Double-Blind Trial of Fluoxetine: Chronic Daily Headache and Migraine

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1 Double-Blind Trial of Fluoxetine: Chronic Daily Headache and Migraine Joel R. Saper, M.D., 1 Stephen D. Silberstein, M.D., 2 Alvin E. Lake III, Ph.D., 1 Marjorie E. Winters, R.N., B.S.N. 1 1 Michigan Head-Pain and Neurological Institute, Ann Arbor, Michigan 2 Comprehensive Headache Center, Germantown Hospital and Medical Center, Philadelphia, Pennsylvania. Address all correspondence to Joel R. Saper, M.D., F.A.C.P., Michigan Head-Pain and Neurological Institute, 3120 Professional Drive, Ann Arbor, MI Accepted for publication March 26, SYNOPSIS This study is the first double-blind placebo-controlled trial of fluoxetine for chronic daily headache (CDH) and migraine. After a one month single-blind baseline on placebo, subjects with CDH (n=64) and migraine (n=58) were randomly assigned to a three month trial of fluoxetine (20 mg) or an identical placebo. Fluoxetine and placebo were increased to 40 mg in the second month, depending on patient response. Patients kept daily headache records, and completed 100 mm visual analogue scales (VAS) of headache and mood each month. For the group of CDH patients on fluoxetine, overall headache status (VAS) after three months compared to the end of the single-blind placebo baseline improved a mean of 50% vs. 11% for those receiving the double-blind placebo ( P =.029), with 47% vs. 23% improving at least 50% (P=.097, n.s.). Fluoxetine patients showed significant improvement in monthly mood ratings compared to placebo (.001 by the end of the study), and modest but significant improvement in daily records of headache frequency (P=.019) but not pain severity. Significant mood improvements preceded improvement in headache, reaching significance by the end of the second month on fluoxetine (P=.013), while headache improvement emerged only during the third month (P=.001). Double-blind investigator judgement identified more headache improvement in fluoxetine than placebo recipients (40% vs. 22%, P=.032). Fluoxetine was not effective on any measure for migraine, with the exception of modest mood improvement at the end of the third month (P=.043). Adverse effects were more frequent but not more severe for fluoxetine, including sleep disturbance (28% vs. 8%, P=.008), tremors (20% vs. 5%, P=.025), and minor stomach pain (13% vs. 0%, P=.008). Fluoxetine appears moderately effective for CDH but not migraine, with a generally tolerable side effect profile. The influence on headache may be linked to its effect on mood. In general, study subjects were not clinically depressed. Future research might focus on subjects with comorbid depression and headache. Key words: Fluoxetine, chronic daily headache, migraine, double-blind study Abbreviations: CDH chronic daily headache, VAS visual analogue scale. (Headache 1994; 34: ) INTRODUCTION Migraine has been linked to a defect in the serotonin system, 1,2 and Raskin has identified modification of serotonergic transmission as the common denominator underlying medications shown to be effective in treating migraine? Consequently, it is reasonable to expect that a selective serotonin reuptake inhibitor such as fluoxetine might be effective in migraine prophylaxis. One brief report of an open label study of fluoxetine for headache found improvement in 59% of 64 patients who had previously been treated with antidepressants. 4 Fluoxetine has been shown to potentiate morphine analgesia. 5 Several case reports suggest the drug's potential for pain control in conditions ranging from chronic abdominal pain 6 to arthritis, 7 phantom limb pain, 8 chronic hand pain, 9 and diabetic neuropathy. 10 However, a randomized, double-blind crossover study of diabetic neuropathic pain failed to show fluoxetine to be more effective than placebo.11 In this paper we report results from two studies examining the effectiveness of fluoxetine for migraine and chronic daily headache. This work represents the first double-blind placebo-controlled evaluation of fluoxetine for head pain. METHODS Subjects. Sixty-four patients with chronic daily headache (CDH) and 58 patients with migraine were recruited at two comprehensive headache centers in Ann Arbor and Philadelphia. To be enrolled in the study, subjects had to be between 18 and 60 years of age and meet International Headache Society criteria for migraine,12 with at least a two-year headache history and 4-12 attacks per month of at least four hours duration. Chronic daily headache was defined as at least 16 headache days per month over the previous three months, which could be periodically accompanied by severe migraine attacks. Potential subjects who met the following criteria were excluded: previous unsuccessful treatment with three or more prophy-

