Fluoxetine Prophylaxis of Migraine
Camran Adly, M.D.,1 John Straumanis, M.D.2 and Andrew Chesson, M.D.3 1,2Department
of Psychiatry, 3Department of Neurology, Louisiana State University School of Medicine, Shreveport, Louisiana.
Accepted for Publication: November 5, 1991. SYNOPSIS
Many patients with severe migraine remain refractory to the current treatment regimens or cannot tolerate the side effects. Since current research implicates serotonin dysregulation in migraine pethogenesis, we investigated in a double blind, placebo controlled study the prophylactic effect of the serotonergic drug fluoxatine. Sixteen subjects were randomly assigned to 8 week fluoxatine treatment and 16 to the placebo group; nine subjects in each group completed the study. Migraine headache scores were obtained for two weeks prior to commencement of treatment, and then for each successive two week period, Zung depression scores were obtained before and after completion of the study. Fluoxetine caused significant reduction in headache scores starting with weeks 3-4 of treatment; there was no significant change with placebo. Depression scores did not differ between groups before treatment, and did not significantly change with either treatment. Fluoxetine appears to be a safe and effective drug for migraine prophylaxis, and deserves further therapeutic trials with larger groups for longer periods of time. Key words: serotonin, fluoxetine, migraine prophylaxis (Headache 1992, 32:101-104) INTRODUCTION
Migraine is a chronic, highly prevalent, disabling disorder presenting with a variable symptom pattern. Currently several medications may prevent migraine attacks, however a significant group of patients remain treatment refractory. Commonly used drugs for prophylactic treatment of migraine.1-9 are tricyclic antidepressants, especially amitriptyline and beta adrenergic blockers. However, these medications often cause side effects that are not tolerated well by a significant proportion of patients with migraine. Fluoxetine is an atypical antidepressant with a safer overall side effect profile than the standard tricyclic antidepressants. It increases CNS serotonin activity by blocking serotonin reuptake and down regulating somatodendritic and terminal presynaptic auto-receptors.10 Currently most theories of the pathophysiology of migraine focus on serotonergic dysregulation.11,12 The therapeutic effects of amitriptyline and beta blockers, therefore, may be explained by their serotonergic effect. Effectiveness of fluoxetine in migraine is proposed because of its serotonergic properties and the clinical observation that some migraine patients improve with fluoxetine. SUBJECTS AND METHODS
Volunteers were solicited through an advertisement in the local newspaper. A research associate then screened the volunteers for the following inclusion criteria: 1) diagnosis of migraine by a physician, 2) presence of one or more severe disabling migraine headaches per week, 3) absence of concomitant medical conditions, 4) no alcohol or drug abuse. Potential candidates were then scheduled for an interview by the principal investigator who confirmed the inclusion criteria and the diagnosis of migraine based on the criteria of the Ad Hoc Committee on Classification of headaches.13 Our study required at least weekly severe, disabling attacks. The Zung Depression Rating Scale was obtained for all subjects during the initial visit and at the last visit.14 Subjects were carefully instructed how to keep a daily diary of their migraine attacks. Participants were asked to rate the intensity of headaches on scale of one to ten, record the time of onset, and termination, the use of any medication or any other intervention to alleviate the pain. Subjects were also required to chart the degree of impairment of normal daily activities and accompanying symptoms such as: nausea, photophobia and sensory or motor changes. This data was used by the principal investigator to quantify the severity of the migraine attacks and the changes with treatment. Subjects were given a prescription for fluoxetine 20 mg to be filled by the hospital pharmacy, which randomly assigned each participant to either the placebo or fluoxetine group. Subjects were instructed to wait fourteen days prior to starting fluoxetine. They were instructed to take the medication every other morning for a period of four weeks, to report any significant side effects immediately to the principal investigator, and to inform him should they change their treatment on the advice of any other physician. All study participants were seen by the investigator approximately six weeks after the initial visit. During this visit, diaries were checked and the clinical changes of migraine assessed. Subjects who showed significant [75% reduction in symptoms] improvement during the first four weeks on the medication, were continued on the same regimen. For subjects with minimal or no improvement, fluoxetine or placebo dosage was increased to twenty milligrams every morning. These subjects were scheduled for their third office visit fourteen days later to evaluate their progress, and side effects. At this time, the dosage of fluoxetine or placebo was increased to 40rag per day for all subjects who did not show significant improvement [75% reduction of symptoms] unless they were unable to tolerate the 20 mg dosage. All subjects were seen by the principal investigator at the completion of the study ten weeks after the initial visit. All patients who completed the study had been drug free prior to entering the study except for two patients in the
