A Comparative Study of Naproxen Sodium, Pizotyline and Placebo in Migraine Prophylaxis
André J. Bellavance, M.D., Ph.D.,1 and Jacques R Meloche, M.D.2 1Service
de Neurologie, Hôpital Charles-LeMoyne, Greenfield Park, Québec, Canada.
2Département
de Neurologie, Hôpital du Sacré-Coeur, Montréal, Québec, Canada.
Reprint requests to: Dr. André Bellavance, Service de Neurologie, Hôpital Charles-LeMoyne, 121, Boulevard Taschereau, Greenfield Park, Québec, J4V 2H1, Canada. Accepted for Publication: September 30, 1990. SYNOPSIS
318 patients satisfying the Ad Hoc Committee's criteria for common or classical migraine were entered into an 8 week single-blind placebo recording phase to establish, by diary cards, the frequency and severity of their attacks. 176 patients completed this and had records indicating 4-8 episodes in the 8 week period, with sufficient severity to reduce activity and/or work; these patients wore randomized by a predetermined code, into three double-blinded groups: naproxen sodium 550 mg bid (60 patients), pizotyline 0.5 mg tid (59 patients), or placebo (57 patients). The patients wore followed at monthly intervals for 12 weeks, with 25 dropping out (3 on naproxen sodium, and 2 each on pizotyline and placebo because of "side effects;" the remaining 18 because of noncompliance or reasons unrelated to therapy). Approximately 25% of patients in each of the 3 groups complained of side effects. Statistical analysis showed that both naproxen sodium and pizotyline were better than placebo, and of overall equivalent (i.e. equal) efficacy in the prophylaxis of migraine. In some respects, naproxen sodium was slightly more effective than pizotyline in the first month of treatment. (Headache 30:710-715, 1990) INTRODUCTION
Migraine is probably the most infamous of headaches, occurring in an estimated 9% of men and 16% of women.1 Migraine headache is defined as a familial disorder characterized by recurrent attacks of headache widely variable in intensity, frequency and duration. Attacks are commonly unilateral in onset, often associated with anorexia, nausea and vomiting. In some cases, they are preceded by or associated with neurological and mood disturbances.2 The etiology of migraine is complex, involving both vascular and neuronal mechanisms. Research has shown that platelets aggregate more readily in migraineurs than in normal subjects,3-7 releasing substances such as adenosine diphosphate, serotonin and prostaglandins8-9 which are thought to be related to some migraine symptoms. Indeed, in 1968, it was reported that intravenous infusions of prostaglandin E1 (PGE1), and later the more potent analogue PG1 (prostacyclin) produced symptoms akin to migraine10-12 with hyperalgesia lasting for several hours. Arterial infusion of PGE1 in monkeys caused an increase in extracranial blood flow and decreased intracranial flow13 changes similar to those seen during acute migraine episodes.14 Naproxen sodium is a potent nonsteroidal, anti-inflammatory and analgesic agent15 which inhibits protaglandin synthesis16 and platelet aggregation.17 Recent studies have shown naproxen and naproxen sodium to be effective in the prophylaxis and treatment of migraine.18-25 Pizotyline is a serotonin and histamine antagonist with sedative and weak anticholinergic effects, indicated for the prophylactic management of vascular headaches. It has been shown to be effective in the prophylactic treatment of migraine.26-34 The objective of the present study was to compare the efficacy and side effects of naproxen sodium with those of pizotyline and placebo in the prophylactic management of common or classical migraine. PATIENTS AND METHODS
Patient Population. Eligible subjects were outpatients having at least a one-year history of common or classical migraine as defined by the Ad Hoc Committee on Classification of Headache.2 Patients of either sex, ranging in age from 18 to 45 years were eligible for inclusion in the study. Informed consent was obtained after explanation of the nature and purpose of the trial in non-medical terms. At the time of selection, the following exclusion criteria applied: • • •
Other types of headache (e.g. cluster headache, ophthalmoplegic or hemiplegic migraine). Treatment of migraine with prophylactic agents in the two months preceding the trial. Major mental disorders or impairment of hepatic, renal, hematopoietic or cardiovascular systems (i.e.
