Predictive models for determining treatment response to nonprescription acute medications in migraine: Results from the American Migraine Prevalence and Prevention Study.

OBJECTIVE: To identify predictors of acute treatment response for nonprescription (over-the-counter [OTC]) medications among people with migraine and develop improved models for predicting treatment response. BACKGROUND: Pain freedom and sustained pain relief are important priorities in the acute treatment of migraine. OTC medications are widely used for migraine; however, it is not clear which treatment works best for each patient without going through the trial and error process. METHODS: A prediction model development study was completed using the 2006 American Migraine Prevalence and Prevention Study survey, from participants who were aged ≥18, met criteria and headache day frequency for episodic migraine, did not take prescription medication for migraine, and used ≥1 of the following acute migraine medication classes: acetaminophen, aspirin, NSAIDs, or caffeine containing combination products (CCP). Two items from the Migraine Treatment Optimization Questionnaire were used to evaluate treatment response, adequate 2-h pain freedom (2hPF) and 24-h pain relief (24hPR), which were defined by a response to treatment ≥half the time at 2 h and 24 h post treatment, respectively. We identified predictors of adequate treatment response and developed models to predict probability of treatment response to each medication class. RESULTS: The sample included 3852 participants (3038 [79.0%] females) with an average age of 45.0 years (SD = 12.8). Only 1602/3852 (41.6%) and 1718/3852 (44.6%) of the participants reported adequate 2hPF and 24hPR, respectively. Adequate treatment-response was significantly predicted by lower average headache pain intensity, less cutaneous allodynia, and lower depressive symptom scores. Lower migraine symptom severity was predictive of adequate 2hPF and fewer monthly headache days was predictive of adequate 24hPR. Among participants reporting OTC monotherapy (n = 2168, 56.3%) individuals taking CCP were more likely to have adequate 2hPF (OR = 1.55, 95% CI 1.23-1.95) and 24hPR (OR = 1.79, 95% CI 1.18-1.88) in comparison with those taking acetaminophen. Predictive models were modestly predictive of responders to OTC medications (c-statistics = 0.65; 95% CI 0.62-0.68). CONCLUSION: These results show that response to acute migraine treatments is not optimized in the majority of people with migraine treating with OTC medications. Predictive models can improve our ability to choose the best therapeutic option for individuals with episodic migraine and increase the proportion of patients with optimized response to treatments.

Determinants of pain interference and headache impact in patients who have chronic migraine with medication overuse: Results from the MOTS trial.

OBJECTIVE: "Pain interference" and "headache impact" refer to negative consequences that pain and headache have on one's life. This study investigated determinants of these negative impacts in a large patient cohort who have chronic migraine with medication overuse. METHODS: Six hundred and eleven adults were enrolled from 34 headache, neurology, and primary care clinics. Negative consequences of chronic migraine with medication overuse were determined using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference 6b questionnaire and the Headache Impact Test 6. Relationships between PROMIS-6b and Headache Impact Test 6 scores with demographics, headache characteristics, medication use, anxiety symptoms, and depression symptoms were assessed with linear regression. Elastic Net regression was used to develop a multiple regression model. RESULTS: PROMIS-6b T-Scores averaged 65.2 (SD 5.4) and Headache Impact Test 6 scores averaged 65.0 (SD 5.3), indicating severe negative consequences of chronic migraine with medication overuse. Chronic migraine with medication overuse interfered with enjoyment of life, concentration, daily activities, doing tasks away from home, and socializing. Depression symptom severity had the strongest relationship with pain interference and headache impact. Moderate-to-severe headache frequency, headache intensity, and anxiety symptoms were also associated with pain interference and headache impact. CONCLUSIONS: Chronic migraine with medication overuse is associated with substantial negative consequences, the extent of which is most strongly related to depression symptoms.

Headache characteristics and burden from chronic migraine with medication overuse headache: Cross-sectional observations from the Medication Overuse Treatment Strategy trial.

