Patterns of migraine medication use in Norway: A nationwide registry-based observational study.

OBJECTIVE: The objective of this study was to describe and discuss patterns of migraine medication use in the entire Norwegian population. METHODS: In this nationwide, observational study, all individuals with a migraine-related prescription between 2010 and 2020 were identified using the Norwegian Prescription Database. The outcomes of interest were the incidence and 1-year prevalence of migraine medication users, as well as individuals with triptan overuse. Patterns of medication use were statistically compared between women and men adjusted for age, year of treatment start, comorbidities and county of residence calculating adjusted odds ratios (aOR) with 95% confidence intervals (CI). RESULTS: We identified 327,904 migraine medication users. The incidence ranged from 0.39% to 0.46%, and the 1-year prevalence increased from 1.99% to 2.99%. Preventive use increased >50% during the study period. Preventives were significantly more often prescribed to women than to men (39.72% vs. 33.75%; aOR 1.41, 95% CI 1.38 to 1.44). Triptan overuse was significantly more common among women, but women with overuse were more often using preventives, as compared to men (56.64% vs 52.69%; aOR = 1.43, 95% CI 1.37 to 1.49). CONCLUSION: The prevalence of medically treated migraine is low. Overuse of triptans is frequent, especially among women. Clinicians should be encouraged to try out different triptans, recognize triptan overuse, and prescribe preventives when indicated.

Evaluation of outcomes of calcitonin gene-related peptide (CGRP)-targeting therapies for acute and preventive migraine treatment based on patient sex.

BACKGROUND: Women show increased prevalence and severity of migraine compared to men. Whether small molecule calcitonin gene-related peptide receptor (CGRP-R) antagonists (i.e., gepants) and monoclonal antibodies targeting either the CGRP-R or the CGRP peptide might show sexually dimorphic outcomes for acute and preventive therapy has not been established. METHODS: We conducted a subpopulation analysis of available published data from FDA reviews to evaluate potential sex differences in the response rates of ubrogepant, rimegepant and zavegepant for acute migraine therapy. Available data from FDA reviews of erenumab, fremanezumab, galcanezumab and eptinezumab, approved CGRP-R and CGRP monoclonal antibodies and of atogepant were examined for prevention outcomes based on patient sex. Preventive outcomes were analyzed separately for patients with episodic migraine and chronic migraine. RESULTS: In women, the three approved gepants produced statistically significant drug effects regardless of dose tested on the FDA mandated co-primary endpoints, the proportion of patients achieving two-hour pain-freedom and the proportion of patients free of their most bothersome symptom at two hours post-dose. In women, the average placebo-subtracted two-hour pain-freedom proportion was 9.5% (CI: 7.4 to 11.6) and the average numbers needed to treat was 11. The free from most bothersome symptom at two hours outcomes were also significant in women. The gepant drugs did not reach statistically significant effects on the two-hour pain-freedom endpoint in the men, with an average drug effect of 2.8% (CI: -2.5 to 8.2) and an average number needed to treat of 36. For freedom from most bothersome symptom at two hours post-dose endpoint, differences were not significant in male patients. The treatment effect in each of the gepant studies was always numerically greater in women than in men. In evaluation of prevention outcomes with the antibodies or atogepant using the change from the specified primary endpoint (e.g., monthly migraine days), the observed treatment effect for episodic migraine patients almost always favored drug over placebo in both women and men. For chronic migraine patients the treatment effects of antibodies were similar in men and women and always favored the drug treated group.Conclusion/Interpretation: Small molecule CGRP-R antagonists are effective in acute migraine therapy in women but available data do not demonstrate effectiveness in men. CGRP-targeting therapies are effective for migraine prevention in both male and female episodic migraine patients but possible sex differences remain uncertain. In male and female chronic migraine patients, CGRP/CGRP-R antibodies were similarly effective. The data highlight possible differential effects of CGRP targeted therapies in different patient populations and the need for increased understanding of CGRP neurobiology in men and women.

Comparative effectiveness and tolerability of calcitonin gene-related peptide (CGRP) monoclonal antibodies and onabotulinumtoxinA in chronic migraine: A multicenter, real-world study in Taiwan.