coronary or peripheral vascular occlusive disease or severe hypertension). • Chronic therapy with analgesics, nonsteroidal anti-inflammatory drugs, anticholinergics, oral contraceptives, anticoagulants, systemic alpha and beta adrenergic agonists or antagonists, vasodilators, antidepressants, psychotropics, serotonin antagonists and/or anticonvulsants. • History of gastrointestinal disorders, including dyspepsia, pyloroduodenal obstruction, ulcers, gastrointestinal bleeding, or active inflammatory disease of the gastrointestinal tract. • Known hypersensitivity to any nonsteroidal, anti-inflammatory drug (including aspirin), or pizotyline. • Females who were lactating, pregnant, or intending to become pregnant during the study. Study Plan. Patients satisfying the entry criteria entered an 8-week single-blind placebo lead-in screening phase to establish the frequency and severity of their migraine attacks. They had a physical examination at their baseline visit and information concerning their medical history and migraine history, including the incidence and severity of migraine, was recorded. They were provided with a supply of placebo tablets and instructed to record on diary cards the time of onset, intensity (slight, moderate, severe) and duration of the attack, the degree of disability during each episode and rescue medications taken. Patients were seen at the end of week 4 and week 8 and at these visits handed in their completed diary cards and provided information on the incidence of side effects and gave a subjective rating of the overall effect of the treatment. The ratings were: complete relief, much relief, some relief, no change or worse. Patients' weights were recorded at each follow-up visit. Patients who had experienced 4-8 episodes or attacks of migraine, whose severity caused a reduction in activity or capacity to work in the preceding 8-week single blind lead-in phase, were eligible for entry into the 12-week double-blind phase. For the purposes of the trial, an episode was defined as having a maximum duration of 24 hours. Thus, if the duration of an episode exceeded 24 hours and was for example, 36 hours, it was recorded as 2 episodes. Following entry into the double-blind phase, patients were assigned to receive, according to a predetermined randomization code, either naproxen sodium 550 mg twice daily, pizotyline 0.5 mg thrice daily, or placebo. The dose of pizotyline was initially 0.5 mg at bedtime and then gradually titrated up over 7 days to 0.5 mg thrice daily for the remainder of the study. The drugs were taken three times daily using a double placebo method. Clinical observation such as those outlined in the screening phase were repeated at each follow-up visit during the treatment phase i.e. months 1, 2 and 3. At each scheduled monthly visit, patients received in addition to their 4-week supply, a few extra days of medication to allow flexibility in scheduling follow-up visits. Concomitant Medications. Restrictions were placed on the concomitant medications allowed during the study (see Exclusion Criteria). Those medication(s) not restricted were recorded at the baseline visit. Any changes in concomitant medication(s) were recorded at monthly follow-up visits. Rescue Medications. The patient and the investigator designated one or more "rescue medications" which the patient had found to be effective for the treatment of migraine attacks. The rescue medications were either narcotic or non-narcotic analgesics, benzodiazepines, or ergotamine compounds. No other medications for migraine were allowed during the study. Statistical Analysis. General Approach. Results were considered statistically significant at p = 0.05. When multiple comparisons were made (e.g., 3 sets of pairwise comparisons for the efficacy analyses), the significance level was set at p > 0.0166 (using the Bonferroni method) to maintain a Type 1 error rate of 0.05. All comparisons between treatment groups were two-tailed. Definition of Efficacy Variables. The following six variables were used to calculate the migraine indices based on data from the two-month placebo lead-in phase and the three-month treatment phase of the study: • • • • • •
number of migraine episodes severity of each episode of migraine duration of each episode of migraine pain intensity level degree of disability amount and strength of rescue medication required
These variables were used to compute migraine indices as shown in Table 1. Other efficacy measures computed and analyzed based on information from the lead-in and double-blind phase were: average duration of headache, number of days incapacitated per week, number of migraine episodes requiring rescue medication per week, and number of vomiting episodes per week. Description of Statistical Analysis. The difference between the two lead-in months, with respect to the nine efficacy measures described above, was analyzed to determine whether the data from these two months could be pooled into a single lead-in period value. Each efficacy measure was analyzed by subtracting the month 2 lead-in value from the month 1 lead-in value and a Wilcoxon Signed Rank test was applied to the data thus obtained. The statistical null hypothesis in this analysis was that there was no difference between the two months with regard to the efficacy measures. In the event that a statistically significant result was obtained, it was concluded that patients responded differently in the two months.
Table 1 Migraine Indices • Headache Unit Index = (frequency of attacks) • Corrected Headache Unit Index = Sum of (severity x duration of each episode) number of treatment days Severity scale:
Duration scale:
number of migraine episodes number of treatment days
1 = Slight 2 = Moderate 3 = Severe 1 = < 8 hours 2 = 8-16 hours 3 = > 16 hours but < 24
•
Pain intensity rating = Sum of (intensity level x number of episodes at that level) number of migraine episodes during treatment days Intensity scale: 1 = Slight 2 = Moderate 3 = Severe • Severity of Disability Rating = Sum of (level of disability x number of episodes at that level) number of migraine episodes during treatment days Disability scale: 1 = No reduction in activity 2 = Moderate reduction in activity 3 = Unable to work/confined to bed • Rescue Medication Index = Sum of (number of doses x strength of rescue medication) number of treatment days Strength scale: 1 = Non-narcotic analgesics or benzodiazepines 2 = Narcotic analgesics 3 = Ergot compounds
