Naproxen Sodium in Menstrual Migraine Prophylaxis: A Double-Blind Placebo Controlled Study
G. Sances, E. Martignoni, L. Fioroni,* F. Blandini, F. Facchinetti* and G. Nappi
University Centre for Headache and Adaptive Disorders: Units of Pavia and Modena.* IRCCS "C. Mondino" Foundation, University of Pavia Italy.
Reprint requests to: Dr. Grazia Sances, Dept. of Neurology III, IRCCS "C. Mondino," Via Palestro, 3 27100 Pavia, Italy. Accepted for Publication: September 30, 1990. SYNOPSIS
In this study, the efficacy of Naproxen sodium (Nxs) in the prophylaxis of Menstrual Migraine (MM) was tested, versus Placebo (PL). Forty women suffering from MM were admitted to a double-blind treatment protocol with Nxs 550 mg twice each day by mouth or Placebo (PL), for 3 months; in the next 3 months all the women were treated with the active drug in an open study. The headache intensity and duration, as well as the number of days of headache and the analgesic consumption, were significantly reduced with Nxs compared to PL. The efficacy of Nxs, shown also in improving premenstrual pain, and its good tolerability, support the use of this drug in the prophylactic therapy of MM. Key words: menstrual migraine, prophylaxis, naproxen, NSAID. (Headache 30:705-709, 1990) INTRODUCTION
Naproxen sodium (Nxs) is a nonsteroidal drug with anti-inflammatory (NSAID) and analgesic effects. The most important action of Nxs is its inhibition of prostaglandin synthesis by reversible binding to cyclooxygenase,1 the first enzyme in the arachidonic acid cascade of prostaglandin synthesis. Prostaglandins (PG), particularly PGE, may be linked to the pathophysiology of migraine in several important ways,2 playing a prominent role in producing sterile inflammation following vasodilatation,3 which by itself is painless. More than 20 years ago Bergstrom and coworkers4 showed that an intravenous infusion of PGE1 could trigger migraine-like attacks in healthy volunteers. PGE1 causes dilatation of the external carotid arteries, whereas PGF2 induces intracerebral vasoconstriction. Several studies have also shown that platelets from some migraine patients aggregate more readily than those from normals.5 If platelet activation is at all involved in migraine, it may be through an occlusion of the brain microvasculature and a release of prostaglandins or secretory substances in the brain.7 A prostaglandin hypothesis for menstrual migraine has been proposed on the basis of a different sensitivity of platelet aggregation in response to prostacyclin and thromboxane.8 In recent years Nxs has been widely used in the treatment of acute migraine attacks9,10,11 and for the prophylactic therapy of migraine12,13,14,15,16 based upon the antiprostaglandin and platelet antiaggregant properties of NSAI drugs. Naproxen is a propionic acid derivative (d-rotated isomer of 2-6-methoxy-2'-napthyl-propionic acid); its sodium salt shows, when compared with similar drugs, some pharmacokinetic differences. On the average, Nxs reaches therapeutically effective serum concentrations after 20 to 30 minutes,17 and the maximum serum concentration is obtained 2 hours following oral administration.17 It is quickly dissolved in the gastric juice and is therefore absorbed more rapidly.17 The mean time for peak plasma levels of Naproxen is less than one hour and its biological half-life is 12-15 hours; the steady state is reached within 2 to 3 days.17 In the present study we evaluated the effectiveness and safety of Nxs compared with placebo (PL) in 40 women affected by menstrual migraine (MM), which is a form of periodical headache that, as is well known, often fails to improve with usual prophylactic treatments.18 SUBJECTS AND METHODS
Forty women aged between 19 and 45 (M±SD: 37.7±6.9) years were included in the study. They fulfilled the criteria established for "migraine without aura" by the Headache Classification Committee of the International Headache Society.19 They had shown a menstrually-related periodicity of migraine for 2 to 30 years, with headaches at every cycle. The MM attacks, lasting from 1 to 4 days, worsened their family relationships and interfered with their working activity. All the women had regular attacks the week before, or during, the menses, sometimes during ovulation, and were headache-free for the rest of the cycle. They had regular cycles between 23 and 31 days. All of them were free from endocrinological, metabolic or other organic abnormalities; none of the women had
