Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: The calcitonin gene-related peptide (CGRP) pathway is important in migraine pathophysiology. We assessed the efficacy and safety of erenumab, a fully human monoclonal antibody against the CGRP receptor, in patients with chronic migraine. METHODS: This was a phase 2, randomised, double-blind, placebo-controlled, multicentre study of erenumab for adults aged 18-65 years with chronic migraine, enrolled from 69 headache and clinical research centres in North America and Europe. Chronic migraine was defined as 15 or more headache days per month, of which eight or more were migraine days. Patients were randomly assigned (3:2:2) to subcutaneous placebo, erenumab 70 mg, or erenumab 140 mg, given every 4 weeks for 12 weeks. Randomisation was centrally executed using an interactive voice or web response system. Patients, study investigators, and study sponsor personnel were masked to treatment assignment. The primary endpoint was the change in monthly migraine days from baseline to the last 4 weeks of double-blind treatment (weeks 9-12). Safety endpoints were adverse events, clinical laboratory values, vital signs, and anti-erenumab antibodies. The efficacy analysis set included patients who received at least one dose of investigational product and completed at least one post-baseline monthly measurement. The safety analysis set included patients who received at least one dose of investigational product. The study is registered with ClinicalTrials.gov, number NCT02066415. FINDINGS: From April 3, 2014, to Dec 4, 2015, 667 patients were randomly assigned to receive placebo (n=286), erenumab 70 mg (n=191), or erenumab 140 mg (n=190). Erenumab 70 mg and 140 mg reduced monthly migraine days versus placebo (both doses -6·6 days vs placebo -4·2 days; difference -2·5, 95% CI -3·5 to -1·4, p<0·0001). Adverse events were reported in 110 (39%) of 282 patients, 83 (44%) of 190 patients, and 88 (47%) of 188 patients in the placebo, 70 mg, and 140 mg groups, respectively. The most frequent adverse events were injection-site pain, upper respiratory tract infection, and nausea. Serious adverse events were reported by seven (2%), six (3%), and two (1%) patients, respectively; none were reported in more than one patient in any group or led to discontinuation. 11 patients in the 70 mg group and three in the 140 mg group had anti-erenumab binding antibodies; none had anti-erenumab neutralising antibodies. No clinically significant abnormalities in vital signs, laboratory results, or electrocardiogram findings were identified. Of 667 patients randomly assigned to treatment, 637 completed treatment. Four withdrew because of adverse events, two each in the placebo and 140 mg groups. INTERPRETATION: In patients with chronic migraine, erenumab 70 mg and 140 mg reduced the number of monthly migraine days with a safety profile similar to placebo, providing evidence that erenumab could be a potential therapy for migraine prevention. Further research is needed to understand long-term efficacy and safety of erenumab, and the applicability of this study to real-world settings. FUNDING: Amgen.

Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease.

OBJECTIVE: To evaluate the efficacy of telcagepant in patients with migraine and coronary artery disease. BACKGROUND: Calcitonin gene-related peptide receptor antagonists, such as telcagepant, may be useful for acute migraine treatment in patients with cardiovascular disease, a population for whom triptans are contraindicated. METHODS: Randomized, double-blind, two-period (6 weeks per period) crossover study in patients with stable coronary artery disease and migraine. Patients were randomized 1:1 to either: (1) Period 1: telcagepant (280-mg tablet/300-mg capsule), Period 2: acetaminophen (1000-mg); or (2) Period 1: placebo for attack 1 then acetaminophen for subsequent attacks, Period 2: telcagepant. Patients could treat up to 12 migraine attacks per period to assess the tolerability of telcagepant. The primary efficacy analysis evaluated telcagepant vs placebo on 2-hour pain freedom during the first attack of Period 1. RESULTS: One hundred and sixty-five of the planned 400 patients were enrolled, and 114 took at least one dose of treatment. Telcagepant was not statistically different from placebo for 2-hour pain freedom (25.0% vs 18.9%, odds ratio = 1.62 [95% confidence interval: 0.62, 4.25]). The median number of attacks treated per period was 3. No cardiovascular thrombotic adverse events occurred within 14 days of dosing. CONCLUSION: The study was underpowered due to enrollment difficulties and did not demonstrate a significant efficacy difference between telcagepant and placebo for the treatment of a migraine attack in patients with stable coronary artery disease. Telcagepant was generally well tolerated for acute intermittent migraine treatment in these patients.