Further statistical analyses involving lead-in and treatment data used pooled data from visits I and 2 during the lead-in period. The three treatment groups, naproxen sodium, pizotyline and placebo were compared at admission with respect to several demographic and disease history variables. The KruskaI-Wallis test was used for age, frequency of attacks, duration of attacks, and duration of migraine history. Sex and classification of migraine were tested by means of a chi-square test. Usual headache severity and usual activity reduction were also compared using the chi-square test. The medians of the migraine indices and the four efficacy measures were compared between the three treatment groups during the placebo lead-in period and treatment period using the KruskaI-Wallis test. For the treatment period, median values were calculated using collective data over the 3 month period. Differences in the lead-in and treatment indices were computed and analyzed using the same method. The differences were taken as lead-in minus treatment, a positive result indicating an improvement while on treatment. This analysis of the change from baseline accounted for differences among patients with respect to their symptom severity during the lead-in phase. Pairwise comparisons of treatments were made using Dunn's method which controls the Type I error rate to 0.05%. A chi-square test was used to compare the 3 treatment groups with respect to the incidence of side effects during the study. RESULTS
Patient Population. Of the 318 patients who entered the placebo lead-in phase of the study, 176 satisfied the entry criteria and were randomized to receive either naproxen sodium (sixty), pizotyline (fifty-nine), or placebo (fifty-seven). Of these, 151 completed the 12 week trial (49 naproxen sodium, 55 pizotyline and 47 placebo patients). Twenty-five patients discontinued treatment prematurely-7 dropped out due to adverse reactions, 4 were lost to follow-up, 4 were noncompliant and 10 dropped out due to reasons unrelated to therapy. Demographics. The analysis of demographics and disease history data was based on 166 analyzable patients (56 naproxen sodium, 58 pizotyline and 52 placebo). The 3 treatment groups did not differ statistically with respect to any of the variables at baseline. The majority (79%) of the patients were female and the average age of the patients was 32.5 years (range: 18-45 years). Ninety-two percent of all patients suffered from common migraine and the mean duration of their migraines was 11.9 years (range: 1-31 years). At the initial visit of the treatment period, patients reported an average of 6.7 episodes of migraine per month (range: 1-28 per month) lasting approximately 41.5 hours (range: 1-240 hours). Pain intensity (headache severity) ratings for migraines were reported as moderate or severe, in equal proportions (49% and 50% respectively). Usual reduction of activities was rated as moderate by 57% of the patients and severe by 42%. Efficacy. Single-blind Placebo Period. The results of the migraine indices and efficacy measures during the first month of the placebo lead-in phase were compared with those of the second month. There was a statistically significant difference (p = 0.05) between the two lead-in months for the headache unit index only. The index was higher in the first lead-in month than in the second, the median difference between the two periods being 0.02. There were no statistically significant differences in the pooled migraine indices between the study groups for any of the other efficacy outcome measures. Double Blind Treatment Period. Comparisons of the different efficacy indices during the lead-in and treatment periods are shown in Tables 2 and 3. Naproxen sodium was statistically superior to placebo in 8 of the 9 efficacy variables as pizotyline was statistically superior to placebo in 3 of the 9 efficacy indices. During each of the 3 months of the treatment phase, naproxen sodium was statistically superior to placebo in decreasing the headaches unit index, corrected headache unit index and reducing rescue
Table 2 Mean Migraine Indices During Placebo Lead-in and Treatment Periods Naproxen Sodium Pizotyline Lead-in Rx Lead-in Rx 1. Headache unit index, #/week 1.58 0.92* 1.53 0.98* 2. Corrected headache unit index, #/week 5.31 2.85* 5.77 3.27 3. Pain intensity rating 2.02 1.64 1.97 1.80 4. Severity of disability rating 1.89 1.58 1.86 1.67 5. Rescue medication index 5.22 2.89* 4.68 3.20 6. Average duration of headache 1.66 1.35 1.67 1.59 7. Days incapacitated, #/week 0.31 0.18* 0.24 0.18 8. Migraines requiring rescue medication, #/week 1.21 0.73* 1.16 0.82 9. Vomiting episodes #/week 0.18 0.25 0.17 0.08 *Indicates change from baseline relative to placebo was statistically significant (p < 0.0166) using the KruskaI-Wallis test.
Placebo Lead-in Rx 1.64 5.56 1.98 1.90 5.83 1.58 0.31 1.47 0.21
1.46 5.08 1.86 1.77 5.10 1.55 0.34 1.26 0.48
Table 3 Summary of Efficacy Outcome
Parameters • Headache unit index • Corrected headache unit index • Pain intensity • Severity of disability • Rescue medication • Average duration of headache • Days incapacitated • Migraines requiring rescue medication • Vomiting episodes
Naproxen Sodium Better then Placebo mth 1,2,3 mth 1,2,3
Pizotyline Better than Placebo mth 1,3 mth 2
Naproxen Sodium Better than Pizotyline ns ns
mth 1 mth 1 mth 1,2,3 mth 1
ns ns ns ns
ns ns mth 1 mth 1
mth 1,2 mth 1,3
mth 1 ns
ns mth 1
ns
ns
ns
ns = not significant for months 1, 2 and 3. medications consumed. As a measure of efficacy, the corrected headache unit index is preferred to the headache unit index as the former includes both the severity and duration of each episode in addition to the number of migraine episodes reported. Patients receiving naproxen sodium experienced fewer and less severe migraine episodes per week (mean 2.85, median 2.00) than those on placebo (mean 5.08, median 3.45). Besides patients on naproxen sodium consumed fewer rescue medications for relief of pain during migraine attacks than those on placebo. Naproxen sodium was also superior to pizotyline during the first month of treatment phase with respect to this parameter. Naproxen sodium was statistically better than placebo in decreasing the number of migraines requiring rescue medications during months 1 and 3 of the treatment phases and this trend was maintained during month 2. Mean values during the treatment period of naproxen sodium and placebo were 0.73 and 1.26 while the medians were 0.52 and 1.09 respectively. During the first month of treatment naproxen sodium was also statistically superior to pizotyline in this efficacy parameter. Patients on naproxen sodium were incapacitated for fewer number of days per week (mean 0.18, median 0.08) than those on placebo (mean 0.34, median 0.24) during the first two months of treatment. Thus naproxen sodium patients missed fewer days of work or were not confined to bed at home as often as the placebo patients. Pizotyline showed a similar effect as naproxen sodium for this efficacy parameter. In other efficacy outcomes such as pain intensity, severity of disability and average duration of headache, naproxen sodium was statistically better than placebo at the