and A.D. Korczyn
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University Ramat Aviv 69978, Israel Reprint requests to: Professor A.D. Korczyn, M.D., M.Sc. Department of Physiology and Pharmacology, Sackler Faculty of Medicine, TeI-Aviv University Ramat Aviv 69978, Israel. Accepted for publication: March 21, 1992 SYNOPSIS
A double-blind parallel study compared the efficacy and safety of naproxen sodium (NPX) and ergotamine tartrate (ERG) as abortive therapy for acute headache in 79 patients with classical or common migraine. The design study was of the double-blind design. Forty-two patients completed the study. Discontinuation of treatment was generally due to lack of efficacy or adverse reactions. NPX was significantly better than ERG in the overall efficacy of treatment rated by the patients (p < 004). NPX was comparable to ERG in reducing the severity and duration of the headache and its associated symptoms. In classical migraine, NPX was better than ERG in alleviating the severity of headache. Patients in the NPX group tended to use less rescue medication. There was no significant difference in the frequency of side-effects reported by the patients under NPX or ERG. This study demonstrates that NPX is as safe as ERG, and somewhat more effective in acute migraine attacks (although the difference is not statistically significant) and that migrainous patients tend to prefer NPX to ERG in treating their acute migraine headaches. Key words: Headache, migraine, treatment, naproxen, ergotamine. Abbreviations:
NPX naproxen sodium, ERG ergotamine tartrate
(Headache 1992, 32:280-282) INTRODUCTION
The pathophysiology of migraine is not elucidated as yet. A neuronal theory1 and a vascular theory with "spreading oligemia''2 have been proposed, but how they are linked together is not known. Nevertheless, vasoactive substances and prostaglandins seem to play important roles in the mechanisms of migraine.3-5 Ergotamine compounds have been used for many years as standard agents in the symptomatic control of migraine; they probably alleviate migraine attacks by vasoconstricting extracerebral arteries.6 However, they are associated with side-effects that limit their use. NPX has been shown to inhibit platelet aggregation and prostaglandin synthesis7,8 and found to be a potent analgesic agent.8 It was also found to be effective in migraine attacks.9-14 The study was therefore undertaken to compare the relative efficacy and safety of Naproxen sodium (NPX) and ergotamine tartrate (ERG) in the treatment of acute migraine attacks. METHODS
The influence of the drugs was evaluated in a double-blind, randomized, parallel study. Patients suffering from classical or common migraine, as defined by the Ad Hoc Committee on Classification of Headache,15 were eligible if they met the following inclusion criteria: duration of migraine for at least one year prior to entry into the study and frequent migraine attacks (2 to 8 per month). Patients were excluded if they had cluster headache or complicated migraine, as well as those patients whose migraine was exacerbated by oral contraceptive therapy, and those with active peptic disease, disorders of the liver, kidney, hemopoietic or cardiovascular systems, and pregnant or breast-feeding women. Drugs were supplied as capsules containing NPX or ERG. At the first sign of an attack, patients had to take an initial dose of either NPX (750 mg) or ERG (2 mg). Thirty minutes after the first dose, if symptoms were still present, a second dose (NPX 500 mg or ERG 1 mg) was to be taken. One hour after the attack began, the patient was allowed to take a third dose (similar to the second) of the drug, if the symptoms improved but did not disappear, or a rescue analgesic (acetaminophen 1 g), if the symptoms were the same or worse. Patients were seen at monthly intervals for 6 months or until they had completed 6 treatments. Following each attack the patient graded the severity of the headache and of the accompanying symptoms (headache, photophobia, nausea, vomiting, light-headedness) as: none, mild, moderate or severe. Also, the duration of the attack and the use of rescue medication were recorded. After each attack, patients evaluated the effect of the drug on the severity and the duration of the symptoms. At the end of the study patients gave an overall rating of the effect of the drug on the treatment of migraine as: no effect, poor, fair, good, very good, or excellent. The comparability of the two treatment groups and the effect of the medications were analyzed using parametric (t-test) and nonparametric (Chi-square, Wilcoxon) tests. Analysis of the effect of the medication on symptoms of migraine attack was performed provided the patient was treated for at least two attacks. Individual migraine attacks were excluded from analyses if vomiting occurred within one hour after taking the first dose of test medication, if other drugs were taken within six hours of the onset of the migraine attack, or if data were incompletely recorded.