Satisfaction with and confidence in needle-free subcutaneous sumatriptan in patients currently treated with triptans.

OBJECTIVE: To evaluate patient satisfaction with and confidence in Sumavel® DosePro® (needle-free subcutaneous sumatriptan) among current triptan users administering Sumavel DosePro for up to 4 migraine attacks. BACKGROUND: Sumavel DosePro is a needle-free, single-use device that facilitates subcutaneous injection of sumatriptan 6 mg and confers relief as early as 10 minutes after dosing. DESIGN/METHODS: In this open-label, multicenter study, Sumavel DosePro was self-administered for ≤4 migraine attacks (over a ≤60-day period) involving moderate or severe baseline pain by adult migraineurs who currently were using triptans (any form, any dosage) and reported being less than very satisfied with their current therapy (i.e., baseline satisfaction ranging from satisfied to very dissatisfied). Treatment satisfaction was measured via the Patient Perception of Migraine Questionnaire, revised (PPMQ-R). RESULTS: Among the 212 patients using Sumavel DosePro to treat ≥1 migraine attack, PPMQ-R Overall Satisfaction (primary endpoint) increased significantly from baseline to the end of treatment (mean ± SD 65.7 ± 19.8 vs. 73.7 ± 29.1, P = .0007), an improvement that met the criterion for clinical significance. From baseline to the end of treatment, PPMQ-R scores also improved significantly for Efficacy (62.2 ± 17.6 vs. 76.2 ± 23.7, P < .0001), Functionality (59.0 ± 22.3 vs. 73.8 ± 25.3, P < .0001), and Tolerability (83.9 ± 13.1 vs. 86.4 ± 15.0, P = .02), but declined for Ease of Use (82.6 ± 15.3 vs 67.8 ± 27.6, P < .0001). For all global satisfaction domains, the percentage of patients satisfied or very satisfied increased from baseline to the end of treatment (Overall Satisfaction 36.3% vs. 64.0%, Satisfaction with Medication Effectiveness 40.1% vs. 68.2%, Satisfaction with Side Effects 48.6% vs. 67.3%). The percentage of patients who were confident or very confident in treating repeated migraine attacks also increased (baseline: 41.0%, 90% confidence interval [CI] 35.4, 46.9 vs. end of treatment: 66.5%, 90% CI 58.9, 70.1). The efficacy results (pain relief, pain-free response, sustained 24-hour pain relief and pain-free response) were consistent with those previously observed with needle-based sumatriptan. CONCLUSIONS: Patients currently treated with triptans and less than very satisfied with their acute migraine therapy experienced a statistically significant and clinically relevant increase in satisfaction with therapy and enhanced confidence in treatment after use of Sumavel DosePro for up to 4 migraine attacks.

Childhood maltreatment and migraine (part III). Association with comorbid pain conditions.