end of month 1 only. Although the severity of the worst headache was not significantly altered by the treatments in this study, 27% of the patients from the naproxen group had become migraine free by the end of the trial, compared to 15% and 4% in the pizotyline and placebo groups, respectively. Pizotyline was statistically superior to placebo in 3 efficacy variables, the headache unit index (month 1 and 3, corrected headache unit index (month 2) and the number of days incapacitated (month 1 ). Naproxen sodium was statistically more effective than pizotyline during the first month of the treatment period with respect to 3 parameters. Patients on naproxen sodium reported shorter migraine episodes, fewer migraines requiring rescue medications and consumed less rescue medications relative to those on pizotyline. Patients' and investigators' overall evaluations of study treatment, as well as treatment comparisons, showed that the patients on the active treatments gave better ratings compared to those on placebo. Good, or excellent, ratings were reported by 69% of naproxen sodium-treated patients, 68% of pizotyline-treated patients and 36% of placebo-treated patients. Similar results were obtained with investigator ratings. Sixty-two percent of investigators rated naproxen sodium-treated patients' response to treatment as being either good or excellent, as compared to 57% and 32% for pizotyline and placebo-treated patients respectively. Comparison of treatment groups
showed naproxen sodium to be statistically superior to placebo at p < 0.001 for both patient and investigator ratings. Pizotyline was also significantly superior to placebo at p = 0.002 and p = 0.005 respectively for patients and investigators ratings. There were no significant differences in overall evaluations between naproxen sodium- and pizotyline-treated patients. Incidence of Side Effects. Side effects reported by patients were generally of mild or moderate intensity. Most did not require treatment. Fifteen of the 58 patients (26%) on naproxen sodium, had at least one complaint, in comparison to 16 patients (28%, N = 58) on pizotyline, and 11 patients (28%, N = 56) on placebo. There were no significant differences between the treatment groups (p = 0.59). Naproxen sodium treated patients complained mostly of gastro-intestinal side effects (13.7%), one patient dropping out because he presented a peptic ulcer, a rather severe but fortunately rare complication. The pizotyline treated patients complained also mostly of gastro-intestinal side effects (12%) in about the same proportion as the Naproxen sodium treated group. The incidence of complaints during the treatment period is summarized in Table 4. At the end of the lead-in phase, no significant differences in body weights between the three treatments were reported. At the end of the treatment phase, however, patients in the pizotyline group had gained an average of 2.72 kg, compared to 0.32 and 0.23 kg for patients in the naproxen sodium and placebo groups, respectively. The differences between pizotyline and the two other groups were statistically significant at p < 0.0001. The difference in patients' body weight in naproxen sodium and placebo groups at the end of the study was not significant. One patient treated with pizotyline dropped out of the study because of weight gain.
• • • • •
Table 4 Number (Percentage) of Patients Reporting Side Effects During Treatment Period Naproxen Sodium Pizotyline Placebo N=58 N=58 N=56 Gastrointestinal 8 (13.7%) 7 (12%) 3 (5.3%) CNS 4 (6.9%) 4 (6.9%) 5 (8.9%) Skin 2 (3.4%) 0 1 (1.7%) Weight gain 0 6 (10.3%) 1 (1.7%) Other 4 (6.9%) 2 (3.4%) 4 (7.1%)
Premature Terminations. During the treatment phase of the study, a total of 7 patients discontinued the study due to side effects-3 on naproxen sodium, and 2 each on pizotyline and placebo. The complaints that led to premature terminations were gastric ulcer (1) and epigastric burning (2) in the naproxen sodium group: weight gain (1) and sleepiness (1) in the pizotyline group and hematoma and epigastric pain (1) and parasthesia (1) in the placebo group. DISCUSSION AND CONCLUSIONS
Previous studies have shown both naproxen sodium and naproxen to be effective in the active and prophylactic treatment of migraine.18,19,21,23,24,25 Naproxen sodium has compared favourably in these studies to placebo as well as with established medications, such as propanolol, ergotamine and pizotyline.22 The results of this study show that naproxen sodium 500 mg twice daily and pizotyline 0.5 mg three times daily are both effective about equally in the prophylactic treatment of common and classical migraine. Naproxen sodium is however slightly more effective than pizotyline during the first month of treatment, in reducing the amount of rescue medication consumed to alleviate an attack, in reducing the average duration of an attack and in reducing the number of migraines requiring rescue medication. Overall evaluations of study treatments by both the patients and the investigators in this study, showed both naproxen sodium and pizotyline to be superior to placebo. A discriminative analysis of the efficacy of the study treatments in common and classical migraine was not possible given the low percentage of patients (8%) with classical migraine. Naproxen sodium was well tolerated and safe, producing no more side effects than patients receiving pizotyline 0.5 mg three times daily or placebo. The side effects reported were generally mild, the incidence of gastrointestinal effects being similar in both the naproxen sodium- and pizotyline-treated groups. However, one patient on naproxen sodium presented a peptic ulcer, a rare but nonetheless significant complication. Based on the results of this study, we believe that naproxen sodium should be considered an alternative prophylactic agent in the therapy of migraine along with agents such as beta blockers, calcium antagonists and pizotyline. It can be of particular benefit in migraine patients with asthma where beta blockers may be contraindicated and in those patients where weight gain can be a problem, providing there is no gastric intolerance. Naproxen sodium, given its anti-inflammatory effects could also be useful in alleviating headache of musculoskeletal origin, which could account for its superiority over pizotyline during the first month of treatment. Acknowledgements. The authors wish to thank Drs. Michel Duplessis, Svetlana Ninkovic, Robert Filiatrault and Antonio Trottier for their assistance with the conduct of the study, Ms. Marie Hu for statistical analyses, and Mrs. Louise Bergeron for technical assistance. REFERENCES
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Nadell J, Bruno J, Varady J, Segre E J: Effect of naproxen and of aspirin on bleeding time and platelet aggregation. J Clin Pharmacol 14:176-182, 1974.