fluoxetine group who discontinued previous treatment with amitriptyline or nalodol three days prior to the study. One patient in the placebo group stopped imipramine therapy three days prior to the study. Subjects were paid forty dollars for study participation. The diaries and the Zung Depression Rating Scales were rated prior to breaking the "double blind". Migraine headache scores were based on patient diaries, subjective record of intensity, duration and the amount of medication used to abort the attacks. Scores were calculated for each day, and summed for each two week period. Migraine headaches scores obtained from the diaries, and the Zung Depression Rating Scale scores were then statistically analyzed for treatment effect. The average age of the subjects who completed the fluoxetine treatment was thirty-four years; forty-one years for the placebo treatment group. The fluoxetine group consisted of seven females and two males; the placebo group had eight females and one male. RESULTS
Thirty-two subjects who met the inclusion criteria and consented to participate in the study were randomly assigned to either the placebo or fluoxetine group. Nine subjects in each group completed the study. In the fluoxetine group one subject terminated due to anxiety and insomnia, two because they felt the medication was not effective after 3 days and 7 weeks of treatment, and four subjects did not keep appointments and could not be reached. Six subjects in the placebo group dropped out during the first stage of the study. Two reported lack of efficacy, two changed their mind about participating in the study, two did not keep their second (6 week) appointment and could not be reached. One subject submitted an incomplete diary and also had started taking another pain relieving medication during the course of the study. This patient was excluded from the study. The incidence of side effects in the fluoxetine group who completed the treatment was low. One subject reported insomnia and anxiety with dose of 20mg per day, one subject reported strange skin sensations (skin coming off body), excitement and insomnia with 40mg of fluoxetine per day. The third subject initially reported a few episodes of a "floating sensation" that resolved spontaneously. In the placebo group, three subjects reported side effects. One reported insomnia and excessive anxiety with 40 mg/day of placebo medication, another reported occasional feelings of weakness, fatigue and "whozziness", and the third subject reported problems sleeping. In the fluoxetine group, six reported excellent improvement such as "feeling a lot better," "tremendously better", and three reported some or moderate improvement. Two subjects made significant improvement with 20 mg every other day and did not tolerate higher dosage of fluoxetine. One subject reported more improvement when the dose of fluoxetine was increased from 20 rag/day to 40 mg/day. All except one expressed willingness to remain on the medication (one subject preferred amitriptyline). In the placebo group four subjects reported an improvement, three reported some improvement and one reported excellent improvement. Table 1 shows migraine headache scores before treatment (weeks 1 and 2) and biweekly for 8 weeks during treatment with fluoxetine or placebo. The Table 1 Headache Scores for Fluoxetine and Placebo Groups FLUOXETINE Subject
1-2 weeks
3-4 weeks
5-6 weeks
7-8 weeks
9-10 weeks
1 2 3 4 5 6 7 8 9
30 19 42 8 29 45 24 65 24
19 24 2 0 3 53 30 34 1
12 16 0 14 13 27 21 32 12
10 11 0 0 0 30 24 43 10
4 12 4 0 0 13 7 13 3
Mean
32
18
16
14
6
PLACEBO 3-4 weeks 5-6 weeks
7-8 weeks
9-10 weeks
Subject
1-2 weeks
1 2 3 4 5 6 7 8 9
34 32 7 55 18 24 82 40 25
10 22 2 25 43 18 44 20 33
20 1 8 9 19 18 24 30 26
22 5 18 28 36 21 59 17 37
15 0 7 11 6 14 105 43 15
Mean
35
24
17
27
24
initial (week 1-2) headache scores did not differ between groups (Mann-Whitney), but the fluoxetine group had less headaches at weeks 9-10 (Mann-Whitney p
Camran Adly, M.D.,1 John Straumanis, M.D.2 and Andrew Chesson, M.D.3 1,2Department
of Psychiatry, 3Department of Neurology, Louisiana State University School of Medicine, Shreveport, Louisiana.