OBJECTIVE: To compare the real-world effectiveness and tolerability of calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) and onabotulinumtoxinA in chronic migraine (CM) patients. METHODS: This multicenter study involved retrospective analysis of prospectively collected data of CM patients treated with CGRP mAbs or onabotulinumtoxinA, including difficult-to-treat (DTT) patients (i.e., ≥3 preventive failures). Treatment outcomes were determined at 6 months based on prospective headache diaries and Migraine Disability Assessment (MIDAS). RESULTS: The study included 316 (55 M/261F, mean age 44.4 ± 13.5 years) and 333 (61 M/272F, mean age 47.9 ± 13.4 years) CM patients treated with CGRP mAbs or onabotulinbumtoxinA, respectively. At 6 months, CGRP mAb treatment was associated with a greater decrease in monthly migraine days (MMDs) (-13.0 vs. -8.7 days/month, p < 0.001) and a higher ≥50% responder rate (RR) (74.7% vs. 50.7%, p < 0.001) compared with onabotulinumtoxinA injections. The findings were consistent in DTT patients (-13.0 vs. -9.1 MMDs, p < 0.001; ≥50% RR: 73.9% vs. 50.3%, p < 0.001) or those with medication-overuse headache (MOH) (-13.3 vs. -9.0 MMDs, p < 0.001; ≥50% RR: 79.0% vs. 51.6%, p < 0.001). Besides, patients receiving CGRP mAbs had greater improvement (-42.2 vs. -11.8, p < 0.001) and a higher ≥50% RR (62.0% vs. 40.0%, p = 0.001) in MIDAS scores and a lower rate of adverse events (AEs) (6.0% vs. 21.0%, p < 0.001). However, none of the patients discontinued treatment due to AEs. CONCLUSIONS: In this multicenter, real-world study, CGRP mAbs were more effective than onabotulinumtoxinA in CM patients, even in DTT or MOH patients. All of these injectables were well tolerated. Further prospective studies are needed to verify these findings.

Utilization, Expenditure, and Treatment Patterns Associated With Calcitonin Gene-Related Peptide Monoclonal Antibodies Reimbursed Subject to a Managed Access Protocol in Ireland.

OBJECTIVES: Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are novel high-cost treatments for the prevention of migraine. This study presents data on utilization, expenditure, and treatment patterns with CGRP mAbs available under a managed access protocol in Ireland, to a cohort of treatment refractory patients (failed 3 or more previous treatments) with chronic migraine. METHODS: Data were extracted from the Primary Care Reimbursement Service High Tech claims database and special drug request online system and analyzed using Microsoft Excel and SAS. Treatment persistence was evaluated by refill patterns, and adherence was evaluated using the proportion of days covered method. Expenditure data were extracted directly from the database. RESULTS: Between September 1, 2021 and April 30, 2023, 1517 applications for reimbursement approval for a CGRP mAb were received; 1458 (96.1%) were approved for reimbursement. Total expenditure on CGRP mAbs in year 1 (September 1, 2021 to August 31, 2022) was €3.2 million. The majority of patients initiated treatment with fremanezumab (60.8%) or erenumab (37.1%). Almost 90% of patients were considered adherent, and treatment persistence was high, with more than 75% of patients receiving more than 12 months of treatment in our 18-month study time frame. CONCLUSIONS: This study demonstrates the importance of active health technology management, after reimbursement, in enabling cost-effective use of high-cost treatments while providing budget certainty for the healthcare payer. High levels of adherence and persistence suggest that treatment is successfully targeted in situations which unmet clinical need is greatest.

Internal stigmatization in patients with chronic migraine and medication overuse headache.

OBJECTIVES: Internalized stigma can have profound effects on how individuals with migraines and other primary headache disorders see themselves and their quality of life. We aimed to investigate internalized stigma in patients with chronic migraines and medication overuse headaches. METHODS: A total of 57 patients (52 women, 5 men) were included in the study, 26 of these patients were affected by chronic migraine, 31 of them were affected by medication overuse headache and chronic migraine. The Internalized Stigma Scale in Mental Illness (Ristsher's stigmatization scale) and General Health Questionnaire were applied to all patients. RESULTS: In Ristsher's stigmatization scale, which measures internalization of stigma, internalized stigmatization was more significant in patients with medication overuse headache than in patients with chronic migraine compared to groups (p:0.05). The subtitle of alienation was statistically significant when the groups were compared to all subscales in the form of alienation, confirmation of stereotypes, perceived discrimination, social withdrawal and resistance to stigma (p:0.05). DISCUSSION: Although internal stigmatize has been observed in chronic migraine patients, medication overuse headache is also a type of headache with intense stigma. In addition, this internal stigma perhaps plays an active role in the transformation of chronic migraine patients to medication overuse headaches patient.

Headache/migraine-related stigma, quality of life, disability, and most bothersome symptom in adults with current versus previous high-frequency headache/migraine and medication overuse: results of the Migraine Report Card survey.

