Migraine ICYMI

Key clinical point: Real-world data support fremanezumab as an effective, safe, and well-tolerated treatment option in patients with difficult-to-treat migraine and multiple preventive treatment failures.

Major finding: Overall, 83.5% and 62.6% of patients with high-frequency episodic migraine (HFEM) and chronic migraine (CM) receiving fremanezumab achieved ≥50% reduction in monthly headache days (MHD), respectively, along with a significant improvement in mean MHD, MHD with peak headache intensity of ≤5, intake of any abortive medications, migraine-related disability, and quality of life (all P < .001). Only 36 cases of mild adverse events were reported.

Study details: This open-label, single-arm, prospective, multicenter, clinical study included 204 patients with HFEM (n = 97) or CM (n = 107) who received ≥3 monthly courses of fremanezumab.

Disclosures: This study did not receive any funding. Some authors declared receiving investigator fees or travel grants from, or serving as consultants or advisory board members for various sources.

Source: Argyriou AA et al. 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. Eur J Neurol. 2023 (Feb 11). Doi: 10.1111/ene.15740

Key clinical point: Real-world data support fremanezumab as an effective, safe, and well-tolerated treatment option in patients with difficult-to-treat migraine and multiple preventive treatment failures.

Major finding: Overall, 83.5% and 62.6% of patients with high-frequency episodic migraine (HFEM) and chronic migraine (CM) receiving fremanezumab achieved ≥50% reduction in monthly headache days (MHD), respectively, along with a significant improvement in mean MHD, MHD with peak headache intensity of ≤5, intake of any abortive medications, migraine-related disability, and quality of life (all P < .001). Only 36 cases of mild adverse events were reported.

Study details: This open-label, single-arm, prospective, multicenter, clinical study included 204 patients with HFEM (n = 97) or CM (n = 107) who received ≥3 monthly courses of fremanezumab.

Disclosures: This study did not receive any funding. Some authors declared receiving investigator fees or travel grants from, or serving as consultants or advisory board members for various sources.

Source: Argyriou AA et al. 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. Eur J Neurol. 2023 (Feb 11). Doi: 10.1111/ene.15740

Key clinical point: Real-world data support fremanezumab as an effective, safe, and well-tolerated treatment option in patients with difficult-to-treat migraine and multiple preventive treatment failures.

Major finding: Overall, 83.5% and 62.6% of patients with high-frequency episodic migraine (HFEM) and chronic migraine (CM) receiving fremanezumab achieved ≥50% reduction in monthly headache days (MHD), respectively, along with a significant improvement in mean MHD, MHD with peak headache intensity of ≤5, intake of any abortive medications, migraine-related disability, and quality of life (all P < .001). Only 36 cases of mild adverse events were reported.

Study details: This open-label, single-arm, prospective, multicenter, clinical study included 204 patients with HFEM (n = 97) or CM (n = 107) who received ≥3 monthly courses of fremanezumab.

Disclosures: This study did not receive any funding. Some authors declared receiving investigator fees or travel grants from, or serving as consultants or advisory board members for various sources.

Source: Argyriou AA et al. 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. Eur J Neurol. 2023 (Feb 11). Doi: 10.1111/ene.15740

Key clinical point: Clinical characteristics differed significantly among patients with migraine who experienced ≥75% (super-responders [SR]) vs ≤25% (non-responders [NR]) reduction in monthly headache days in the third month after initiating prophylactic treatment with calcitonin gene-related peptide receptor (CGRP-R) monoclonal antibodies (mAb).

Major finding: SR vs NR were more likely to report vomiting (P = .031) and a significant improvement in acute migraine headache with triptan treatment (P = .010). However, NR vs SR experienced chronic migraine (P = .001), medication overuse headache (P = .024), and concomitant depression (P = .005) more frequently.

Study details: This was a retrospective real-world study including 260 patients with migraine who received ≥1 treatment with CGRP-R mAbs for migraine prevention, of which 29 and 26 were SR and NR, respectively.

Disclosures: This study did not report the source of funding. Four authors declared receiving research grants, personal fees, or honoraria for consulting and lectures from various sources.

Source: Raffaelli B et al. Clinical evaluation of super-responders vs non-responders to CGRP(-receptor) monoclonal antibodies: A real-world experience. J Headache Pain. 2023;24(1):16 (Feb 27). Doi: 10.1186/s10194-023-01552-x

Key clinical point: Clinical characteristics differed significantly among patients with migraine who experienced ≥75% (super-responders [SR]) vs ≤25% (non-responders [NR]) reduction in monthly headache days in the third month after initiating prophylactic treatment with calcitonin gene-related peptide receptor (CGRP-R) monoclonal antibodies (mAb).

Major finding: SR vs NR were more likely to report vomiting (P = .031) and a significant improvement in acute migraine headache with triptan treatment (P = .010). However, NR vs SR experienced chronic migraine (P = .001), medication overuse headache (P = .024), and concomitant depression (P = .005) more frequently.

Study details: This was a retrospective real-world study including 260 patients with migraine who received ≥1 treatment with CGRP-R mAbs for migraine prevention, of which 29 and 26 were SR and NR, respectively.

Disclosures: This study did not report the source of funding. Four authors declared receiving research grants, personal fees, or honoraria for consulting and lectures from various sources.

Source: Raffaelli B et al. Clinical evaluation of super-responders vs non-responders to CGRP(-receptor) monoclonal antibodies: A real-world experience. J Headache Pain. 2023;24(1):16 (Feb 27). Doi: 10.1186/s10194-023-01552-x

Key clinical point: Clinical characteristics differed significantly among patients with migraine who experienced ≥75% (super-responders [SR]) vs ≤25% (non-responders [NR]) reduction in monthly headache days in the third month after initiating prophylactic treatment with calcitonin gene-related peptide receptor (CGRP-R) monoclonal antibodies (mAb).

Major finding: SR vs NR were more likely to report vomiting (P = .031) and a significant improvement in acute migraine headache with triptan treatment (P = .010). However, NR vs SR experienced chronic migraine (P = .001), medication overuse headache (P = .024), and concomitant depression (P = .005) more frequently.

Study details: This was a retrospective real-world study including 260 patients with migraine who received ≥1 treatment with CGRP-R mAbs for migraine prevention, of which 29 and 26 were SR and NR, respectively.