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Sargent J, Solbach P, Damasio H, Baumel B, Corbett J, Eisner L, Jessen B, Kudrow L, Mathew N, Medina J, et al: A comparison of naproxen sodium to propranolol hydrochloride and a placebo control for the prophylaxis of migraine headache. Headache 25:320-324, 1985.
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André J. Bellavance, M.D., Ph.D.,1 and Jacques R Meloche, M.D.2 1Service
de Neurologie, Hôpital Charles-LeMoyne, Greenfield Park, Québec, Canada.
2Département
de Neurologie, Hôpital du Sacré-Coeur, Montréal, Québec, Canada.
Reprint requests to: Dr. André Bellavance, Service de Neurologie, Hôpital Charles-LeMoyne, 121, Boulevard Taschereau, Greenfield Park, Québec, J4V 2H1, Canada. Accepted for Publication: September 30, 1990. SYNOPSIS
318 patients satisfying the Ad Hoc Committee's criteria for common or classical migraine were entered into an 8 week single-blind placebo recording phase to establish, by diary cards, the frequency and severity of their attacks. 176 patients completed this and had records indicating 4-8 episodes in the 8 week period, with sufficient severity to reduce activity and/or work; these patients wore randomized by a predetermined code, into three double-blinded groups: naproxen sodium 550 mg bid (60 patients), pizotyline 0.5 mg tid (59 patients), or placebo (57 patients). The patients wore followed at monthly intervals for 12 weeks, with 25 dropping out (3 on naproxen sodium, and 2 each on pizotyline and placebo because of "side effects;" the remaining 18 because of noncompliance or reasons unrelated to therapy). Approximately 25% of patients in each of the 3 groups complained of side effects. Statistical analysis showed that both naproxen sodium and pizotyline were better than placebo, and of overall equivalent (i.e. equal) efficacy in the prophylaxis of migraine. In some respects, naproxen sodium was slightly more effective than pizotyline in the first month of treatment. (Headache 30:710-715, 1990) INTRODUCTION
Migraine is probably the most infamous of headaches, occurring in an estimated 9% of men and 16% of women.1 Migraine headache is defined as a familial disorder characterized by recurrent attacks of headache widely variable in intensity, frequency and duration. Attacks are commonly unilateral in onset, often associated with anorexia, nausea and vomiting. In some cases, they are preceded by or associated with neurological and mood disturbances.2 The etiology of migraine is complex, involving both vascular and neuronal mechanisms. Research has shown that platelets aggregate more readily in migraineurs than in normal subjects,3-7 releasing substances such as adenosine diphosphate, serotonin and prostaglandins8-9 which are thought to be related to some migraine symptoms. Indeed, in 1968, it was reported that intravenous infusions of prostaglandin E1 (PGE1), and later the more potent analogue PG1 (prostacyclin) produced symptoms akin to migraine10-12 with hyperalgesia lasting for several hours. Arterial infusion of PGE1 in monkeys caused an increase in extracranial blood flow and decreased intracranial flow13 changes similar to those seen during acute migraine episodes.14 Naproxen sodium is a potent nonsteroidal, anti-inflammatory and analgesic agent15 which inhibits protaglandin synthesis16 and platelet aggregation.17 Recent studies have shown naproxen and naproxen sodium to be effective in the prophylaxis and treatment of migraine.18-25 Pizotyline is a serotonin and histamine antagonist with sedative and weak anticholinergic effects, indicated for the prophylactic management of vascular headaches. It has been shown to be effective in the prophylactic treatment of migraine.26-34 The objective of the present study was to compare the efficacy and side effects of naproxen sodium with those of pizotyline and placebo in the prophylactic management of common or classical migraine. PATIENTS AND METHODS
Patient Population. Eligible subjects were outpatients having at least a one-year history of common or classical migraine as defined by the Ad Hoc Committee on Classification of Headache.2 Patients of either sex, ranging in age from 18 to 45 years were eligible for inclusion in the study. Informed consent was obtained after explanation of the nature and purpose of the trial in non-medical terms. At the time of selection, the following exclusion criteria applied: • • •
Other types of headache (e.g. cluster headache, ophthalmoplegic or hemiplegic migraine). Treatment of migraine with prophylactic agents in the two months preceding the trial. Major mental disorders or impairment of hepatic, renal, hematopoietic or cardiovascular systems (i.e.