OBJECTIVE: To evaluate in a headache clinic population the relationship of childhood maltreatment on the prevalence of pain conditions comorbid with migraine. BACKGROUND: Childhood maltreatment is highly prevalent and has been frequently associated with recurrent headache. The relationship of maltreatment and pain has, however, been a subject of some debate. METHODS: Cross-sectional data on self-reported physician-diagnosed pain conditions were electronically collected from persons with migraine (diagnosed according to International Classification of Headache Disorders-2), seeking treatment in headache clinics at 11 centers across the US and Canada. These included irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), fibromyalgia (FM), interstitial cystitis (IC), arthritis, endometriosis, and uterine fibroids. Other information included demographics, migraine characteristics (frequency, headache-related disability), remote and current depression (The Patient Health Questionnaire-9), and remote and current anxiety (The Beck Anxiety Inventory). Patients also completed the Childhood Trauma Questionnaire regarding sexual, emotional, and physical abuse, and emotional and physical neglect under the age of 18 years old. Statistical analyses accounted for the survey design and appropriate procedures in SAS such as surveymeans, surveyfreq, and surveylogistic were applied to the weighted data. RESULTS: A total of 1348 migraineurs (88% women) were included in this study (mean age 41 years). Based on physician diagnosis or validated criteria, 31% had IBS, 16% had CFS, and 10% had FM. Diagnosis of IC was reported by 6.5%, arthritis by 25%, and in women, endometriosis was reported by 15% and uterine fibroids by 14%. At least 1 comorbid pain condition was reported by 61%, 2 conditions by 18%, and 3 or more by 13%. Childhood maltreatment was reported by 58% of the patients. Emotional abuse was associated with increased prevalence of IBS, CFS, arthritis, and physical neglect with arthritis. In women, physical abuse was associated with endometriosis and physical neglect with uterine fibroids. Emotional abuse, and physical abuse and neglect (P < .0001 for all) were also associated with increased total number of comorbid conditions. In ordinal logistic regression models, adjusted for sociodemographics and current depression (prevalence 28%) and anxiety (prevalence 56%), emotional abuse (odds ratios [OR] = 1.69, 95% confidence intervals [CI]: 1.224-2.33) and physical neglect (OR = 1.73, 95% CI: 1.22-2.46) were independently associated with an increased number of pain conditions. The cohort of women, similarly, had associations of emotional abuse (OR = 1.94, 95% CI: 1.40-2.72) and physical neglect (OR = 1.90, 95% CI: 1.34-2.68) with an increased number of pain comorbidities. CONCLUSION: The association of childhood maltreatment and pain was stronger in those reporting multiple pain conditions and multiple maltreatment types. This finding suggests that in migraineurs childhood maltreatment may be a risk factor for development of comorbid pain disorders.

Childhood maltreatment and migraine (part I). Prevalence and adult revictimization: a multicenter headache clinic survey.

OBJECTIVES: To examine the prevalence of childhood maltreatment and adult revictimization in migraineurs and the association with sociodemographic factors, depression and anxiety. BACKGROUND: Population and practice-based studies have demonstrated an association of childhood abuse and headache in adults, although further details on headache diagnoses, characteristics, and comorbid conditions are lacking. There are mounting data suggesting substantial impact of early maltreatment on adult physical and mental health. METHODS: Electronic surveys were completed by patients seeking treatment in 11 headache centers across the United States and Canada. Physicians determined the primary headache diagnoses based on the International Classification of Headache Disorders-2 criteria and average monthly headache frequency. Self-reported information on demographics (including body mass index), social history, and physician-diagnosed depression and anxiety was collected. The survey also included validated screening measures for current depression (Patient Health Questionnaire-9) and anxiety (The Beck Anxiety Inventory). History and severity of childhood (<18 years) abuse (sexual, emotional, and physical) and neglect (emotional and physical) was gathered using the Childhood Trauma Questionnaire. There were also queries regarding adult physical and sexual abuse, including age of occurrence. Analysis includes all persons with migraine with aura, and migraine without aura. RESULTS: A total of 1348 migraineurs (88% women) were included (mean age 41 years). Diagnosis of migraine with aura was recorded in 40% and chronic headache (>or=15 days/month) was reported by 34%. The prevalence of childhood maltreatment types was as follows: physical abuse 21%, sexual abuse 25%, emotional abuse 38%, physical neglect 22%, and emotional neglect 38%. Nine percent reported all 3 categories of childhood abuse (physical, sexual, and emotional) and 17% reported both physical and emotional neglect. Overlap between maltreatment types ranged between 40% and 81%. Of those reporting childhood abuse, 43% reported abuse in adulthood, but infrequently (17%) over the age of 30 years. In logistic regression models adjusted for sociodemographic variables, current depression was associated with physical (P = .003), sexual (P = .007), and emotional abuse (P < .001), and physical and emotional neglect (P = .001 for both). Current anxiety was also associated with all childhood abuse and neglect categories (P < .001 for all). A graded relationship was observed between the number of childhood maltreatment types and remote or current depression and anxiety. In adjusted logistic regression analysis, migraineurs reporting 3 or more categories of childhood trauma were more likely to have received diagnoses of both depression and anxiety (odds ratios [OR] = 6.91, 95% confidence interval [CI]: 3.97-12.03), or either depression or anxiety (OR = 3.66, 95% CI: 2.28-5.88) as compared with those without childhood abuse or neglect. CONCLUSION: Reports of childhood maltreatment, especially emotional abuse and neglect, are prevalent in outpatients with migraine. There is extensive overlap of maltreatment types and a high rate of revictimization in adulthood. All types of childhood abuse and neglect are strongly associated with remote and current depression and anxiety, and the relationship strengthens with an increasing number of maltreatment types.