OBJECTIVE: To describe headache characteristics, medication use, disability, and quality of life in a large patient cohort from the United States who have chronic migraine (CM) and medication overuse headache (MOH). METHODS: In all, 610 adult patients were enrolled into the Medication Overuse Treatment Strategy trial from 34 healthcare clinics, including headache specialty, general neurology, and primary care clinics. Descriptive statistics characterize baseline demographics, headache characteristics, medication use, disability (Headache Impact Test 6 [HIT-6] and Migraine Functional Impact Questionnaire [MFIQ]), pain interference (PROMIS Pain Interference), and quality of life (EQ-5D-5L). Relationships with headache frequency were assessed. RESULTS: Mean age was 45 years (SD 13) and 531/608 (87.3%) were females. Mean headache days per 30 was 24.3 (SD 5.5), including 13.6 (SD 7.1) with moderate to severe headache. Daily headaches were reported by 36.1% (219/607) of patients. Acute headache medications were used on 21.5 (SD 7.5) per 30 days. The most commonly overused medications were simple analgesics (378/607, 62% of patients), combination analgesics (246/607, 41%), and triptans (128/607, 21%). HIT-6, MFIQ, PROMIS Pain Interference, and EQ-5D-5L scores demonstrated substantial negative impact from CM with MOH on patient functioning and quality of life. Higher headache frequency was associated with more moderate-severe headache days, more frequent acute headache medication use, greater headache-related disability, and lower quality of life. Only 272/606 (44.9%) were taking migraine preventive medication. CONCLUSIONS: CM with MOH is associated with a large burden on patients in the United States. Higher headache frequency is associated with greater impact on functioning, pain interference, and quality of life.

Ovarian hormones, age and pubertal development and their association with days of headache onset in girls with migraine: An observational cohort study.

Background Fifty-three percent of adolescent girls report headaches at the onset of menses, suggesting fluctuations of ovarian hormones trigger migraine during puberty. Aims To determine if urinary metabolites of estrogen and progesterone are associated with days of headache onset (HO) or severity in girls with migraine. Methods This was a pilot study and included 34 girls with migraine balanced across three age strata (pre-pubertal (8-11), pubertal (12-15), and post-pubertal (16-17) years of age). They collected daily urine samples and recorded the occurrence and severity of headache in a daily diary. Urine samples were assayed for estrone glucuronide (E1G) and pregnandiol glucuronide (PdG) and the daily change was calculated (ΔE1G, ΔPdG). Pubertal development was assessed by age, pubertal development score (PDS), and menstrual cycle variance. The primary outcome measures were HO days and headache severity. Generalized linear mixed models were used, and included the hormonal variables and three different representations of pubertal development as covariates. Results Models of HO days demonstrate a significant age*PdG interaction (OR 0.85 [95% CI 0.75, 0.97]) for a 1 standard deviation increase in PdG and three-year increase in age. A separate model showed a significant PDS*PdG interaction (OR -0.85 [95% CI; 0.76, 0.95]). ΔPDG was associated with headache severity in unadjusted models ( p < 0.017). Conclusion Age and pubertal development could moderate the effect of ovarian hormones on days of headache onset in girls with migraine.

Identifying Natural Subgroups of Migraine Based on Comorbidity and Concomitant Condition Profiles: Results of the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study.

OBJECTIVE: To identify natural subgroups of people with migraine based on profiles of comorbidities and concomitant conditions, hereafter referred to as comorbidities. BACKGROUND: Migraine is a heterogeneous disease. Identifying natural subgroups (endophenotypes) may facilitate biological and genetic characterization and the development of personalized treatment. METHODS: The Chronic Migraine Epidemiology and Outcomes Study is a prospective web-based survey study designed to characterize the course of migraine and related comorbidities in a systematic US sample of people with migraine. Respondents were asked if they ever had a specific comorbidity and, if present, whether the comorbidity was confirmed/diagnosed by a "doctor"; 62 comorbidities were available for analysis. Latent class analysis (LCA) modeling determined the optimal number of classes and a parsimonious set of comorbidities. RESULTS: Of the 12,810 respondents with migraine, 11,837 reported ≥1 comorbidity and were included in this analysis. After statistical analysis and clinical judgment reduced the number of comorbidities, we selected an 8-class model based on 22 comorbidities. Each class had a distinct pattern summarized as follows: Class 1, Most Comorbidities; Class 2, Respiratory/Psychiatric; Class 3, Respiratory/Pain; Class 4, Respiratory; Class 5, Psychiatric; Class 6, Cardiovascular; Class 7, Pain; Class 8, Fewest Comorbidities. The distribution of individuals across models was variable, with one-third of respondents in Class 8 (Fewest Comorbidities) and <10% in Class 1 (Most Comorbidities). Demographic and headache characteristics, not used in assigning class membership, varied across classes. For example, comparing Class 1 (Most Comorbidities) and Class 8 (Fewest Comorbidities), Class 1 had a greater proportion of individuals with severe disability (Migraine Disability Assessment grade IV; 48.1% vs 22.3% of overall individuals) and higher rates of allodynia (67.6% vs 47.0%), medication overuse (36.4% vs 15.0%), chronic migraine (23.1% vs 9.1%), and aura (40.1% vs 28.8%). CONCLUSIONS: LCA modeling identified 8 natural subgroups of persons with migraine based on comorbidity profiles. These classes show differences in demographic and headache features not used to form the classes. Subsequent research will assess prognostic and biologic differences among the classes.