coronary or peripheral vascular occlusive disease or severe hypertension). • Chronic therapy with analgesics, nonsteroidal anti-inflammatory drugs, anticholinergics, oral contraceptives, anticoagulants, systemic alpha and beta adrenergic agonists or antagonists, vasodilators, antidepressants, psychotropics, serotonin antagonists and/or anticonvulsants. • History of gastrointestinal disorders, including dyspepsia, pyloroduodenal obstruction, ulcers, gastrointestinal bleeding, or active inflammatory disease of the gastrointestinal tract. • Known hypersensitivity to any nonsteroidal, anti-inflammatory drug (including aspirin), or pizotyline. • Females who were lactating, pregnant, or intending to become pregnant during the study. Study Plan. Patients satisfying the entry criteria entered an 8-week single-blind placebo lead-in screening phase to establish the frequency and severity of their migraine attacks. They had a physical examination at their baseline visit and information concerning their medical history and migraine history, including the incidence and severity of migraine, was recorded. They were provided with a supply of placebo tablets and instructed to record on diary cards the time of onset, intensity (slight, moderate, severe) and duration of the attack, the degree of disability during each episode and rescue medications taken. Patients were seen at the end of week 4 and week 8 and at these visits handed in their completed diary cards and provided information on the incidence of side effects and gave a subjective rating of the overall effect of the treatment. The ratings were: complete relief, much relief, some relief, no change or worse. Patients' weights were recorded at each follow-up visit. Patients who had experienced 4-8 episodes or attacks of migraine, whose severity caused a reduction in activity or capacity to work in the preceding 8-week single blind lead-in phase, were eligible for entry into the 12-week double-blind phase. For the purposes of the trial, an episode was defined as having a maximum duration of 24 hours. Thus, if the duration of an episode exceeded 24 hours and was for example, 36 hours, it was recorded as 2 episodes. Following entry into the double-blind phase, patients were assigned to receive, according to a predetermined randomization code, either naproxen sodium 550 mg twice daily, pizotyline 0.5 mg thrice daily, or placebo. The dose of pizotyline was initially 0.5 mg at bedtime and then gradually titrated up over 7 days to 0.5 mg thrice daily for the remainder of the study. The drugs were taken three times daily using a double placebo method. Clinical observation such as those outlined in the screening phase were repeated at each follow-up visit during the treatment phase i.e. months 1, 2 and 3. At each scheduled monthly visit, patients received in addition to their 4-week supply, a few extra days of medication to allow flexibility in scheduling follow-up visits. Concomitant Medications. Restrictions were placed on the concomitant medications allowed during the study (see Exclusion Criteria). Those medication(s) not restricted were recorded at the baseline visit. Any changes in concomitant medication(s) were recorded at monthly follow-up visits. Rescue Medications. The patient and the investigator designated one or more "rescue medications" which the patient had found to be effective for the treatment of migraine attacks. The rescue medications were either narcotic or non-narcotic analgesics, benzodiazepines, or ergotamine compounds. No other medications for migraine were allowed during the study. Statistical Analysis. General Approach. Results were considered statistically significant at p = 0.05. When multiple comparisons were made (e.g., 3 sets of pairwise comparisons for the efficacy analyses), the significance level was set at p > 0.0166 (using the Bonferroni method) to maintain a Type 1 error rate of 0.05. All comparisons between treatment groups were two-tailed. Definition of Efficacy Variables. The following six variables were used to calculate the migraine indices based on data from the two-month placebo lead-in phase and the three-month treatment phase of the study: • • • • • •
number of migraine episodes severity of each episode of migraine duration of each episode of migraine pain intensity level degree of disability amount and strength of rescue medication required
These variables were used to compute migraine indices as shown in Table 1. Other efficacy measures computed and analyzed based on information from the lead-in and double-blind phase were: average duration of headache, number of days incapacitated per week, number of migraine episodes requiring rescue medication per week, and number of vomiting episodes per week. Description of Statistical Analysis. The difference between the two lead-in months, with respect to the nine efficacy measures described above, was analyzed to determine whether the data from these two months could be pooled into a single lead-in period value. Each efficacy measure was analyzed by subtracting the month 2 lead-in value from the month 1 lead-in value and a Wilcoxon Signed Rank test was applied to the data thus obtained. The statistical null hypothesis in this analysis was that there was no difference between the two months with regard to the efficacy measures. In the event that a statistically significant result was obtained, it was concluded that patients responded differently in the two months.
Table 1 Migraine Indices • Headache Unit Index = (frequency of attacks) • Corrected Headache Unit Index = Sum of (severity x duration of each episode) number of treatment days Severity scale:
Duration scale:
number of migraine episodes number of treatment days
1 = Slight 2 = Moderate 3 = Severe 1 = < 8 hours 2 = 8-16 hours 3 = > 16 hours but < 24
•
Pain intensity rating = Sum of (intensity level x number of episodes at that level) number of migraine episodes during treatment days Intensity scale: 1 = Slight 2 = Moderate 3 = Severe • Severity of Disability Rating = Sum of (level of disability x number of episodes at that level) number of migraine episodes during treatment days Disability scale: 1 = No reduction in activity 2 = Moderate reduction in activity 3 = Unable to work/confined to bed • Rescue Medication Index = Sum of (number of doses x strength of rescue medication) number of treatment days Strength scale: 1 = Non-narcotic analgesics or benzodiazepines 2 = Narcotic analgesics 3 = Ergot compounds