2 lactic agents; migraine events occurring more than twice a week or where severe neurological accompaniments were present; continuing use of other prophylactic treatment or daily analgesics; unwillingness to abstain from known headache-provoking foods or other triggers; renal or hepatic dysfunction; history of eating disorder, nutritional deficits, or recent weight loss over 5 pounds; multiple drug allergies; significantly abnormal or changing neurological examinations; known severe psychological disturbance; use of investigational drugs in the preceding 35 days; known drug dependence or narcotic tolerance; pregnancy, lactation, or women of child-bearing potential not using medically acceptable contraception; use of MAOIs in the preceding four weeks; reliance on other antidepressant drugs; history of seizures; and critical illness or any major health event within the past 6 months. Measurement Instruments. Subjects and a "significant other" completed 100 mm Visual Analogue Scales (VAS) (overall headache status, headache frequency, average headache intensity, mood, and energy level) at the time of enrollment, the conclusion of the placebo washout phase, and again at 4-week intervals until the conclusion of the study, for a total of five measures for the five experimental phases. All subjects kept a daily headache diary, rating headache level four times a day on a 5-point scale.13 The headache diary was used to calculate a headache index, days per week with severe headache, and the number of headache-free days per week. At the conclusion of the study, investigators made a double-blind judgement of patient response. Patients completed the Beck Depression Inventory14 on enrollment, after the one month placebo washout, and at the end of the final month. Weight was recorded on admission and at each subsequent investigator visit at 4-week intervals. The distribution of subjects by diagnosis, treatment condition, sex, age, and Beck scores is shown in Table 1. None of the differences between fluoxetine and placebo groups were statistically significant. Study Design. The investigation was conducted at two geographically separate centers, utilizing a 16-week, randomized, double-blind, parallel-group design, with an initial 4-week single-blind placebo washout phase (baseline) beginning on visit 1 and ending on visit 2. The initial single-blind placebo condition in the experimental design requires that the drug effect be significantly greater than the initial placebo effect for patients receiving active treatment. After completing the placebo baseline, subjects were randomly assigned to active or placebo treatments. Only one member of the investigative team had access to randomization lists, and the code was not bro- Table 1. - Patient Demographics: Sex, Age, and Beck Depression Scores at Enrollment Chronic Daily Headache Migraine Fluoxetine Placebo Fluoxetine Placebo Sex Female Male Age Mean S.D Range Low High Beck Score Mean S.D Range Low High Note: Beck < 10 = Within Normal Limits. ken until all subjects had completed the study. For the remaining 12 weeks of the study, subjects received identically appearing capsules of either fluoxetine or placebo, beginning with 20 mg/day. After the second month (visit 3), if no therapeutic response had occurred but the drug was tolerated, the dose was increased to two capsules of either fluoxetine or placebo each day for the remaining eight weeks. Fluoxetine blood levels were taken at the end of month 2 (initial 20 mg dose) and month 3 (final adjusted dose up to 40 mg). The final adjusted dose of fluoxetine was 40 mg for 26 out of 29 CDH subjects (90%) and 25 out of 29 migraineurs (86%). Mean total fluoxetine blood levels at the end of month 3 were ng/ml (SD = ) for the CDH group, and ng/ml (S.D. = ) for migraine. Compliance with the prescription protocol was assessed at each monthly visit by investigator count of remaining medication. Mean compliance was greater than 94% for all diagnosis-drug combinations. Subjects were allowed to use rescue medications including Anaprox(r) or other NSAIDs, Midrin(r), or Cafergot(r), with some individual allowance of other simple or combination analgesics. Simple analgesics were limited to no more than three days per week; combination analgesics and Cafergot(r) were limited to two days per week maximum. Informed consent was obtained before subjects entered the study. This research protocol was approved by an appropriate institutional review board for participating centers. Safety Assessments/Diagnostic Tests. Laboratory screening tests included a hematology panel, chemistry, and urinalysis. All subjects completed a headache and neurological history, and received neurological examinations and electrocardiograms. Beginning with the placebo washout, patients were requested to report the type and severity of any adverse events. Statistical Analysis. Data analysis was performed with the SYSTAT statistical program for MS-DOS systems, using repeated measures analysis of variance to analyze main and interactional effects over the five experimental phases (initial enrollment, single-blind placebo, and the three months of active treatment), with post hoc paired and/or independent t-tests when the ANOVA revealed significant effects. Nonparametric tests were applied to analyses based on the number of subjects meeting selected criteria (eg double-blind investigator judgement of outcome). P values of <.050 were considered significant. RESULTS Headache. Visual Analogue Scales. For Chronic Daily Headache, repeated measures analysis of variance on Overall Headache Status revealed significant effects for phases [F(4,196)=17.61, P=.001] and a drug x phase interaction [F(4,196)=2.50, P=.044]. Post hoc analyses using paired t-tests showed that both the fluoxetine [t(29)=3.12, P=.004] and placebo groups [t(23)=4.27, P=.001] improved from enrollment until the end of the single-blind placebo phase, indicating a significant initial placebo effect. However, the primary comparisons of interest lie between the end of the single-blind placebo baseline and the active treatment phases. In this case, the only significant effect occurred for fluoxetine subjects at the conclusion of the final month of treatment (i.e. second month on the final adjusted dose) [t(49)=4.49, P=.001]. These results are depicted graphically in Figure 1.