Childhood maltreatment and migraine (part II). Emotional abuse as a risk factor for headache chronification.

OBJECTIVES: To assess in a headache clinic population the relationship of childhood abuse and neglect with migraine characteristics, including type, frequency, disability, allodynia, and age of migraine onset. BACKGROUND: Childhood maltreatment is highly prevalent and has been associated with recurrent headache. Maltreatment is associated with many of the same risk factors for migraine chronification, including depression and anxiety, female sex, substance abuse, and obesity. METHODS: Electronic surveys were completed by patients seeking treatment in headache clinics at 11 centers across the United States and Canada. Physician-determined data for all participants included the primary headache diagnoses based on the International Classification of Headache Disorders-2 criteria, average monthly headache frequency, whether headaches transformed from episodic to chronic, and if headaches were continuous. Analysis includes all persons with migraine with aura, and migraine without aura. Questionnaire collected information on demographics, social history, age at onset of headaches, migraine-associated allodynic symptoms, headache-related disability (The Headache Impact Test-6), current depression (The Patient Health Questionnaire-9), and current anxiety (The Beck Anxiety Inventory). History and severity of childhood (<18 years) abuse (sexual, emotional, and physical) and neglect (emotional and physical) was gathered using the Childhood Trauma Questionnaire. RESULTS: A total of 1348 migraineurs (88% women) were included (mean age 41 years). Diagnosis of migraine with aura was recorded in 40% and chronic headache (>or=15 days/month) was reported by 34%. Transformation from episodic to chronic was reported by 26%. Prevalence of current depression was 28% and anxiety was 56%. Childhood maltreatment was reported as follows: physical abuse 21%, sexual abuse 25%, emotional abuse 38%, physical neglect 22%, and emotional neglect 38%. In univariate analyses, physical abuse and emotional abuse and neglect were significantly associated with chronic migraine and transformed migraine. Emotional abuse was also associated with continuous daily headache, severe headache-related disability, and migraine-associated allodynia. After adjusting for sociodemographic factors and current depression and anxiety, there remained an association between emotional abuse in childhood and both chronic (odds ratio [OR] = 1.77, 95% confidence intervals [CI]: 1.19-2.62) and transformed migraine (OR = 1.89, 95% CI: 1.25-2.85). Childhood emotional abuse was also associated with younger median age of headache onset (16 years vs 19 years, P = .0002). CONCLUSION: Our findings suggest that physical abuse, emotional abuse, and emotional neglect may be risk factors for development of chronic headache, including transformed migraine. The association of maltreatment and headache frequency appears to be independent of depression and anxiety, which are related to both childhood abuse and chronic daily headache. The finding that emotional abuse was associated with an earlier age of migraine onset may have implications for the role of stress responses in migraine pathophysiology.

Safety and tolerability of short-term preventive frovatriptan: a combined analysis.