Further statistical analyses involving lead-in and treatment data used pooled data from visits I and 2 during the lead-in period. The three treatment groups, naproxen sodium, pizotyline and placebo were compared at admission with respect to several demographic and disease history variables. The KruskaI-Wallis test was used for age, frequency of attacks, duration of attacks, and duration of migraine history. Sex and classification of migraine were tested by means of a chi-square test. Usual headache severity and usual activity reduction were also compared using the chi-square test. The medians of the migraine indices and the four efficacy measures were compared between the three treatment groups during the placebo lead-in period and treatment period using the KruskaI-Wallis test. For the treatment period, median values were calculated using collective data over the 3 month period. Differences in the lead-in and treatment indices were computed and analyzed using the same method. The differences were taken as lead-in minus treatment, a positive result indicating an improvement while on treatment. This analysis of the change from baseline accounted for differences among patients with respect to their symptom severity during the lead-in phase. Pairwise comparisons of treatments were made using Dunn's method which controls the Type I error rate to 0.05%. A chi-square test was used to compare the 3 treatment groups with respect to the incidence of side effects during the study. RESULTS
Patient Population. Of the 318 patients who entered the placebo lead-in phase of the study, 176 satisfied the entry criteria and were randomized to receive either naproxen sodium (sixty), pizotyline (fifty-nine), or placebo (fifty-seven). Of these, 151 completed the 12 week trial (49 naproxen sodium, 55 pizotyline and 47 placebo patients). Twenty-five patients discontinued treatment prematurely-7 dropped out due to adverse reactions, 4 were lost to follow-up, 4 were noncompliant and 10 dropped out due to reasons unrelated to therapy. Demographics. The analysis of demographics and disease history data was based on 166 analyzable patients (56 naproxen sodium, 58 pizotyline and 52 placebo). The 3 treatment groups did not differ statistically with respect to any of the variables at baseline. The majority (79%) of the patients were female and the average age of the patients was 32.5 years (range: 18-45 years). Ninety-two percent of all patients suffered from common migraine and the mean duration of their migraines was 11.9 years (range: 1-31 years). At the initial visit of the treatment period, patients reported an average of 6.7 episodes of migraine per month (range: 1-28 per month) lasting approximately 41.5 hours (range: 1-240 hours). Pain intensity (headache severity) ratings for migraines were reported as moderate or severe, in equal proportions (49% and 50% respectively). Usual reduction of activities was rated as moderate by 57% of the patients and severe by 42%. Efficacy. Single-blind Placebo Period. The results of the migraine indices and efficacy measures during the first month of the placebo lead-in phase were compared with those of the second month. There was a statistically significant difference (p = 0.05) between the two lead-in months for the headache unit index only. The index was higher in the first lead-in month than in the second, the median difference between the two periods being 0.02. There were no statistically significant differences in the pooled migraine indices between the study groups for any of the other efficacy outcome measures. Double Blind Treatment Period. Comparisons of the different efficacy indices during the lead-in and treatment periods are shown in Tables 2 and 3. Naproxen sodium was statistically superior to placebo in 8 of the 9 efficacy variables as pizotyline was statistically superior to placebo in 3 of the 9 efficacy indices. During each of the 3 months of the treatment phase, naproxen sodium was statistically superior to placebo in decreasing the headaches unit index, corrected headache unit index and reducing rescue
Table 2 Mean Migraine Indices During Placebo Lead-in and Treatment Periods Naproxen Sodium Pizotyline Lead-in Rx Lead-in Rx 1. Headache unit index, #/week 1.58 0.92* 1.53 0.98* 2. Corrected headache unit index, #/week 5.31 2.85* 5.77 3.27 3. Pain intensity rating 2.02 1.64 1.97 1.80 4. Severity of disability rating 1.89 1.58 1.86 1.67 5. Rescue medication index 5.22 2.89* 4.68 3.20 6. Average duration of headache 1.66 1.35 1.67 1.59 7. Days incapacitated, #/week 0.31 0.18* 0.24 0.18 8. Migraines requiring rescue medication, #/week 1.21 0.73* 1.16 0.82 9. Vomiting episodes #/week 0.18 0.25 0.17 0.08 *Indicates change from baseline relative to placebo was statistically significant (p < 0.0166) using the KruskaI-Wallis test.
Placebo Lead-in Rx 1.64 5.56 1.98 1.90 5.83 1.58 0.31 1.47 0.21
1.46 5.08 1.86 1.77 5.10 1.55 0.34 1.26 0.48
Table 3 Summary of Efficacy Outcome
Parameters • Headache unit index • Corrected headache unit index • Pain intensity • Severity of disability • Rescue medication • Average duration of headache • Days incapacitated • Migraines requiring rescue medication • Vomiting episodes
Naproxen Sodium Better then Placebo mth 1,2,3 mth 1,2,3
Pizotyline Better than Placebo mth 1,3 mth 2
Naproxen Sodium Better than Pizotyline ns ns
mth 1 mth 1 mth 1,2,3 mth 1
ns ns ns ns
ns ns mth 1 mth 1
mth 1,2 mth 1,3
mth 1 ns
ns mth 1
ns
ns
ns
ns = not significant for months 1, 2 and 3. medications consumed. As a measure of efficacy, the corrected headache unit index is preferred to the headache unit index as the former includes both the severity and duration of each episode in addition to the number of migraine episodes reported. Patients receiving naproxen sodium experienced fewer and less severe migraine episodes per week (mean 2.85, median 2.00) than those on placebo (mean 5.08, median 3.45). Besides patients on naproxen sodium consumed fewer rescue medications for relief of pain during migraine attacks than those on placebo. Naproxen sodium was also superior to pizotyline during the first month of treatment phase with respect to this parameter. Naproxen sodium was statistically better than placebo in decreasing the number of migraines requiring rescue medications during months 1 and 3 of the treatment phases and this trend was maintained during month 2. Mean values during the treatment period of naproxen sodium and placebo were 0.73 and 1.26 while the medians were 0.52 and 1.09 respectively. During the first month of treatment naproxen sodium was also statistically superior to pizotyline in this efficacy parameter. Patients on naproxen sodium were incapacitated for fewer number of days per week (mean 0.18, median 0.08) than those on placebo (mean 0.34, median 0.24) during the first two months of treatment. Thus naproxen sodium patients missed fewer days of work or were not confined to bed at home as often as the placebo patients. Pizotyline showed a similar effect as naproxen sodium for this efficacy parameter. In other efficacy outcomes such as pain intensity, severity of disability