3 For CDH patients as a group, the mean percent improvement in Overall Headache Status at the end of the study compared to the end of the single blind placebo baseline was 53% vs. 17% for double-blind placebo [t(49)= 2.18, P=.029]. Fourteen (14) of 30 fluoxetine patients (47%) improved at least 50% on this variable vs. only 5 of 21 placebo patients (24%), although this difference only approached statistical significance [X2 (1) =2.76, P=.097]. ANOVA for migraine cases revealed a significant phases effect [F(4,204) = 12.01, P=.000] but no interaction effect. Post hoc t-tests did not show any significant improvement in either the fluoxetine or placebo group after conclusion of the initial single-blind placebo. Other than the expected phases effects, none of the analyses of other headache-related VAS measures (frequency, intensity, energy level) or ratings by significant others reached significance for either diagnosis. Headache Diary. For CDH, a repeated measures analysis of variance for the number of Headache-Free Days (per week) revealed both the expected phases effect [F(3,150)=15.31, P=.001] and a drug x phase interaction [F(3,150)=3.42, P=.019]. In this case, similar increases in Headache-Free Days were observed in both the fluoxetine and placebo groups. For fluoxetine, Headache-Free Days increased from 1.57/week during the single-blind placebo baseline to 2.67 during the third month [t(28)=3.93, P=.001]; for placebo, Headache-free Days increased from 1.12/week to 2.27 [t(23)=3.72, P=.001]. ANOVAs for Headache Index and Severe Headaches/week yielded the expected significant phases effect, showing improvement for both fluoxetine and placebo over time, but no interaction effect that would support differential efficacy. For migraine, ANOVAs for Headache-Free Days, Headache Index, and Severe Days also showed significant phases effects but no significant interaction or drug effects. Double-Blind Investigator Judgement. At the conclusion of the study, investigators at each site judged patient response as improved (i.e., "good" or "fair") or unimproved ("poor") based on the information available at that time. For CDH, 25 of 30 subjects receiving fluoxetine (83%) were judged to be improved vs. only 13 of 23 subjects (57%) receiving double-blind placebo. These results were statistically significant [X2(1)=4.61, P=.032]. For migraine, 22 of 31 fluoxetine patients (71%) were judged as improved vs. 15 of 27 (56%) on placebo [X2(1)=1.48, n.s.]. Mood. Visual Analogue Scale. Repeated measures analysis of variance on VAS Mood ratings were completed, analogous to the ANOVA for Overall Headache Status. For CDH, analysis revealed a significant phases effect [F(4,196)=10.67, P=.001], and a significant drug x phases interaction [F(4,196)=2.77, P=.028] supporting differential effectiveness favoring fluoxetine. Compared to the Mood rating at the end of the single-blind placebo baseline, Mood showed significant improvement by the end of the second month on fluoxetine [t(29)=2.49, P=.019] and further improved by the end of the third month [t(28)=3.86, P=.001]. There was no significant improvement for the placebo patients beyond the initial single-blind placebo baseline. These results are depicted in Figure 2. Continuing the CDH analysis, the mean percent improvement in Mood at the end of the third month compared to the end of single-blind baseline for the group as a whole was [t(49)=2.38, P=.019]. Twelve of 29 patients on fluoxetine (41%) showed at least a 50% improvement in Mood vs. only 3 of 22 subjects (14%) on placebo [X 2 (1) =4.64, P=.031. For migraine cases, analysis revealed the expected phases effect [F(4,208)=8.49, P=.001], but no drug x phase interaction. Post-hoc analysis did show a significant improvement in Mood for migraine patients by the end of the third month

4 compared to the end of the single-blind placebo baseline [t(29)=2.12, P=.043], but no further improvement for those on double-blind placebo. Relationship of Mood to Headache Improvement. Several analyses were performed in order to assess the relationship between improvement in Mood and headache improvement. As shown in Figure 3, CDH fluoxetine subjects who demonstrated at least 50% improvement in VAS Mood ratings at the end of the second and third months were significantly more likely to demonstrate at least a 50% improvement in Overall Headache Status at the end of the study [X2(1)=9.81, P=.002; X2(1)=12.27, P=.001]. In other words, Mood improvement at the end of the second month preceded and was significantly associated with improvement in Overall Headache Status at the end of the third month. For CDH Fluoxetine patients (n=29), Pearson correlations were significant or near-significant between