OBJECTIVE: To assess the safety and tolerability profile of the 5-HT(1B/1D) agonist frovatriptan (Frova(R), Endo Pharmaceuticals Inc., Chadds Ford, PA, USA) when used as a 6-day regimen for the short-term prevention of menstrual migraine scheduled over multiple perimenstrual periods. BACKGROUND: Two randomized controlled trials have established the efficacy of a 6-day regimen of frovatriptan for reducing the incidence and severity of menstrual migraine over 1 to 3 perimenstrual periods; long-term data are needed to further assess the safety and tolerability profile of this regimen. METHODS: Two multinational trials were included in the analysis: Study 1 was a randomized, placebo-controlled double-blind parallel trial (3 perimenstrual periods treated) with an open-label extension (3 additional perimenstrual periods treated), and Study 2 was a long-term (12 perimenstrual periods treated over 12-15 months) open-label study. Enrolled women experienced menstrual migraine defined as predictable migraine attacks that started -2 days to +3 (Study 1) or +4 (Study 2) days relative to the first day of menses and that occurred in at least 2 out of 3 menstrual cycles. Frovatriptan or placebo was given 2 days before anticipated menstrual migraine and continued for 6 days. Adverse events, serious adverse events, vital signs, cardiovascular events, electrocardiograms, and laboratory parameters were assessed and recorded periodically and summarized using descriptive statistics. Adverse event data from Study 1 and Study 2 were compared using event rates. RESULTS: The demographic characteristics of the 2 study populations were similar: the mean age was approximately 38 years, > or =94% of participants were white, and 85% reported menstrual migraine began on days -2 to +1 of the menstrual cycle. The mean reported history of menstrual migraine was approximately 11 years. A large percentage of the respective safety populations completed each study or study period: 87% (362/416) and 88% (273/309) completed the double-blind period and open-label periods of Study 1, respectively, and 59% (308/525) completed treatment of 12 perimenstrual periods in Study 2. Major reasons for discontinuation in Study 1 included adverse events (5%, double-blind period) and "other" (10% double-blind period and 5% open-label period). In Study 2, major reasons for discontinuation included patient request (17.3%) and adverse event (10.2%). The most common treatment emergent adverse events in the double-blind period of Study 1 (placebo vs frovatriptan twice daily) were upper respiratory infection (9% vs 9%), nausea (6% vs 8%), dizziness (7% vs 7%), fatigue (4% vs 7%), dysmenorrhea (3% vs 7%), influenza (3% vs 6%), neck pain (4% vs 6%), and migraine (4% vs 4%). With the exception of migraine (which was reported using a different method in each study), prevalence rates for Studies 1 and 2 were numerically similar. The most frequently reported cardiovascular adverse events during double-blind treatment (placebo vs frovatriptan twice daily) were chest discomfort (2% and 3%), chest pain (2% and 2%), and hypertension (0 and 2%). The corresponding adverse event rates in Study 2 were 2% (chest pain), 3% (chest discomfort), and 3% (hypertension). In both studies, most adverse events were of mild or moderate intensity and their incidence numerically declined with each perimenstrual period/cycle, as did the incidence of menstrual migraine. The observed rate of intercurrent migraine in Study 2 over 12 perimenstrual periods was 1.5 per month, compared with 1.7 at baseline. There was no observable increase in the first occurrence of migraine in the 5 days following the perimenstrual period, indicating a lack of rebound headache. CONCLUSIONS: During treatment of up to 12 perimenstrual periods over a 12- to 15-month period, the safety and tolerability of frovatriptan for short-term prevention of menstrual migraine was similar to that observed with acute use of triptans. Adverse events were generally mild or moderate in severity, there was no evidence of an increased risk of cardiovascular adverse events relative to acute treatment, and rebound headache was not evident. A short-term regimen with frovatriptan presents a safe and viable treatment option for preventing predictable migraine such as menstrual migraine.

Allodynia in migraine: association with comorbid pain conditions.

