Headache & Migraine

Key clinical point: Both cinnarizine and amitriptyline effectively improved migraine symptoms in children and adolescents with migraine, but amitriptyline was a more preferable treatment option since it reduced headache frequency and duration more effectively than cinnarizine.

Major finding: Amitriptyline was more effective than cinnarizine in reducing headache frequency at 4 weeks (mean difference [MD] −8.81 attacks/months; P = .004) and headache duration at 4 (MD −123.0 minutes; P = .017), 8 (MD −110.3 minutes; P = .033), and 12 (MD −123.3 minutes; P = .018) weeks. However, there were no significant differences in headache severity and migraine-related disability between the groups at 4, 8, and 12 weeks (all P > .005).

Study details: Findings are from a randomized, double-blind controlled trial including 43 children with migraine (age 4-17 years) who were randomly assigned to receive cinnarizine (n = 22) and amitriptyline (n = 21).

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Olfat M, Hosseinpour S, Masoumi S, et al. A comparative study on prophylactic efficacy of cinnarizine and amitriptyline in childhood migraine: A randomized double-blind clinical trial. Cephalalgia. 2024 (Apr 20). doi: 10.1177/03331024241230963 Source

Key clinical point: Both cinnarizine and amitriptyline effectively improved migraine symptoms in children and adolescents with migraine, but amitriptyline was a more preferable treatment option since it reduced headache frequency and duration more effectively than cinnarizine.

Major finding: Amitriptyline was more effective than cinnarizine in reducing headache frequency at 4 weeks (mean difference [MD] −8.81 attacks/months; P = .004) and headache duration at 4 (MD −123.0 minutes; P = .017), 8 (MD −110.3 minutes; P = .033), and 12 (MD −123.3 minutes; P = .018) weeks. However, there were no significant differences in headache severity and migraine-related disability between the groups at 4, 8, and 12 weeks (all P > .005).

Study details: Findings are from a randomized, double-blind controlled trial including 43 children with migraine (age 4-17 years) who were randomly assigned to receive cinnarizine (n = 22) and amitriptyline (n = 21).

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Olfat M, Hosseinpour S, Masoumi S, et al. A comparative study on prophylactic efficacy of cinnarizine and amitriptyline in childhood migraine: A randomized double-blind clinical trial. Cephalalgia. 2024 (Apr 20). doi: 10.1177/03331024241230963 Source

Key clinical point: Both cinnarizine and amitriptyline effectively improved migraine symptoms in children and adolescents with migraine, but amitriptyline was a more preferable treatment option since it reduced headache frequency and duration more effectively than cinnarizine.

Major finding: Amitriptyline was more effective than cinnarizine in reducing headache frequency at 4 weeks (mean difference [MD] −8.81 attacks/months; P = .004) and headache duration at 4 (MD −123.0 minutes; P = .017), 8 (MD −110.3 minutes; P = .033), and 12 (MD −123.3 minutes; P = .018) weeks. However, there were no significant differences in headache severity and migraine-related disability between the groups at 4, 8, and 12 weeks (all P > .005).

Study details: Findings are from a randomized, double-blind controlled trial including 43 children with migraine (age 4-17 years) who were randomly assigned to receive cinnarizine (n = 22) and amitriptyline (n = 21).

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Olfat M, Hosseinpour S, Masoumi S, et al. A comparative study on prophylactic efficacy of cinnarizine and amitriptyline in childhood migraine: A randomized double-blind clinical trial. Cephalalgia. 2024 (Apr 20). doi: 10.1177/03331024241230963 Source

Key clinical point: This cross-sectional study demonstrated a significant association between severe headache or migraine and erectile dysfunction (ED) in adult men in the US; however, the results should be interpreted carefully as it did not investigate the effects of depression and anxiety on ED.

Major finding: Presence vs absence of severe headache or migraine was associated with 51% increased risk of ED (adjusted odd ratio 1.51; P = .0036). Age of 40-60 years (P = 0.0292), body mass index < 25 kg/m² (P = .0406) or ≥30 kg/m² (P = .0222), metabolic disorders, such as hypertension (P = .0029), diabetes mellitus (P < .001), and hyperlipidemia (P = .0281), were significant risk factors for ED in those with severe headache or migraine.

Study details: This cross-sectional study included 3117 adult men with (n = 582) and without (n = 2535) history of ED from the US National Health and Nutrition Examination Survey (2001-2 and 2003-4), of whom 16.85% had severe headache or migraine.

Disclosures: This study was funded by National Natural Science Foundation of China. The authors declared no competing interests.

Source: Wu X, Zhang Y, Liu G, et al. Association between severe headache or migraine and erectile dysfunction in American adults: A cross-sectional of data study from the NHANES. Int J Impot Res. 2024 (Apr 12). doi: 10.1038/s41443-024-00867-w Source

Key clinical point: This cross-sectional study demonstrated a significant association between severe headache or migraine and erectile dysfunction (ED) in adult men in the US; however, the results should be interpreted carefully as it did not investigate the effects of depression and anxiety on ED.

Major finding: Presence vs absence of severe headache or migraine was associated with 51% increased risk of ED (adjusted odd ratio 1.51; P = .0036). Age of 40-60 years (P = 0.0292), body mass index < 25 kg/m² (P = .0406) or ≥30 kg/m² (P = .0222), metabolic disorders, such as hypertension (P = .0029), diabetes mellitus (P < .001), and hyperlipidemia (P = .0281), were significant risk factors for ED in those with severe headache or migraine.

Study details: This cross-sectional study included 3117 adult men with (n = 582) and without (n = 2535) history of ED from the US National Health and Nutrition Examination Survey (2001-2 and 2003-4), of whom 16.85% had severe headache or migraine.

Disclosures: This study was funded by National Natural Science Foundation of China. The authors declared no competing interests.

Source: Wu X, Zhang Y, Liu G, et al. Association between severe headache or migraine and erectile dysfunction in American adults: A cross-sectional of data study from the NHANES. Int J Impot Res. 2024 (Apr 12). doi: 10.1038/s41443-024-00867-w Source

Key clinical point: This cross-sectional study demonstrated a significant association between severe headache or migraine and erectile dysfunction (ED) in adult men in the US; however, the results should be interpreted carefully as it did not investigate the effects of depression and anxiety on ED.