Disclosures: This study did not report the source of funding. Four authors declared receiving research grants, personal fees, or honoraria for consulting and lectures from various sources.

Source: Raffaelli B et al. Clinical evaluation of super-responders vs non-responders to CGRP(-receptor) monoclonal antibodies: A real-world experience. J Headache Pain. 2023;24(1):16 (Feb 27). Doi: 10.1186/s10194-023-01552-x

Key clinical point: Patients with traumatic brain injury (TBI) were at a significantly higher risk for subsequent migraine, with the risk being even higher among patients with TBI who were hospitalized and those who had a major trauma.

Major finding: The risk for migraine was significantly higher among patients with vs without TBI (adjusted hazard ratio [aHR] 1.484), with migraine incidence being higher after major vs minor trauma (aHR 1.670) and among hospitalized patients vs patients visiting the outpatient department (aHR 1.557; all P < .001).

Study details: This retrospective cohort study included 151,098 patients with newly diagnosed TBI and 604,394 propensity score-matched patients without TBI.

Disclosures: This study was supported by the National Science and Technology Council of the Republic of China, Cardinal Tien Hospital, and Tri-Service General Hospital Research Foundation. The authors declared no conflicts of interest.

Source: Chen MH et al. Risk of migraine after traumatic brain injury and effects of injury management levels and treatment modalities: A nationwide population-based cohort study in Taiwan. J Clin Med. 2023;12(4):1530 (Feb 15). Doi: 10.3390/jcm12041530

Key clinical point: Patients with traumatic brain injury (TBI) were at a significantly higher risk for subsequent migraine, with the risk being even higher among patients with TBI who were hospitalized and those who had a major trauma.

Major finding: The risk for migraine was significantly higher among patients with vs without TBI (adjusted hazard ratio [aHR] 1.484), with migraine incidence being higher after major vs minor trauma (aHR 1.670) and among hospitalized patients vs patients visiting the outpatient department (aHR 1.557; all P < .001).

Study details: This retrospective cohort study included 151,098 patients with newly diagnosed TBI and 604,394 propensity score-matched patients without TBI.

Disclosures: This study was supported by the National Science and Technology Council of the Republic of China, Cardinal Tien Hospital, and Tri-Service General Hospital Research Foundation. The authors declared no conflicts of interest.

Source: Chen MH et al. Risk of migraine after traumatic brain injury and effects of injury management levels and treatment modalities: A nationwide population-based cohort study in Taiwan. J Clin Med. 2023;12(4):1530 (Feb 15). Doi: 10.3390/jcm12041530

Key clinical point: Patients with traumatic brain injury (TBI) were at a significantly higher risk for subsequent migraine, with the risk being even higher among patients with TBI who were hospitalized and those who had a major trauma.

Major finding: The risk for migraine was significantly higher among patients with vs without TBI (adjusted hazard ratio [aHR] 1.484), with migraine incidence being higher after major vs minor trauma (aHR 1.670) and among hospitalized patients vs patients visiting the outpatient department (aHR 1.557; all P < .001).

Study details: This retrospective cohort study included 151,098 patients with newly diagnosed TBI and 604,394 propensity score-matched patients without TBI.

Disclosures: This study was supported by the National Science and Technology Council of the Republic of China, Cardinal Tien Hospital, and Tri-Service General Hospital Research Foundation. The authors declared no conflicts of interest.

Source: Chen MH et al. Risk of migraine after traumatic brain injury and effects of injury management levels and treatment modalities: A nationwide population-based cohort study in Taiwan. J Clin Med. 2023;12(4):1530 (Feb 15). Doi: 10.3390/jcm12041530

Key clinical point: Patients with benign paroxysmal positional vertigo (BPPV) are at a higher risk for migraine diagnosis, with female sex, hyperlipidemia, and anxiety being significant risk factors for migraine among patients with BPPV.

Major finding: In 11 years of follow-up, 1.35% vs 0.41% of participants with vs without BPPV had migraine, respectively. The risk for migraine was 2.96-fold higher among those with BPPV (adjusted hazard ratio [aHR] 2.96; 95% CI 2.30-3.80; P < .001) and significantly higher among women (aHR 2.91; 95% CI 2.30-3.80), those with hyperlipidemia (aHR 1.77; 95% CI 1.16-2.70), and those with anxiety (aHR 1.49; 95% CI 1.03-2.14).

Study details: Findings are from a retrospective cohort study including 1386 patients with BPPV and 5544 age- and sex-matched control individuals without a history of BPPV or migraine.

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

Source: Shih I-A et al. Benign paroxysmal positional vertigo is associated with an increased risk for migraine diagnosis: A nationwide population-based cohort study. Int J Environ Res Public Health. 2023;20(4):3563 (Feb 17). Doi: 10.3390/ijerph20043563

Key clinical point: Patients with benign paroxysmal positional vertigo (BPPV) are at a higher risk for migraine diagnosis, with female sex, hyperlipidemia, and anxiety being significant risk factors for migraine among patients with BPPV.

Major finding: In 11 years of follow-up, 1.35% vs 0.41% of participants with vs without BPPV had migraine, respectively. The risk for migraine was 2.96-fold higher among those with BPPV (adjusted hazard ratio [aHR] 2.96; 95% CI 2.30-3.80; P < .001) and significantly higher among women (aHR 2.91; 95% CI 2.30-3.80), those with hyperlipidemia (aHR 1.77; 95% CI 1.16-2.70), and those with anxiety (aHR 1.49; 95% CI 1.03-2.14).

Study details: Findings are from a retrospective cohort study including 1386 patients with BPPV and 5544 age- and sex-matched control individuals without a history of BPPV or migraine.

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

Source: Shih I-A et al. Benign paroxysmal positional vertigo is associated with an increased risk for migraine diagnosis: A nationwide population-based cohort study. Int J Environ Res Public Health. 2023;20(4):3563 (Feb 17). Doi: 10.3390/ijerph20043563

Key clinical point: Patients with benign paroxysmal positional vertigo (BPPV) are at a higher risk for migraine diagnosis, with female sex, hyperlipidemia, and anxiety being significant risk factors for migraine among patients with BPPV.