BACKGROUND: Cutaneous allodynia (CA) in migraine is a clinical manifestation of central nervous system sensitization. Several chronic pain syndromes and mood disorders are comorbid with migraine. In this study we examine the relationship of migraine-associated CA with these comorbid conditions. We also evaluate the association of CA with factors such as demographic profiles, migraine characteristics, and smoking status that may have an influence on the relationships of CA to pain and mood. METHODS: Data are from a cross-sectional multicenter study of comorbid conditions in persons seeking treatment in headache clinics. Diagnosis of migraine was determined by a physician based on the International Classification of Headache Disorders-II criteria. Participants completed a self-administered questionnaire ascertaining sociodemographics, migraine-associated allodynia, physician-diagnosed comorbid medical and psychiatric disorders, headache-related disability, current depression, and anxiety. RESULTS: A total of 1413 migraineurs (mean age = 42 years, 89% women) from 11 different headache treatment centers completed a survey on the prevalence of comorbid conditions. Aura was reported by 38% and chronic headache by 35% of the participants. Sixty percent of the study population reported at least one migraine-related allodynic symptom, 10% reported > or =4 symptoms. Symptoms of CA were associated with female gender, body mass index, current smoking, presence of aura, chronic headaches, transformed headaches, severe headache-related disability, and duration of migraine illness from onset. The prevalence of self-reported physician diagnosis of comorbid pain conditions (irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia) and psychiatric conditions (current depression and anxiety) was also associated with symptoms of CA. Adjusted ordinal regression indicated a significant association between number of pain conditions and severity of CA (based on symptom count). Adjusting for sociodemographics, migraine characteristics, and current depression and anxiety, the likelihood of reporting symptoms of severe allodynia was much higher in those with 3 or more pain conditions (odds ratio = 3.03, 95% confidence interval: 1.78-5.17), and 2 pain conditions (odds ratio = 2.67, 95% confidence interval: 1.78-4.01) when compared with those with no comorbid pain condition. CONCLUSION: Symptoms of CA in migraine were associated with current anxiety, depression, and several chronic pain conditions. A graded relationship was observed between number of allodynic symptoms and the number of pain conditions, even after adjusting for confounding factors. This study also presents the novel association of CA symptoms with younger age of migraine onset, and with cigarette smoking, in addition to confirming several previously reported findings.

Posttraumatic stress disorder in migraine.

OBJECTIVE: To evaluate the relative frequency of posttraumatic stress disorder (PTSD) in episodic migraine (EM) and chronic daily headache (CDH) sufferers and the impact on headache-related disability. BACKGROUND: Approximately 8% of the population is estimated to have PTSD. Recent studies suggest a higher frequency of PTSD in headache disorders. The association of PTSD and headache-related disability has not been examined. METHODS: A prospective study was conducted at 6 headache centers. PTSD was assessed using the life events checklist and PTSD checklist, civilian version (PCL-C). We compared data from EM to CDH, and migraine with PTSD to migraine without PTSD. The PHQ-9 was used to assess depression, and headache impact test (HIT-6) to assess disability. RESULTS: Of 767 participants, 593 fulfilled criteria for EM or CDH and were used in this analysis. The mean age was 42.2 years and 92% were women. The frequency of PTSD was greater in CDH than in EM (30.3% vs 22.4%, P = .043), but not after adjusting for demographics and depression (P = .87). However, participants with major depression and PTSD were more likely to have CDH than EM (24.6% vs 15.79%, P < .002). Disability was greater in migraineurs with PTSD, even after adjustments (65.2 vs 61.7, P = .002). CONCLUSION: The frequency of PTSD in migraineurs, whether episodic or chronic, is higher than the historically reported prevalence of PTSD in the general population. In addition, in the subset of migraineurs with depression, PTSD frequency is greater in CDH sufferers than in episodic migraineurs. Finally, the presence of PTSD is independently associated with greater headache-related disability in migraineurs.

Depression and anxiety: effect on the migraine-obesity relationship.

OBJECTIVE: To discern the effects of depression and anxiety on the migraine-obesity relationship. BACKGROUND: Migraine and obesity are highly prevalent conditions and are both independently linked to psychiatric conditions, mainly depression and anxiety. METHODS: Data are from an ongoing cross-sectional multicenter study on comorbid conditions in clinic patients seeking treatment for headache. The diagnosis of migraine was determined by the examining physician based on the International Classification of Headache Disorders (ICHD)-II criteria. Participants completed a self-administered questionnaire with information on demographics, headache features, and physician-diagnosed comorbid medical and psychiatric disorders. The questionnaire included scales for measuring current depression (PHQ-9), anxiety (BAI), and headache-related disability (HIT-6). RESULTS: A total of 721 migraineurs (88% women) from 8 different headache treatment centers were included in this study (mean age = 42 years, SD = 12). Aura was reported in 45% and chronic headache (>or=15 headache days/month) in 35% of the participants. Prevalence of obesity in our population was 30% and only 38% had normal weight. Obesity was more common in men (P= .004), African Americans (P= .026), and in lower education (P= .05) and household income (P=.05) groups. Current depression (PHQ-9 score >or=10) was noted in 42% and current anxiety (BAI score >or=8) in 70% of the obese migraineurs. In ordinal logistic regression, obesity was associated with current depression (odds ratio [OR]= 1.86, 95% confidence interval [CI]: 1.25 to 2.78) and anxiety (OR = 1.58, 95% CI: 1.12 to 2.22). A significant effect of depression on the body mass index (BMI) and headache frequency relationship was noted. Obese migraineurs with depression were more likely to have higher headache frequency (OR = 4.16, 95% CI: 1.92 to 8.99) and headache-related disability (OR = 7.10, 95% CI: 2.69 to 18.77) compared to normal weight migraineurs without depression. Similarly, obese migraineurs with anxiety were more likely to have higher headache frequency (OR = 1.96, 95% CI: 1.07 to 3.61) and headache-related disability (OR = 3.59, 95% CI: 1.64 to 7.86) compared to normal weight migraineurs without depression. Compared to migraineurs with either current depression or anxiety, those with both these conditions were more likely to have higher headache frequency (OR = 3.18, 95% CI: 1.86 to 5.43) and headache disability (OR = 6.13, 95% CI: 2.58 to 14.59). CONCLUSION: Depression and anxiety were common in obese migraineurs. The relationship of obesity with migraine frequency and migraine-related disability is modified by depression and by anxiety, with the strongest effect observed in migraineurs with both depression and anxiety.