undertaken any prophylactic treatment for migraine or taken oral contraceptives during the previous 6 months. After a 2-month observation period (run-in), a 3-month double-blind treatment with Nxs 550 mg twice per day by mouth (Primeral, Masterpharma, Italy) or PL (indistinguishable tablets) was performed (phase 1). The treatment lasted from the 7th day before the expected menses through the 6th day of the menstrual flow, for 3 cycles. In the following 3 cycles all the women wore treated with the active drug in an open study (phase 2). Intensity and duration of migraine attacks and analgesic consumption were evaluated over all the months of the study. Headache severity was calculated by the Pain Total Index (PTI)20 calculated from a daily diary filled in by the patients during the premenstrual and menstrual period; this index was calculated taking into account the number of attacks (N), their duration in hours (H) and their severity (s) (1 =mild; 2=moderate; 3=severe) [PTI= N+(H x S)]. The number of analgesics taken during each attack was also considered. We labeled as "Responders" (R) to the treatment those patients whose PTI was reduced by at least 50% as compared with the basal period. The daily diary included also the self-administered Menstrual Distress Questionnaire (MDQ) by Moos,21 in order to evaluate the premenstrual symptomatology.22 The 17-b-estradiol (52), progesterone (Pg) and prolactin (PRL) levels were determined during the follicular (7th to 9th) and late luteal (-2,-5 days) phases of the cycle in the 2nd month of the run-in period and in the 3rd and 6th months of the treatment to exclude anovulatory cycles and/or other cycle disturbances. The plasma 52, Pg and PRL assay was performed by RIA with commercially available materials supplied by RADIM (Rome, Italy). Informed consent was obtained from each patient. STATISTICAL ANALYSIS
The results were evaluated using the Student's t test for unpaired data, the coefficent correlation, the Wilcoxon signed-ranks nonparametric test, the chi-square test and one-way ANOVA. RESULTS
Thirty-five women completed the study; 18 received naproxen sodium (NXs group) for 6 months and 17 received placebo for 3 months and naproxen sodium for the remaining 3 months (PL group). Five patients dropped out in the first cycle of the study: 3 due to reasons unrelated to the treatment and 2 due to severe gastralgia and nausea. The two groups were comparable by age (NXs: 35.5±6.1; PL: 32.6±5.7) and history of disease. Migraine attack features were similar in both groups. E2, Pg and PRL values were normal for all patients in each cycle in which they were tested (Table 1 ). The percentage of response to the treatment did not significantly differ between Nxs and PL groups in phase 1, although it was higher in NXs group during the 2nd and 3rd month (1st month: Nxs=27.8 vs PL=41.1; 2nd month: 33.3 vs 11.8; 3rd month: 33.3 vs 5.9). During phase 2 this percentage became almost equal in the two groups (4th month: 50 vs 64.8; 5th month: 61 vs 64.8; 6th month: 66.6 vs 58.8). Moreover in the Nxs group, 3 (16.7%) patients in the 1st month and 6 (33%) in the 2nd and 3rd month reported absence of migraine, whereas none of the patients were headache-free in the PL group. An improvement over 50% was reached only after 3 months of treatment in both the groups. With regard to PTI (Pain Total Index)changes table 2), in the NXF group PTI showed a significant Table 1 Plasma E2, Pg and PRL levels (M±S D) in the two phases of the cycle. E2 Pg PRL
Follicular phase 69±28.5 pg/ml (range: 49-101 ) 1.3±1.9 ng/ml (range: 0.2-2.4) 178±79.5 ulU/ml (range: 90-210)
Luteal phase 105±70.3 pg/ml (range: 69-203) 15.4±9 ng/ml (range: 6.4-25) 150±72 ulU/ml (range: 72-195)
Table 2 PTI variations: comparison with basal values (Wilcoxon signed-ranks).
months Naproxen sd. mean SD median range P< Placebo mean SD median range p
G. Sances, E. Martignoni, L. Fioroni,* F. Blandini, F. Facchinetti* and G. Nappi
University Centre for Headache and Adaptive Disorders: Units of Pavia and Modena.* IRCCS "C. Mondino" Foundation, University of Pavia Italy.