Headache Disorders May Be a Risk Factor for the Development of New Onset Hypothyroidism.

OBJECTIVE: To determine whether headache disorders are a risk factor for the development of new onset hypothyroidism. BACKGROUND: Past studies have reported associations between headache disorders and hypothyroidism, but the directionality of the association is unknown. METHODS: This was a longitudinal retrospective cohort study using data from the Fernald Medical Monitoring Program (FMMP). Residents received physical examinations and thyroid function testing every 3 years during the 20 year program. Residents were excluded from the cohort if there was evidence of past thyroid disease or abnormal thyroid function tests at the first office visit. A diagnosis of a headache disorder was established by self-report of "frequent headaches," use of any headache-specific medication, or a physician diagnosis of a headache disorder. The primary outcome measure was new onset hypothyroidism defined as the initiation of thyroid replacement therapy or TSH ≥ 10 without thyroid medication. A Cox survival analysis with time dependent variables were used for the model. Headache disorders, age, sex, body mass index, income, smoking, narcotic use, and hypothyroidism-producing medications were independent variables in the model. RESULTS: Data from 8412 residents enrolled in the FMMP were used in the current study. Headache disorders were present in about 26% of the residents and new onset hypothyroidism developed in ∼7%. The hazard ratio for the development of new onset hypothyroidism was 1.21 (95% CI = 1.001, 1.462) for those with headache disorders. CONCLUSIONS: Headache disorders may be associated with an increased risk for the development of new onset hypothyroidism.

Forecasting Individual Headache Attacks Using Perceived Stress: Development of a Multivariable Prediction Model for Persons With Episodic Migraine.

OBJECTIVE: To develop and validate a prediction model that forecasts future migraine attacks for an individual headache sufferer. BACKGROUND: Many headache patients and physicians believe that precipitants of headache can be identified and avoided or managed to reduce the frequency of headache attacks. Of the numerous candidate triggers, perceived stress has received considerable attention for its association with the onset of headache in episodic and chronic headache sufferers. However, no evidence is available to support forecasting headache attacks within individuals using any of the candidate headache triggers. METHODS: This longitudinal cohort with forecasting model development study enrolled 100 participants with episodic migraine with or without aura, and N = 95 contributed 4626 days of electronic diary data and were included in the analysis. Individual headache forecasts were derived from current headache state and current levels of stress using several aspects of the Daily Stress Inventory, a measure of daily hassles that is completed at the end of each day. The primary outcome measure was the presence/absence of any headache attack (head pain > 0 on a numerical rating scale of 0-10) over the next 24 h period. RESULTS: After removing missing data (n = 431 days), participants in the study experienced a headache attack on 1613/4195 (38.5%) days. A generalized linear mixed-effects forecast model using either the frequency of stressful events or the perceived intensity of these events fit the data well. This simple forecasting model possessed promising predictive utility with an AUC of 0.73 (95% CI 0.71-0.75) in the training sample and an AUC of 0.65 (95% CI 0.6-0.67) in a leave-one-out validation sample. This forecasting model had a Brier score of 0.202 and possessed good calibration between forecasted probabilities and observed frequencies but had only low levels of resolution (ie, sharpness). CONCLUSIONS: This study demonstrates that future headache attacks can be forecasted for a diverse group of individuals over time. Future work will enhance prediction through improvements in the assessment of stress as well as the development of other candidate domains to use in the models.

Diet and Headache: Part 2.