Major finding: Presence vs absence of severe headache or migraine was associated with 51% increased risk of ED (adjusted odd ratio 1.51; P = .0036). Age of 40-60 years (P = 0.0292), body mass index < 25 kg/m² (P = .0406) or ≥30 kg/m² (P = .0222), metabolic disorders, such as hypertension (P = .0029), diabetes mellitus (P < .001), and hyperlipidemia (P = .0281), were significant risk factors for ED in those with severe headache or migraine.

Study details: This cross-sectional study included 3117 adult men with (n = 582) and without (n = 2535) history of ED from the US National Health and Nutrition Examination Survey (2001-2 and 2003-4), of whom 16.85% had severe headache or migraine.

Disclosures: This study was funded by National Natural Science Foundation of China. The authors declared no competing interests.

Source: Wu X, Zhang Y, Liu G, et al. Association between severe headache or migraine and erectile dysfunction in American adults: A cross-sectional of data study from the NHANES. Int J Impot Res. 2024 (Apr 12). doi: 10.1038/s41443-024-00867-w Source

Key clinical point: Presence of migraine poses a strong risk for incident venous thromboembolism (VTE), whereas VTE is modest risk factor for the onset of migraine.

Major finding: The risk of developing VTE was significantly higher in patients with vs without migraine (odds ratio [OR] 96.155; P = .004). Conversely, the risk for migraine was modestly higher in patients with vs without VTE (OR 1.002; P = .016).

Study details: This two-sample bidirectional Mendelian randomization study evaluated the causal association between migraine and VTE using single-nucleotide polymorphisms as instrumental variables obtained from large-scale Genome-Wide Association Studies public databases (IEU Open GWAS project, FinnGen).

Disclosures: The study did not disclose any funding. The authors declared no conflicts of interest.

Source: Wang Y, Hu X, Wang X, et al. Exploring the two-way link between migraines and venous thromboembolism: A bidirectional two-sample Mendelian randomization study. Thromb Haemost. 2024 (Apr 24). doi: 10.1055/a-2313-0311 Source

Key clinical point: Presence of migraine poses a strong risk for incident venous thromboembolism (VTE), whereas VTE is modest risk factor for the onset of migraine.

Major finding: The risk of developing VTE was significantly higher in patients with vs without migraine (odds ratio [OR] 96.155; P = .004). Conversely, the risk for migraine was modestly higher in patients with vs without VTE (OR 1.002; P = .016).

Study details: This two-sample bidirectional Mendelian randomization study evaluated the causal association between migraine and VTE using single-nucleotide polymorphisms as instrumental variables obtained from large-scale Genome-Wide Association Studies public databases (IEU Open GWAS project, FinnGen).

Disclosures: The study did not disclose any funding. The authors declared no conflicts of interest.

Source: Wang Y, Hu X, Wang X, et al. Exploring the two-way link between migraines and venous thromboembolism: A bidirectional two-sample Mendelian randomization study. Thromb Haemost. 2024 (Apr 24). doi: 10.1055/a-2313-0311 Source

Key clinical point: Presence of migraine poses a strong risk for incident venous thromboembolism (VTE), whereas VTE is modest risk factor for the onset of migraine.

Major finding: The risk of developing VTE was significantly higher in patients with vs without migraine (odds ratio [OR] 96.155; P = .004). Conversely, the risk for migraine was modestly higher in patients with vs without VTE (OR 1.002; P = .016).

Study details: This two-sample bidirectional Mendelian randomization study evaluated the causal association between migraine and VTE using single-nucleotide polymorphisms as instrumental variables obtained from large-scale Genome-Wide Association Studies public databases (IEU Open GWAS project, FinnGen).

Disclosures: The study did not disclose any funding. The authors declared no conflicts of interest.

Source: Wang Y, Hu X, Wang X, et al. Exploring the two-way link between migraines and venous thromboembolism: A bidirectional two-sample Mendelian randomization study. Thromb Haemost. 2024 (Apr 24). doi: 10.1055/a-2313-0311 Source

Key clinical point: Very low-quality evidence showed that serum pituitary adenylates cyclase–activating polypeptide (PACAP) levels were lower in adults with a longer history of migraine.

Major finding: Serum levels of PACAP were inversely associated with history of migraine duration in adults with migraine (summary r −0.35; P < .01). It was also seen that serum PACAP levels were higher during the ictal vs interictal period in both adults and children with migraine (standardized mean difference 0.41; 95% CI 0.17-0.66).

Study details: Findings are from a meta-analysis of eight observational studies including 674 patients with migraine and 371 control individuals without migraine.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Zhu G, Wang M, Kong F. Blood serum levels of PACAP and migraine onset: A systematic review and meta-analysis of observational studies. Headache. 2024 (Apr 24). doi: 10.1111/head.14711 Source

Key clinical point: Very low-quality evidence showed that serum pituitary adenylates cyclase–activating polypeptide (PACAP) levels were lower in adults with a longer history of migraine.

Major finding: Serum levels of PACAP were inversely associated with history of migraine duration in adults with migraine (summary r −0.35; P < .01). It was also seen that serum PACAP levels were higher during the ictal vs interictal period in both adults and children with migraine (standardized mean difference 0.41; 95% CI 0.17-0.66).

Study details: Findings are from a meta-analysis of eight observational studies including 674 patients with migraine and 371 control individuals without migraine.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Zhu G, Wang M, Kong F. Blood serum levels of PACAP and migraine onset: A systematic review and meta-analysis of observational studies. Headache. 2024 (Apr 24). doi: 10.1111/head.14711 Source

Key clinical point: Very low-quality evidence showed that serum pituitary adenylates cyclase–activating polypeptide (PACAP) levels were lower in adults with a longer history of migraine.

Major finding: Serum levels of PACAP were inversely associated with history of migraine duration in adults with migraine (summary r −0.35; P < .01). It was also seen that serum PACAP levels were higher during the ictal vs interictal period in both adults and children with migraine (standardized mean difference 0.41; 95% CI 0.17-0.66).