Accepted for Publication: November 5, 1991. SYNOPSIS
Many patients with severe migraine remain refractory to the current treatment regimens or cannot tolerate the side effects. Since current research implicates serotonin dysregulation in migraine pethogenesis, we investigated in a double blind, placebo controlled study the prophylactic effect of the serotonergic drug fluoxatine. Sixteen subjects were randomly assigned to 8 week fluoxatine treatment and 16 to the placebo group; nine subjects in each group completed the study. Migraine headache scores were obtained for two weeks prior to commencement of treatment, and then for each successive two week period, Zung depression scores were obtained before and after completion of the study. Fluoxetine caused significant reduction in headache scores starting with weeks 3-4 of treatment; there was no significant change with placebo. Depression scores did not differ between groups before treatment, and did not significantly change with either treatment. Fluoxetine appears to be a safe and effective drug for migraine prophylaxis, and deserves further therapeutic trials with larger groups for longer periods of time. Key words: serotonin, fluoxetine, migraine prophylaxis (Headache 1992, 32:101-104) INTRODUCTION
Migraine is a chronic, highly prevalent, disabling disorder presenting with a variable symptom pattern. Currently several medications may prevent migraine attacks, however a significant group of patients remain treatment refractory. Commonly used drugs for prophylactic treatment of migraine.1-9 are tricyclic antidepressants, especially amitriptyline and beta adrenergic blockers. However, these medications often cause side effects that are not tolerated well by a significant proportion of patients with migraine. Fluoxetine is an atypical antidepressant with a safer overall side effect profile than the standard tricyclic antidepressants. It increases CNS serotonin activity by blocking serotonin reuptake and down regulating somatodendritic and terminal presynaptic auto-receptors.10 Currently most theories of the pathophysiology of migraine focus on serotonergic dysregulation.11,12 The therapeutic effects of amitriptyline and beta blockers, therefore, may be explained by their serotonergic effect. Effectiveness of fluoxetine in migraine is proposed because of its serotonergic properties and the clinical observation that some migraine patients improve with fluoxetine. SUBJECTS AND METHODS
Volunteers were solicited through an advertisement in the local newspaper. A research associate then screened the volunteers for the following inclusion criteria: 1) diagnosis of migraine by a physician, 2) presence of one or more severe disabling migraine headaches per week, 3) absence of concomitant medical conditions, 4) no alcohol or drug abuse. Potential candidates were then scheduled for an interview by the principal investigator who confirmed the inclusion criteria and the diagnosis of migraine based on the criteria of the Ad Hoc Committee on Classification of headaches.13 Our study required at least weekly severe, disabling attacks. The Zung Depression Rating Scale was obtained for all subjects during the initial visit and at the last visit.14 Subjects were carefully instructed how to keep a daily diary of their migraine attacks. Participants were asked to rate the intensity of headaches on scale of one to ten, record the time of onset, and termination, the use of any medication or any other intervention to alleviate the pain. Subjects were also required to chart the degree of impairment of normal daily activities and accompanying symptoms such as: nausea, photophobia and sensory or motor changes. This data was used by the principal investigator to quantify the severity of the migraine attacks and the changes with treatment. Subjects were given a prescription for fluoxetine 20 mg to be filled by the hospital pharmacy, which randomly assigned each participant to either the placebo or fluoxetine group. Subjects were instructed to wait fourteen days prior to starting fluoxetine. They were instructed to take the medication every other morning for a period of four weeks, to report any significant side effects immediately to the principal investigator, and to inform him should they change their treatment on the advice of any other physician. All study participants were seen by the investigator approximately six weeks after the initial visit. During this visit, diaries were checked and the clinical changes of migraine assessed. Subjects who showed significant [75% reduction in symptoms] improvement during the first four weeks on the medication, were continued on the same regimen. For