BACKGROUND: Comprehensive diets do not require the exclusion of a specific provocative food or ingredient, but regulate the quantities of core components of foods such as vitamins, ions, proteins, carbohydrates, and fats. OBJECTIVES: To review the evidence supporting the use of comprehensive diets in the prevention of migraine and other headache disorders and to discuss the mechanisms through which food, and ingredients within foods and beverages might trigger attacks of headache METHODS: This represents Part 2 of a narrative review of the role of diet in the prevention of migraine and other headache disorders. A PubMed search was performed with the following search terms: "folate," "vitamin D," "low fat diet," "omega-3 and omega-6 fatty acid diet," "ketogenic diet," "Atkins diet," and "sodium." Each of these search terms was then crossreferenced with "headache" and "migraine" to identify relevant studies. Only studies that were written in English were included in this review. RESULTS: Low fat and high omega-3/low omega-6 fatty diets decrease the frequency of attacks of migraine and/or other headache disorders as demonstrated in two separate randomized controlled trials. A ketogenic diet was more effective than a standard diet in reducing the frequency of migraine in a single nonrandomized clinical study. An observation study found that dietary consumption of folate was inversely associated with the frequency of migraine attacks in persons with migraine with aura that have the C variant of the methylene tetrahydrofolate reductase gene. The mechanisms though which diets may precipitate headache include their effects on neuropeptides, neuro-receptors and ion channels, inflammation, sympathetic nervous system, release of nitric oxide, vasodilation, and cerebral glucose metabolism. CONCLUSIONS: Evidence exists to support the use of comprehensive diets in the prevention of migraine and other headache disorders. However, the results of these studies should be considered preliminary until replicated in larger randomized controlled clinical trials.

Diet and Headache: Part 1.

BACKGROUND: The role of diet in the management of the headache patient is a controversial topic in the headache field. OBJECTIVES: To review the evidence supporting the hypothesis that specific foods or ingredients within foods and beverages trigger attacks of headache and/or migraine and to discuss the use of elimination diets in the prevention of headache disorders METHODS: This represents part 1 of a narrative review of the role of diet in the prevention of migraine and other headache disorders. A PubMed search was performed with the following search terms: "monosodium glutamate," "caffeine," "aspartame," "sucralose," "histamine intolerance syndrome," "tyramine," "alcohol," "chocolate," "nitrites," "IgG elimination diets," and "gluten." Each of these search terms was then cross-referenced with "headache" and "migraine" to identify relevant studies. Only studies that were written in English were included in this review. RESULTS: Caffeine withdrawal and administration of MSG (dissolved in liquid) has the strongest evidence for triggering attacks of headache as evidenced by multiple positive provocation studies. Aspartame has conflicting evidence with two positive and two negative provocation studies. Observational studies provide modest evidence that gluten- and histamine-containing foods as well as alcohol may precipitate headaches in subgroups of patients. Two of three randomized controlled trials reported that an elimination diet of IgG positive foods significantly decreased frequency of headache/migraine during the treatment as compared to baseline time period. CONCLUSIONS: Certain foods, beverages, and ingredients within foods may trigger attacks of headache and/or migraine in susceptible individuals. Elimination diets can prevent headaches in subgroups of persons with headache disorders.

Asthma is a risk factor for new onset chronic migraine: Results from the American migraine prevalence and prevention study.

OBJECTIVES: To test the hypothesis that in persons with episodic migraine (EM), asthma is a risk factor for the onset of chronic migraine (CM). BACKGROUND: Migraine and asthma are comorbid chronic disorders with episodic attacks thought to involve inflammatory and neurological mechanisms. Herein, we assess the influence of asthma on the clinical course of EM. METHODS: To be eligible for this observational cohort study, AMPP Study participants had to meet criteria for EM in 2008, complete the validated six-item asthma questionnaire from the European Community Respiratory Health Survey (ECRHS) in 2008, and provide follow-up data in 2009. Using the ECRHS, we defined asthma as a binary variable (present or absent) based on an empirical cut score and developed a Respiratory Symptom Severity Score (RSSS) based on the number of positive responses (no severity = 0 positive responses, low severity = 1-2 positive responses, moderate severity = 3-4 positive responses, high severity = 5-6 positive responses). Chronic migraine was the primary outcome measure and was defined as those with ≥15 headache days per month on the 2009 AMPP Study survey. We used logistic regression in separate models to assess the influence of asthma as a binary variable (Model 1) and RSSS score categories (Model 2 using no respiratory symptoms as the reference) on CM onset after adjusting for sociodemographic factors, headache day frequency, migraine preventive medication use, and medication overuse. RESULTS: The eligible sample for this study included 4446 individuals with EM in 2008 of whom 17% had asthma. This group had a mean age of 50.4 and was 80.8% female. In 2009, new onset CM developed in 2.9% (131/4446) of the 2008 EM cohort, including 5.4% (40/746) of the asthma subgroup and 2.5% (91/3700) of the non-asthma subgroup. In comparison to those without asthma, the adjusted odds for individuals with asthma and EM in 2008 to develop CM in 2009 were greater than two (adjusted odds ratio [aOR] 2.1; 95% CI: 1.4-3.1). Using the RSSS, the aOR for CM onset increased with the number of asthma symptoms, but only those in the high RSSS category showed a statistically significant increase in the odds of chronic migraine onset in comparison with the no RSSS reference group (aOR 3.3; 95% CI 1.7-6.2). CONCLUSIONS: Asthma is associated with an increased risk of new onset CM 1 year later among individuals with EM, with the highest risk being among those with the greatest number of respiratory symptoms. The exact mechanisms underlying this association are unknown, but could suggest mast cell degranulation, autonomic dysfunction, or shared genetic or environmental factors.