Botulinum toxin type a prophylactic treatment of episodic migraine: a randomized, double-blind, placebo-controlled exploratory study.

OBJECTIVE: This exploratory trial evaluated the safety and efficacy of multiple treatments of botulinum toxin type A (BoNTA; BOTOX, Allergan, Inc., Irvine, CA, USA) as prophylactic treatment of episodic migraine headaches. DESIGN AND METHODS: This was an 11-month randomized, double-blind, placebo-controlled, exploratory study. Patients were screened during a 30-day baseline period, and eligible patients with 4 or more migraine episodes and < or =15 headache days entered a single-blind 30-day placebo run-in period. Patients were classified as placebo nonresponders (PNR) if they had at least 4 moderate-to-severe migraine episodes and did not experience at least a 50% decrease from baseline in the frequency of migraine episodes following their placebo treatment. All other subjects were classified as placebo responders (PR). Patients were randomized within each stratum (PNR, PR) to 3 treatments with BoNTA (110 to 260 U of BoNTA per treatment cycle) or placebo at 90-day intervals using a modified follow-the-pain treatment paradigm. The primary efficacy outcome measure was the mean change from baseline in the frequency of migraine episodes for the 30 days prior to day 180 in the PNR group. Secondary efficacy measures included the proportion of patients with a decrease from baseline of 50% or more migraine episodes per 30-day period. Patients were allowed to take concomitant acute and prophylactic headache medications. Adverse events were reported. RESULTS: A total of 809 patients were screened and 369 patients (89.2% female; mean age, 45 years; range, 20 to 65 years) entered the placebo run-in period and were subsequently randomized to BoNTA or placebo. The mean total dose of BoNTA was 190.5 units (U) (range, 110 U to 260 U). The predetermined primary efficacy endpoint was not met. Substantial mean improvements of 2.4 and 2.2 fewer migraine episodes per month at day 180 in the PNR stratum treated with BoNTA and placebo, respectively, were observed (P > .999). From day 180 through the end of the study (day 270) at least 50% of all patients in each treatment group had a decrease from baseline of 50% or more migraine episodes per 30-day period. However, in the group of patients with > or =12 headache days at baseline (and < or =15 headache days), BoNTA patients experienced a mean change from baseline of -4.0 headache episodes at day 180 compared with -1.9 headache episodes in the placebo group (P= .048). The majority of treatment-related adverse events were transient and mild to moderate in severity. Only 7 patients (1.9%) discontinued the study due to adverse events (6 BoNTA, 1 placebo). CONCLUSION: There were no statistically significant between-group differences in the mean change from baseline in the frequency of migraine episodes per 30-day period. There were substantial, sustained improvements during the course of the study in all groups. Multiple treatments with BoNTA were shown to be safe and well tolerated over an active treatment period lasting 9 months.

Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine. METHODS: This was a randomized, placebo-controlled, parallel-group, multicenter study consisting of 16 weeks of double-blind treatment. Subjects aged 18 to 65 years with 15 or more headache days per month, at least half of which were migraine/migrainous headaches, were randomized 1:1 to either topiramate 100 mg/day or placebo. An initial dose of topiramate 25 mg/day (or placebo) was titrated upward in weekly increments of 25 mg/day to a maximum of 100 mg/day (or to the maximum tolerated dose). Concomitant preventive migraine treatment was not allowed, and acute headache medication use was not to exceed 4 days per week during the double-blind maintenance period. The primary efficacy endpoint was the change from baseline in the mean monthly number of migraine/migrainous days; the change in the mean monthly number of migraine days also was analyzed. A fixed sequence approach (ie, gatekeeper approach) using analysis of covariance was used to analyze the efficacy endpoints. Assessments of safety and tolerability included physical and neurologic examinations, clinical laboratory parameters, and spontaneous reports of clinical adverse events. RESULTS: The intent-to-treat population included 306 (topiramate, n = 153; placebo, n = 153) of 328 randomized subjects who provided at least 1 efficacy assessment; 55.8% of the topiramate group and 55.2% on placebo were trial completers. The mean final topiramate maintenance dose was 86.0 mg/day. The mean duration of therapy was 91.7 days for the topiramate group and 90.6 days for the placebo group. Topiramate treatment resulted in a statistically significant mean reduction of migraine/migrainous headache days (topiramate -6.4 vs placebo -4.7, P= .010) and migraine headache days relative to baseline (topiramate -5.6 vs placebo -4.1, P= .032). Treatment-emergent adverse events occurred in 132 (82.5%) and 113 (70.2%) of topiramate-treated and placebo-treated subjects, respectively, and were generally of mild or moderate severity. Most commonly reported adverse events in the topiramate group were paresthesia (n = 46, 28.8%), upper respiratory tract infection (n = 22, 13.8%), and fatigue (n = 19, 11.9%). The most common adverse events in the placebo group were upper respiratory tract infection (n = 20, 12.4%), fatigue (n = 16, 9.9%), and nausea (n = 13, 8.1%). Discontinuations due to adverse events occurred in 18 (10.9%) topiramate subjects and 10 (6.1%) placebo subjects. There were no serious adverse events or deaths. CONCLUSIONS: Topiramate treatment at daily doses of approximately 100 mg resulted in statistically significant improvements compared with placebo in mean monthly migraine/migrainous and migraine headache days. Topiramate is safe and generally well tolerated in this group of subjects with chronic migraine, a burdensome condition with important unmet treatment needs. Safety and tolerability of topiramate were consistent with experience in previous clinical trials involving the drug.

Montelukast for migraine prophylaxis: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and tolerability of montelukast 20 mg in the prophylactic treatment of migraine. BACKGROUND: A previous small open-label study in migraine patients suggested prophylactic efficacy for montelukast, an antagonist of the cysteinyl leukotriene receptor that is used in the treatment of asthma. We sought to confirm these findings in a randomized controlled trial. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-groups study enrolled adult migraine outpatients who experienced > or =3 and < or =8 migraine attacks per month for the last 6 months. Patients were entered into a 2-month, single-blind, placebo run-in phase. Only patients who experienced > or =3 migraine attacks in the second month were eligible to enter the subsequent 3-month, double-blind treatment phase of the study. The primary efficacy endpoint was the percentage of patients reporting at least a 50% decrease in migraine attack frequency per month during the double-blind treatment period (months 3-5) compared to baseline (run-in month 2). RESULTS: A total of 93 patients were randomized to montelukast 20 mg and 84 patients to placebo at the end of the placebo run-in month 2; 76 patients on montelukast and 72 patients on placebo completed the double-blind treatment period. Over 3 months of treatment, there was no significant difference between the two groups in the percentage of patients who reported at least a 50% decrease in migraine attack frequency per month: 15.4% for montelukast versus 10.3% for placebo (P= .304). In addition, montelukast 20 mg was not significantly superior to placebo on any of the secondary endpoints. There were no differences between treatment groups for adverse events. CONCLUSION: Montelukast 20 mg was well tolerated in migraine patients but was not an effective prophylactic for prevention of migraine.