Major finding: In 11 years of follow-up, 1.35% vs 0.41% of participants with vs without BPPV had migraine, respectively. The risk for migraine was 2.96-fold higher among those with BPPV (adjusted hazard ratio [aHR] 2.96; 95% CI 2.30-3.80; P < .001) and significantly higher among women (aHR 2.91; 95% CI 2.30-3.80), those with hyperlipidemia (aHR 1.77; 95% CI 1.16-2.70), and those with anxiety (aHR 1.49; 95% CI 1.03-2.14).

Study details: Findings are from a retrospective cohort study including 1386 patients with BPPV and 5544 age- and sex-matched control individuals without a history of BPPV or migraine.

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

Source: Shih I-A et al. Benign paroxysmal positional vertigo is associated with an increased risk for migraine diagnosis: A nationwide population-based cohort study. Int J Environ Res Public Health. 2023;20(4):3563 (Feb 17). Doi: 10.3390/ijerph20043563

Key clinical point: About two-thirds of patients with chronic migraine (CM) showed response to galcanezumab, and everyday headache, presence of depression, and absence of accompanying symptoms were independent predictors of a poor response to galcanezumab treatment.

Major finding: After 3 months, 64.3% of patients receiving galcanezumab achieved ≥50% reduction in monthly migraine days, with everyday headache (odds ratio [OR] 0.351; P = .017), presence of depression (OR 0.439; P = .024), and absence of accompanying symptoms (OR 0.314; P = .020) being significant predictors of response to galcanezumab.

Study details: The data come from a real-world, prospective observational study including 238 patients aged ≥18 years with CM who received preventive treatment with galcanezumab injections for 3 months.

Disclosures: This study did not report the source of funding. BK Kim declared receiving honoraria and personal fees, serving on advisory boards, and being a principal investigator of trials sponsored by various sources.

Source: Lee HC et al. Predictors of response to galcanezumab in patients with chronic migraine: A real-world prospective observational study. Neurol Sci. 2023 (Feb 24). Doi: 10.1007/s10072-023-06683-2.

Key clinical point: About two-thirds of patients with chronic migraine (CM) showed response to galcanezumab, and everyday headache, presence of depression, and absence of accompanying symptoms were independent predictors of a poor response to galcanezumab treatment.

Major finding: After 3 months, 64.3% of patients receiving galcanezumab achieved ≥50% reduction in monthly migraine days, with everyday headache (odds ratio [OR] 0.351; P = .017), presence of depression (OR 0.439; P = .024), and absence of accompanying symptoms (OR 0.314; P = .020) being significant predictors of response to galcanezumab.

Study details: The data come from a real-world, prospective observational study including 238 patients aged ≥18 years with CM who received preventive treatment with galcanezumab injections for 3 months.

Disclosures: This study did not report the source of funding. BK Kim declared receiving honoraria and personal fees, serving on advisory boards, and being a principal investigator of trials sponsored by various sources.

Source: Lee HC et al. Predictors of response to galcanezumab in patients with chronic migraine: A real-world prospective observational study. Neurol Sci. 2023 (Feb 24). Doi: 10.1007/s10072-023-06683-2.

Key clinical point: About two-thirds of patients with chronic migraine (CM) showed response to galcanezumab, and everyday headache, presence of depression, and absence of accompanying symptoms were independent predictors of a poor response to galcanezumab treatment.

Major finding: After 3 months, 64.3% of patients receiving galcanezumab achieved ≥50% reduction in monthly migraine days, with everyday headache (odds ratio [OR] 0.351; P = .017), presence of depression (OR 0.439; P = .024), and absence of accompanying symptoms (OR 0.314; P = .020) being significant predictors of response to galcanezumab.

Study details: The data come from a real-world, prospective observational study including 238 patients aged ≥18 years with CM who received preventive treatment with galcanezumab injections for 3 months.

Disclosures: This study did not report the source of funding. BK Kim declared receiving honoraria and personal fees, serving on advisory boards, and being a principal investigator of trials sponsored by various sources.

Source: Lee HC et al. Predictors of response to galcanezumab in patients with chronic migraine: A real-world prospective observational study. Neurol Sci. 2023 (Feb 24). Doi: 10.1007/s10072-023-06683-2.

Key clinical point: Galcanezumab significantly reduced interictal burden, as measured by the 4-item Migraine Interictal Burden Scale (MIBS-4), in patients with episodic or chronic migraine and multiple prior migraine preventive treatment failures.

Major finding: At 3 months, the mean MIBS-4 score reduced significantly with galcanezumab vs placebo in the overall population (least-squares mean change [Δ] −1.9 vs −0.8; P < .0001) and in patients with episodic (Δ −1.8 vs −1.1; P = .033) and chronic (Δ −1.8 vs −0.3; P < .001) migraine.

Study details: This was a post hoc analysis of the CONQUER study including 462 patients with chronic or episodic migraine and multiple prior migraine preventive treatment failures who were randomly assigned to receive galcanezumab or placebo.

Disclosures: This study was funded by Eli Lilly and Company. Some authors declared receiving research funding or support from various pharmaceutical sources, including Eli Lilly and Company. Some others declared being employees and minor stockholders of Eli Lilly and Company.

Source: Lipton RB et al. Changes in migraine interictal burden following treatment with galcanezumab: Results from a phase III randomized, placebo-controlled study. Headache. 2023 (Feb 16). Doi: 10.1111/head.14460

Key clinical point: Galcanezumab significantly reduced interictal burden, as measured by the 4-item Migraine Interictal Burden Scale (MIBS-4), in patients with episodic or chronic migraine and multiple prior migraine preventive treatment failures.

Major finding: At 3 months, the mean MIBS-4 score reduced significantly with galcanezumab vs placebo in the overall population (least-squares mean change [Δ] −1.9 vs −0.8; P < .0001) and in patients with episodic (Δ −1.8 vs −1.1; P = .033) and chronic (Δ −1.8 vs −0.3; P < .001) migraine.

Study details: This was a post hoc analysis of the CONQUER study including 462 patients with chronic or episodic migraine and multiple prior migraine preventive treatment failures who were randomly assigned to receive galcanezumab or placebo.

Disclosures: This study was funded by Eli Lilly and Company. Some authors declared receiving research funding or support from various pharmaceutical sources, including Eli Lilly and Company. Some others declared being employees and minor stockholders of Eli Lilly and Company.