Headache-Free Days and Mood at the end of the month for the single-blind placebo baseline (R=.403, P=.030), month 1 (R=.526, P=.003), month 2 (R=.328, P=.083), and month 3 (R=.334, P=.076), indicating that Mood accounted for between 10.76% to 27.67% of the variance in headache-free days/week. However, there was no relationship between Mood improvement and any of the other variables from the Headache Diary. Depression. Beck Depression Inventory scores declined significantly over time for all groups, due to a significant decrease between enrollment and the end of the single-blind placebo baseline [F(2,178)=21.641, P=.001]. By the end of the baseline, the mean Beck score of 6.08 (SD=5.04) was well within normal limits (under 10), and showed no further improvement at the end of the study (mean=5.33, SD=5.21). There were no significant differences for Beck scores between diagnoses or drug treatments. Initial Beck scores did not predict treatment outcome. Comparison of Results by Treatment Center. Analyses of variance including treatment center as a factor did not reveal any significant differences in outcome for any of the dependent variables studied. Adverse Effects and Dropouts. CDH and migraine patients were combined for the analysis of adverse effects. For fluoxetine, 51 of 61 patients (84%) reported the presence of some adverse ef-

5 fects vs. 33 of 50 patients (66%) on placebo [X2(1)=4.63, P=.031]. However, for those patients reporting adverse events, the rated severity of effects did not differ significantly between groups [X2(1)=1.37,n.s.]. Only 5 of 61 fluoxetine patients (8%) reported severe adverse effects (fatigue, restlessness, sleep disturbance, stomach pain, blurred vision) compared to 2 of the 50 placebo patients (4%), a nonsignificant difference. As shown in Table 2, only three adverse effects were significantly more prevalent in the fluoxetine than placebo groups: sleep disturbance, tremors, and stomach pain. It is of interest to note that fatigue was frequently noted as a moderately disturbing adverse event by roughly equal percentages of subjects in both the fluoxetine (25%) and placebo groups (26%). Five patients on fluoxetine reported moderately disturbing weight loss from 9 to 15 pounds (mean=11.20) vs. only one placebo patient reporting a mildly disturbing weight loss of five pounds, although these differences were not statistically significant. Table 2.-Adverse Effects More Prevalent for Fluoxetine than Placebo Combined CDH and Migraine Patients Effect Drug N % P Sleep Problem Fluoxetine 17/ Placebo 11/50 8 Tremors Fluoxetine 12/ Placebo 3/50 5 Stomach Pain Fluoxetine 8/ Placebo 0/50 0 No patient dropped out of the study due to adverse events. Six patients were dropped from the initially recruited fluoxetine subjects for the following reasons: noncompliance (2), analgesic overuse (2), use of a concurrent antimigraine prophylactic (1), with one subject lost to follow-up. Eight patients were dropped from or decided to leave the initial placebo group due to drug inefficacy (3), fear of side effects (1), pregnancy (1), abnormal CT scan (1), and two subjects (one each from the migraine-placebo and CDH-fluoxetine groups) were lost to follow-up for reasons unknown. DISCUSSION In regard to headache, this study found statistically significant fluoxetine effects for Overall Headache Status (VAS), Headache-Free Days, and Double-Blind Investigator Judgement for chronic daily headache but not intermittent migraine. Significant treatment effects did not emerge until the third month on fluoxetine (second month on adjusted dose). By the end of the study, the fluoxetine group showed an additional statistically significant 53% improvement in Overall Headache Status above the level at the end of the single-blind placebo period, in contrast to only 17% additional improvement for the double-blind placebo group. With the exception of the modest increase in Headache-Free Days, fluoxetine did not differentially affect headache measures of severity and overall headache index based on the Headache Diary, considered the "gold standard" of headache assessment.13 Although availability and limits on use of rescue medications remained constant throughout the study, such abortives might be expected to place an upper limit on measures of headache severity and duration, and would therefore be expected to affect a combined measure such as headache index. Consequently, measures of headache frequency (eg Headache-Free Days) may in fact be the most reliable parameter from the Headache Diary under the current experimental design. Our results suggest that the overall impact of fluoxetine on headache in CDH sufferers was associated with an impact on mood. Fluoxetine