BACKGROUND: High-frequency headache/migraine (HFM) and overuse of acute medication (medication overuse [MO]) are associated with increased disability and impact. Experiencing both HFM and MO can potentially compound impacts, including stigma; however, evidence of this is limited. The objective of this report was to evaluate self-reported stigma, health-related quality of life (HRQoL), disability, and migraine symptomology in US adults with HFM + MO from the Harris Poll Migraine Report Card survey. METHODS: US adults (≥ 18 yrs., no upper age limit) who screened positive for migraine per the ID Migraine™ screener completed an online survey. Participants were classified into "current HFM + MO" (≥ 8 days/month with headache/migraine and ≥ 10 days/month of acute medication use over last few months) or "previous HFM + MO" (previously experienced HFM + MO, headaches now occur ≤ 7 days/month with ≤ 9 days/month of acute medication use). Stigma, HRQoL, disability, and most bothersome symptom (MBS) were captured. The validated 8-item Stigma Scale for Chronic Illnesses (SSCI-8) assessed internal and external stigma (scores ≥ 60 are clinically significant). Raw data were weighted to the US adult population. Statistically significant differences were determined by a standard t-test of column proportions and means at the 90% (p < 0.1) and 95% (p < 0.05) confidence levels. RESULTS: Participants (N = 550) were categorized as having current (n = 440; mean age 41.1 years; 54% female; 57% White, not Hispanic; 24% Hispanic; 11% Black, not Hispanic) or previous (n = 110; mean age 47.2 years; 49% female; 75% White, not Hispanic; 13% Hispanic; 4% Black, not Hispanic) HFM + MO. Compared to those with previous HFM + MO (21%), adults with current HFM + MO were more likely to experience clinically significant levels of stigma (47%). Men with current HFM + MO (52% compared to men with previous HFM + MO [25%] and women with current [41%] or previous [18%] HFM + MO), non-Hispanic Black (51% compared to White, not Hispanic [45%] and Hispanic [48%] current HFM + MO groups and White, not Hispanic previous HFM + MO [12%]), current HFM + MO aged 18-49 years (50% compared to those with current HFM + MO aged ≥ 50 years [33%] and those with previous HFM + MO aged 18-49 [34%] and ≥ 50 years [4%]), and employed respondents (53% current and 29% previous compared to those not employed [32% current and 12% previous]) reported higher rates of clinically significant stigma. Those with current HFM + MO were more likely to have worse HRQoL and disability due to headache/migraine. Respondents aged ≥ 50 years with current HFM + MO were more likely than respondents aged 18-49 years with current HFM + MO to indicate that their overall quality of life (66% vs. 52%) and their ability to participate in hobbies/activities they enjoy were negatively impacted by headache/migraine (61% vs. 49%). Pain-related symptoms were identified as the MBS. CONCLUSIONS: Together these data suggest that current and previous HFM + MO can be associated with undesirable outcomes, including stigma and reduced HRQoL, which were greatest among people with current HFM + MO, but still considerable for people with previous HFM + MO.

A Dutch cost-effectiveness analysis of fremanezumab versus best supportive care in patients with chronic migraine and inadequate response to prior preventive therapy.

BACKGROUND: Chronic migraine (CM) is the most severe and burdensome subtype of migraine. Fremanezumab is a monoclonal antibody that targets the calcitonin gene-related peptide pathway as a migraine preventive therapy. This study aimed to conduct a cost-effectiveness analysis of fremanezumab from a societal perspective in the Netherlands, using a Markov cohort simulation model. METHODS: The base-case cost-effectiveness analysis adhered to the Netherlands Authority guidelines. Fremanezumab was compared with best supportive care (BSC; acute migraine treatment only) in patients with CM and an inadequate response to topiramate or valproate and onabotulinumtoxinA (Dutch patient group [DPG]). A supportive analysis was conducted in the broader group of CM patients with prior inadequate response to 2-4 different classes of migraine preventive treatments. One-way sensitivity, probabilistic sensitivity, and scenario analyses were conducted. RESULTS: Over a lifetime horizon, fremanezumab is cost saving compared with BSC in the DPG (saving of €2514 per patient) and led to an increase of 1.45 quality-adjusted life-years (QALYs). In the broader supportive analysis, fremanezumab was cost effective compared with BSC, with an incremental cost-effectiveness ratio of €2547/QALY gained. Fremanezumab remained cost effective in all sensitivity and scenario analyses. CONCLUSION: In comparison to BSC, fremanezumab is cost saving in the DPG and cost effective in the broader population.

Clinical factors associated with day-to-day peak pain severity in individuals with chronic migraine: A cohort study using daily prospective diary data.