Source: Lipton RB et al. Changes in migraine interictal burden following treatment with galcanezumab: Results from a phase III randomized, placebo-controlled study. Headache. 2023 (Feb 16). Doi: 10.1111/head.14460

Key clinical point: Galcanezumab significantly reduced interictal burden, as measured by the 4-item Migraine Interictal Burden Scale (MIBS-4), in patients with episodic or chronic migraine and multiple prior migraine preventive treatment failures.

Major finding: At 3 months, the mean MIBS-4 score reduced significantly with galcanezumab vs placebo in the overall population (least-squares mean change [Δ] −1.9 vs −0.8; P < .0001) and in patients with episodic (Δ −1.8 vs −1.1; P = .033) and chronic (Δ −1.8 vs −0.3; P < .001) migraine.

Study details: This was a post hoc analysis of the CONQUER study including 462 patients with chronic or episodic migraine and multiple prior migraine preventive treatment failures who were randomly assigned to receive galcanezumab or placebo.

Disclosures: This study was funded by Eli Lilly and Company. Some authors declared receiving research funding or support from various pharmaceutical sources, including Eli Lilly and Company. Some others declared being employees and minor stockholders of Eli Lilly and Company.

Source: Lipton RB et al. Changes in migraine interictal burden following treatment with galcanezumab: Results from a phase III randomized, placebo-controlled study. Headache. 2023 (Feb 16). Doi: 10.1111/head.14460

Key clinical point: Network meta-analysis confirms the overall safety of anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies and gepants for migraine prevention, with rare instances of treatment discontinuation.

Major finding: The risk for serious adverse events was not significantly different with active treatments and placebo, with 30 mg eptinezumab being the only treatment significantly associated with higher odds of adverse events leading to treatment discontinuation (odds ratio [OR] 2.62; 95% CI 1.03-6.66). Compared with placebo, the risk for treatment-emergent adverse events was not significantly different with 30 mg and 100 mg eptinezumab and was the highest with 240 mg galcanezumab (OR 1.63; 95% CI 1.33-2.00) and 120 mg galcanezumab (OR 1.40; 95% CI 1.16-1.70), with the most frequent being injection site erythema, induration, and pruritus.

Study details: The data come from a network meta-analysis of 19 phase 3 randomized controlled trials including 14,584 patients with migraine.

Disclosures: This study did not report the source of funding. The authors declared no conflicts of interest.

Source: Messina R et al. Safety and tolerability of monoclonal antibodies targeting the CGRP pathway and gepants in migraine prevention: A systematic review and network meta-analysis. Cephalalgia. 2023;43(3):3331024231152169 (Feb 14). Doi: 10.1177/03331024231152169

Key clinical point: Network meta-analysis confirms the overall safety of anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies and gepants for migraine prevention, with rare instances of treatment discontinuation.

Major finding: The risk for serious adverse events was not significantly different with active treatments and placebo, with 30 mg eptinezumab being the only treatment significantly associated with higher odds of adverse events leading to treatment discontinuation (odds ratio [OR] 2.62; 95% CI 1.03-6.66). Compared with placebo, the risk for treatment-emergent adverse events was not significantly different with 30 mg and 100 mg eptinezumab and was the highest with 240 mg galcanezumab (OR 1.63; 95% CI 1.33-2.00) and 120 mg galcanezumab (OR 1.40; 95% CI 1.16-1.70), with the most frequent being injection site erythema, induration, and pruritus.

Study details: The data come from a network meta-analysis of 19 phase 3 randomized controlled trials including 14,584 patients with migraine.

Disclosures: This study did not report the source of funding. The authors declared no conflicts of interest.

Source: Messina R et al. Safety and tolerability of monoclonal antibodies targeting the CGRP pathway and gepants in migraine prevention: A systematic review and network meta-analysis. Cephalalgia. 2023;43(3):3331024231152169 (Feb 14). Doi: 10.1177/03331024231152169

Key clinical point: Network meta-analysis confirms the overall safety of anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies and gepants for migraine prevention, with rare instances of treatment discontinuation.

Major finding: The risk for serious adverse events was not significantly different with active treatments and placebo, with 30 mg eptinezumab being the only treatment significantly associated with higher odds of adverse events leading to treatment discontinuation (odds ratio [OR] 2.62; 95% CI 1.03-6.66). Compared with placebo, the risk for treatment-emergent adverse events was not significantly different with 30 mg and 100 mg eptinezumab and was the highest with 240 mg galcanezumab (OR 1.63; 95% CI 1.33-2.00) and 120 mg galcanezumab (OR 1.40; 95% CI 1.16-1.70), with the most frequent being injection site erythema, induration, and pruritus.

Study details: The data come from a network meta-analysis of 19 phase 3 randomized controlled trials including 14,584 patients with migraine.

Disclosures: This study did not report the source of funding. The authors declared no conflicts of interest.

Source: Messina R et al. Safety and tolerability of monoclonal antibodies targeting the CGRP pathway and gepants in migraine prevention: A systematic review and network meta-analysis. Cephalalgia. 2023;43(3):3331024231152169 (Feb 14). Doi: 10.1177/03331024231152169

Key clinical point: Zavegepant nasal spray was effective in the acute treatment of migraine, with favorable tolerability and safety profiles.

Major finding: At 2 hours post-dose, higher proportions of patients treated with zavegepant vs placebo were free from pain (risk difference 8.8 percentage points; P < .0001) and from their most bothersome symptom (risk difference 8.7 percentage points; P = .0012). Dysgeusia (21% vs 5%), nasal discomfort (4% vs 1%), and nausea (3% vs 1%) were the most common adverse events in the zavegepant vs placebo group.

Study details: Findings are from a phase 3 trial including 1405 patients with ≥1-year history of migraine with or without aura who were randomly assigned to receive zavegepant 10 mg nasal spray (n = 703) or matching placebo (n = 702).

Disclosures: This study was funded by Biohaven Pharmaceuticals. Some authors declared being employees of and holding stocks or stock options in Biohaven Pharmaceuticals. Some others declared ties with various sources, including Biohaven Pharmaceuticals.

Source: Lipton RB et al. Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: A phase 3, double-blind, randomised, placebo-controlled multicentre trial. Lancet Neurol. 2023;22(3):209-217 (Mar). Doi: 10.1016/S1474-4422(22)00517-8

Key clinical point: Zavegepant nasal spray was effective in the acute treatment of migraine, with favorable tolerability and safety profiles.

