A 12-week randomized double-blind clinical trial of eicosapentaenoic acid intervention in episodic migraine.

Omega-3 polyunsaturated fatty acids (PUFAs) may benefit migraine improvement, though prior studies are inconclusive. This study evaluated the effect of eicosapentaenoic acid (EPA) on episodic migraine (EM) prevention. Seventy individuals with EM participated in a 12-week randomized, double-blind, placebo-controlled trial from March 2020 and May 2022. They were randomly assigned to either the EPA (N = 35, 2 g fish oil with 1.8 g of EPA as a stand-alone treatment daily), or the placebo group (N = 35, 2 g soybean oil daily). Migraine frequency and headache severity were assessed using the monthly migraine days, visual analog scale (VAS), Migraine Disability Assessment (MIDAS), Hospital Anxiety and Depression Scale (HADS), Migraine-Specific Quality-of-Life Questionnaire (MSQ), and Pittsburgh Sleep Quality Index (PSQI) in comparison to baseline measurements. The EPA group significantly outperformed the placebo in reducing monthly migraine days (-4.4 ± 5.1 days vs. - 0.6 ± 3.5 days, p = 0.001), days using acute headache medication (-1.3 ± 3.0 days vs. 0.1 ± 2.3 days, p = 0.035), improving scores for headache severity (ΔVAS score: -1.3 ± 2.4 vs. 0.0 ± 2.2, p = 0.030), disability (ΔMIDAS score: -13.1 ± 16.2 vs. 2.6 ± 20.2, p = 0.001), anxiety and depression (ΔHADS score: -3.9 ± 9.4 vs. 1.1 ± 9.1, p = 0.025), and quality of life (ΔMSQ score: -11.4 ± 19.0 vs. 3.1 ± 24.6, p = 0.007). Notably, female particularly benefited from EPA, underscoring its potential in migraine management. In conclusion, high-dose EPA has significantly reduced migraine frequency and severity, improved psychological symptoms and quality of life in EM patients, and shown no major adverse events, suggesting its potential as a prophylactic for EM.

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.

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.

Effects of fremanezumab on migraine-associated symptoms and medication use in Japanese and Korean patients with episodic migraine: Exploratory endpoint analysis of a multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To describe exploratory endpoints from a previous phase 2b/3 placebo-controlled trial conducted in Japan and Korea, specifically investigating the effect of fremanezumab or placebo on migraine-associated symptoms and acute headache medication use in patients with episodic migraine (EM). BACKGROUND: EM is associated with non-head pain symptoms, including nausea, vomiting, photophobia, or phonophobia, which contribute substantially to the disease burden, healthcare resource utilization, and impaired quality of life. Current EM treatments include a mix of nonspecific/migraine-specific acute headache medications, but medication overuse can induce headaches and progression from EM to chronic migraine (CM). In multiple phase 2b/3 trials, the monoclonal antibody fremanezumab significantly reduced the average number of monthly migraine days experienced by patients with EM/CM compared with placebo. METHODS: This was a prespecified analysis of exploratory endpoints in a multicenter, randomized, double-blind, placebo-controlled, phase 2b/3 trial conducted in Japanese and Korean patients with EM (NCT03303092). Patients were randomized to receive fremanezumab, either monthly or quarterly, or matching placebo, administered subcutaneously at 4-week/28-day ("monthly") intervals to maintain blinding. Exploratory endpoints reported here were the mean change from baseline in the number of days/month with (i) the use of any acute headache medication, (ii) the use of any migraine-specific acute headache medication, (iii) nausea or vomiting, and (iv) photophobia and phonophobia. RESULTS: Overall, 357 Japanese and Korean patients with EM received either monthly (n = 121) or quarterly (n = 119) fremanezumab or placebo (n = 117). Compared with placebo, fremanezumab administered monthly or quarterly was associated with a significant reduction from baseline in the average number of days/month with acute headache medication use over three months (difference vs. placebo -2.81 [95% confidence interval (CI) -3.52, -2.11]; p < 0.001 and -2.79 [95% CI -3.50, -2.08]; p < 0.001, respectively). Similar findings were observed in the monthly average number of days with migraine-specific acute headache medications (difference vs. placebo with monthly and quarterly fremanezumab, -2.63 [95% CI -3.31, -1.95] for both; p < 0.001), the average number of days/month with nausea or vomiting (difference vs. placebo -1.09 [95% CI -1.60, -0.58]; p < 0.001 for monthly fremanezumab and -1.37 [95% CI -1.88, -0.86]; p < 0.001 for quarterly fremanezumab), and the average number of days with photophobia and phonophobia (difference vs. placebo -1.22 [95% CI -1.80, -0.65]; p < 0.001 and -1.64 [95% CI -2.22, -1.06]; p < 0.001, respectively). CONCLUSION: Monthly and quarterly administered fremanezumab effectively prevented EM in Japanese and Korean patients. Fremanezumab also improved other disease aspects including the need for acute headache medications and the frequency of migraine-associated symptoms.