OBJECTIVE: To describe the association between day-to-day peak pain severity and clinical factors in individuals with chronic migraine (CM). BACKGROUND: Little is known about how clinical factors relate to day-to-day pain severity in individuals with CM. METHODS: Adults with CM were enrolled into this observational prospective cohort study that collected daily data about headache, associated symptoms, and lifestyle factors using a digital health platform (N1-Headache™) for 90 days. "Migraine days" were defined as days in which a headache occurred that had features described by the International Classification of Headache Disorders criteria. On these days, peak pain severity was recorded on a 4-point scale; on non-headache days peak pain severity was imputed as "0/none". The associations between peak pain severity and 12 clinical factors were modeled and adjusted for sex, age, daily headache, presence of menstrual bleeding, day of the week, and disability. All numerical and Likert scale variables were standardized prior to analysis. RESULTS: Data were available for 392 participants (35,280 tracked days). The sample was predominantly female (90.6%), with a mean (standard deviation) age of 39.9 (12.8) years. In the final multivariable model with random intercept and slopes, higher than typical self-reported levels of standardized stress (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.04-1.11), standardized irritability (OR 1.05, 95% CI 1.02-1.08), standardized sadness (OR 1.05, 95% CI 1.02-1.07), fatigue (OR 1.25, 95% CI 1.15-1.36), eyestrain (OR 1.38, 95% CI 1.26-1.52), neck pain (OR 1.94, 95% CI 1.76-2.13), skin sensitivity (OR 1.61, 95% CI 1.44-1.80), and dehydration (OR 1.29, 95% CI 1.18-1.42) were associated with higher reported peak pain severity levels, while standardized sleep quality (OR 0.96, 95% CI 0.93-0.99) and standardized waking feeling refreshed (OR 0.84, 95% CI 0.81-0.88) were associated with lower reported peak pain severity levels. The inclusion of a random intercept and random slopes improved upon more parsimonious models and illustrated large differences in individuals' reporting of peak severity according to the levels of the associated clinical factors. CONCLUSION: Our data showed that the experience of CM, from a pain severity perspective, is complex, related to multiple clinical variables, and highly individualized. These results suggest that future work should aim to study a personalized approach to both medical and behavioral interventions for CM based on which clinical factors relate to the individual's experience of pain severity.

Substance use in a Dutch migraine cohort compared with the general population.

OBJECTIVE: To evaluate self-reported substance user profiles for individuals with migraine and compare these to the general population. BACKGROUND: There is increasing attention to lifestyle influences such as substance use as presumed migraine triggers. METHODS: Data on substance use were collected by survey in a large migraine cohort and from the biannual survey in the general Dutch population for substances. A representative cohort of Dutch patients with migraine (n = 5176) and the Dutch general population (n = 8370) was included. Patients with migraine were subdivided into episodic (EM) and chronic migraine (CM). Substance consumption was compared between the general population and patients with migraine, and between migraine subgroups after standardization for sex and level of education. RESULTS: Included patients with migraine were 83.4% female (4319/5176) and had a mean (standard deviation) age of 44.8 (11.3) years. Patients with migraine reported less illicit drug use (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.42-0.55; p < 0.001), less current and lifetime smoking (OR 0.60, 95% CI 0.55-0.65; p < 0.001 and OR 0.75, 95% CI 0.71-0.79; p < 0.001), and less current alcohol consumption (OR 0.66, 95% CI 0.62-0.70; p < 0.001) compared with the general population. Prevalence of substance use was compared between CM and EM participants and showed higher illicit drug use (OR 1.73, 95% CI 1.11-2.69; p = 0.011), higher current smoking (OR 1.61, 95% CI 1.22-2.11; p < 0.001) but less alcohol use (OR 0.54, 95% CI 0.43-0.68; p < 0.001) for participants with CM compared with EM. No differences were found for a history of smoking (OR 1.18, 95% CI 0.92-1.50, p = 0.19). CONCLUSIONS: Individuals with migraine are less likely to use illicit drugs, smoke, or drink alcohol compared with the general population. Patients with CM less often consume alcohol, while they more often use illicit drugs and smoke compared to those with EM.

Impact of duration of chronic migraine on long-term effectiveness of monoclonal antibodies targeting the calcitonin gene-related peptide pathway-A real-world study.

OBJECTIVE: We assessed whether the effectiveness of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway changes according to the duration of chronic migraine (CM) over 12 months. BACKGROUND: In most patients, CM is a progressive disease starting with episodic migraine. Longer CM duration might be associated with more difficult treatment, probably because the mechanisms underlying chronicization are strengthened. Therefore, early treatment of CM could lead to better outcomes compared with later treatment. METHODS: This cohort study included individuals with CM treated with anti-CGRP mAbs in two tertiary headache centers from April 2019 to May 2023. The primary outcome included a change in monthly migraine days (MMDs) from baseline to the third trimester of treatment, 10-12 months. Secondary outcomes established whether response to anti-CGRP mAbs has a more rapid onset in individuals with shorter CM duration compared with longer duration; they included change in MMDs, monthly headache days (MHDs), and days and number of intakes of acute medication during each trimester compared to baseline. Additional outcomes included persisting MMDs, MHDs, and days and number of intakes of acute medication during each trimester of treatment. Patients were compared across tertiles of the overall CM duration. RESULTS: The study included 335 individuals with CM, with a median (interquartile range [IQR]) age of 48 (39-57) years; 270 (80.6%) were women. Patients in the highest tertile of CM duration (aged 18-60 years) were older than patients in the lower duration tertiles (0-7 years and 8-18 years, respectively), with a median (IQR) age of 56 (48-64) years compared with 42 (31-50) years, and 48 (39-56)years, respectively (p = 0.025); however, this difference was likely due to a correlation between age and disease duration. The change in MMDs from baseline to the last trimester of treatment (10-12 months) was comparable across tertiles of CM duration (median [IQR] -12 [-18 to -5] days, -12 [-17 to -6] days, and -12 [-18 to -4] days; p = 0.946). No difference emerged in secondary outcomes, suggesting a similar time to onset of anti-CGRP mAbs effect across all tertiles of CM duration. CONCLUSIONS: Our data showed that anti-CGRP mAbs are effective and have a rapid onset of action in CM regardless of disease duration.