Major finding: At 2 hours post-dose, higher proportions of patients treated with zavegepant vs placebo were free from pain (risk difference 8.8 percentage points; P < .0001) and from their most bothersome symptom (risk difference 8.7 percentage points; P = .0012). Dysgeusia (21% vs 5%), nasal discomfort (4% vs 1%), and nausea (3% vs 1%) were the most common adverse events in the zavegepant vs placebo group.

Study details: Findings are from a phase 3 trial including 1405 patients with ≥1-year history of migraine with or without aura who were randomly assigned to receive zavegepant 10 mg nasal spray (n = 703) or matching placebo (n = 702).

Disclosures: This study was funded by Biohaven Pharmaceuticals. Some authors declared being employees of and holding stocks or stock options in Biohaven Pharmaceuticals. Some others declared ties with various sources, including Biohaven Pharmaceuticals.

Source: Lipton RB et al. Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: A phase 3, double-blind, randomised, placebo-controlled multicentre trial. Lancet Neurol. 2023;22(3):209-217 (Mar). Doi: 10.1016/S1474-4422(22)00517-8

Key clinical point: Zavegepant nasal spray was effective in the acute treatment of migraine, with favorable tolerability and safety profiles.

Major finding: At 2 hours post-dose, higher proportions of patients treated with zavegepant vs placebo were free from pain (risk difference 8.8 percentage points; P < .0001) and from their most bothersome symptom (risk difference 8.7 percentage points; P = .0012). Dysgeusia (21% vs 5%), nasal discomfort (4% vs 1%), and nausea (3% vs 1%) were the most common adverse events in the zavegepant vs placebo group.

Study details: Findings are from a phase 3 trial including 1405 patients with ≥1-year history of migraine with or without aura who were randomly assigned to receive zavegepant 10 mg nasal spray (n = 703) or matching placebo (n = 702).

Disclosures: This study was funded by Biohaven Pharmaceuticals. Some authors declared being employees of and holding stocks or stock options in Biohaven Pharmaceuticals. Some others declared ties with various sources, including Biohaven Pharmaceuticals.

Source: Lipton RB et al. Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: A phase 3, double-blind, randomised, placebo-controlled multicentre trial. Lancet Neurol. 2023;22(3):209-217 (Mar). Doi: 10.1016/S1474-4422(22)00517-8

Headache treatment before the early 1990s was marked by decades of improvisation with mostly unapproved agents, followed by an explosion of scientific interest and new treatments developed specifically for migraine.

For practicing neurologists today, headache is one subspecialty in which options and opportunities abound. But this is largely thanks to the sea change that occurred 30 years ago.

In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, past president of the International Headache Society and clinical professor of neurology at UCLA’s David Geffen School of Medicine in Los Angeles, recalled what it was like to treat patients before and after triptan medications came onto the market.

After the first of these anti-migraine agents, sumatriptan, was approved by the Food and Drug Administration in late December 1992, headache specialists found themselves with a powerful, approved treatment that validated their commitment to solving the disorder, and helped put to rest a persistent but mistaken notion that migraine was a psychiatric condition affecting young women.

But in the 1970s and 1980s, “there wasn’t great science explaining the pathophysiology of common primary headaches like tension-type headache, cluster headache, and migraine,” Dr. Rapoport recalled. “There is often comorbid depression and anxiety with migraine, and sometimes more serious psychiatric disease, but it doesn’t mean migraine is caused by psychological issues. Now we see it clearly as a disease of the brain, but it took years of investigation to prove that.”
 

The early years

Dr. Rapoport’s journey with headache began in 1972, when he joined a private neurology practice in Stamford and Greenwich, Conn. Neurologists were frowned upon then for having too much interest in headache, he said. There was poor remuneration for doctors treating headache patients, who were hard to properly diagnose and effectively care for. Few medications could effectively stop a migraine attack or reliably reduce the frequency of headaches or the disability they caused.

On weekends Dr. Rapoport covered emergency departments and ICUs at three hospitals, where standard treatment for a migraine attack was injectable opiates. Not only did this treatment aggravate nausea, a common migraine symptom, “but it did not stop the migraine process.” Once the pain relief wore off, patients woke up with the same headache, Dr. Rapoport recalled. “The other drug that was available was ergotamine tartrate” – a fungal alkaloid used since medieval times to treat headache – “given sublingually. It helped the headache slightly but increased the nausea. DHE, or dihydroergotamine, was available only by injection and not used very much.”

DHE, a semi-synthetic molecule based on ergotamine, had FDA approval for migraine, but was complicated to administer. Like the opioids, it provoked vomiting when given intravenously, in patients already suffering migraine-induced nausea. But Dr. Rapoport, along with some of his colleagues, felt that there was a role for DHE for the most severe subtypes of patients, those with long histories of frequent migraines.

“We put people in the hospital and we gave them intravenous DHE. Eventually I got the idea to give it intramuscularly or subcutaneously in the emergency room or my office. When you give it that way, it doesn’t work as quickly but has fewer side effects.” Dr. Rapoport designed a cocktail by coadministering promethazine for nausea, and eventually added a steroid, dexamethasone. The triple shots worked on most patients experiencing severe daily or near-daily migraine attacks, Dr. Rapoport saw, and he began administering the drug combination at The New England Center for Headache in Stamford and Greenwich, Conn., which he opened with Dr. Fred D. Sheftell in 1979.

“The triple shots really worked,” Dr. Rapoport recalled. “There was no need to keep patients in the office or emergency room for intravenous therapy. The patients never called to complain or came back the next day,” he said, as often occurred with opioid treatment.

Dr. Rapoport had learned early in his residency, in the late 1960s, from Dr. David R. Coddon, a neurologist at Mount Sinai hospital in New York, that a tricyclic antidepressant, imipramine, could be helpful in some patients with frequent migraine attacks. As evidence trickled in that other antidepressants, beta-blockers, and antiepileptic drugs might have preventive properties, Dr. Rapoport and others prescribed them for certain patients. But of all the drugs in the headache specialists’ repertoire, few were approved for either treatment or prevention. “And this continued until the triptans,” Dr. Rapoport said.
 