Cost per treatment responder analysis of atogepant compared to rimegepant for the preventive treatment of episodic migraine.

OBJECTIVE: To estimate the number needed to treat and cost per additional responder for atogepant and rimegepant versus placebo for the preventive treatment of episodic migraine (EM) in the United States. BACKGROUND: Migraine has an enormous impact on a person's daily activities and quality of life, and results in significant clinical and economic burden to both individuals and society. It is important to understand the comparative efficacy and economic value of oral calcitonin gene-related peptide receptor antagonists (gepants) for preventive treatment of EM. Currently, atogepant and rimegepant are US Food and Drug Administration approved for preventive treatment of migraine (rimegepant for EM and atogepant for EM and for chronic migraine). In the absence of head-to-head trials, we utilized an indirect treatment comparison on efficacy data from clinical trials conducted for the preventive treatment of EM. We estimated number needed to treat, a valuable metric used in clinical practice to compare treatment efficacy, and cost per additional responder, which can be used to establish the cost effectiveness of a treatment. METHODS: An indirect treatment comparison was conducted to compare the efficacy of atogepant 60 mg once daily and rimegepant 75 mg once every other day as preventive treatments for EM using published data from the registrational trials of atogepant (ADVANCE) and rimegepant (BHV3000-305). The efficacy outcome of interest was ≥50% reduction from baseline in mean monthly migraine/headache days (≥50% responder rate), which was variably defined for a base case and two scenario analyses. Number needed to treat and cost per additional responder versus placebo were calculated and compared between both treatments (weeks 9-12 in the base case analysis; weeks 1-12 and 9-12 for atogepant and during weeks 9-12 for rimegepant in the scenario analyses). RESULTS: In the base case analysis, ≥50% responder rates were 64.9% (95% confidence interval [CI], 53.9-74.5) for atogepant and 51.8% (95% CI, 42.9-60.6) for rimegepant, compared to 44.1% (95% CI, 39.4-49.0) for placebo. The median number needed to treat versus placebo in the base case scenario was 4.8 (95% CI, 3.1-9.0) for atogepant compared to 13.0 (95% CI, 5.9-75.1) for rimegepant. The cost per additional responder versus placebo in the base case scenario was estimated to be $15,823 (95% CI, $11,079-$29,516) for atogepant compared to $73,029 (95% CI, $32,901-$422,104) for rimegepant. Results of the two scenario analyses were consistent with the base case analysis. CONCLUSIONS: Atogepant had substantially lower numbers needed to treat and costs per additional responder versus placebo than rimegepant for the preventive treatment of EM across all evaluated scenarios. These analyses suggest that atogepant may be more cost effective than rimegepant for the preventive treatment of EM. Limitations include differences in inclusion/exclusion criteria and in reporting of the ≥50% responder rates between trials.

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.

Review on the Burden of Episodic Migraine and Utilization of Patient Reported Outcome Measures.

PURPOSE OF REVIEW: Migraine affects a large portion of the world's population. Migraine encompasses a broad range of symptoms, with broad reaching ramifications in the form of Health-Related Quality of Life (HRQoL) factors. In our review we sought to understand the aspects encompassing the burden of disease on both an individual and population level. Furthermore, we reviewed the development and incorporation of Patient Reported Outcome Measures (PROM), questionnaires that assess HRQoL in real time, in how they have been incorporated in clinical research up to now and how they can be utilized in clinical practice moving forward. RECENT FINDINGS: It has been shown that there is much heterogeneity within the field in PROM development processes as well as their utilization in episodic migraine (EM) clinical trials. Furthermore, they are inconsistently used in clinical practice. Among the most commonly used PROMs, the MSQv2.1 is among the most valid and reliable. Beyond that, it also shows promise to help in guidance of clinical management of migraine.