Reprint requests to: Dr. Grazia Sances, Dept. of Neurology III, IRCCS "C. Mondino," Via Palestro, 3 27100 Pavia, Italy. Accepted for Publication: September 30, 1990. SYNOPSIS
In this study, the efficacy of Naproxen sodium (Nxs) in the prophylaxis of Menstrual Migraine (MM) was tested, versus Placebo (PL). Forty women suffering from MM were admitted to a double-blind treatment protocol with Nxs 550 mg twice each day by mouth or Placebo (PL), for 3 months; in the next 3 months all the women were treated with the active drug in an open study. The headache intensity and duration, as well as the number of days of headache and the analgesic consumption, were significantly reduced with Nxs compared to PL. The efficacy of Nxs, shown also in improving premenstrual pain, and its good tolerability, support the use of this drug in the prophylactic therapy of MM. Key words: menstrual migraine, prophylaxis, naproxen, NSAID. (Headache 30:705-709, 1990) INTRODUCTION
Naproxen sodium (Nxs) is a nonsteroidal drug with anti-inflammatory (NSAID) and analgesic effects. The most important action of Nxs is its inhibition of prostaglandin synthesis by reversible binding to cyclooxygenase,1 the first enzyme in the arachidonic acid cascade of prostaglandin synthesis. Prostaglandins (PG), particularly PGE, may be linked to the pathophysiology of migraine in several important ways,2 playing a prominent role in producing sterile inflammation following vasodilatation,3 which by itself is painless. More than 20 years ago Bergstrom and coworkers4 showed that an intravenous infusion of PGE1 could trigger migraine-like attacks in healthy volunteers. PGE1 causes dilatation of the external carotid arteries, whereas PGF2 induces intracerebral vasoconstriction. Several studies have also shown that platelets from some migraine patients aggregate more readily than those from normals.5 If platelet activation is at all involved in migraine, it may be through an occlusion of the brain microvasculature and a release of prostaglandins or secretory substances in the brain.7 A prostaglandin hypothesis for menstrual migraine has been proposed on the basis of a different sensitivity of platelet aggregation in response to prostacyclin and thromboxane.8 In recent years Nxs has been widely used in the treatment of acute migraine attacks9,10,11 and for the prophylactic therapy of migraine12,13,14,15,16 based upon the antiprostaglandin and platelet antiaggregant properties of NSAI drugs. Naproxen is a propionic acid derivative (d-rotated isomer of 2-6-methoxy-2'-napthyl-propionic acid); its sodium salt shows, when compared with similar drugs, some pharmacokinetic differences. On the average, Nxs reaches therapeutically effective serum concentrations after 20 to 30 minutes,17 and the maximum serum concentration is obtained 2 hours following oral administration.17 It is quickly dissolved in the gastric juice and is therefore absorbed more rapidly.17 The mean time for peak plasma levels of Naproxen is less than one hour and its biological half-life is 12-15 hours; the steady state is reached within 2 to 3 days.17 In the present study we evaluated the effectiveness and safety of Nxs compared with placebo (PL) in 40 women affected by menstrual migraine (MM), which is a form of periodical headache that, as is well known, often fails to improve with usual prophylactic treatments.18 SUBJECTS AND METHODS
Forty women aged between 19 and 45 (M±SD: 37.7±6.9) years were included in the study. They fulfilled the criteria established for "migraine without aura" by the Headache Classification Committee of the International Headache Society.19 They had shown a menstrually-related periodicity of migraine for 2 to 30 years, with headaches at every cycle. The MM attacks, lasting from 1 to 4 days, worsened their family relationships and interfered with their working activity. All the women had regular attacks the week before, or during, the menses, sometimes during ovulation, and were headache-free for the rest of the cycle. They had regular cycles between 23 and 31 days. All of them were free from endocrinological, metabolic or other organic abnormalities; none of the women had