The triptan era

Sumatriptan was developed by Glaxo for the acute treatment of migraine. The medication, first available only as self-administered subcutaneous injections, was originally designed to bind to vascular serotonin receptors to allow selective constriction of cranial vessels that dilate, causing pain, during a migraine attack. (Years later it was discovered that triptans also worked as anti-inflammatory agents that decreased the release of the neurotransmitter calcitonin gene-related peptide, or CGRP.)

Triptans “changed the world for migraine patients and for me,” Dr. Rapoport said. “I could now prescribe a medication that people could take at home to decrease or stop the migraine process in an hour or two.” The success of the triptans prompted pharmaceutical companies to search for new, more effective ways to treat migraine attacks, with better tolerability.

Seven different triptans were developed, some as injections or tablets and others as nasal sprays. “If one triptan didn’t work, we’d give a second and rarely a third,” Dr. Rapoport said. “We learned that if oral triptans did not work, the most likely issue was that it was not rapidly absorbed from the small intestine, as migraine patients have nausea, poor GI absorption, and slow transit times. This prompted the greater use of injections and nasal sprays.” Headache specialists began combining triptan treatment with nonsteroidal anti-inflammatory drugs, offering further relief for the acute care of migraine.
 

Medication overuse headache

The years between 1993 and 2000, which saw all the current triptan drugs come onto the market, was an exhilarating one for headache specialists. But even those who were thrilled by the possibilities of the triptans, like Dr. Rapoport, soon came to recognize their limitations, in terms of side effects and poor tolerability for some patients.

Specialists also noticed something unsettling about the triptans: that patients’ headaches seemed to recur within a day, or occur more frequently over time, with higher medication use.

Medication overuse headache (MOH) was known to occur when patients treated migraine too often with acute care medications, especially over-the-counter analgesics and prescription opioids and barbiturates. Dr. Rapoport began warning at conferences and in seminars that MOH seemed to occur with the triptans as well. “In the beginning other doctors didn’t think the triptans could cause MOH, but I observed that patients who were taking triptans daily or almost daily were having increased headache frequency and the triptans stopped being effective. If they didn’t take the drug they were overusing, they were going to get much worse, almost like a withdrawal.”

Today, all seven triptans are now generic, and they remain a mainstay of migraine treatment: “Almost all of my patients are using, or have used a triptan,” Dr. Rapoport said. Yet researchers came to recognize the need for treatments targeting different pathways, both for prevention and acute care.
 

The next revolution: CGRP and gepants

Studies in the early 2000s began to show a link between the release of one ubiquitous nervous system neurotransmitter, calcitonin gene-related peptide, or CGRP, and migraine. They also noticed that blocking meningeal inflammation could lead to improvement in headache. Two new drug classes emerged from this science: monoclonal antibodies against CGRP or its receptor that had to be given by injection, and oral CGRP receptor blockers that could be used both as a preventive or as an acute care medication.

In 2018 the first monoclonal antibody against the CGRP receptor, erenumab (Aimovig, marketed by Amgen), delivered by injection, was approved for migraine prevention. Three others followed, most given by autoinjector, and one by IV infusion in office or hospital settings. “Those drugs are great,” Dr. Rapoport said. “You take one shot a month or every 3 months, and your headaches drop by 50% or more with very few side effects. Some patients actually see their migraines disappear.”

The following year ubrogepant (Ubrelvy, marketed by AbbVie), the first of a novel class of oral CGRP receptor blockers known as “gepants,” was approved to treat acute migraine. The FDA soon approved another gepant, rimegepant (Nurtec, marketed by Pfizer), which received indications both for prevention and for stopping a migraine attack acutely.

Both classes of therapies – the antibodies and the gepants – are far costlier than the triptans, which are all generic, and may not be needed for every migraine patient. With the gepants, for example, insurers may restrict use to people who have not responded to triptans or for whom triptans are contraindicated or cause too many adverse events. But the CGRP-targeted therapies as a whole “have been every bit as revolutionary” as the triptans, Dr. Rapoport said. The treatments work quickly to resolve headache and disability and get the patient functioning within an hour or two, and there are fewer side effects.

In a review article published in CNS Drugs in 2021, Dr. Rapoport and his colleagues reported that the anti-CGRP treatment with gepants did not appear linked to medication overuse headache, as virtually all previous acute care medication classes did, and could be used in patients who had previously reported MOH. “I am confident that over the next few years, more people will be using them as insurance coverage will improve for patients living with migraine,” he said.
 

Headache treatment today

Migraine specialists and patients now have a staggering range of therapeutic options. Approved treatments now include prevention of migraine with onabotulinumtoxinA (Botox, marketed by the Allergan division of AbbVie) injections, which work alone and with other medicines; acute care treatment with ditans like lasmiditan (Reyvow, marketed by Lilly*), a category of acute care medicines that work like triptans but target different serotonin receptors. Five devices have been cleared for migraine and other types of headache by the FDA. These work alone or along with medication and can be used acutely or preventively. The devices “should be used more,” Dr. Rapoport said, but are not yet well covered by insurance.

Thirty years after the triptans, scientists and researchers continue to explore the pathophysiology of headache disorders, finding new pathways and identifying new potential targets.

“There are many parts of the brain and brain stem that are involved, as well as the thalamus and hypothalamus,” Dr. Rapoport said. “It’s interesting that the newer medications, and some of the older ones, work in the peripheral nervous system, outside the brain stem in the trigeminovascular system, to modulate the central nervous system. We also know that the CGRP system is involved with cellular second-order messengers. Stimulating and blocking this chain of reactions with newer drugs may become treatments in the future.”

Recent research has focused on a blood vessel dilating neurotransmitter, pituitary adenylate-cyclase-activating polypeptide, or PACAP-38, as a potential therapeutic target. Psychedelic medications such as psilocybin, strong pain medications such as ketamine, and even cannabinoids such as marijuana have all been investigated in migraine. Biofeedback therapies, mindfulness, and other behavioral interventions also have proved effective.

“I expect the next 2-5 years to bring us many important clinical trials on new types of pharmacological treatments,” Dr. Rapoport said. “This is a wonderful time to be a doctor or nurse treating patients living with migraine. When I started out treating headache, 51 years ago, we had only ergotamine tartrate. Today we have so many therapies and combinations of therapies that I hardly know where to start.”