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.

Efficacy of a dual task protocol on neurophysiological and clinical outcomes in migraine: a randomized control trial.

The main aim of this study was to investigate the efficacy of a dual task protocol in people with episodic migraine with respect to both active exercises only and cognitive task only treatments, concerning some neurophysiological and clinical outcomes. A randomized control trial was adopted in people with episodic migraine without aura. Some neurophysiological and clinical outcomes were collected (t0): resting motor threshold (rMT), short intracortical inhibition (SICI) and facilitation (ICF), pressure pain threshold (PPT), trail making test (TMT), frontal assessment battery (FAB), headache-related disability (MIDAS) and headache parameters. Then, participants were randomized into three groups: active exercise only (n = 10), cognitive task only (n = 10) and dual task protocol (n = 10). After 3 months of each treatment and after 1-month follow-up the same neurophysiological and clinical outcomes were revaluated. A significant time x group effect was only found for the trapezius muscle (p = 0.012, pη2 = 0.210), suggesting that PPT increased significantly only in active exercise and dual task protocol groups. A significant time effect was found for rMT (p < 0.001, pη2 = 0.473), MIDAS (p < 0.001, pη2 = 0.426), TMT (p < 0.001, pη2 = 0.338) and FAB (p < 0.001, pη2 = 0.462). A repeated measures ANOVA for SICI at 3 ms highlighted a statistically significant time effect for the dual task group (p < 0.001, pη2 = 0.629), but not for the active exercises group (p = 0.565, pη2 = 0.061), and for the cognitive training (p = 0.357, pη2 = 0.108). The dual task protocol seems to have a more evident effect on both habituation and sensitization outcomes than the two monotherapies taken alone in people with migraine.

Differences in Neuropathology between Nitroglycerin-Induced Mouse Models of Episodic and Chronic Migraine.

Multiple animal models of migraine have been used to develop new therapies. Understanding the transition from episodic (EM) to chronic migraine (CM) is crucial. We established models mimicking EM and CM pain and assessed neuropathological differences. EM and CM models were induced with single NTG or multiple injections over 9 days. Mechanical hypersensitivity was assessed. Immunofluorescence utilized c-Fos, NeuN, and Iba1. Proinflammatory and anti-inflammatory markers were analyzed. Neuropeptides (CGRP, VIP, PACAP, and substance P) were assessed. Mechanical thresholds were similar. Notable neuropathological distinctions were observed in Sp5C and ACC. ACC showed increased c-Fos and NeuN expression in CM (p < 0.001) and unchanged in EM. Sp5C had higher c-Fos and NeuN expression in EM (p < 0.001). Iba1 was upregulated in Sp5C of EM and ACC of CM (p < 0.001). Proinflammatory markers were strongly expressed in Sp5C of EM and ACC of CM. CGRP expression was elevated in both regions and was higher in CM. VIP exhibited higher levels in the Sp5C of EM and ACC of CM, whereas PACAP and substance P were expressed in the Sp5C in both models. Despite similar thresholds, distinctive neuropathological differences in Sp5C and ACC between EM and CM models suggest a role in the EM to CM transformation.

Shifts in structural connectome organization in the limbic and sensory systems of patients with episodic migraine.

Migraine is a complex neurological condition characterized by recurrent headaches, which is often accompanied by various neurological symptoms. Magnetic resonance imaging (MRI) is a powerful tool for investigating whole-brain connectivity patterns; however, systematic assessment of structural connectome organization has rarely been performed. In the present study, we aimed to examine the changes in structural connectivity in patients with episodic migraines using diffusion MRI. First, we computed structural connectivity using diffusion MRI tractography, after which we applied dimensionality reduction techniques to the structural connectivity and generated three low-dimensional eigenvectors. We subsequently calculated the manifold eccentricity, defined as the Euclidean distance between each data point and the center of the data in the manifold space. We then compared the manifold eccentricity between patients with migraines and healthy controls, revealing significant between-group differences in the orbitofrontal cortex, temporal pole, and sensory/motor regions. Between-group differences in subcortico-cortical connectivity further revealed significant changes in the amygdala, accumbens, and caudate nuclei. Finally, supervised machine learning effectively classified patients with migraines and healthy controls using cortical and subcortical structural connectivity features, highlighting the importance of the orbitofrontal and sensory cortices, in addition to the caudate, in distinguishing between the groups. Our findings confirmed that episodic migraine is related to the structural connectome changes in the limbic and sensory systems, suggesting its potential utility as a diagnostic marker for migraine.