RESULTS
From 79 patients (NPX 38, ERG 41) who entered the study, 37 (NPX 17, ERG 20) terminated the trial prematurely. The reasons for interruptions are given in Table 1. Eight patients were excluded from the efficacy analysis: five were lost to follow-up (NPX 3, ERG 2), one had more than 8 attacks per month, and two (NPX 1, ERG 1) violated the protocol by taking additional medication. There were no significant differences between the two groups regarding patients' age, duration of disease, type of migraine, frequency and duration of attacks, or for the severity of the pain or symptoms. All patients had a history of either moderate or severe headaches. NPX was significantly better than ERG in the overall efficacy of treatment rated by the patients (Table 2). Patients in the NPX group used less rescue medication than those from the ERG group (23% and 29%, respectively), although this difference is not statistically significant. The effect of treatment on the severity of the individual symptoms was not statistically different between the two treatment groups although there was a trend in favor of NPX (Table 3). The duration of the symptoms was not significantly shorter in either group, nevertheless, headache tended to be of less duration in the NPX group (Table 4). On separate analysis, based on classification of migraine, NPX was found to afford more relief than ERG in the severity of pain in patients with classical migraine (p = 0.05). In the same group, a reduction in the duration of pain approached significance in favor of NPX. This difference was not observed for patients with common migraine. Table 1 Premature terminations of treatment Treatment Group Naproxen Ergotamine Presumed lack of efficacy 7 Reported adverse reactions 6 Lost to follow-up* 3 Protocol violations* 1 TotaI 17 * Patients withdrawn from efficacy analysis.
14 2 2 2 20
Total 21 8 5 3 37
Table 2 Overall efficacy rating to treatment Effect Naproxen Ergotamine (n = 34) (n = 37) None 6 (17.6%) 10 (27.0%) Poor 5 (14.7%) 9 (24.3%) Fair 5 (14.7%) 8 (21.6%) Good 6 (17.6%) 4 (10.8%) Very good 10 (29.4%) 6 (16.2%) Excellent 2 (5.9%) 0 (0.0%)
Wilcoxon rank sum test, p = 0.04 Adverse reactions were reported in 3 patients under ERG (nausea 2, dizziness 1) and in 8 patients under NPX (gastro-intestinal discomfort 7, generalized weakness 1). Because of these side-effects, 2 patients under ERG and 6 under NPX discontinued the medication (Table 5). The difference in the occurrence of side-effects was not statistically different among the two treatment groups. DISCUSSION
NPX has already been found to be effective in the prophylactic treatment of migraine.9-11 In acute migraine attacks, the drug, versus a placebo, has been shown to efficacious.12,13 However, NPX and ERG have been compared directly previously only to a limited extent.14 In this randomized, double-blind, parallel study, NPX was at least as efficacious as ERG in the treatTable 3 Effect of treatment on severity of symptoms* Symptom severity Naproxen Ergotamine p-value** Mean No Mean No Headache 2.35 34 2.10 37 0.17 Nausea 2.17 26 2.34 32 0.16 Vomiting 2.67 12 2.36 14 0.20 Photophobia 2.30 27 2.26 31 0.60 Lightheadedness 2.37 19 2.06 17 0.20 * Improvement scale: 5 = abolished completely, 4 = substantially better, 3 = slightly better, 2 = usual severity, 1 = worse. ** Two-tailed Wilcoxon rank sum test.
Table 4 Effect of treatment on duration of symptoms* Symptom duration
Naproxen Ergotamine Mean No Mean No Headache 2.62 34 2.28 37 Nausea 2.42 26 2.48 32 Vomiting 2.73 12 2.64 14 Photophobia 2.61 27 2.39 31 Lightheadedness 2.61 19 2.15 17 * Improvement scale: 5 = abolished completely, 4 = substantially shorter, 3 2 = usual duration, 1 = longer than usual. ** Two-tailed Wilcoxon rank sum test.