Study details: Findings are from a meta-analysis of eight observational studies including 674 patients with migraine and 371 control individuals without migraine.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Zhu G, Wang M, Kong F. Blood serum levels of PACAP and migraine onset: A systematic review and meta-analysis of observational studies. Headache. 2024 (Apr 24). doi: 10.1111/head.14711 Source

Key clinical point: Rimegepant orally disintegrating tablet (ODT) offers pain relief within 2 hours of treatment in adults with migraine, with a tolerable safety profile.

Major finding: At 2 hours post dose, rimegepant was more effective than placebo in providing freedom from pain (risk difference 7.6; P = .0004) and the most bothersome symptom (risk difference 16.2; P < .0001). The overall rates of treatment-emergent adverse events were comparable between the rimegepant and placebo groups (15.2% and 16.4%, respectively).

Study details: This subgroup analysis of a double-blind, randomized, placebo-controlled phase 3 clinical trial included 1075 patients with acute migraine with or without aura (age ≥ 18 years) who were randomly assigned to receive either 75 mg rimegepant ODT (n = 538) or placebo (n = 537).

Disclosures: This study was funded by BioShin, a wholly owned subsidiary of Biohaven Pharmaceuticals, which was acquired by Pfizer. Pfizer provided writing support. Five authors declared being employees or stock owners of Biohaven, BioShin, or Pfizer. The remaining authors declared no conflicts of interest.

Source: Yu S, Guo A, Wang Z, et al. Rimegepant orally disintegrating tablet 75 mg for acute treatment of migraine in adults from China: A subgroup analysis of a double-blind, randomized, placebo-controlled, phase 3 clinical trial. J Headache Pain. 2024;25:57 (Apr 16). Source

Key clinical point: Rimegepant orally disintegrating tablet (ODT) offers pain relief within 2 hours of treatment in adults with migraine, with a tolerable safety profile.

Major finding: At 2 hours post dose, rimegepant was more effective than placebo in providing freedom from pain (risk difference 7.6; P = .0004) and the most bothersome symptom (risk difference 16.2; P < .0001). The overall rates of treatment-emergent adverse events were comparable between the rimegepant and placebo groups (15.2% and 16.4%, respectively).

Study details: This subgroup analysis of a double-blind, randomized, placebo-controlled phase 3 clinical trial included 1075 patients with acute migraine with or without aura (age ≥ 18 years) who were randomly assigned to receive either 75 mg rimegepant ODT (n = 538) or placebo (n = 537).

Disclosures: This study was funded by BioShin, a wholly owned subsidiary of Biohaven Pharmaceuticals, which was acquired by Pfizer. Pfizer provided writing support. Five authors declared being employees or stock owners of Biohaven, BioShin, or Pfizer. The remaining authors declared no conflicts of interest.

Source: Yu S, Guo A, Wang Z, et al. Rimegepant orally disintegrating tablet 75 mg for acute treatment of migraine in adults from China: A subgroup analysis of a double-blind, randomized, placebo-controlled, phase 3 clinical trial. J Headache Pain. 2024;25:57 (Apr 16). Source

Key clinical point: Rimegepant orally disintegrating tablet (ODT) offers pain relief within 2 hours of treatment in adults with migraine, with a tolerable safety profile.

Major finding: At 2 hours post dose, rimegepant was more effective than placebo in providing freedom from pain (risk difference 7.6; P = .0004) and the most bothersome symptom (risk difference 16.2; P < .0001). The overall rates of treatment-emergent adverse events were comparable between the rimegepant and placebo groups (15.2% and 16.4%, respectively).

Study details: This subgroup analysis of a double-blind, randomized, placebo-controlled phase 3 clinical trial included 1075 patients with acute migraine with or without aura (age ≥ 18 years) who were randomly assigned to receive either 75 mg rimegepant ODT (n = 538) or placebo (n = 537).

Disclosures: This study was funded by BioShin, a wholly owned subsidiary of Biohaven Pharmaceuticals, which was acquired by Pfizer. Pfizer provided writing support. Five authors declared being employees or stock owners of Biohaven, BioShin, or Pfizer. The remaining authors declared no conflicts of interest.

Source: Yu S, Guo A, Wang Z, et al. Rimegepant orally disintegrating tablet 75 mg for acute treatment of migraine in adults from China: A subgroup analysis of a double-blind, randomized, placebo-controlled, phase 3 clinical trial. J Headache Pain. 2024;25:57 (Apr 16). Source

Key clinical point: Combination therapy with two parenteral agents or monotherapy with either neuroleptics or metoclopramide can be considered as a first-line treatment option for the management of acute migraine pain in the emergency department (ED) settings.

Major finding: Combination therapy of two parenteral agents vs placebo was an effective treatment option in reducing pain intensity scores (mean difference −3.36; 95% CI −4.64 to −2.08) and increasing the rate of achievement of pain relief (risk ratio 2.83; 95% CI 1.74-4.61). Monotherapy with neuroleptics and metoclopramide also provided pain relief and helped patients achieve pain-free status prior to discharge from the ED but increased the risk for adverse events, especially akathisia.

Study details: This meta-analysis of 97 randomized controlled trials evaluated the effectiveness of various parenteral agents for pain relief in patients with acute migraine presenting to the ED.

Disclosures: This study was funded by the Emergency Medicine Research Group, Canada. The authors declared no conflicts of interest.

Source: Kirkland SW, Visser L, Meyer J, et al. The effectiveness of parenteral agents for pain reduction in patients with migraine presenting to emergency settings: A systematic review and network analysis. Headache. 2024;64(4):424-447. doi: 10.1111/head.14704 Source

Key clinical point: Combination therapy with two parenteral agents or monotherapy with either neuroleptics or metoclopramide can be considered as a first-line treatment option for the management of acute migraine pain in the emergency department (ED) settings.

Major finding: Combination therapy of two parenteral agents vs placebo was an effective treatment option in reducing pain intensity scores (mean difference −3.36; 95% CI −4.64 to −2.08) and increasing the rate of achievement of pain relief (risk ratio 2.83; 95% CI 1.74-4.61). Monotherapy with neuroleptics and metoclopramide also provided pain relief and helped patients achieve pain-free status prior to discharge from the ED but increased the risk for adverse events, especially akathisia.

Study details: This meta-analysis of 97 randomized controlled trials evaluated the effectiveness of various parenteral agents for pain relief in patients with acute migraine presenting to the ED.

Disclosures: This study was funded by the Emergency Medicine Research Group, Canada. The authors declared no conflicts of interest.