and average duration of headache, naproxen sodium was statistically better than placebo at the end of month 1 only. Although the severity of the worst headache was not significantly altered by the treatments in this study, 27% of the patients from the naproxen group had become migraine free by the end of the trial, compared to 15% and 4% in the pizotyline and placebo groups, respectively. Pizotyline was statistically superior to placebo in 3 efficacy variables, the headache unit index (month 1 and 3, corrected headache unit index (month 2) and the number of days incapacitated (month 1 ). Naproxen sodium was statistically more effective than pizotyline during the first month of the treatment period with respect to 3 parameters. Patients on naproxen sodium reported shorter migraine episodes, fewer migraines requiring rescue medications and consumed less rescue medications relative to those on pizotyline. Patients' and investigators' overall evaluations of study treatment, as well as treatment comparisons, showed that the patients on the active treatments gave better ratings compared to those on placebo. Good, or excellent, ratings were reported by 69% of naproxen sodium-treated patients, 68% of pizotyline-treated patients and 36% of placebo-treated patients. Similar results were obtained with investigator ratings. Sixty-two percent of investigators rated naproxen sodium-treated patients' response to treatment as being either good or excellent, as compared to 57% and 32% for pizotyline and placebo-treated patients respectively. Comparison of treatment groups
showed naproxen sodium to be statistically superior to placebo at p < 0.001 for both patient and investigator ratings. Pizotyline was also significantly superior to placebo at p = 0.002 and p = 0.005 respectively for patients and investigators ratings. There were no significant differences in overall evaluations between naproxen sodium- and pizotyline-treated patients. Incidence of Side Effects. Side effects reported by patients were generally of mild or moderate intensity. Most did not require treatment. Fifteen of the 58 patients (26%) on naproxen sodium, had at least one complaint, in comparison to 16 patients (28%, N = 58) on pizotyline, and 11 patients (28%, N = 56) on placebo. There were no significant differences between the treatment groups (p = 0.59). Naproxen sodium treated patients complained mostly of gastro-intestinal side effects (13.7%), one patient dropping out because he presented a peptic ulcer, a rather severe but fortunately rare complication. The pizotyline treated patients complained also mostly of gastro-intestinal side effects (12%) in about the same proportion as the Naproxen sodium treated group. The incidence of complaints during the treatment period is summarized in Table 4. At the end of the lead-in phase, no significant differences in body weights between the three treatments were reported. At the end of the treatment phase, however, patients in the pizotyline group had gained an average of 2.72 kg, compared to 0.32 and 0.23 kg for patients in the naproxen sodium and placebo groups, respectively. The differences between pizotyline and the two other groups were statistically significant at p < 0.0001. The difference in patients' body weight in naproxen sodium and placebo groups at the end of the study was not significant. One patient treated with pizotyline dropped out of the study because of weight gain.
• • • • •
Table 4 Number (Percentage) of Patients Reporting Side Effects During Treatment Period Naproxen Sodium Pizotyline Placebo N=58 N=58 N=56 Gastrointestinal 8 (13.7%) 7 (12%) 3 (5.3%) CNS 4 (6.9%) 4 (6.9%) 5 (8.9%) Skin 2 (3.4%) 0 1 (1.7%) Weight gain 0 6 (10.3%) 1 (1.7%) Other 4 (6.9%) 2 (3.4%) 4 (7.1%)
Premature Terminations. During the treatment phase of the study, a total of 7 patients discontinued the study due to side effects-3 on naproxen sodium, and 2 each on pizotyline and placebo. The complaints that led to premature terminations were gastric ulcer (1) and epigastric burning (2) in the naproxen sodium group: weight gain (1) and sleepiness (1) in the pizotyline group and hematoma and epigastric pain (1) and parasthesia (1) in the placebo group. DISCUSSION AND CONCLUSIONS
Previous studies have shown both naproxen sodium and naproxen to be effective in the active and prophylactic treatment of migraine.18,19,21,23,24,25 Naproxen sodium has compared favourably in these studies to placebo as well as with established medications, such as propanolol, ergotamine and pizotyline.22 The results of this study show that naproxen sodium 500 mg twice daily and pizotyline 0.5 mg three times daily are both effective about equally in the prophylactic treatment of common and classical migraine. Naproxen sodium is however slightly more effective than pizotyline during the first month of treatment, in reducing the amount of rescue medication consumed to alleviate an attack, in reducing the average duration of an attack and in reducing the number of migraines requiring rescue medication. Overall evaluations of study treatments by both the patients and the investigators in this study, showed both naproxen sodium and pizotyline to be superior to placebo. A discriminative analysis of the efficacy of the study treatments in common and classical migraine was not possible given the low percentage of patients (8%) with classical migraine. Naproxen sodium was well tolerated and safe, producing no more side effects than patients receiving pizotyline 0.5 mg three times daily or placebo. The side effects reported were generally mild, the incidence of gastrointestinal effects being similar in both the naproxen sodium- and pizotyline-treated groups. However, one patient on naproxen sodium presented a peptic ulcer, a rare but nonetheless significant complication. Based on the results of this study, we believe that naproxen sodium should be considered an alternative prophylactic agent in the therapy of migraine along with agents such as beta blockers, calcium antagonists and pizotyline. It can be of particular benefit in migraine patients with asthma where beta blockers may be contraindicated and in those patients where weight gain can be a problem, providing there is no gastric intolerance. Naproxen sodium, given its anti-inflammatory effects could also be useful in alleviating headache of musculoskeletal origin, which could account for its superiority over pizotyline during the first month of treatment. Acknowledgements. The authors wish to thank Drs. Michel Duplessis, Svetlana Ninkovic, Robert Filiatrault and Antonio Trottier for their assistance with the conduct of the study, Ms. Marie Hu for statistical analyses, and Mrs. Louise Bergeron for technical assistance. REFERENCES
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