Effectiveness and tolerability of eptinezumab in treating patients with migraine resistant to conventional preventive medications and CGRP (receptor) antibodies: a multicentre retrospective real-world analysis from Germany.

BACKGROUND: Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP mAb) and is used for migraine prophylaxis. Efficacy data are mainly from clinical trials, real-world data are hardly available yet. Reimbursement policy in Germany leads to eptinezumab mainly being used in patients having failed pre-treatment with other CGRP mAb. To date, it is unclear whether eptinezumab is efficacious and well tolerated in this population and how the treatment response differs from patients who are naive to CGRP mAbs. METHODS: We analysed clinical routine data of 79 patients (episodic migraine (EM): n = 19; chronic migraine (CM): n = 60) from four different centres in Germany. All patients were treated with eptinezumab (100mg). Differences in monthly headache (MHD), migraine (MMD) and acute medication days (AMD) after three months were analysed. The correlation of response with the number of CGRP mAb failures was evaluated. Significance level has been corrected (alpha = 0.017). RESULTS: After three months MHD, MMD and AMD were significantly reduced. In EM, the median reduction for MHD was 4.0 days (IQR: -6.5 to -1.0; p = 0.001), for MMD 3.0 days (IQR: -5.5 to -1.5; p < 0.001) and for AMD 2.0 days (IQR: -5.0 to -0.5; p = 0.006). In CM, median reduction of MHD was 4 days (IQR: -8.0 to 0.0; p < 0.001), 3.0 days (IQR: -6.0 to-1.0; p < 0.001) for MMD and 1.0 day (IQR: -5.0 to 0.0; p < 0.001) for AMD. All patients were resistant to conventional preventive therapies and most to CGRP mAbs. Fourteen patients had never received a CGRP mAb and 65 patients had received at least one mAb without sufficient effectiveness and/or intolerability (one: n = 20, two: n = 28, three: n = 17). There was a significant association between the number of prior therapies and the 30% MHD responder rate (none: 78.6%, one: 45.0%, two: 32.1%, three: 23.5%, p = 0.010). Regarding tolerability, 10.4% (8/77) reported mild side effects. CONCLUSIONS: The effectiveness of eptinezumab is significantly reduced in patients who have not previously responded to other CGRP mAbs. However, limitations such as the retrospective nature of the analysis, the small sample size and the short treatment period with only the lower dose of eptinezumab must be considered when interpreting the results.

Is erenumab an efficient alternative for the prevention of episodic and chronic migraine in Spain? Results of a cost-effectiveness analysis.

BACKGROUND: The reimbursement of erenumab in Spain and other European countries is currently restricted because of the cost of this novel therapy to patients with migraine who have experienced previous failures to traditional preventive treatments. However, this reimbursement policy should be preferably based on cost-effectiveness studies, among other criteria. This study performed a cost-effectiveness analysis of erenumab versus topiramate for the prophylactic treatment of episodic migraine (EM) and versus placebo for chronic migraine (CM). METHODS: A Markov model with a 10-year time horizon, from the perspective of the Spanish National Healthcare System, was constructed based on data from responder and non-responder patients. A responder was defined as having a minimum 50% reduction in the number of monthly migraine days (MMD). A hypothetical cohort of patients with EM with one or more prior preventive treatment failures and patients with CM with more than two treatment failures was considered. The effectiveness score was measured as an incremental cost per quality-adjusted life year (QALY) gained and cost per migraine day (MD) avoided. Data from clinical outcomes and patient characteristics were obtained from erenumab clinical trials (NCT02066415, STRIVE, ARISE, LIBERTY and HER-MES). Deterministic and probabilistic sensitivity analyses were performed to validate the robustness of the model. RESULTS: After a 10-year follow-up, the estimated QALYs were 5.88 and 6.11 for patients with EM treated with topiramate and erenumab, respectively. Erenumab showed an incremental cost per patient of €4,420 vs topiramate. For CM patients, erenumab resulted in 0.756 QALYs gained vs placebo; and an incremental cost of €1,814. Patients treated with erenumab achieved reductions in MD for both EM and CM (172 and 568 MDs, respectively). The incremental cost per QALY gained with erenumab was below the Spanish threshold of €30,000/QALY for both health and societal perspectives (EM €19,122/QALY and CM €2,398/QALY). CONCLUSIONS: Erenumab is cost-effective versus topiramate as a preventive treatment for EM and versus placebo for patients with CM from the perspective of the Spanish National Health System.