Source: Kirkland SW, Visser L, Meyer J, et al. The effectiveness of parenteral agents for pain reduction in patients with migraine presenting to emergency settings: A systematic review and network analysis. Headache. 2024;64(4):424-447. doi: 10.1111/head.14704 Source

Key clinical point: Combination therapy with two parenteral agents or monotherapy with either neuroleptics or metoclopramide can be considered as a first-line treatment option for the management of acute migraine pain in the emergency department (ED) settings.

Major finding: Combination therapy of two parenteral agents vs placebo was an effective treatment option in reducing pain intensity scores (mean difference −3.36; 95% CI −4.64 to −2.08) and increasing the rate of achievement of pain relief (risk ratio 2.83; 95% CI 1.74-4.61). Monotherapy with neuroleptics and metoclopramide also provided pain relief and helped patients achieve pain-free status prior to discharge from the ED but increased the risk for adverse events, especially akathisia.

Study details: This meta-analysis of 97 randomized controlled trials evaluated the effectiveness of various parenteral agents for pain relief in patients with acute migraine presenting to the ED.

Disclosures: This study was funded by the Emergency Medicine Research Group, Canada. The authors declared no conflicts of interest.

Source: Kirkland SW, Visser L, Meyer J, et al. The effectiveness of parenteral agents for pain reduction in patients with migraine presenting to emergency settings: A systematic review and network analysis. Headache. 2024;64(4):424-447. doi: 10.1111/head.14704 Source

Key clinical point: Women with migraine tend to exclusively breastfeed their infants for a shorter duration than those without migraine.

Major finding: There was no significant difference between the proportions of women with and without migraine who did not breastfeed their infants (adjusted odds ratio [aOR] 1.03; 95% CI 0.74-1.27), but the odds of exclusively breastfeeding infants for 6 months and more were 16% lower in women with vs without migraine (aOR 0.84; 95% CI 0.71-0.99; P = .033).

Study details: Findings are from a cross-sectional study including 5282 women (age 20-49 years) who had given birth in the last 5 years, of whom 862 (16.3%) had migraine.

Disclosures: The study did not receive any specific funding. Christine Lay declared receiving research support from and serving on ad boards for various sources. The other authors declared no conflicts of interest.

Source: Vyas MV, Lee N, Lay C. Association between migraine and exclusive breastfeeding: A cross-sectional study. Headache. 2024 (Apr 21). doi: 10.1111/head.14713 Source

Key clinical point: Women with migraine tend to exclusively breastfeed their infants for a shorter duration than those without migraine.

Major finding: There was no significant difference between the proportions of women with and without migraine who did not breastfeed their infants (adjusted odds ratio [aOR] 1.03; 95% CI 0.74-1.27), but the odds of exclusively breastfeeding infants for 6 months and more were 16% lower in women with vs without migraine (aOR 0.84; 95% CI 0.71-0.99; P = .033).

Study details: Findings are from a cross-sectional study including 5282 women (age 20-49 years) who had given birth in the last 5 years, of whom 862 (16.3%) had migraine.

Disclosures: The study did not receive any specific funding. Christine Lay declared receiving research support from and serving on ad boards for various sources. The other authors declared no conflicts of interest.

Source: Vyas MV, Lee N, Lay C. Association between migraine and exclusive breastfeeding: A cross-sectional study. Headache. 2024 (Apr 21). doi: 10.1111/head.14713 Source

Key clinical point: Women with migraine tend to exclusively breastfeed their infants for a shorter duration than those without migraine.

Major finding: There was no significant difference between the proportions of women with and without migraine who did not breastfeed their infants (adjusted odds ratio [aOR] 1.03; 95% CI 0.74-1.27), but the odds of exclusively breastfeeding infants for 6 months and more were 16% lower in women with vs without migraine (aOR 0.84; 95% CI 0.71-0.99; P = .033).

Study details: Findings are from a cross-sectional study including 5282 women (age 20-49 years) who had given birth in the last 5 years, of whom 862 (16.3%) had migraine.

Disclosures: The study did not receive any specific funding. Christine Lay declared receiving research support from and serving on ad boards for various sources. The other authors declared no conflicts of interest.

Source: Vyas MV, Lee N, Lay C. Association between migraine and exclusive breastfeeding: A cross-sectional study. Headache. 2024 (Apr 21). doi: 10.1111/head.14713 Source

Key clinical point: In patients with migraine, greater severity of photophobia is significantly associated with worse sleep-related outcomes, such as sleep quality (SQ), sleep disturbance (SDi), sleep onset latency (SOL), sleep-related impairment (SRI), and insomnia.

Major finding: Compared with patients with migraine and without photophobia, those with migraine and photophobia presented significantly poorer SQ (β 0.15; P < .001), longer SOL (β 0.10; P = .011), higher levels of SDi (β 0.12; P < .001) and SRI (β 0.08; P = .020), and a higher prevalence of insomnia (β 0.11; P = .005).

Study details: This cross-sectional observational study evaluated the association between photophobia and sleep-related outcomes in 852 patients with migraine using data from the American Registry for Migraine Research.

Disclosures: This study did not receive any specific funding. Some authors declared receiving compensation for consulting from, serving as consultants for, or having other ties with various sources.

Source: Sharp N, Burish MJ, Digre KB, et al. Photophobia is associated with lower sleep quality in individuals with migraine: Results from the American Registry for Migraine Research (ARMR). J Headache Pain. 2024;25:55. doi: 10.1186/s10194-024-01756-9 Source

Key clinical point: In patients with migraine, greater severity of photophobia is significantly associated with worse sleep-related outcomes, such as sleep quality (SQ), sleep disturbance (SDi), sleep onset latency (SOL), sleep-related impairment (SRI), and insomnia.

Major finding: Compared with patients with migraine and without photophobia, those with migraine and photophobia presented significantly poorer SQ (β 0.15; P < .001), longer SOL (β 0.10; P = .011), higher levels of SDi (β 0.12; P < .001) and SRI (β 0.08; P = .020), and a higher prevalence of insomnia (β 0.11; P = .005).

Study details: This cross-sectional observational study evaluated the association between photophobia and sleep-related outcomes in 852 patients with migraine using data from the American Registry for Migraine Research.