Early effect of onabotulinumtoxinA on EEG-based functional connectivity in patients with chronic migraine: A pilot study.

OBJECTIVE: In this pilot prospective cohort study, we aimed to evaluate, using high-density electroencephalography (HD-EEG), the longitudinal changes in functional connectivity (FC) in patients with chronic migraine (CM) treated with onabotulinumtoxinA (OBTA). BACKGROUND: OBTA is a treatment for CM. Several studies have shown the modulatory action of OBTA on the central nervous system; however, research on migraine is limited. METHODS: This study was conducted at the Neurology Unit of "Policlinico Tor Vergata," Rome, Italy, and included 12 adult patients with CM treated with OBTA and 15 healthy controls (HC). Patients underwent clinical scales at enrollment (T0) and 3 months (T1) from the start of treatment. HD-EEG was recorded using a 64-channel system in patients with CM at T0 and T1. A source reconstruction method was used to identify brain activity. FC in δ-θ-α-ß-low-γ bands was analyzed using the weighted phase-lag index. FC changes between HCs and CM at T0 and T1 were assessed using cross-validation methods to estimate the results' reliability. RESULTS: Compared to HCs at T0, patients with CM showed hyperconnected networks in δ (p = 0.046, area under the receiver operating characteristic curve [AUC: 0.76-0.98], Cohen's κ [0.65-0.93]) and ß (p = 0.031, AUC [0.68-0.95], Cohen's κ [0.51-0.84]), mainly involving orbitofrontal, occipital, temporal pole and orbitofrontal, superior temporal, occipital, cingulate areas, and hypoconnected networks in α band (p = 0.029, AUC [0.80-0.99], Cohen's κ [0.42-0.77]), predominantly involving cingulate, temporal pole, and precuneus. Patients with CM at T1, compared to T0, showed hypoconnected networks in δ band (p = 0.032, AUC [0.73-0.99], Cohen's κ [0.53-0.90]) and hyperconnected networks in α band (p = 0.048, AUC [0.58-0.93], Cohen's κ [0.37-0.78]), involving the sensorimotor, orbitofrontal, cingulate, and temporal cortex. CONCLUSION: These preliminary results showed that patients with CM presented disrupted EEG-FC compared to controls restored by a single session of OBTA treatment, suggesting a primary central modulatory action of OBTA.

The safety and efficacy of onabotulinumtoxinA injections for children and adolescents with chronic migraine: A systematic review and meta-analysis.

OBJECTIVE: To qualitatively and quantitatively summarize the evidence for the use of onabotulinumtoxinA injections in children and adolescents with migraine. BACKGROUND: There are limited evidence-based treatment options for youth with migraine, especially youth with chronic migraine (CM). OnabotulinumtoxinA injections are an established evidence-based treatment for adults with CM. While several studies have assessed their safety and efficacy among adolescents with CM, there are no published systematic reviews summarizing the pediatric evidence. METHODS: We carried out a systematic review, reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis, aiming to identify studies that included five or more children and adolescents aged ≤18 years with a diagnosis of migraine, who were treated with ≥50 units (U) of onabotulinumtoxinA and had outcomes assessed ≥4 weeks after one or more injection cycle. Both observational studies and randomized controlled trials (RCTs) were eligible for inclusion. Two investigators independently carried out the first (titles and abstracts) and second (full text) screening stages, as well as data extraction and quality appraisal. The American Academy of Neurology risk of bias grading scheme was used to assess study risk of bias. Studies with adequate data were pooled using random effects meta-analyses, and Hedge's g standardized mean differences with 95% confidence intervals (CIs) were generated to estimate the effect sizes of the continuous outcomes included. Studies lacking data required for meta-analysis were summarized qualitatively. RESULTS: We screened 634 studies and included 14 studies comprising 491 participants, of whom 489 had CM. Two studies were RCTs, 12 were observational uncontrolled studies, and all but one study included only youth with CM. Five Class IV observational uncontrolled studies were amenable to pooling in meta-analyses. After a mean of 2-2.6 injection cycles, headache frequency was shown to decrease significantly after treatment with onabotulinumtoxinA (Hedge's g = 0.97, 95% CI 0.58-1.35; p < 0.0001), as did severity (Hedge's g = 1.24, 95% CI 0.55-1.94; p = 0.0005), with both estimates having a large effect size magnitude. A Class I parallel-group RCT of one injection series (155 U, 74 U, or placebo), powered to detect a change in 4 headache days per month, did not find outcome differences between the active and placebo treatment arms. A Class IV crossover RCT showed superiority of active (155 U) versus placebo injections. The remaining Class IV observational studies that were excluded from the meta-analyses all showed improved outcomes with onabotulinumtoxinA injections over time. No serious adverse events related to treatment occurred. CONCLUSION: OnabotulinumtoxinA injections have established safety for use in children and adolescents with CM and are likely effective in reducing headache frequency and severity over time. However, in the absence of an adequately powered parallel-group RCT assessing the efficacy of multiple injection cycles, it remains unclear if this intervention is superior to placebo.