undertaken any prophylactic treatment for migraine or taken oral contraceptives during the previous 6 months. After a 2-month observation period (run-in), a 3-month double-blind treatment with Nxs 550 mg twice per day by mouth (Primeral, Masterpharma, Italy) or PL (indistinguishable tablets) was performed (phase 1). The treatment lasted from the 7th day before the expected menses through the 6th day of the menstrual flow, for 3 cycles. In the following 3 cycles all the women wore treated with the active drug in an open study (phase 2). Intensity and duration of migraine attacks and analgesic consumption were evaluated over all the months of the study. Headache severity was calculated by the Pain Total Index (PTI)20 calculated from a daily diary filled in by the patients during the premenstrual and menstrual period; this index was calculated taking into account the number of attacks (N), their duration in hours (H) and their severity (s) (1 =mild; 2=moderate; 3=severe) [PTI= N+(H x S)]. The number of analgesics taken during each attack was also considered. We labeled as "Responders" (R) to the treatment those patients whose PTI was reduced by at least 50% as compared with the basal period. The daily diary included also the self-administered Menstrual Distress Questionnaire (MDQ) by Moos,21 in order to evaluate the premenstrual symptomatology.22 The 17-b-estradiol (52), progesterone (Pg) and prolactin (PRL) levels were determined during the follicular (7th to 9th) and late luteal (-2,-5 days) phases of the cycle in the 2nd month of the run-in period and in the 3rd and 6th months of the treatment to exclude anovulatory cycles and/or other cycle disturbances. The plasma 52, Pg and PRL assay was performed by RIA with commercially available materials supplied by RADIM (Rome, Italy). Informed consent was obtained from each patient. STATISTICAL ANALYSIS
The results were evaluated using the Student's t test for unpaired data, the coefficent correlation, the Wilcoxon signed-ranks nonparametric test, the chi-square test and one-way ANOVA. RESULTS
Thirty-five women completed the study; 18 received naproxen sodium (NXs group) for 6 months and 17 received placebo for 3 months and naproxen sodium for the remaining 3 months (PL group). Five patients dropped out in the first cycle of the study: 3 due to reasons unrelated to the treatment and 2 due to severe gastralgia and nausea. The two groups were comparable by age (NXs: 35.5±6.1; PL: 32.6±5.7) and history of disease. Migraine attack features were similar in both groups. E2, Pg and PRL values were normal for all patients in each cycle in which they were tested (Table 1 ). The percentage of response to the treatment did not significantly differ between Nxs and PL groups in phase 1, although it was higher in NXs group during the 2nd and 3rd month (1st month: Nxs=27.8 vs PL=41.1; 2nd month: 33.3 vs 11.8; 3rd month: 33.3 vs 5.9). During phase 2 this percentage became almost equal in the two groups (4th month: 50 vs 64.8; 5th month: 61 vs 64.8; 6th month: 66.6 vs 58.8). Moreover in the Nxs group, 3 (16.7%) patients in the 1st month and 6 (33%) in the 2nd and 3rd month reported absence of migraine, whereas none of the patients were headache-free in the PL group. An improvement over 50% was reached only after 3 months of treatment in both the groups. With regard to PTI (Pain Total Index)changes table 2), in the NXF group PTI showed a significant Table 1 Plasma E2, Pg and PRL levels (M±S D) in the two phases of the cycle. E2 Pg PRL
Follicular phase 69±28.5 pg/ml (range: 49-101 ) 1.3±1.9 ng/ml (range: 0.2-2.4) 178±79.5 ulU/ml (range: 90-210)
Luteal phase 105±70.3 pg/ml (range: 69-203) 15.4±9 ng/ml (range: 6.4-25) 150±72 ulU/ml (range: 72-195)
Table 2 PTI variations: comparison with basal values (Wilcoxon signed-ranks).
months Naproxen sd. mean SD median range P< Placebo mean SD median range p