Disclosures: This study did not receive any specific funding. Some authors declared receiving compensation for consulting from, serving as consultants for, or having other ties with various sources.

Source: Sharp N, Burish MJ, Digre KB, et al. Photophobia is associated with lower sleep quality in individuals with migraine: Results from the American Registry for Migraine Research (ARMR). J Headache Pain. 2024;25:55. doi: 10.1186/s10194-024-01756-9 Source

Key clinical point: In patients with migraine, greater severity of photophobia is significantly associated with worse sleep-related outcomes, such as sleep quality (SQ), sleep disturbance (SDi), sleep onset latency (SOL), sleep-related impairment (SRI), and insomnia.

Major finding: Compared with patients with migraine and without photophobia, those with migraine and photophobia presented significantly poorer SQ (β 0.15; P < .001), longer SOL (β 0.10; P = .011), higher levels of SDi (β 0.12; P < .001) and SRI (β 0.08; P = .020), and a higher prevalence of insomnia (β 0.11; P = .005).

Study details: This cross-sectional observational study evaluated the association between photophobia and sleep-related outcomes in 852 patients with migraine using data from the American Registry for Migraine Research.

Disclosures: This study did not receive any specific funding. Some authors declared receiving compensation for consulting from, serving as consultants for, or having other ties with various sources.

Source: Sharp N, Burish MJ, Digre KB, et al. Photophobia is associated with lower sleep quality in individuals with migraine: Results from the American Registry for Migraine Research (ARMR). J Headache Pain. 2024;25:55. doi: 10.1186/s10194-024-01756-9 Source

Key clinical point: Patients with migraine had an increased risk for vascular dementia (VaD), with the risk being significantly higher in those with chronic vs episodic migraine.

Major finding: Compared with individuals without migraine, patients with migraine had a 1.21-fold higher risk for VaD (adjusted hazard ratio [aHR] 1.21; 95% CI 1.17-1.25), with the cumulative incidence of migraine being significantly higher in patients with chronic vs episodic migraine (log-rank P < .001).

Study details: This 10-year retrospective population-based cohort study included 212,836 patients with migraine and 5,863,348 participants without migraine, of whom 3914 (1.8%) and 60,259 (1.0%), respectively, were diagnosed with VaD during the follow-up period.

Disclosures: This study was funded by a grant from the National Research Foundation, Republic of Korea, and others. The authors declared no conflicts of interest.

Source: Shin H, Ha WS, Kim J, et al. Association between migraine and the risk of vascular dementia: A nationwide longitudinal study in South Korea. PLoS One. 2024;19:e0300379. doi: 10.1371/journal.pone.0300379 Source

Key clinical point: Patients with migraine had an increased risk for vascular dementia (VaD), with the risk being significantly higher in those with chronic vs episodic migraine.

Major finding: Compared with individuals without migraine, patients with migraine had a 1.21-fold higher risk for VaD (adjusted hazard ratio [aHR] 1.21; 95% CI 1.17-1.25), with the cumulative incidence of migraine being significantly higher in patients with chronic vs episodic migraine (log-rank P < .001).

Study details: This 10-year retrospective population-based cohort study included 212,836 patients with migraine and 5,863,348 participants without migraine, of whom 3914 (1.8%) and 60,259 (1.0%), respectively, were diagnosed with VaD during the follow-up period.

Disclosures: This study was funded by a grant from the National Research Foundation, Republic of Korea, and others. The authors declared no conflicts of interest.

Source: Shin H, Ha WS, Kim J, et al. Association between migraine and the risk of vascular dementia: A nationwide longitudinal study in South Korea. PLoS One. 2024;19:e0300379. doi: 10.1371/journal.pone.0300379 Source

Key clinical point: Patients with migraine had an increased risk for vascular dementia (VaD), with the risk being significantly higher in those with chronic vs episodic migraine.

Major finding: Compared with individuals without migraine, patients with migraine had a 1.21-fold higher risk for VaD (adjusted hazard ratio [aHR] 1.21; 95% CI 1.17-1.25), with the cumulative incidence of migraine being significantly higher in patients with chronic vs episodic migraine (log-rank P < .001).

Study details: This 10-year retrospective population-based cohort study included 212,836 patients with migraine and 5,863,348 participants without migraine, of whom 3914 (1.8%) and 60,259 (1.0%), respectively, were diagnosed with VaD during the follow-up period.

Disclosures: This study was funded by a grant from the National Research Foundation, Republic of Korea, and others. The authors declared no conflicts of interest.

Source: Shin H, Ha WS, Kim J, et al. Association between migraine and the risk of vascular dementia: A nationwide longitudinal study in South Korea. PLoS One. 2024;19:e0300379. doi: 10.1371/journal.pone.0300379 Source

Outcomes of Acute and Preventive Migraine Therapy Based on Patient Sex

I previously have addressed myths about migraine as they pertain to men and women. When I found an interesting study recently published in Cephalalgia investigating the effectiveness of calcitonin gene-related peptide receptor (CGRP-R) antagonists (gepants) for acute care and prevention of episodic migraine and CGRP monoclonal antibodies for preventive treatment of episodic and chronic migraine in men and women, I thought I would discuss it here.

The study’s aim was to discern if patient sex contributed to outcomes in each specific treatment arm. Female sex hormones have been recognized as factors in promoting migraine, and women show increased severity, persistence, and comorbidity in migraine profiles, and increased prevalence of migraine relative to men.

Gepants used for acute therapy (ubrogepant, rimegepant, zavegepant) and preventive therapy (atogepant, rimegepant) were studied in this trial. Erenumab, fremanezumab, galcanezumab, and eptinezumab are monoclonal antibodies that either sit on the CGRP receptor (erenumab) or inactivate the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab) and are used for migraine prevention. CGRP-based therapies are not effective in all patients and understanding which patient groups respond preferentially could reduce trial and error in treatment selection. The effectiveness of treatments targeting CGRP or the CGRP receptor may not be uniform in men and women, highlighting the need for further research and understanding of CGRP neurobiology in both sexes.