Perimenopause and Menopause Are Associated With High Frequency Headache in Women With Migraine: Results of the American Migraine Prevalence and Prevention Study.

OBJECTIVES: To examine the relationship of headache frequency to the stages of the menopausal transition in mid-life women with migraine. BACKGROUND: Past studies suggest that the perimenopause is associated with an increased prevalence of migraine, particularly in those with a history of premenstrual syndrome. The effect of the menopausal transition on the frequency of headache attacks in women with migraine has not been explored. METHODS: This was a cross-sectional observational study. Using data from the 2006 American Migraine, Prevalence and Prevention study survey, women meeting modified ICHD-3 beta criteria for migraine between the ages of 35-65 years were included in analyses. Women who had never menstruated or were pregnant, breastfeeding, or using exogenous sex hormones were excluded. The 2006 survey was selected because it included detailed questions on the menstrual cycle. The stages of the menopausal transition were defined based upon the self-reported cycle length and/or duration of amenorrhea. The primary outcome, high vs low headache frequency, was defined using a cut score of ≥10 headache days per month. Binary logistic regression models were used to assess the influence of menopausal stage on headache frequency category using premenopause as the reference group. Adjustments for stage of menopausal transition and sociodemographics (eg, age and income) were included in the first model, while the second model included sociodemographics, depression, body mass index, preventative medications, and medication overuse. RESULTS: The study sample included 3664 women at a mean age of 46 years. Among women who were premenopausal, 8.0% (99/1242) were in the high frequency headache group in comparison with 12.2% (154/1266) of perimenopausal and 12.0% (131/1095) of postmenopausal women. Compared with premenopausal women, the adjusted odds of being in the high frequency headache group was 1.62 (95% CI = 1.23, 2.12) for perimenopausal and 1.76 (95% CI = 1.23, 2.52) for postmenopausal women (Model 1). In model 2, high frequency headache was only increased in perimenopausal women with an OR of 1.42 (95% CI = 1.03, 1.94). CONCLUSIONS: The risk of high frequency headache is increased in women during the perimenopause compared to premenopause in the fully adjusted model. The fact that the increased risk of high frequency headache was not statistically significant for menopause in the fully adjusted models suggests that different mechanisms might account for the increased risk for this stage of the menopausal transition. Recognition of the increased risk of high frequency headache during the menopausal transition suggests a need for optimized preventive treatment of migraine during this time of women's life.

Chronic rhinitis and its association with headache frequency and disability in persons with migraine: results of the American Migraine Prevalence and Prevention (AMPP) Study.