The introduction of the CGRP monoclonal antibodies and their effect on the prescription patterns of chronic migraine preventive medications in a tertiary headache center: A retrospective, observational analysis.

OBJECTIVE: To determine the effect of the introduction of the calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) in 2018 on the prescribing of older medications for the prevention of chronic migraine. BACKGROUND: Prior to 2018, the preventive treatment of migraine borrowed from medications intended to treat other illnesses with the last medication, onabotulinumtoxinA, receiving Food and Drug Administration (FDA) approval for the prevention of chronic migraine in 2010. The FDA approval of three CGRP mAbs in 2018 provided the ideal natural experiment to assess how the introduction of these medications, and a fourth in 2020, affected the generally stable migraine preventive medications market. METHODS: We performed a retrospective cohort analysis using the aggregated de-identified data of 6595 patients. The percentage of patients with chronic migraine who had been prescribed one of ten most prescribed oral preventive medications or onabotulinumtoxinA, or any of the four CGRP mAbs, were calculated relative to the total number of patients with chronic migraine who received a prescription for any medication from our clinic during the pre-CGRP mAb years of 2015-2017 and post-approval years of 2019-2021. RESULTS: We observed a statistically significant decrease in the prescription of the top 10 most prescribed medications after the introduction of the CGRP mAbs overall (1456/3144, 46.3%, to 1995/4629, 43.1%, p = 0.001), as well as with most individual medications, including large decreases in verapamil (230/3144, 7.3%, to 125/4629, 2.7%; p < 0.001), the tricyclic antidepressants (494/3144, 15.7%, to 532/4629, 11.5%; p < 0.001), topiramate (566/3144, 18.0%, to 653/4629, 14.1%; p < 0.001), and onabotulinumtoxinA (861/3144, 27.4%, to 1134/4629, 24.5%; p = 0.001). CONCLUSION: The introduction of the CGRP mAbs during 2018 resulted in a decrease in utilization of most oral medications and onabotulinumtoxinA for the prevention of migraine. Future work should continue to observe how the prescription patterns of these medications evolve with time.

Differences in circulating alpha-calcitonin gene-related peptide levels in inflammatory bowel disease and its relation to migraine comorbidity: A cross-sectional study.

OBJECTIVE: To analyze the specificity of calcitonin gene-related peptide (CGRP) levels, we measured alpha-CGRP circulating levels in a large series of patients with a recent diagnosis of inflammatory bowel disease (IBD) who were interviewed regarding comorbid headache. BACKGROUND: Several studies have found an association between migraine and IBD. METHODS: In this cross-sectional study performed in an IBD clinic, morning serum alpha-CGRP levels were measured by enzyme-linked immunosorbent assay in 96 patients who were recently diagnosed with IBD and compared to those from 50 similar patients with chronic migraine (CM) and 50 healthy controls (HC). RESULTS: Alpha-CGRP levels were higher in patients with IBD (median [interquartile range] 56.9 [35.6-73.9] pg/mL) and patients with CM (53.0 [36.7-73.9] pg/mL) compared to HC (37.2 [30.0-51.8] pg/mL; p = 0.003; p = 0.019, respectively). Regarding IBD diagnostic subtypes, alpha-CGRP levels for ulcerative colitis (67.2 ± 49.3 pg/mL; 57.0 [35.6-73.4] pg/mL) and Crohn's disease (54.9 ± 27.5 pg/mL; 57.7 [29.1-76.1] pg/mL) were significantly higher than those of HC (p = 0.013, p = 0.040, respectively). Alpha-CGRP levels were further different in patients with IBD with migraine (70.9 [51.8-88.7] pg/mL) compared to HC (p < 0.001), patients with IBD without headache (57.5 [33.3-73.8] pg/mL; p = 0.049), and patients with IBD with tension-type headache but without migraine (41.7 [28.5-66.9] pg/mL; p = 0.004), though alpha-CGRP levels in patients with IBD without migraine (53.7 [32.9-73.5] pg/mL) remained different over HC (p = 0.028). CONCLUSION: Together with CM, circulating alpha-CGRP levels are different in patients with IBD, perhaps reflecting a chronic inflammatory state. IBD is an example of how alpha-CGRP levels are not a totally specific migraine biomarker. However, alpha-CGRP levels were further increased in patients with IBD who have a history of migraine, which reinforces its role as a biomarker in migraine patients, always bearing in mind their comorbidities.