Key findings:

• In the trial by Porreca et al: In women, the 3 gepants approved by the FDA for the acute care of migraine (ubrogepant, rimegepant, zavegepant) produced a statistically significant drug effect for the 2-hour pain freedom (2h-PF) endpoint, with an average drug effect of 9.5% (CI: 7.4 to 11.6) and an average number needed to treat (NNT) of 11.
• Men did not show statistically significant effects with the acute use of gepants. The average drug effect was 2.8%, and the average NNT was 36.
• For both men and women, CGRP-targeting therapies for prevention of migraine (the 4 monoclonal antibodies) were equally effective; however, possible sex differences remain uncertain and need further study.
• In patients with chronic migraine, CGRP/CGRP-R antibodies were similarly effective in both men and women.
• For the 2-hour freedom from most bothersome symptom (2h-MBS) endpoint when gepants were given acutely, the effects were much better in women than men, with an average drug effect of 10.2% and an average NNT of 10.
• In men, these medications produced observed treatment effects on 2h-MBS with an average drug effect of 3.2% and an average NNT of 32.
• In men, 5 out of 12 estimates favored placebo over the active treatment, suggesting a treatment with little to no effect.
• The pooled treatment effects for women were 3 times as large, at 9.2% and 10.2%, respectively.
• The placebo response rates for 2 of the 3 ubrogepant studies and one of 2 zavegepant studies were higher in men than in women.

The study concludes that, while small molecule CGRP-R antagonists are dramatically effective for acute therapy of migraine in women, available data do not demonstrate effectiveness in men. The treatment effect was found to always favor active treatment numerically for both men and women for prevention of episodic and chronic migraine. 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. The study also emphasizes the need to understand which patient groups preferentially respond to CGRP-based therapies to reduce trial and error in treatment. Note that rimegepant data on prevention were not available for analysis at the time of the writing.

It would be interesting to perform a meta-analysis of multiple well-done, large, real-world studies to see if the same differences and similarities are found in men versus women for acute care of migraine and prevention of episodic and chronic migraine. I suspect that we would find that acute care results favor women but that some men do well.

The Effectiveness of Prednisolone for Treating Medication Overuse Headache

I often discuss medication overuse headache (MOH), as it is difficult to diagnose and treat, so I wanted to comment on another pertinent study. It is a post hoc analysis of the Registry for Load and Management of Medication Overuse Headache (RELEASE). The RELEASE trial is an ongoing, multicenter, observational, cohort study of MOH that has been conducted in Korea since April 2020. Findings were recently published in Headache by Lee et al.

MOH is a secondary headache disorder that develops in patients with a preexisting primary headache when they overuse acute care headache medications of any type except gepants. This includes prescription medications such as triptans, ergots, butalbital-containing medications; opioids; aspirin; acetaminophen; any type of combination medication often containing caffeine; or a combination of medications. This condition significantly impacts patients’ quality of life and productivity, usually increasing the frequency of headaches per month and leading to higher healthcare-related costs.

Treating MOH is challenging due to the lack of high-quality drug trials specifically designed for MOH and doctor inexperience. Current evidence is based largely on subgroup analyses of drug trials for the treatment of chronic migraine that contain these patient types.

Withdrawal of acute care headache medications that are being overused has traditionally been considered an important aspect of MOH treatment, although this may be changing. Withdrawal symptoms, such as increased intensity of headache pain, frequency of headaches, and other symptoms like agitation and sleep disturbance, can prevent patients from discontinuing overused medications. Systemic corticosteroids are widely used to reduce these withdrawal headaches, but clinical trials are sparse and have failed to meet proper endpoints. Despite this, corticosteroids have shown potential benefits, such as decreasing withdrawal headaches, reducing the use of rescue medications, and lowering headache intensity at certain time points after treatment.

Given these findings, this published study hypothesized that prednisolone may play a role in converting MOH to non-MOH at 3 months after treatment. The objective was to evaluate the outcome of prednisolone therapy in reversing medication overuse at 3 months posttreatment in patients with MOH using prospective multicenter registry data. Prednisolone was prescribed to 59 out of 309 patients (19.1%) enrolled during this observational study period, with doses ranging from 10 to 40 mg/day for 5-14 days. Of these patients, 228 (73.8%) completed the 3-month follow-up period.

Key findings:

• The MOH reversal rates at 3 months postbaseline were 76% (31/41) in the prednisolone group and 57.8% (108/187) in the no prednisolone group (p = 0.034).
• The steroid effect remained significant (adjusted odds ratio, 2.78; 95% confidence interval 1.27-6.1, p = 0.010) after adjusting for the number of monthly headache days at baseline, mode of discontinuation of overused medication, use of early preventive medications, and the number of combined preventive medications.

The study had several strengths, including the multicenter collection of data, prospective follow-ups, and comprehensiveness of data acquisition. However, it also had significant limitations, such as the noninterventional, observational nature of the study, potential bias in steroid prescription (every doctor prescribed what they wanted), and heterogeneity in the patient population. Also, there were a variety of treatments, and they were not standardized. Further external validation may be necessary before generalizing the study results.

Despite these limitations, the results do suggest that prednisolone may be one part of a valid treatment option for patients with MOH. I suspect, if the proper studies are done, we will see that using a good preventive medication, with few adverse events, and with careful education of the patient, formal detoxification will not be necessary when treating many patients with MOH. This has been my experience with MOH treatment utilizing the newer anti-CGRP preventive medications, including the older monoclonal antibodies and the newer gepants.

Outcomes of Acute and Preventive Migraine Therapy Based on Patient Sex

I previously have addressed myths about migraine as they pertain to men and women. When I found an interesting study recently published in Cephalalgia investigating the effectiveness of calcitonin gene-related peptide receptor (CGRP-R) antagonists (gepants) for acute care and prevention of episodic migraine and CGRP monoclonal antibodies for preventive treatment of episodic and chronic migraine in men and women, I thought I would discuss it here.

The study’s aim was to discern if patient sex contributed to outcomes in each specific treatment arm. Female sex hormones have been recognized as factors in promoting migraine, and women show increased severity, persistence, and comorbidity in migraine profiles, and increased prevalence of migraine relative to men.

Gepants used for acute therapy (ubrogepant, rimegepant, zavegepant) and preventive therapy (atogepant, rimegepant) were studied in this trial. Erenumab, fremanezumab, galcanezumab, and eptinezumab are monoclonal antibodies that either sit on the CGRP receptor (erenumab) or inactivate the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab) and are used for migraine prevention. CGRP-based therapies are not effective in all patients and understanding which patient groups respond preferentially could reduce trial and error in treatment selection. The effectiveness of treatments targeting CGRP or the CGRP receptor may not be uniform in men and women, highlighting the need for further research and understanding of CGRP neurobiology in both sexes.