BACKGROUND: Rhinitis is a comorbidity of migraine, but its relationship to migraine headache frequency and headache-related disability is unknown. OBJECTIVES: To determine if rhinitis and its subtypes are associated with an increased frequency and associated disability of migraine. METHODS: The AMPP Study is a longitudinal study of individuals with "severe" headache from the US population. Respondents meeting ICHD-2 criteria for migraine in 2008 were identified and the presence of rhinitis was determined using the European Community Respiratory Health Survey (ECRHS). Those with rhinitis were subtyped as allergic, non-allergic, mixed and unclassified based on a rhinitis questionnaire. The primary outcome measures were categories of headache-day frequency and headache-related disability as measured by the Migraine Disability Assessment Scale (MIDAS). Logistic regression for ordered categories was used for modeling each outcome separately, adjusted for sociodemographics profile, headache features, headache treatments and comorbidities. RESULTS: The AMPP Study questionnaire was mailed to 17,892 persons and returned by 60.1% of respondents. Among the migraine sample ( N = 5849), 66.8% had rhinitis with mixed rhinitis as the most common form. The presence of rhinitis of any type was associated with headache frequency after adjusting for sociodemographic variables only (OR 1.33; 95% CI 1.16, 1.53) and in the fully adjusted model (OR 1.25; 95% CI 1.05-1.49). Headache-related disability (MIDAS category) was associated with rhinitis after adjusting for sociodemographic features (OR 1.30; 95% CI 1.17-1.46), but lost significance in the fully adjusted model (OR 1.10; 95% CI 0.96-1.26). Mixed rhinitis was associated with an increased headache frequency category in the model adjusted for sociodemographics (OR 1.45; 95% CI 1.24-1.70) and in that adjusted for all covariates (OR 1.28; 95% CI 1.05-1.57). The odds ratio for MIDAS categories were similarly increased in both models for the mixed rhinitis group. CONCLUSIONS: The frequency and disability of migraine are higher in persons with rhinitis, particularly those with mixed rhinitis. These results, however, should be considered preliminary until confirmed in future studies because of the modest questionnaire response rate in this study.

Joint hypermobility and headache: understanding the glue that binds the two together--part 1.

BACKGROUND: Heritable connective tissue disorders (HCTD) present with a wide array of findings, including headache. Because of their unusual substrate, headaches in HCTD can derive from both common and uncommon circumstances. METHODS: Literature review. RESULTS: Ehlers-Danlos hypermobile type can be recognized by multiple joint findings and its tendency to progress to a multisystem chronic pain syndrome. Ehlers-Danlos classic type also manifests joint laxity and similar pain complaints, but is differentiated by its skin laxity and fragility. Ehlers-Danlos vascular type presents the most severe risk due to blood vessel and hollow organ rupture. Marfan syndrome demonstrates skeletal abnormalities, lens dislocations, and aortic root dilation that can result in dissection. CONCLUSIONS: In a headache patient, recognizing the presence of an HCTD improves the strategy for diagnosis and management. A brief review of findings related to joints, skin, and arteries may prompt further investigation into the HCTDs.

Joint hypermobility and headache: the glue that binds the two together--part 2.

BACKGROUND: Past studies have reported that connective tissue disorders (CTDs) are more common in patients with specific types of headache disorders. OBJECTIVES: The objectives of this study are (1) to review and critique the clinical studies reporting an association between joint hypermobility, CTDs and headache and (2) to postulate mechanisms though which CTDs might predispose to headache disorders. METHODS: PubMed was searched for relevant articles with search terms that included joint hypermobility, Ehlers-Danlos syndrome, Marfan syndrome, and specific headache disorders. A narrative review was performed of these articles as well as those identified from the bibliography of these articles. RESULTS: Case reports and case control studies confirm an association between CTDs and migraine, coat-hanger headaches, carotid arterial dissections, intracranial hypotension, Arnold Chiari malformations-type 1, cervical spine disorders, and temporomandibular joint disorders. CONCLUSIONS: Observational cross-sectional studies suggest that the prevalence of CTDs is increased in patients with specific types of headache disorders. It is unknown if the CTDs directly cause these headaches disorders or are associated with them through other mechanisms.

Comparing the efficacy of eletriptan for migraine in women during menstrual and non-menstrual time periods: a pooled analysis of randomized controlled trials.