Dr. Rapoport has served as a consultant to or speaker for AbbVie, Amgen, Biohaven, Cala Health, Lundbeck, Satsuma, and Teva, among others.

*Correction, 3/30/23: An earlier version of this article misstated the name of the company that markets Reyvow.

Headache treatment before the early 1990s was marked by decades of improvisation with mostly unapproved agents, followed by an explosion of scientific interest and new treatments developed specifically for migraine.

For practicing neurologists today, headache is one subspecialty in which options and opportunities abound. But this is largely thanks to the sea change that occurred 30 years ago.

In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, past president of the International Headache Society and clinical professor of neurology at UCLA’s David Geffen School of Medicine in Los Angeles, recalled what it was like to treat patients before and after triptan medications came onto the market.

After the first of these anti-migraine agents, sumatriptan, was approved by the Food and Drug Administration in late December 1992, headache specialists found themselves with a powerful, approved treatment that validated their commitment to solving the disorder, and helped put to rest a persistent but mistaken notion that migraine was a psychiatric condition affecting young women.

But in the 1970s and 1980s, “there wasn’t great science explaining the pathophysiology of common primary headaches like tension-type headache, cluster headache, and migraine,” Dr. Rapoport recalled. “There is often comorbid depression and anxiety with migraine, and sometimes more serious psychiatric disease, but it doesn’t mean migraine is caused by psychological issues. Now we see it clearly as a disease of the brain, but it took years of investigation to prove that.”
 

The early years

Dr. Rapoport’s journey with headache began in 1972, when he joined a private neurology practice in Stamford and Greenwich, Conn. Neurologists were frowned upon then for having too much interest in headache, he said. There was poor remuneration for doctors treating headache patients, who were hard to properly diagnose and effectively care for. Few medications could effectively stop a migraine attack or reliably reduce the frequency of headaches or the disability they caused.

On weekends Dr. Rapoport covered emergency departments and ICUs at three hospitals, where standard treatment for a migraine attack was injectable opiates. Not only did this treatment aggravate nausea, a common migraine symptom, “but it did not stop the migraine process.” Once the pain relief wore off, patients woke up with the same headache, Dr. Rapoport recalled. “The other drug that was available was ergotamine tartrate” – a fungal alkaloid used since medieval times to treat headache – “given sublingually. It helped the headache slightly but increased the nausea. DHE, or dihydroergotamine, was available only by injection and not used very much.”

DHE, a semi-synthetic molecule based on ergotamine, had FDA approval for migraine, but was complicated to administer. Like the opioids, it provoked vomiting when given intravenously, in patients already suffering migraine-induced nausea. But Dr. Rapoport, along with some of his colleagues, felt that there was a role for DHE for the most severe subtypes of patients, those with long histories of frequent migraines.

“We put people in the hospital and we gave them intravenous DHE. Eventually I got the idea to give it intramuscularly or subcutaneously in the emergency room or my office. When you give it that way, it doesn’t work as quickly but has fewer side effects.” Dr. Rapoport designed a cocktail by coadministering promethazine for nausea, and eventually added a steroid, dexamethasone. The triple shots worked on most patients experiencing severe daily or near-daily migraine attacks, Dr. Rapoport saw, and he began administering the drug combination at The New England Center for Headache in Stamford and Greenwich, Conn., which he opened with Dr. Fred D. Sheftell in 1979.

“The triple shots really worked,” Dr. Rapoport recalled. “There was no need to keep patients in the office or emergency room for intravenous therapy. The patients never called to complain or came back the next day,” he said, as often occurred with opioid treatment.

Dr. Rapoport had learned early in his residency, in the late 1960s, from Dr. David R. Coddon, a neurologist at Mount Sinai hospital in New York, that a tricyclic antidepressant, imipramine, could be helpful in some patients with frequent migraine attacks. As evidence trickled in that other antidepressants, beta-blockers, and antiepileptic drugs might have preventive properties, Dr. Rapoport and others prescribed them for certain patients. But of all the drugs in the headache specialists’ repertoire, few were approved for either treatment or prevention. “And this continued until the triptans,” Dr. Rapoport said.
 

The triptan era

Sumatriptan was developed by Glaxo for the acute treatment of migraine. The medication, first available only as self-administered subcutaneous injections, was originally designed to bind to vascular serotonin receptors to allow selective constriction of cranial vessels that dilate, causing pain, during a migraine attack. (Years later it was discovered that triptans also worked as anti-inflammatory agents that decreased the release of the neurotransmitter calcitonin gene-related peptide, or CGRP.)

Triptans “changed the world for migraine patients and for me,” Dr. Rapoport said. “I could now prescribe a medication that people could take at home to decrease or stop the migraine process in an hour or two.” The success of the triptans prompted pharmaceutical companies to search for new, more effective ways to treat migraine attacks, with better tolerability.

Seven different triptans were developed, some as injections or tablets and others as nasal sprays. “If one triptan didn’t work, we’d give a second and rarely a third,” Dr. Rapoport said. “We learned that if oral triptans did not work, the most likely issue was that it was not rapidly absorbed from the small intestine, as migraine patients have nausea, poor GI absorption, and slow transit times. This prompted the greater use of injections and nasal sprays.” Headache specialists began combining triptan treatment with nonsteroidal anti-inflammatory drugs, offering further relief for the acute care of migraine.
 

Medication overuse headache

The years between 1993 and 2000, which saw all the current triptan drugs come onto the market, was an exhilarating one for headache specialists. But even those who were thrilled by the possibilities of the triptans, like Dr. Rapoport, soon came to recognize their limitations, in terms of side effects and poor tolerability for some patients.

Specialists also noticed something unsettling about the triptans: that patients’ headaches seemed to recur within a day, or occur more frequently over time, with higher medication use.

Medication overuse headache (MOH) was known to occur when patients treated migraine too often with acute care medications, especially over-the-counter analgesics and prescription opioids and barbiturates. Dr. Rapoport began warning at conferences and in seminars that MOH seemed to occur with the triptans as well. “In the beginning other doctors didn’t think the triptans could cause MOH, but I observed that patients who were taking triptans daily or almost daily were having increased headache frequency and the triptans stopped being effective. If they didn’t take the drug they were overusing, they were going to get much worse, almost like a withdrawal.”