Key findings:

• In the trial by Porreca et al: In women, the 3 gepants approved by the FDA for the acute care of migraine (ubrogepant, rimegepant, zavegepant) produced a statistically significant drug effect for the 2-hour pain freedom (2h-PF) endpoint, with an average drug effect of 9.5% (CI: 7.4 to 11.6) and an average number needed to treat (NNT) of 11.
• Men did not show statistically significant effects with the acute use of gepants. The average drug effect was 2.8%, and the average NNT was 36.
• For both men and women, CGRP-targeting therapies for prevention of migraine (the 4 monoclonal antibodies) were equally effective; however, possible sex differences remain uncertain and need further study.
• In patients with chronic migraine, CGRP/CGRP-R antibodies were similarly effective in both men and women.
• For the 2-hour freedom from most bothersome symptom (2h-MBS) endpoint when gepants were given acutely, the effects were much better in women than men, with an average drug effect of 10.2% and an average NNT of 10.
• In men, these medications produced observed treatment effects on 2h-MBS with an average drug effect of 3.2% and an average NNT of 32.
• In men, 5 out of 12 estimates favored placebo over the active treatment, suggesting a treatment with little to no effect.
• The pooled treatment effects for women were 3 times as large, at 9.2% and 10.2%, respectively.
• The placebo response rates for 2 of the 3 ubrogepant studies and one of 2 zavegepant studies were higher in men than in women.

The study concludes that, while small molecule CGRP-R antagonists are dramatically effective for acute therapy of migraine in women, available data do not demonstrate effectiveness in men. The treatment effect was found to always favor active treatment numerically for both men and women for prevention of episodic and chronic migraine. 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. The study also emphasizes the need to understand which patient groups preferentially respond to CGRP-based therapies to reduce trial and error in treatment. Note that rimegepant data on prevention were not available for analysis at the time of the writing.

It would be interesting to perform a meta-analysis of multiple well-done, large, real-world studies to see if the same differences and similarities are found in men versus women for acute care of migraine and prevention of episodic and chronic migraine. I suspect that we would find that acute care results favor women but that some men do well.

The Effectiveness of Prednisolone for Treating Medication Overuse Headache

I often discuss medication overuse headache (MOH), as it is difficult to diagnose and treat, so I wanted to comment on another pertinent study. It is a post hoc analysis of the Registry for Load and Management of Medication Overuse Headache (RELEASE). The RELEASE trial is an ongoing, multicenter, observational, cohort study of MOH that has been conducted in Korea since April 2020. Findings were recently published in Headache by Lee et al.

MOH is a secondary headache disorder that develops in patients with a preexisting primary headache when they overuse acute care headache medications of any type except gepants. This includes prescription medications such as triptans, ergots, butalbital-containing medications; opioids; aspirin; acetaminophen; any type of combination medication often containing caffeine; or a combination of medications. This condition significantly impacts patients’ quality of life and productivity, usually increasing the frequency of headaches per month and leading to higher healthcare-related costs.

Treating MOH is challenging due to the lack of high-quality drug trials specifically designed for MOH and doctor inexperience. Current evidence is based largely on subgroup analyses of drug trials for the treatment of chronic migraine that contain these patient types.

Withdrawal of acute care headache medications that are being overused has traditionally been considered an important aspect of MOH treatment, although this may be changing. Withdrawal symptoms, such as increased intensity of headache pain, frequency of headaches, and other symptoms like agitation and sleep disturbance, can prevent patients from discontinuing overused medications. Systemic corticosteroids are widely used to reduce these withdrawal headaches, but clinical trials are sparse and have failed to meet proper endpoints. Despite this, corticosteroids have shown potential benefits, such as decreasing withdrawal headaches, reducing the use of rescue medications, and lowering headache intensity at certain time points after treatment.

Given these findings, this published study hypothesized that prednisolone may play a role in converting MOH to non-MOH at 3 months after treatment. The objective was to evaluate the outcome of prednisolone therapy in reversing medication overuse at 3 months posttreatment in patients with MOH using prospective multicenter registry data. Prednisolone was prescribed to 59 out of 309 patients (19.1%) enrolled during this observational study period, with doses ranging from 10 to 40 mg/day for 5-14 days. Of these patients, 228 (73.8%) completed the 3-month follow-up period.

Key findings:

• The MOH reversal rates at 3 months postbaseline were 76% (31/41) in the prednisolone group and 57.8% (108/187) in the no prednisolone group (p = 0.034).
• The steroid effect remained significant (adjusted odds ratio, 2.78; 95% confidence interval 1.27-6.1, p = 0.010) after adjusting for the number of monthly headache days at baseline, mode of discontinuation of overused medication, use of early preventive medications, and the number of combined preventive medications.

The study had several strengths, including the multicenter collection of data, prospective follow-ups, and comprehensiveness of data acquisition. However, it also had significant limitations, such as the noninterventional, observational nature of the study, potential bias in steroid prescription (every doctor prescribed what they wanted), and heterogeneity in the patient population. Also, there were a variety of treatments, and they were not standardized. Further external validation may be necessary before generalizing the study results.

Despite these limitations, the results do suggest that prednisolone may be one part of a valid treatment option for patients with MOH. I suspect, if the proper studies are done, we will see that using a good preventive medication, with few adverse events, and with careful education of the patient, formal detoxification will not be necessary when treating many patients with MOH. This has been my experience with MOH treatment utilizing the newer anti-CGRP preventive medications, including the older monoclonal antibodies and the newer gepants.

Outcomes of Acute and Preventive Migraine Therapy Based on Patient Sex

I previously have addressed myths about migraine as they pertain to men and women. When I found an interesting study recently published in Cephalalgia investigating the effectiveness of calcitonin gene-related peptide receptor (CGRP-R) antagonists (gepants) for acute care and prevention of episodic migraine and CGRP monoclonal antibodies for preventive treatment of episodic and chronic migraine in men and women, I thought I would discuss it here.