Table 5 Adverse reactions Treatment group Naproxen Ergotamine Gastro-intestinal 7 (6) 2 (1) GeneraI weakness 1 Lightheadedness 1 (1) Total 8 (6) 3 (2) Number of patients who discontinued the medication due to the adverse experience is given in brackets.
p-value** 0.08 0.97 0.71 0.16 0.10 = slightly shorter,
ment of acute migraine attacks (Tables 2-4). It was significantly superior on global assessment. Analyzing the effect on individual symptoms, NPX tended to be more effective on the duration than on the severity of the headache. This finding differs from Pradalier et al.'s results,14 who, in a study similar to ours, observed better effect of NPX than of ERG on the severity of the pain, although overall efficacy assessments were similar. The benefit of NPX was found to be more salient on classical than common migraine, no previous similar analysis was conducted for comparison of NPX and ERG. Our results show that side-effects were reported in both treatments (Table 5). Nevertheless, we have to keep in mind that the more severe side-effects of ERG may appear only at high doses.16 In the setting of an experimental study, patients are not expected to exceed the recommended dose. On free medication, severe toxic effects could more likely occur with ERG than with NPX. In addition, it will be helpful to find out whether patients who have not responded to one of the drugs may respond to the other. This question was not addressed in the present study and could only be answered by a crossover design. REFERENCES
1.
Pearce JMS: Is migraine explained by Leão's spreading depression? Lancet 1985; 2(8458):763-766.
2.
Lauritzen M, Olsen ST, Lassen NA, and Paulson OB: Regulation of regional cerebral blood flow during and between migraine attacks. Ann Neurol 1983; 14:569-572.
3.
Harrobin DF. Prostglandins and migraine. Headache 1977; 17:113-117.
4.
Dvilansky A, Rishpon S, Nathan I, Zolotow Z, and Korczyn AD: Release of platelet 5-hydroxytryptamine by plasma taken from patients during and between migraine attacks. Pain 1976; 2:315-318.
5.
Kruglak L, Nathan I, Korczyn AD, Berginer V, and Dvilansky A: Platelet aggregability, disaggregability and serotonin uptake in migraine. Cephalalgia 1984; 4:221-225.
6.
Fanchamps A: Pharmacodynamic principles and anti-migraine therapy. Headache 1975; 15:79-90.
7.
Tomlinson RV, Ringold H, Quereshi MC, and Forchielli E: Relationship between inhibition of prostaglandin synthesis and drug efficacy: support for the current theory on mode of action of aspirin-like drugs. Biochem Biophys Res Comm 1972; 45:552-559.
8.
Nadell J, Bruno J, Varady J, Segre EJ: Effect of naproxen and of aspirin on bleeding time and platelet aggregation. J Clin Pharmacol 1974; 14:176-182.
9.
Lindegaard KF, Ovrelid L, and Sjaastad O: Naproxen in the prevention of migraine attacks. A double-blind placebo-controlled cross-over study. Headache 1980; 20:96-98.
10.
Welch KMA, Ellis DJ, Keenan PA: Successful migraine phophylaxis with Naproxen sodium. Neurology 1985: 35:1304-1310.
11.
Ziegler DK, and Ellis DJ: Naproxen in prophylaxis of migraine. Arch Neurol 1985; 42:582-584.
12.
Johnson ES, Ratcliffe DM, and Wilkinson M: Naproxen sodium in the treatment of migraine. Cephalalgia 1985; 5:5-10.
13.
Nestvold K, Kloster R, Partinen M, and Sulkava R: Treatment of acute migraine attack: Naproxen and placebo compared. Cephalalgia 1985; 5:115-119.
14.
Pradalier A, Rancurel G, Dordain G, Verdure L, Rascol A, and Dry J: Acute migraine attack therapy: comparison of Naproxen sodium and an ergotamine tartrate compound. Cephalalgia 1985; 5:107-113.
15.
Ad Hoc Committee on Classification of Headache: Classification of headache. JAMA 1962; 179:717-718.
16.
Rall TW, Schleifer LS: Oxytocin, prostaglandins, ergot alkaloids, and other drugs; tocolytic agents. In: Goodman Gilman A, Goodman LS, Rail TW, Murad F (eds). The Pharmacological Basis of Therapeutics, seventh edition. New York: Macmillan Publishing Co., 1985:926-945.