Assessment of prolonged safety and tolerability of erenumab in migraine patients in a long-term open-label study (APOLLON).

BACKGROUND: Efficacy and safety of human monoclonal antibody erenumab used for migraine prophylaxis have been shown in clinical studies. APOLLON is an open-label, multi-center, single arm study, which permits dose adjustments of erenumab and includes an option for a drug holiday. The findings contribute to the accumulating long-term evidence regarding erenumab's tolerability and safety profile in individuals experiencing episodic and chronic migraines. METHODS: The study population consisted of adult patients with episodic or chronic migraine, who had successfully completed the HER-MES study (NCT03828539). Patients were treated with erenumab for 128 weeks at a flexible dose of either 70 mg or 140 mg. Treatment discontinuation attempts were allowed as voluntary single treatment interruption ('drug holiday') of up to 24 weeks. RESULTS: 701 patients were enrolled in APOLLON. The exposure associated incidence rate (EAIR) of adverse events (AEs) (N = 601) per 100 subject years was 101.71 (95% CI [92.28; 111.14]) meaning a patient could expect having about one adverse event per each year of treatment. EAIR was higher in females (n = 524, EAIR: 104.40, 95% CI [93.93; 114.86]) than in males (n = 77, EAIR: 86.55, 95% CI [65.39; 107.71]) and increased with initial monthly migraine days (MMD) and prior prophylactic treatment failures. A total of 155 patients discontinued erenumab treatment during open-label treatment phase. Of these, 29 were due to AEs (4.1% of total cohort) and out of these 65.5% (N = 19) were considered treatment-related. Safety parameters were in line with HER-MES data and did not reveal new safety signals. Drug holidays were realized by 108 patients (15.4%), of which 64.8% (N = 70) returned to treatment. The mean number of monthly headache days (MHDs), MMDs, and days with acute headache medication significantly increased during drug holiday. After resumption of erenumab treatment, a rapid reduction of the migraine parameters was observed. CONCLUSIONS: APOLLON provides long-term safety and tolerability data confirming the beneficial safety profile of erenumab over a period of 128 weeks. In addition, reversibility of migraine deterioration during drug holiday was shown and most patients returned to their treatment with similar response rates compared to initial treatment. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04084314 ( https://clinicaltrials.gov/study/NCT04084314 ), First submitted: 2019-09-06.

Imbalanced temporal states of cortical blood-oxygen-level-dependent signal variability during rest in episodic migraine.

BACKGROUND: Migraine has been associated with functional brain changes including altered connectivity and activity both during and between headache attacks. Recent studies established that the variability of the blood-oxygen-level-dependent (BOLD) signal is an important attribute of brain activity, which has so far been understudied in migraine. In this study, we investigate how time-varying measures of BOLD variability change interictally in episodic migraine patients. METHODS: Two independent resting state functional MRI datasets acquired on 3T (discovery cohort) and 1.5T MRI scanners (replication cohort) including 99 episodic migraine patients (n3T = 42, n1.5T=57) and 78 healthy controls (n3T = 46, n1.5T=32) were analyzed in this cross-sectional study. A framework using time-varying measures of BOLD variability was applied to derive BOLD variability states. Descriptors of BOLD variability states such as dwell time and fractional occupancy were calculated, then compared between migraine patients and healthy controls using Mann-Whitney U-tests. Spearman's rank correlation was calculated to test associations with clinical parameters. RESULTS: Resting-state activity was characterized by states of high and low BOLD signal variability. Migraine patients in the discovery cohort spent more time in the low variability state (mean dwell time: p = 0.014, median dwell time: p = 0.022, maximum dwell time: p = 0.013, fractional occupancy: p = 0.013) and less time in the high variability state (mean dwell time: p = 0.021, median dwell time: p = 0.021, maximum dwell time: p = 0.025, fractional occupancy: p = 0.013). Higher uptime of the low variability state was associated with greater disability as measured by MIDAS scores (maximum dwell time: R = 0.45, p = 0.007; fractional occupancy: R = 0.36, p = 0.035). Similar results were observed in the replication cohort. CONCLUSION: Episodic migraine patients spend more time in a state of low BOLD variability during rest in headache-free periods, which is associated with greater disability. BOLD variability states show potential as a replicable functional imaging marker in episodic migraine.