The study’s aim was to discern if patient sex contributed to outcomes in each specific treatment arm. Female sex hormones have been recognized as factors in promoting migraine, and women show increased severity, persistence, and comorbidity in migraine profiles, and increased prevalence of migraine relative to men.

Gepants used for acute therapy (ubrogepant, rimegepant, zavegepant) and preventive therapy (atogepant, rimegepant) were studied in this trial. Erenumab, fremanezumab, galcanezumab, and eptinezumab are monoclonal antibodies that either sit on the CGRP receptor (erenumab) or inactivate the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab) and are used for migraine prevention. CGRP-based therapies are not effective in all patients and understanding which patient groups respond preferentially could reduce trial and error in treatment selection. The effectiveness of treatments targeting CGRP or the CGRP receptor may not be uniform in men and women, highlighting the need for further research and understanding of CGRP neurobiology in both sexes.

Key findings:

• In the trial by Porreca et al: In women, the 3 gepants approved by the FDA for the acute care of migraine (ubrogepant, rimegepant, zavegepant) produced a statistically significant drug effect for the 2-hour pain freedom (2h-PF) endpoint, with an average drug effect of 9.5% (CI: 7.4 to 11.6) and an average number needed to treat (NNT) of 11.
• Men did not show statistically significant effects with the acute use of gepants. The average drug effect was 2.8%, and the average NNT was 36.
• For both men and women, CGRP-targeting therapies for prevention of migraine (the 4 monoclonal antibodies) were equally effective; however, possible sex differences remain uncertain and need further study.
• In patients with chronic migraine, CGRP/CGRP-R antibodies were similarly effective in both men and women.
• For the 2-hour freedom from most bothersome symptom (2h-MBS) endpoint when gepants were given acutely, the effects were much better in women than men, with an average drug effect of 10.2% and an average NNT of 10.
• In men, these medications produced observed treatment effects on 2h-MBS with an average drug effect of 3.2% and an average NNT of 32.
• In men, 5 out of 12 estimates favored placebo over the active treatment, suggesting a treatment with little to no effect.
• The pooled treatment effects for women were 3 times as large, at 9.2% and 10.2%, respectively.
• The placebo response rates for 2 of the 3 ubrogepant studies and one of 2 zavegepant studies were higher in men than in women.

The study concludes that, while small molecule CGRP-R antagonists are dramatically effective for acute therapy of migraine in women, available data do not demonstrate effectiveness in men. The treatment effect was found to always favor active treatment numerically for both men and women for prevention of episodic and chronic migraine. 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. The study also emphasizes the need to understand which patient groups preferentially respond to CGRP-based therapies to reduce trial and error in treatment. Note that rimegepant data on prevention were not available for analysis at the time of the writing.

It would be interesting to perform a meta-analysis of multiple well-done, large, real-world studies to see if the same differences and similarities are found in men versus women for acute care of migraine and prevention of episodic and chronic migraine. I suspect that we would find that acute care results favor women but that some men do well.

The Effectiveness of Prednisolone for Treating Medication Overuse Headache

I often discuss medication overuse headache (MOH), as it is difficult to diagnose and treat, so I wanted to comment on another pertinent study. It is a post hoc analysis of the Registry for Load and Management of Medication Overuse Headache (RELEASE). The RELEASE trial is an ongoing, multicenter, observational, cohort study of MOH that has been conducted in Korea since April 2020. Findings were recently published in Headache by Lee et al.

MOH is a secondary headache disorder that develops in patients with a preexisting primary headache when they overuse acute care headache medications of any type except gepants. This includes prescription medications such as triptans, ergots, butalbital-containing medications; opioids; aspirin; acetaminophen; any type of combination medication often containing caffeine; or a combination of medications. This condition significantly impacts patients’ quality of life and productivity, usually increasing the frequency of headaches per month and leading to higher healthcare-related costs.

Treating MOH is challenging due to the lack of high-quality drug trials specifically designed for MOH and doctor inexperience. Current evidence is based largely on subgroup analyses of drug trials for the treatment of chronic migraine that contain these patient types.

Withdrawal of acute care headache medications that are being overused has traditionally been considered an important aspect of MOH treatment, although this may be changing. Withdrawal symptoms, such as increased intensity of headache pain, frequency of headaches, and other symptoms like agitation and sleep disturbance, can prevent patients from discontinuing overused medications. Systemic corticosteroids are widely used to reduce these withdrawal headaches, but clinical trials are sparse and have failed to meet proper endpoints. Despite this, corticosteroids have shown potential benefits, such as decreasing withdrawal headaches, reducing the use of rescue medications, and lowering headache intensity at certain time points after treatment.

Given these findings, this published study hypothesized that prednisolone may play a role in converting MOH to non-MOH at 3 months after treatment. The objective was to evaluate the outcome of prednisolone therapy in reversing medication overuse at 3 months posttreatment in patients with MOH using prospective multicenter registry data. Prednisolone was prescribed to 59 out of 309 patients (19.1%) enrolled during this observational study period, with doses ranging from 10 to 40 mg/day for 5-14 days. Of these patients, 228 (73.8%) completed the 3-month follow-up period.

Key findings:

• The MOH reversal rates at 3 months postbaseline were 76% (31/41) in the prednisolone group and 57.8% (108/187) in the no prednisolone group (p = 0.034).
• The steroid effect remained significant (adjusted odds ratio, 2.78; 95% confidence interval 1.27-6.1, p = 0.010) after adjusting for the number of monthly headache days at baseline, mode of discontinuation of overused medication, use of early preventive medications, and the number of combined preventive medications.

The study had several strengths, including the multicenter collection of data, prospective follow-ups, and comprehensiveness of data acquisition. However, it also had significant limitations, such as the noninterventional, observational nature of the study, potential bias in steroid prescription (every doctor prescribed what they wanted), and heterogeneity in the patient population. Also, there were a variety of treatments, and they were not standardized. Further external validation may be necessary before generalizing the study results.

Despite these limitations, the results do suggest that prednisolone may be one part of a valid treatment option for patients with MOH. I suspect, if the proper studies are done, we will see that using a good preventive medication, with few adverse events, and with careful education of the patient, formal detoxification will not be necessary when treating many patients with MOH. This has been my experience with MOH treatment utilizing the newer anti-CGRP preventive medications, including the older monoclonal antibodies and the newer gepants.