OBJECTIVE: To assess the efficacy and tolerability of eletriptan in treating migraine attacks occurring within the defined menstrual time period of 1 day before and 4 days after onset of menstruation (menses days -1 to +4) compared with attacks occurring during non-menstrual time periods (occurring outside of menses days -1 to +4). BACKGROUND: Migraine attacks during menses have been associated with longer duration, higher recurrence rates, greater treatment resistance, and greater functional disability than those not associated with menses. The efficacy of eletriptan in treating migraine attacks associated with menstruation vs those outside a defined menstrual period has not been evaluated. METHODS: Data were pooled from 5 similarly designed, double-blind, randomized, placebo-controlled trials of eletriptan 20 mg/40 mg/80 mg. Two groups were defined for this analysis: women with a single index migraine beginning during the menstrual (group 1) and non-menstrual (group 2) time periods. End points of interest were headache response at 2 hours, migraine recurrence and sustained responses for nausea, photo/phonophobia, and function. Logistic regression was used to compare group 1 vs group 2 and each eletriptan dose (20, 40, or 80 mg) vs. placebo. Adverse events were also assessed. RESULTS: Of 3217 subjects pooled from 5 studies, 2216 women were either in group 1 (n = 630) or group 2 (n = 1586). Rates of headache response at 2 hours were similar in group 1 vs. group 2 (odds ratio [OR] = 1.11 [95% confidence interval (CI) 0.91, 1.36]; P = .2944). The rate of headache recurrence was significantly higher in group 1 vs group 2 (26.8% vs. 18.6%; OR = 1.67 [95% CI 1.23, 2.26]; P < .001). The odds of achieving sustained nausea responses were significantly lower in group 1 than in group 2 (OR = 0.70 [95% CI 0.54, 0.92]; P = .0097). There was no significant difference between group 1 and group 2 in the odds of achieving a sustained photo/phonophobia and functional response (OR = 0.96 [95% CI 0.77, 1.20]; P = .7269 and OR = 1.14 [95% CI 0.87, 1.50]; P = .3425, respectively). Adverse events were comparable between group 1 and group 2. CONCLUSIONS: Two-hour headache outcome measures were similar in women treated with eletriptan both within and outside of the defined menstrual time period (menses days -1 to +4). The main treatment differences between the 2 groups occurred 2-24 hours post-treatment, with higher recurrence rates and lower sustained response rates for nausea in the group treated during the menstrual time period.

Migraine and the menopausal transition.

The menopausal transition or "perimenopause" represents a time period of turbulent changes in ovarian hormones as middle-aged women progress into menopause. The purpose of this article is to review the literature to determine the effect of the menopausal transition on migraine headaches and to develop a rational treatment approach to these patients. The menopausal transition is divided into early and stages based upon patterns of menstruation and specific reproductive hormones. Studies would suggest that the prevalence of migraine and other climacteric symptoms tend to peak during the late menopausal transition particularly in those with a past history of premenstrual stress disorder. Treatment approaches vary by stage of the menopausal transition and include conventional daily preventatives, mini-prophylaxis and hormonal therapies.

Lightning and its association with the frequency of headache in migraineurs: an observational cohort study.

AIM: The aim of this article is to determine if lightning is associated with the frequency of headache in migraineurs. METHODS: Participants fulfilling diagnostic criteria for International Headache Society-defined migraine were recruited from sites located in Ohio ( N = 23) and Missouri ( N = 67). They recorded headache activity in a daily diary for three to six months. A generalized estimating equations (GEE) logistic regression determined the odds ratio (OR) of headache on lightning days compared to non-lightning days. Other weather factors associated with thunderstorms were also added as covariates to the GEE model to see how they would attenuate the effect of lightning on headache. RESULTS: The mean age of the study population was 44 and 91% were female. The OR for headache was 1.31 (95% confidence limits (CL); 1.07, 1.66) during lighting days as compared to non-lightning days. The addition of thunderstorm-associated weather variables as covariates were only able to reduce the OR for headache on lightning days to 1.18 (95% CL; 1.02, 1.37). The probability of having a headache on lightning days was also further increased when the average current of lightning strikes for the day was more negative. CONCLUSION: This study suggests that lightning represents a trigger for headache in migraineurs that cannot be completely explained by other meteorological factors. It is unknown if lightning directly triggers headaches through electromagnetic waves or indirectly through production of bioaerosols (e.g. ozone), induction of fungal spores or other mechanisms. These results should be interpreted cautiously until replicated in a second dataset.

Mid-cycle headaches and their relationship to different patterns of premenstrual stress symptoms.

BACKGROUND: Recent research has shown that affective changes associated with the menstrual cycle may follow diverse patterns, including a classic premenstrual syndrome pattern, as well as the mirror opposite pattern, referred to as a mid-cycle pattern. OBJECTIVE: Test for the presence of a mid-cycle pattern of headaches, in addition to a menstrual pattern and a noncyclic pattern; test for an association between experiencing a specific pattern of headaches and a specific (previously identified) pattern of depression/anxiety; and test for mean-level differences, across headache pattern groups, in average headache index and depression/anxiety scores (averaged across 2 menstrual cycles for each participant). METHODS: A sample of 213 female university students completed daily questionnaires regarding symptoms of headaches and depression/anxiety for 2 menstrual cycles. Hierarchical linear modeling, polynomial multiple regression, analyses of variance, and chi-square analyses were used to test the hypotheses. RESULTS: Confirmed the existence of a mid-cycle pattern of headaches (16%), in addition to a menstrual pattern (51%), and a noncyclic pattern of headaches (33%). Patterns of headaches and affective change were significantly associated (χ(2) = 21.33, P = .0003; 54% correspondence), as were the average headache index and depression/anxiety scores (r = .49; P < .0001). No significant mean-level differences were found between the headache pattern groups on the average headache index scores or depression/anxiety scores. CONCLUSIONS: A significant number of women experience a mid-cycle pattern of headaches during the menstrual cycle. Moreover, women often, but not always, demonstrate the same pattern of headaches and depression/anxiety symptoms.

Causality and headache triggers.

OBJECTIVE: The objective of this study was to explore the conditions necessary to assign causal status to headache triggers. BACKGROUND: The term "headache trigger" is commonly used to label any stimulus that is assumed to cause headaches. However, the assumptions required for determining if a given stimulus in fact has a causal-type relationship in eliciting headaches have not been explicated. METHODS: A synthesis and application of Rubin's Causal Model is applied to the context of headache causes. From this application, the conditions necessary to infer that 1 event (trigger) causes another (headache) are outlined using basic assumptions and examples from relevant literature. RESULTS: Although many conditions must be satisfied for a causal attribution, 3 basic assumptions are identified for determining causality in headache triggers: (1) constancy of the sufferer, (2) constancy of the trigger effect, and (3) constancy of the trigger presentation. A valid evaluation of a potential trigger's effect can only be undertaken once these 3 basic assumptions are satisfied during formal or informal studies of headache triggers. CONCLUSIONS: Evaluating these assumptions is extremely difficult or infeasible in clinical practice, and satisfying them during natural experimentation is unlikely. Researchers, practitioners, and headache sufferers are encouraged to avoid natural experimentation to determine the causal effects of headache triggers. Instead, formal experimental designs or retrospective diary studies using advanced statistical modeling techniques provide the best approaches to satisfy the required assumptions and inform causal statements about headache triggers.

Risk factors for migraine disease progression: a narrative review for a patient-centered approach.

BACKGROUND: In individuals with migraine, attacks may increase in frequency, severity, or both. Preventing migraine progression has emerged as a treatment goal in headache subspecialty practice, but there may be less awareness in general neurology or primary care settings where most people with migraine who seek treatment consult. Herein, we review the definition of and risk factors for migraine progression and consider strategies that could reduce its risk. METHODS: A group of headache expert healthcare professionals, clinicians, and researchers reviewed published evidence documenting factors associated with increased or decreased rates of migraine progression and established expert opinions for disease management recommendations. Strength of evidence was rated as good, moderate, or based solely on expert opinion, using modified criteria for causation developed by AB Hill. RESULTS: Migraine progression is commonly operationally defined as the transition from ≤ 15 to ≥ 15 monthly headache days among people with migraine; however, this does not necessarily constitute a fundamental change in migraine biology and other definitions should be considered. Established and theoretical key risk factors for migraine progression were categorized into five domains: migraine disease characteristics, treatment-related factors, comorbidities, lifestyle/exogenous factors, and demographic factors. Within these domains, good evidence supports the following risk factors: poorly optimized acute headache treatment, cutaneous allodynia, acute medication overuse, selected psychiatric symptoms, extra-cephalic chronic pain conditions, metabolism-related comorbidities, sleep disturbances, respiratory conditions, former/current high caffeine intake, physical inactivity, financial constraints, tobacco use, and personal triggers as risk factors. Protective actions that may mitigate migraine progression are sparsely investigated in published literature; our discussion of these factors is primarily based on expert opinion. CONCLUSIONS: Recognizing risk factors for migraine progression will allow healthcare providers to suggest protective actions against migraine progression (Supplementary Fig. 1). Intervention studies are needed to weight the risk factors and test the clinical benefit of hypothesized mitigation strategies that emerge from epidemiological evidence.