Decoding pain through facial expressions: a study of patients with migraine.

BACKGROUND: The present study used the Facial Action Coding System (FACS) to analyse changes in facial activities in individuals with migraine during resting conditions to determine the potential of facial expressions to convey information about pain during headache episodes. METHODS: Facial activity was recorded in calm and resting conditions by using a camera for both healthy controls (HC) and patients with episodic migraine (EM) and chronic migraine (CM). The FACS was employed to analyse the collected facial images, and intensity scores for each of the 20 action units (AUs) representing expressions were generated. The groups and headache pain conditions were then examined for each AU. RESULTS: The study involved 304 participants, that is, 46 HCs, 174 patients with EM, and 84 patients with CM. Elevated headache pain levels were associated with increased lid tightener activity and reduced mouth stretch. In the CM group, moderate to severe headache attacks exhibited decreased activation in the mouth stretch, alongside increased activation in the lid tightener, nose wrinkle, and cheek raiser, compared to mild headache attacks (all corrected p < 0.05). Notably, lid tightener activation was positively correlated with the Numeric Rating Scale (NRS) level of headache (p = 0.012). Moreover, the lip corner depressor was identified to be indicative of emotional depression severity (p < 0.001). CONCLUSION: Facial expressions, particularly lid tightener actions, served as inherent indicators of headache intensity in individuals with migraine, even during resting conditions. This indicates that the proposed approach holds promise for providing a subjective evaluation of headaches, offering the benefits of real-time assessment and convenience for patients with migraine.

Efficacy and safety of eptinezumab for migraine prevention in patients with prior preventive treatment failures: subgroup analysis of the randomized, placebo-controlled DELIVER study.

BACKGROUND: Migraine is a disabling neurological disease adversely affecting many aspects of life. Most patients are still required to have failed several older oral preventive therapies before being reimbursed for a preventive, migraine-specific anti-calcitonin gene-related peptide treatment. In the 24-week placebo-controlled portion of DELIVER, eptinezumab was shown to reduce migraine frequency and resulted in higher migraine responder rates compared with placebo in patients with two to four previous preventive treatment failures. This subgroup analysis assessed if demographic or clinical characteristics were associated with differences in preventive benefits. METHODS: Migraine frequency reductions and responder rates (i.e., the proportion of patients reaching a ≥50% and ≥75% reduction in monthly migraine days relative to baseline) were determined in the total population and predefined subgroups by sex, age, migraine frequency (chronic migraine, episodic migraine, high-frequency episodic migraine, low-frequency episodic migraine), medication overuse, medication-overuse headache, and previous preventive treatment failures (2, >2). The primary endpoint was change from baseline in monthly migraine days over weeks 1-12. RESULTS: Eptinezumab 100 and 300 mg reduced monthly migraine days more than placebo over weeks 1-12 (-4.8 and -5.3 vs -2.1, respectively; p < 0.0001). In most subgroups, eptinezumab-treated patients demonstrated larger monthly migraine days reductions from baseline over weeks 1-12 than patients receiving placebo, with reductions maintained or increased over weeks 13-24. For ≥50% and ≥75% migraine responder rates, the odds ratios versus placebo all numerically favored eptinezumab. CONCLUSION: Eptinezumab had larger monthly migraine days reductions and higher responder rates than placebo across clinically relevant subgroups showing that, across different demographic populations and clinical characteristics, eptinezumab is effective in patients with migraine and prior preventive treatment failures.Trial Registration: ClinicalTrials.gov (Identifier: NCT04418765).

Efficacy and safety of fremanezumab for migraine prophylaxis in patients with at least three previous preventive failures: Prospective, multicenter, real-world data from a Greek registry.

OBJECTIVE: To prospectively assess the efficacy and safety of fremanezumab for migraine prophylaxis in patients with failure of at least three previous preventive treatments. Changes in disability as quality-of-life outcomes after fremanezumab treatment were also examined. METHODS: Two hundred and four patients with either high-frequency EM (HFEM) or chronic migraine (CM), who attained at least three consecutive monthly sessions with fremanezumab 225 mg and otherwise met the inclusion criteria, were included in the study. The crude response (at least 50% reduction in monthly headache days [MHD]) rates to fremanezumab were assessed. Scores in the following efficacy outcomes were then compared from baseline to the last efficacy evaluation follow-up: (i) MHD, (ii) monthly days with moderate/severe peak headache intensity, and (iii) monthly days with intake of abortive medication. The disability was evaluated with the Migraine Disability Assessment; the quality of life (QOL) status was assessed with the Headache Impact-6 Test, and the EQ-5D questionnaire. RESULTS: In the majority of HFEM cases (n = 81/97; 83.5%) and CM patients (n = 67/107; 62.6%), fremanezumab proved effective in reducing the MHDs by at least 50% and was associated with clinically meaningful improvement in all other efficacy variables. The migraine-related disability experienced by our patients decreased and their QOL increased. We recorded just 36 cases reporting mild adverse events, including pain, rash or pruritus (n = 26), flu-like symptoms (n = 8), and hair loss (n = 2). CONCLUSION: With our prospective results, we provide further real-world data to support the favorable benefit/risk profile of fremanezumab in the prophylaxis of both HFEM and CM.

L-arginine and aged garlic extract for the prevention of migraine: a study protocol for a randomised, double-blind, placebo-controlled, phase-II trial (LARGE trial).

BACKGROUND: Migraine is a common and distressing neurological condition characterised by recurrent throbbing headaches, nausea and heightened sensitivity to light and sound. Accumulating evidence suggests that cerebral arteries dilate during migraine, causing distal microvessels to constrict, which could activate nociceptors and cause onset of headache pain. If so, preventing or attenuating chronic microvascular constriction, and promoting a dilatory phenotype, may reduce frequency and/or severity of migraines. The primary aim of the L-Arginine and Aged Garlic Extract (LARGE) trial is to investigate whether oral treatment with dietary nutraceuticals, L-arginine and aged garlic extract (AGE), both systemic vasodilatory agents, will alleviate migraine frequency, duration and severity in adults with chronic frequent episodic migraines. METHODS: The study is a randomised double-blind placebo-controlled phase-II single-site clinical trial conducted in Perth, Australia. The target sample is to recruit 240 participants diagnosed with chronic frequent episodic migraines between 18 and 80 years of age. Participants will be randomised to one of four treatment groups for 14 weeks (placebo induction for 2 weeks, followed by 12 weeks on one of the respective treatment arms): placebo, L-arginine, AGE, or a combination of L-arginine and AGE. The doses of L-arginine and AGE are 1.5 g and 1 g daily, respectively. The primary outcome is to assess migraine response using change in migraine frequency and intensity between baseline and 12 weeks. Secondary outcomes include the impact of L-arginine and/or AGE on photosensitivity, retinal vessel changes, and blood biomarker concentrations of vascular tone, following a 12-week intervention. DISCUSSION: The protocol describes the oral administration of 2 nutraceutical-based interventions as possible prophylactic treatments for chronic frequent episodic migraines, with potential for direct clinical translation of outcomes. Potential limitations of the study include the fixed-dose design of each treatment arm and that in vivo neuroimaging methods, such as magnetic resonance imaging (MRI), will not be conducted to determine putative cerebro-vasodilatory changes to coincide with the outcome measures. Dose-response studies may be indicated. TRIAL REGISTRATION: The trial was retrospectively registered with the Australian New Zealand Clinical Trials Registry ACTRN12621001476820 (Universal Trial Number: U1111-1268-1117) on 04/08/2021. This is protocol version 1, submitted on 25/11/2022.