had a significant effect on overall Mood beginning in the second month, further increasing in the third month of treatment. As noted, headache improvement was not observed until the end of the third month. Mood improvement was a precursor of headache improvement: those patients who showed Mood improvement in the second month were most likely to report headache improvement in the third month. It should be noted that Mood and Overall Headache Status were both measured in the same way (Visual Analogue Scale). Due to shared method variance, we would expect higher correlations between Mood and the VAS measure of headache than between Mood and Headache Diary measures. However, significant Mood improvement in the month prior to improvement in headache ratings, as well as borderline to significant correlations between Mood and Headache-Free Days for CDH patients (ranging from R=.328, P=.083 to R=.526, P=.003 over the experimental phases) argue against method variance as the sole explanation of the Mood-headache connection. Over 85% of the patients had initial Beck Depression scores within normal limits. Mood and headache improvement were not limited to depressed patients, and Beck scores did not predict treatment outcome. However, depression is not uncommon in headache patients. Epidemiological research has

6 shown a higher rate of major depression in migraine (27%) than in the nonmigraine population (9%).15 Since its introduction in 1988, over 11,000 patients have participated in clinical trials of fluoxetine throughout the world, with convincing evidence of its efficacy for treating depression.16 It remains possible that fluoxetine may be most beneficial to the chronic daily headache patient or even migraine patient with comorbid depression. This area merits further research. Fluoxetine was well tolerated at 40 mg by 86% (migraine) to 90% (CDH) of the patients, with no dropouts due to adverse events. Controlled studies for depression have found that patients can tolerate higher doses, in the mg range.17,18 Results for headache may be greater with higher doses, another area worthy of future research exploration. In summary, fluoxetine appears moderately effective for prophylaxis of CDH but not migraine, with a generally tolerable side effect profile. Pending further research, its use as an alternative pharmacotherapy for patients with chronic daily headache, including those unable to tolerate adverse effects from other medications, appears justifiable at this time. Acknowledgment: Appreciation is extended to the Eli Lilly Company for financial support. REFERENCES 1. Ferrari MD, Saxena PR. On serotonin and migraine: a clinical and pharmacological review. Cephalalgia 1993; 13: Fozard JR. 5-HT in migraine: evidence from 5-HT receptor antagonists for a neuronal aetiology. In: Sandler M, Collins GM. editors. Migraine: a spectrum of ideas. New York: Oxford University Press, 1990; Raskin NH. Headache. 2nd Ed. New York: Churchill Livingstone, 1988: Diamond S, Freitag FG. The use of fluoxetine in the treatment of headache. Clin J Pain 1989; 5: Hynes MD, Lochner MA, Bemis KG, Hymson DL. Fluoxetine, a selective inhibitor of serotonin uptake, potentiates morphine analgesia without altering its discriminative stimulus properties or affinity for opioid receptors. Life Sci 1985; 36: Eisendrath S J, Kodama KT. Fluoxetine management of chronic abdominal pain. Psychosomatics 1992; 33: Petitto JM, Mundle LB, Nagy BR, et al. Improvement of arthritis with fluoxetine. Psychosomatics 1992; 33: Power-Smith P, Turkington D. Fluoxetine in phantom limb pain. Br J Psychiatry 1993;163: Sullivan M. Integrated treatment of a woman with chronic hand pain. Hosp Community Psychiatry 1991; 42: Theesen KA, Marsh WR. Relief of diabetic neuropathy with fluoxetine. DICP 1989; 23: Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992; 326: International Headache Society. Headache Classification Committee. Proposed classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(suppl 7): Blanchard EB, Andrasik F, Neff DF et al. Social validation of the headache diary. Behav Ther 1981; 12: Beck AT. Depression inventory. Philadelphia: Center for Cognitive Therapy, Breslau N, Davis GC, Andreski P. Migraine, psychiatric disorders, and suicide attempts: an epidemiologic study of young adults. Psychiat Res 1991; 37: Stokes PE. Fluoxetine: a five-year review. Clinical Therapeutics 1993; 15: Stark P, Hardison CD. A review of multicenter controlled studies of fluoxetine vs. imipramine and placebo in out-patients with major depressive disorder. J Clin Psychiatry 1985; 46: Usher RW, Beasley CM, Bosomworth JC. Efficacy and safety of morning versus evening fluoxetine administration. J Clin Psychiatry 1991; 52: