Effect of galcanezumab in women with episodic migraine meeting criteria for menstrually related migraine: A post hoc analysis of EVOLVE-1 and EVOLVE-2.

BACKGROUND: We evaluated galcanezumab for migraine prevention in patients who met International Classification of Headache Disorders, 3rd edition criteria for menstrually related migraine (MRM). METHODS: Patients were identified post hoc from three double-blind, randomized, phase 3 clinical trials in patients with episodic migraine. Patients completed a 1-month prospective baseline period and up to 6 months (EVOLVE-1 and -2, studies pooled) of double-blind treatment with galcanezumab (120 mg/month) or placebo. Menses and headache information were recorded by electronic daily diary. Patients with a migraine attack starting during the 5-day perimenstrual interval (first day of bleeding ± 2 days) for ≥2 of their first three diary-recorded menstrual cycles were categorized as having MRM. The primary efficacy measure was mean change in monthly migraine headache days from baseline, averaged over Months 4 through 6. Response rates, change in monthly perimenstrual migraine headache days, monthly non-perimenstrual migraine headache days, and quality of life were also assessed. RESULTS: Post hoc MRM analysis criteria were met by 462/1133 women (41%). Mean (standard deviation) baseline monthly migraine headache days were 9.7 (±3.1; n = 146) for galcanezumab-treated patients and 9.6 (±2.8; n = 316) for placebo-treated patients. The mean change (standard error [SE]) in migraine headache days over Months 4 through 6 was -5.1 days (±0.39) for galcanezumab versus -3.2 (±0.35) for placebo (p < 0.001). The mean change (SE) in perimenstrual migraine headache days over Months 4 through 6 was -0.75 days (±0.08) for galcanezumab versus -0.49 (±0.07) for placebo (p = 0.004). For migraine headache days outside the perimenstrual period, the mean change in migraine headache days was -4.6 (±0.38) for galcanezumab and -2.8 (±0.33) for placebo (p < 0.001). Improvements in response rates and the Migraine-Specific Quality of Life Questionnaire were also observed over Months 4 through 6. CONCLUSION: Galcanezumab was effective for migraine prevention in women with MRM.

Safety and efficacy of ubrogepant for the acute treatment of perimenstrual migraine attacks: A post hoc analysis.

OBJECTIVE: To evaluate the efficacy and safety of ubrogepant for the acute treatment of perimenstrual migraine (pmM) attacks. BACKGROUND: Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine in adults. METHODS: After completing one of two phase 3 trials, participants could enroll in a phase 3, 52-week, open-label, long-term safety extension trial and were re-randomized 1:1:1 to usual care, ubrogepant 50 mg, or ubrogepant 100 mg. This post hoc analysis evaluated the efficacy of ubrogepant in a subset of women who treated ≥1 pmM or non-pmM attack with ubrogepant. A pmM attack started on or between 2 days before and the first 3 days of menstrual bleeding. Mean (standard deviation [SD]) percentages of ubrogepant-treated attacks achieving 2-h pain freedom and pain relief were reported, with outcomes weighted equally by participant. RESULTS: Of 734 women in the modified intent-to-treat population, 354 reported ≥1 menstrual cycle start date and a ubrogepant-treated headache day in the same month. A qualifying pmM and non-pmM attack was reported by 278 and 716 women, respectively. Pain freedom at 2 h was achieved in a mean (SD) of 28.7% (37.4) of pmM attacks and 22.1% (26.9) of non-pmM attacks treated with ubrogepant 50 mg (p = 0.054) and 29.7% (35.2) versus 25.3% (26.3) of attacks treated with ubrogepant 100 mg (p = 0.757). No difference was found in the mean percentage of ubrogepant-treated pmM and non-pmM attacks that achieved 2-h pain relief with ubrogepant 50 mg (64.8% [39.9] vs. 65.2% [32.4]; p = 0.683) and with 100 mg (67.1% [37.4] vs. 68.4% [30.2]; p = 0.273). Treatment-related treatment-emergent adverse events were reported by 8.8% (12/137) and 12.8% (18/141) in the ubrogepant 50 and 100 mg pmM subgroups, respectively. CONCLUSIONS: Ubrogepant demonstrated similar efficacy for the treatment of pmM and non-pmM attacks. No new safety signals were identified.

Efficacy of lasmiditan for the acute treatment of perimenstrual migraine.

BACKGROUND: Perimenstrual migraine attacks in women with menstrual migraine is difficult to treat. This post-hoc analysis evaluated the efficacy of lasmiditan, a high affinity and selective 5-HT1F receptor agonist, for perimenstrual attacks. METHODS: Patients from two randomized, double-blind, placebo-controlled clinical trials (MONONOFU and CENTURION) were instructed to treat an attack with a single dose of study medication within four hours of pain onset. After dosing, the proportion of patients who achieved freedom from migraine-related head pain, most bothersome symptom, and disability was reported at baseline up to 48 hours after dose and pooled data were evaluated. RESULTS: A total of 303 patients (MONONOFU N = 78; CENTURION N = 225) treated perimenstrual migraine attacks with lasmiditan 50 mg (N = 24), 100 mg (N = 90), 200 mg (N = 110), and placebo (N = 79). More patients achieved migraine-related head pain freedom with lasmiditan 200 mg versus placebo at all time points assessed. At 2 hours, 33.6% of patients in the 200-mg group (p < 0.001), and 16.7% of patients in the 100-mg (p = 0.11) and 50-mg (p = 0.19) groups were pain free, compared with 7.6% in the placebo group. CONCLUSIONS: Lasmiditan treatment of perimenstrual migraine attacks was associated with freedom from migraine-related head pain at two hours, early onset of efficacy, and sustained efficacy.Clinical Trial registration: NCT03962738 and NCT03670810.

Time trends in contraceptive prescribing in UK primary care 2000-2018: a repeated cross-sectional study.

BACKGROUND: Over the last 20 years, new contraceptive methods became available and incentives to increase contraceptive uptake were introduced. We aimed to describe temporal trends in non-barrier contraceptive prescribing in UK primary care for the period 2000-2018. METHODS: A repeated cross-sectional study using patient data from the IQVIA Medical Research Data (IMRD) database. The proportion (95% CI) of women prescribed non-barrier contraception per year was captured. RESULTS: A total of 2 705 638 women aged 15-49 years were included. Between 2000 and 2018, the proportion of women prescribed combined hormonal contraception (CHC) fell from 26.2% (26.0%-26.3%) to 14.3% (14.2%-14.3%). Prescriptions for progestogen-only pills (POPs) and long-acting reversible contraception (LARC) rose from 4.3% (4.3%-4.4%) to 10.8% (10.7%-10.9%) and 4.2% (4.1%-4.2%) to 6.5% (6.5%-6.6%), respectively. Comparing 2018 data for most deprived versus least deprived areas, women from the most deprived areas were more likely to be prescribed LARC (7.7% (7.5%-7.9%) vs 5.6% (5.4%-5.8%)) while women from the least deprived areas were more likely to be prescribed contraceptive pills (20.8% (21.1%-21.5%) vs 26.2% (26.5%-26.9%)). In 2009, LARC prescriptions increased irrespective of age and social deprivation in line with a pay-for-performance incentive. However, following the incentive's withdrawal in 2014, LARC prescriptions for adolescents aged 15-19 years fell from 6.8% (6.6%-7.0%) in 2013 to 5.6% (5.4%-5.8%) in 2018. CONCLUSIONS: CHC prescribing fell by 46% while POP prescribing more than doubled. The type of contraception prescribed was influenced by social deprivation. Withdrawal of a pay-for-performance incentive may have adversely affected adolescent LARC uptake, highlighting the need for further intervention to target this at-risk group.

Need of guidance in disabling and chronic migraine identification in the primary care setting, results from the european MyLife anamnesis survey.

BACKGROUND: Migraine affects 80.8 million people in Western Europe and is the first cause of disability among people between ages 15 and 49 worldwide. Despite being a highly prevalent and disabling condition, migraine remains under-diagnosed and poorly managed. METHODS: An international, online survey was conducted among 201 general practitioners (GPs) from 5 European countries (France, Germany, Italy, Spain and the UK) who are experienced in the management of headache disorders. RESULTS: The majority of GPs (82%) did not refer patients with chronic migraine (CM) to migraine specialists. Among those patients, the participants estimated that around 55% received preventive medication. Some differences between countries were observed regarding referral rate and prescription of preventive treatment. Most GPs (87%) reported a lack of training or the need to be updated on CM management. Accordingly, 95% of GPs considered that a migraine anamnesis guide could be of use. Overall, more than 95% of GPs favoured the use of a patient diary, a validated diagnostic tool and a validated scale to assess impact of migraine on patients' daily life. Similarly, 96% of the GPs considered that the inclusion of warning features (red flags) in an anamnesis guide would be useful and 90% favoured inclusion of referral recommendations. CONCLUSIONS: The results from this survey indicate that more education on diagnosis and management of CM is needed in primary care. Better knowledge on the recognition and management of migraine in primary care would improve both prognosis and diagnosis and reduce impact of migraine on patients' lives, healthcare utilization and societal burden.

Menstrual migraine: a distinct disorder needing greater recognition.

The term menstrual migraine refers to migraine that is associated with menstruation by more than chance, but it does not define pathophysiology. Menstrual migraine affects about 20-25% of female migraineurs in the general population, and 22-70% of patients presenting to headache clinics. In women diagnosed with menstrual migraine, perimenstrual migraine attacks are associated with substantially greater disability than their non-menstrual attacks. Loose interpretation of diagnostic criteria has led to conflicting results in studies on prevalence figures, clinical characteristics, and response to treatment. Importantly, clinical trials often do not distinguish between perimenstrual attacks in women diagnosed with menstrual migraine and attacks associated with menstruation by chance. Two pathophysiological mechanisms have been identified: oestrogen withdrawal and prostaglandin release. Although management strategies targeting these mechanisms might be effective, the evidence is not robust. Given how common and debilitating this distinct condition is, more research investment is needed to expand understanding of its pathophysiology and to develop more effective treatment strategies.

Current clinical practice in disabling and chronic migraine in the primary care setting: results from the European My-LIFE anamnesis survey.

BACKGROUND: Migraine is a prevalent and disabling headache disorder that affects more than 1.04 billion individuals world-wide. It can result in reduction in quality of life, increased disability, and high socio-economic burden. Nevertheless, and despite the availability of evidence-based national and international guidelines, the management of migraine patients often remains suboptimal, especially for chronic migraine (CM) patients. METHODS: My-LIFE anamnesis project surveyed 201 General practitioners (GPs) from 5 European countries (France, Germany, Italy, Spain, and the UK) with the aim of understanding chronic migraine (CM) patients' management in the primary care setting. RESULTS: In our survey, GPs diagnosed episodic migraine (EM) more often than CM (87% vs 61%, p < 0.001). We found that many CM patients were not properly managed or referred to specialists, in contrast to guidelines recommendations. The main tools used by primary-care physicians included clinical interview, anamnesis guide, and patient diary. Tools used at the first visit differed from those used at follow-up visits. Up to 82% of GPs reported being responsible for management of patients diagnosed with disabling or CM and did not refer them to a specialist. Even when the GP had reported referring CM patients to a specialist, 97% of them were responsible for their follow-up. Moreover, the treatment prescribed, both acute and preventive, was not in accordance with local and international recommendations. GPs reported that they evaluated the efficacy of the treatment prescribed mainly through patient perception, and the frequency of follow-up visits was not clearly established in the primary care setting. These results suggest that CM is underdiagnosed and undertreated; thereby its management is suboptimal in the primary care. CONCLUSIONS: There is a need of guidance in the primary care setting to both leverage the management of CM patients and earlier referral to specialists, when appropriate.

Menstrual and perimenopausal migraine: A narrative review.

Migraine is affected by the changing hormone environment, with perimenopause associated with increased migraine, particularly menstrual migraine. Menstrual attacks are recognised to be more disabling and less responsive to treatment compared with non-menstrual attacks. Perimenstrual estrogen 'withdrawal' is implicated in the pathophysiology of menstrual migraine, with increased prevalence of migraine in perimenopause associated with unpredictable estrogen fluctuations. Perimenopausal women often have contraceptive needs as well as menopause symptoms and it is important to understand the potential effects of exogenous hormones on migraine. Maintaining stable estrogen levels with exogenous hormones can benefit migraine but clinical trial data are limited. This short narrative review addresses the diagnosis and management of menstrual migraine in perimenopausal women, and discusses the management of menopause symptoms in peri- and postmenopausal women with migraine.

Migraine start, course and features over the cycle of combined hormonal contraceptive users with menstrual migraine - temporal relation to bleeding and hormone withdrawal: a prospective diary-based study.

BACKGROUND: Many studies have described the features of menstrually-related migraines (MRM) in the natural cycle and the efficacy of prevention. MRM in combined hormonal contraceptive (CHC) users has scarcely been researched. Estrogen and progestin withdrawal in CHC users are both more abrupt and from higher hormone levels compared with the natural cycle. An advantage for prevention of MRM in CHC users is that the hormone withdrawal is predictable. It is unknown, whether the attacks during the hormone-free interval are associated with the hormone withdrawal or onset of bleeding. Improved understanding of this relation might contribute to better define and shorten the time interval for prevention. METHODS: For this prospective diary-based trial we collected migraine and bleeding data from CHC users with MRM in at least two of three cycles. We analyzed frequency of migraines over the whole CHC cycle. During the hormone-free phase the relation between onset of migraine and onset of bleeding was studied. We compared pain intensity and identified prolonged-migraine attacks during hormone use and the hormone-free phase. RESULTS: During the hormone-free interval the number of migraine days and the pain score/migraine day were significantly higher in comparison with the mean during hormone use. The prevalence of migraine attacks was fourfold on hormone-free days 3-6. Migraine typically started on days 1-4. Migraine in relation to bleeding mostly occurred on days - 1 to + 4. In 78% of the cycles the first migraine day occurred during bleeding days 1 ± 2 and 48% started on days - 1 and day 1. The predictability of the first bleeding day was very high. CONCLUSION: The day of hormone-withdrawal migraine and the first bleeding day are highly predictable in CHC users. Migraine onset is mostly day - 1 and 1 of the bleeding and on days 1-4 of the hormone-free interval. Migraine attacks of CHC users in the hormone-free interval are severe and long lasting. Further trials are necessary to investigate if this knowledge can be used to optimise prevention.

A Markov chain method for counting and modelling migraine attacks.

To ensure reproducibility in research quantifying episodic migraine attacks, and identifying attack onset, a sound theoretical model of a migraine attack, paired with a uniform standard for counting them, is necessary. Many studies report on migraine frequencies-e.g. the fraction of migraine-days of the observed days-without paying attention to the number of discrete attacks. Furthermore, patients' diaries frequently contain single, migraine-free days between migraine-days, and we argue here that such 'migraine-locked days' should routinely be interpreted as part of a single attack. We tested a simple Markov model of migraine attacks on headache diary data and estimated transition probabilities by mapping each day of each diary to a unique Markov state. We explored the validity of imputing migraine days on migraine-locked entries, and estimated the effect of imputation on observed migraine frequencies. Diaries from our patients demonstrated significant clustering of migraine days. The proposed Markov chain model was shown to approximate the progression of observed migraine attacks satisfactorily, and imputing on migraine-locked days was consistent with the conceptual model for the progression of migraine attacks. Hence, we provide an easy method for quantifying the number and duration of migraine attacks, enabling researchers to procure data of high inter-study validity.

Migraine, low-dose combined hormonal contraceptives, and ischemic stroke in young women: a systematic review and suggestions for future research.

Introduction: Migraine and combined hormonal contraceptives (CHCs) increase the risk of ischemic stroke in young women; however, the contribution of low-dose (<50 µg ethinylestradiol) CHCs to the risk of ischemic stroke in young women with migraine is not well defined.Areas covered: The authors performed a systematic review of observational studies indexed in PubMed and Scopus from inception to 22 May 2019, reporting the effect sizes of ischemic stroke in women with migraine using low-dose CHCs compared with those without migraine not using CHCs. All the four included case-control studies, including a total of 12,256 women, reported increased odds of ischemic stroke in women with migraine and low-dose CHC use compared with those without migraine not using CHCs. A meta-analysis was not feasible due to significant heterogeneity.Expert opinion: Strong data on the joint effect of migraine and CHC use on risk of ischemic stroke are lacking especially referring to the role of aura and headache frequency. Evidence suggests that the association with ischemic stroke is driven by migraine with aura. More robust data are needed to assess whether CHCs remain viable for women with migraine without aura, and whether their use could extend to some women with migraine with aura.

Identifying menstrual migraine- improving the diagnostic criteria using a statistical method.

OBJECTIVE: To develop a robust statistical tool for the diagnosis of menstrually related migraine. BACKGROUND: The International Classification of Headache Disorders (ICHD) has diagnostic criteria for menstrual migraine within the appendix. These include the requirement for menstrual attacks to occur within a 5-day window in at least [Formula: see text] menstrual cycles ([Formula: see text]-criterion). While this criterion has been shown to be sensitive, it is not specific. Yet in some circumstances, for example to establish the underlying pathophysiology of menstrual attacks, specificity is also important, to ensure that only women in whom the relationship between migraine and menstruation is more than a chance occurrence are recruited. METHODS: Using a simple mathematical model, a Markov chain, to model migraine attacks we developed a statistical criterion to diagnose menstrual migraine (sMM). We then analysed a data set of migraine diaries using both the [Formula: see text]-criterion and the sMM. RESULTS: sMM was superior to the [Formula: see text]-criterion for varying numbers of menstrual cycles and increased in accuracy with more cycle data. In contrast, the [Formula: see text]-criterion showed maximum sensitivity only for three cycles, although specificity increased with more cycle data. CONCLUSIONS: While the ICHD [Formula: see text]-criterion is a simple screening tool for menstrual migraine, the sMM provides a more specific diagnosis and can be applied irrespective of the number of menstrual cycles recorded. It is particularly useful for clinical trials of menstrual migraine where a chance association between migraine and menstruation must be excluded.

Symptoms of premenstrual syndrome in female migraineurs with and without menstrual migraine.

BACKGROUND: Menstrual migraine (MM) and premenstrual syndrome (PMS) are two conditions linked to specific phases of the menstrual cycle. The exact pathophysiological mechanisms are not fully understood, but both conditions are hypothesized to be triggered by female sex hormones. Co-occurrence of MM and PMS is controversial. The objective of this population-based study was to compare self-assessed symptoms of PMS in female migraineurs with and without MM. A total of 237 women from the general population who self-reported migraine in at least50% of their menstruations in a screening questionnaire were invited to a clinical interview and diagnosed by a neurologist according to the International Classification of Headache Disorders II (ICHD II), including the appendix criteria for MM. All women were asked to complete a self-administered form containing 11 questions about PMS-symptoms adapted from the Diagnostic and Statistical Manual of Mental Disorders. The number of PMS symptoms was compared among migraineurs with and without MM. In addition, each participant completed the Headache Impact test (HIT-6) and Migraine Disability Assessment Score (MIDAS). FINDINGS: A total of 193 women returned a complete PMS questionnaire, of which 67 women were excluded from the analyses due to current use of hormonal contraception (n = 61) or because they did not fulfil the ICHD-criteria for migraine (n = 6). Among the remaining 126 migraineurs, 78 had MM and 48 non-menstrually related migraine. PMS symptoms were equally frequent in migraineurs with and without MM (5.4 vs. 5.9, p = 0.84). Women with MM reported more migraine days/month, longer lasting migraine attacks and higher HIT-6 scores than those without MM, but MIDAS scores were similar. CONCLUSION: We did not find any difference in number of self-reported PMS-symptoms between migraineurs with and without MM.

The 7-day contraceptive hormone-free interval should be consigned to history.

AIM: This review summarises the available data on the disadvantages of the 7-day contraceptive-free interval (CFI) of combined oral contraceptives (COCs), in contrast to shorter CFIs or continuous use - including flexible regimens - and provides recommendations for practice. METHODS: Relevant papers were identified by Medline and PubMed. The final reference list was generated on the basis of relevance to the review, with priority given to systematic reviews and randomised controlled trials. RESULTS: There is considerable inter- and intra-individual variation in the absorption and metabolism of COCs. Even with perfect use, the loss of endocrine suppression during the standard 7-day CFI allows follicular development with the risk of escape ovulation in a vulnerable minority. This risk increases in typical users whenever the CFI is prolonged: late restarts are a common reason for pill omissions. Shortening or eliminating the CFI improves contraceptive efficacy using the lowest doses available, without evidence to date of compromised safety. CONCLUSIONS: There is no scientific evidence to support a 7-day CFI and it should be replaced either by a continuous flexible regimen, or extended regimens with a shortened CFI, prescribed first-line. In women preferring a monthly 'bleed', a 4-day CFI similarly provides a greater safety margin when pills are omitted.

Migraine, menopause and hormone replacement therapy.

Perimenopause marks a period of increased migraine prevalence in women and many women also report troublesome vasomotor symptoms. Migraine is affected by fluctuating estrogen levels with evidence to support estrogen 'withdrawal' as a trigger of menstrual attacks of migraine without aura, while high estrogen levels can trigger migraine aura. Maintaining a stable estrogen environment with estrogen replacement can benefit estrogen-withdrawal migraine particularly in women who would also benefit from relief of vasomotor symptoms. In contrast to contraceptive doses of ethinylestradiol, migraine aura does not contraindicate use of physiological doses of natural estrogen. In women with migraine with or without aura, using only the lowest doses of transdermal estrogen necessary to control vasomotor symptoms minimizes the risk of unwanted side effects. Cyclical progestogens can have an adverse effect on migraine so continuous progestogens, as provided by the levonorgestrel intrauterine system or in continuous combined transdermal preparation, are preferred. There are no data on the effect of micronized progesterone on migraine, either cyclical or continuous. Non-hormonal options for both conditions are limited but there is evidence of efficacy for escitalopram and venflaxine.

Migraine.

This issue provides a clinical overview of migraine, focusing on risk, prevention, diagnosis, treatment, follow-up, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers.

Investigation of polymorphisms in genes involved in estrogen metabolism in menstrual migraine.

Migraine is a common, disabling headache disorder, which is influenced by multiple genes and environmental triggers. After puberty, the prevalence of migraine in women is three times higher than in men and >50% of females suffering from migraine report a menstrual association, suggesting hormonal fluctuations can influence the risk of migraine attacks. It has been hypothesized that the drop in estrogen during menses is an important trigger for menstrual migraine. Catechol-O-methyltransferase (COMT) and Cytochrome P450 (CYP) enzymes are involved in estrogen synthesis and metabolism. Functional polymorphisms in these genes can influence estrogen levels and therefore may be associated with risk of menstrual migraine. In this study we investigated four single nucleotide polymorphisms in three genes involved in estrogen metabolism that have been reported to impact enzyme levels or function, in a specific menstrual migraine cohort. 268 menstrual migraine cases and 142 controls were genotyped for rs4680 in COMT (Val158Met), rs4646903 and rs1048943 in CYP1A1 (T3801C and Ile462Val) and rs700519 in CYP19A1 (Cys264Arg). Neither genotype nor allele frequencies for the COMT and CYP SNPs genotyped were found to be significantly different between menstrual migraineurs and controls by chi-square analysis (P>0.05). Therefore we did not find association of functional polymorphisms in the estrogen metabolism genes COMT, CYP1A1 or CYP19A1 with menstrual migraine. Further studies are required to assess whether menstrual migraine is genetically distinct from the common migraine subtypes and identify genes that influence risk.