Blood serum levels of PACAP and migraine onset: A systematic review and meta-analysis of observational studies.

OBJECTIVE: We conducted a systematic review and meta-analysis to explore the relationship between blood pituitary adenylate cyclase-activating polypeptide (PACAP) levels and migraine. BACKGROUND: PACAP is involved in the onset of migraine, but the results from clinical studies on PACAP level variations across different periods of migraine are conflicting. METHODS: We systematically searched for observational studies that reported PACAP levels in people with migraine and non-migraine controls published in English from the PubMed, Web of Science, and Ovid electronic databases, or in Chinese from the Chinese National Knowledge Infrastructure and the WanFang Med database. The Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the included studies. The quality of evidence for each outcome was assessed according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidelines. RESULTS: Of the 514 identified studies, 8 were eligible for inclusion. There was a "very low" level of evidence suggesting that the PACAP level is negatively correlated with migraine disease duration in adults with migraine (summary r = -0.35, 95% confidence interval [CI] -0.49 to -0.22) and that the PACAP is higher in people with migraine during the ictal period than in the interictal period (standardized mean difference = 0.41, 95% CI 0.17 to 0.66) for both adults and children with migraine. Adult patients with episodic migraine (weighted mean difference [WMD] = -9.58 pg/mL, 95% CI -13.41 to -5.75 pg/mL) or chronic migraine (WMD = -10.93 pg/mL, 95% CI -15.57 to -6.29 pg/mL) had lower blood PACAP levels than non-migraine controls during the interictal period, supported by a "low" or "very low" quality of evidence, respectively, according to the GRADE rules. CONCLUSION: There is a very low certainty of evidence suggesting that the PACAP level is negatively correlated with migraine disease duration of adults with migraine and it varies greatly among different periods of migraine of both adults and children with migraine.

Alcohol Use Disorder in Patients with Chronic Migraine: A Retrospective, Observational Study.

OBJECTIVE: The relationship between migraine and alcohol consumption is unclear. We assessed the association between chronic migraine and alcohol use disorder(AUD), relative to chronic disease controls, and in conjunction with common comorbidities. METHODS: We conducted a retrospective, observational study. The primary outcome was the odds ratio for AUD in patients with chronic migraine or with chronic migraine and additional comorbidities relative to controls. RESULTS: A total of 3701 patients with chronic migraine, 4450 patients with low back pain, and 1780 patients with type 2 diabetes mellitus met inclusion criteria. Patients with chronic migraine had a lower risk of AUD relative to both controls of low back pain (OR 0.37; 95% CI: 0.29-0.47, p < 0.001) and type 2 diabetes mellitus (OR 0.39; 95% CI: 0.29-0.52, p < 0.001). Depression was associated with the largest OR for AUD in chronic migraine (OR 8.62; 95% CI: 4.99-14.88, p < 0.001), followed by post-traumatic stress disorder (OR 6.63; 95% CI: 4.13-10.64, p < 0.001) and anxiety (OR 3.58; 95% CI: 2.23-5.75, p < 0.001). CONCLUSION: Patients with chronic migraine had a lower odds ratio of AUD relative to controls. But in patients with chronic migraine, those with comorbid depression, anxiety, or PTSD are at higher risk of AUD. When patients establish care, comorbid factors should be assessed and for those at higher risk, AUD should be screened for at every visit.

Long-term persistence to onabotulinumtoxinA to prevent chronic migraine: results from 11 years of patient data from a tertiary headache center.

OBJECTIVE: To determine if patients with chronic migraine continue onabotulinumtoxinA (onabotA) long-term. METHODS: We performed a retrospective cohort analysis using aggregated, de-identified patient data from the Stanford Headache Center. We included patients in California who received at least one prescription for onabotA during the years of 2011-2021. The primary outcome was the number of onabotA treatments each patient received. Secondary outcomes included sex, age, race, ethnicity, body mass index (BMI), distance to the treatment facility, and zip code income quartile. RESULTS: A total of 1551 patients received a mean of 7.60 ± 7.26 treatments and a median of 5 treatments, with 16.2% of patients receiving only one treatment and 10.6% receiving at least 19. Time-to-event survival analysis suggested 26.0% of patients would complete at least 29 treatments if able. Younger age and female sex were associated with statistically significant differences between quartile groups of number of onabotA treatments (P = .007, P = .015). BMI, distance to treatment facility, and zip code income quartile were not statistically significantly different between quartile groups (P > .500 for all). Prescriptions of both triptans and non-onabotA preventive medications showed a statistically significant increase with each higher quartile of number of onabotA treatments (P < .001; P < .001). DISCUSSION: We show long-term persistence to onabotA is high and that distance to treatment facility and income are not factors in continuation. Our work also demonstrates that as patients continue onabotA over time, there may be an increased need for adjunctive or alternative treatments.