subjects with minimal or no improvement, fluoxetine or placebo dosage was increased to twenty milligrams every morning. These subjects were scheduled for their third office visit fourteen days later to evaluate their progress, and side effects. At this time, the dosage of fluoxetine or placebo was increased to 40rag per day for all subjects who did not show significant improvement [75% reduction of symptoms] unless they were unable to tolerate the 20 mg dosage. All subjects were seen by the principal investigator at the completion of the study ten weeks after the initial visit. All patients who completed the study had been drug free prior to entering the study except for two patients in the
fluoxetine group who discontinued previous treatment with amitriptyline or nalodol three days prior to the study. One patient in the placebo group stopped imipramine therapy three days prior to the study. Subjects were paid forty dollars for study participation. The diaries and the Zung Depression Rating Scales were rated prior to breaking the "double blind". Migraine headache scores were based on patient diaries, subjective record of intensity, duration and the amount of medication used to abort the attacks. Scores were calculated for each day, and summed for each two week period. Migraine headaches scores obtained from the diaries, and the Zung Depression Rating Scale scores were then statistically analyzed for treatment effect. The average age of the subjects who completed the fluoxetine treatment was thirty-four years; forty-one years for the placebo treatment group. The fluoxetine group consisted of seven females and two males; the placebo group had eight females and one male. RESULTS
Thirty-two subjects who met the inclusion criteria and consented to participate in the study were randomly assigned to either the placebo or fluoxetine group. Nine subjects in each group completed the study. In the fluoxetine group one subject terminated due to anxiety and insomnia, two because they felt the medication was not effective after 3 days and 7 weeks of treatment, and four subjects did not keep appointments and could not be reached. Six subjects in the placebo group dropped out during the first stage of the study. Two reported lack of efficacy, two changed their mind about participating in the study, two did not keep their second (6 week) appointment and could not be reached. One subject submitted an incomplete diary and also had started taking another pain relieving medication during the course of the study. This patient was excluded from the study. The incidence of side effects in the fluoxetine group who completed the treatment was low. One subject reported insomnia and anxiety with dose of 20mg per day, one subject reported strange skin sensations (skin coming off body), excitement and insomnia with 40mg of fluoxetine per day. The third subject initially reported a few episodes of a "floating sensation" that resolved spontaneously. In the placebo group, three subjects reported side effects. One reported insomnia and excessive anxiety with 40 mg/day of placebo medication, another reported occasional feelings of weakness, fatigue and "whozziness", and the third subject reported problems sleeping. In the fluoxetine group, six reported excellent improvement such as "feeling a lot better," "tremendously better", and three reported some or moderate improvement. Two subjects made significant improvement with 20 mg every other day and did not tolerate higher dosage of fluoxetine. One subject reported more improvement when the dose of fluoxetine was increased from 20 rag/day to 40 mg/day. All except one expressed willingness to remain on the medication (one subject preferred amitriptyline). In the placebo group four subjects reported an improvement, three reported some improvement and one reported excellent improvement. Table 1 shows migraine headache scores before treatment (weeks 1 and 2) and biweekly for 8 weeks during treatment with fluoxetine or placebo. The Table 1 Headache Scores for Fluoxetine and Placebo Groups FLUOXETINE Subject
1-2 weeks
3-4 weeks
5-6 weeks
7-8 weeks
9-10 weeks
1 2 3 4 5 6 7 8 9
30 19 42 8 29 45 24 65 24
19 24 2 0 3 53 30 34 1
12 16 0 14 13 27 21 32 12
10 11 0 0 0 30 24 43 10
4 12 4 0 0 13 7 13 3
Mean
32
18
16
14
6
PLACEBO 3-4 weeks 5-6 weeks
7-8 weeks
9-10 weeks
Subject
1-2 weeks
1 2 3 4 5 6 7 8 9
34 32 7 55 18 24 82 40 25
10 22 2 25 43 18 44 20 33
20 1 8 9 19 18 24 30 26
22 5 18 28 36 21 59 17 37
15 0 7 11 6 14 105 43 15
Mean
35
24
17
27
24
initial (week 1-2) headache scores did not differ between groups (Mann-Whitney), but the fluoxetine group had less headaches at weeks 9-10 (Mann-Whitney p