Effectiveness of fremanezumab treatment in patients with migraine headache.

OBJECTIVE: To evaluate the efficacy and safety of fremanezumab for migraine prevention. DESIGN: Retrospective, single-center, real-world study. SETTING: Regional tertiary headache center in Japan. SUBJECTS: Adult individuals with migraine (n = 165, male = 17, female = 148; average age = 45.5 ± 16.0 years) who received fremanezumab between September 2021 and August 2022. METHODS: Fremanezumab was administered subcutaneously at a monthly dose of 225 mg or quarterly dose of 675 mg based on patient preferences. Patients received fremanezumab treatment for up to 1 year unless it was discontinued. Monthly data were collected on migraine days, headache days, and days requiring acute medication. RESULTS: Of the 165 patients, 125 (75.7%) received fremanezumab as their first anti-calcitonin gene-related peptide-related antibody drug. Significant reductions in monthly migraine days, headache days, and days requiring acute medication were observed in those with episodic and chronic migraines. The baseline monthly headache days was 8.1 ± 4.0 in the episodic migraine group, which reduced to 6.1 ± 4.8, 5.8 ± 4.4, 4.7 ± 3.6, and 4.6 ± 3.3 days at 1, 3, 6, and 12 months, respectively; in the chronic migraine group, the baseline monthly headache days was 20.9 ± 6.1, which reduced to 17.0 ± 8.9, 15.0 ± 9.2, 13.0 ± 7.7, and 12.0 ± 9.1 days at 1, 3, 6, and 12 months, respectively. Treatment benefits were enhanced after 6 months of administering fremanezumab in the chronic migraine group. CONCLUSIONS: In this real-world study of patients with migraine, fremanezumab appears to be effective and safe. Further studies are required to identify additional predictors of treatment success and failure with fremanezumab.

Lack of association between TRPV1 gene polymorphisms and risk of migraine chronification: a case-control study and meta-analysis.

OBJECTIVE: To confirm a previously reported association of TRPV1 rs8065080 with the risk of transformation from episodic (EM) to chronic migraine (CM) and to extend knowledge about the role of other TRPV1 single nucleotide polymorphisms (SNPs), we first investigated the impact of three TRPV1 SNPs (rs8065080, rs222747 and rs222749) on the risk of migraine chronification in a case-control study. A systematic review and meta-analysis were then conducted to summarize the accumulated findings. METHODS: Genotyping of the selected TRPV1 SNPs was performed using TaqMan real-time PCR in 167 EM and 182 CM participants. Crude and adjusted odds ratios with associated 95% confidence intervals were calculated in the log-additive, dominant, and recessive genetic models. A comprehensive literature search was performed in PubMed, Web of Knowledge, Cochrane Library, and OpenGrey until February 2024. RESULTS: In our case-control study, no association was found between TRPV1 SNPs and the risk of migraine chronification, both in the unadjusted logistic regression models and after adjustment for confounding clinical variables. The results of the meta-analysis with a total of 241 participants with EM and 223 with CM confirmed no association between TRPV1 SNPs and the risk of migraine chronification in any of the genetic models tested. CONCLUSION: The results of the present case-control study and meta-analysis exclude a major role of TRPV1 rs8065080, rs222747, and rs222749 as risk factors for migraine chronification. However, further research is needed to investigate the gene-gene and gene-environment interactions of TRPV1 SNPs on the risk of transformation from episodic to chronic migraine.

Somatic amplification and addiction profile as risk factors for medication overuse headache with chronic migraine.

INTRODUCTION: Overuse of analgesics can lead to medication-overuse headache (MOH) in chronic migraine (CM) patients, and is often linked to addiction. This study explores the addiction-related characteristics and somatic amplification in patients with, CM with medication overuse headache (CM+MOH), CM, and healthy controls. METHODS: 73 CM patients and 70 CM+MOH, along with 63 healthy controls, participated in the study. Assessments included a Sociodemographic Form, Migraine Disability Assessment Scale (MIDAS), Addiction Profile Index (API), Addiction Profile Index-Clinical Version (API-C), and the Somatosensory Amplification Scale (SSAS). RESULTS: Substance use characteristics, craving, motivation for use, and addiction severity scores were higher in the CM+MOH group than in both the CM and the control group. Specifically, the SSAS scores within the CM+MOH group surpassed those of both the CM and control groups. In the CM+MOH group, SSAS scores were a strong predictor of the amount of analgesic usage. Besides, craving and motivation for substance use scores significantly predicted the number of days analgesic taken per month in the CM+MOH group CONCLUSION: CM patients with MOH exhibit a pronounced association with addiction, and a heightened manifestation of somatic symptoms. Addressing addiction characteristics and psychosomatic amplification is important to ensure comprehensive management.