Today, all seven triptans are now generic, and they remain a mainstay of migraine treatment: “Almost all of my patients are using, or have used a triptan,” Dr. Rapoport said. Yet researchers came to recognize the need for treatments targeting different pathways, both for prevention and acute care.
 

The next revolution: CGRP and gepants

Studies in the early 2000s began to show a link between the release of one ubiquitous nervous system neurotransmitter, calcitonin gene-related peptide, or CGRP, and migraine. They also noticed that blocking meningeal inflammation could lead to improvement in headache. Two new drug classes emerged from this science: monoclonal antibodies against CGRP or its receptor that had to be given by injection, and oral CGRP receptor blockers that could be used both as a preventive or as an acute care medication.

In 2018 the first monoclonal antibody against the CGRP receptor, erenumab (Aimovig, marketed by Amgen), delivered by injection, was approved for migraine prevention. Three others followed, most given by autoinjector, and one by IV infusion in office or hospital settings. “Those drugs are great,” Dr. Rapoport said. “You take one shot a month or every 3 months, and your headaches drop by 50% or more with very few side effects. Some patients actually see their migraines disappear.”

The following year ubrogepant (Ubrelvy, marketed by AbbVie), the first of a novel class of oral CGRP receptor blockers known as “gepants,” was approved to treat acute migraine. The FDA soon approved another gepant, rimegepant (Nurtec, marketed by Pfizer), which received indications both for prevention and for stopping a migraine attack acutely.

Both classes of therapies – the antibodies and the gepants – are far costlier than the triptans, which are all generic, and may not be needed for every migraine patient. With the gepants, for example, insurers may restrict use to people who have not responded to triptans or for whom triptans are contraindicated or cause too many adverse events. But the CGRP-targeted therapies as a whole “have been every bit as revolutionary” as the triptans, Dr. Rapoport said. The treatments work quickly to resolve headache and disability and get the patient functioning within an hour or two, and there are fewer side effects.

In a review article published in CNS Drugs in 2021, Dr. Rapoport and his colleagues reported that the anti-CGRP treatment with gepants did not appear linked to medication overuse headache, as virtually all previous acute care medication classes did, and could be used in patients who had previously reported MOH. “I am confident that over the next few years, more people will be using them as insurance coverage will improve for patients living with migraine,” he said.
 

Headache treatment today

Migraine specialists and patients now have a staggering range of therapeutic options. Approved treatments now include prevention of migraine with onabotulinumtoxinA (Botox, marketed by the Allergan division of AbbVie) injections, which work alone and with other medicines; acute care treatment with ditans like lasmiditan (Reyvow, marketed by Lilly*), a category of acute care medicines that work like triptans but target different serotonin receptors. Five devices have been cleared for migraine and other types of headache by the FDA. These work alone or along with medication and can be used acutely or preventively. The devices “should be used more,” Dr. Rapoport said, but are not yet well covered by insurance.

Thirty years after the triptans, scientists and researchers continue to explore the pathophysiology of headache disorders, finding new pathways and identifying new potential targets.

“There are many parts of the brain and brain stem that are involved, as well as the thalamus and hypothalamus,” Dr. Rapoport said. “It’s interesting that the newer medications, and some of the older ones, work in the peripheral nervous system, outside the brain stem in the trigeminovascular system, to modulate the central nervous system. We also know that the CGRP system is involved with cellular second-order messengers. Stimulating and blocking this chain of reactions with newer drugs may become treatments in the future.”

Recent research has focused on a blood vessel dilating neurotransmitter, pituitary adenylate-cyclase-activating polypeptide, or PACAP-38, as a potential therapeutic target. Psychedelic medications such as psilocybin, strong pain medications such as ketamine, and even cannabinoids such as marijuana have all been investigated in migraine. Biofeedback therapies, mindfulness, and other behavioral interventions also have proved effective.

“I expect the next 2-5 years to bring us many important clinical trials on new types of pharmacological treatments,” Dr. Rapoport said. “This is a wonderful time to be a doctor or nurse treating patients living with migraine. When I started out treating headache, 51 years ago, we had only ergotamine tartrate. Today we have so many therapies and combinations of therapies that I hardly know where to start.”

Dr. Rapoport has served as a consultant to or speaker for AbbVie, Amgen, Biohaven, Cala Health, Lundbeck, Satsuma, and Teva, among others.

*Correction, 3/30/23: An earlier version of this article misstated the name of the company that markets Reyvow.

Headache treatment before the early 1990s was marked by decades of improvisation with mostly unapproved agents, followed by an explosion of scientific interest and new treatments developed specifically for migraine.

For practicing neurologists today, headache is one subspecialty in which options and opportunities abound. But this is largely thanks to the sea change that occurred 30 years ago.

In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, past president of the International Headache Society and clinical professor of neurology at UCLA’s David Geffen School of Medicine in Los Angeles, recalled what it was like to treat patients before and after triptan medications came onto the market.

After the first of these anti-migraine agents, sumatriptan, was approved by the Food and Drug Administration in late December 1992, headache specialists found themselves with a powerful, approved treatment that validated their commitment to solving the disorder, and helped put to rest a persistent but mistaken notion that migraine was a psychiatric condition affecting young women.

But in the 1970s and 1980s, “there wasn’t great science explaining the pathophysiology of common primary headaches like tension-type headache, cluster headache, and migraine,” Dr. Rapoport recalled. “There is often comorbid depression and anxiety with migraine, and sometimes more serious psychiatric disease, but it doesn’t mean migraine is caused by psychological issues. Now we see it clearly as a disease of the brain, but it took years of investigation to prove that.”
 

The early years

Dr. Rapoport’s journey with headache began in 1972, when he joined a private neurology practice in Stamford and Greenwich, Conn. Neurologists were frowned upon then for having too much interest in headache, he said. There was poor remuneration for doctors treating headache patients, who were hard to properly diagnose and effectively care for. Few medications could effectively stop a migraine attack or reliably reduce the frequency of headaches or the disability they caused.

On weekends Dr. Rapoport covered emergency departments and ICUs at three hospitals, where standard treatment for a migraine attack was injectable opiates. Not only did this treatment aggravate nausea, a common migraine symptom, “but it did not stop the migraine process.” Once the pain relief wore off, patients woke up with the same headache, Dr. Rapoport recalled. “The other drug that was available was ergotamine tartrate” – a fungal alkaloid used since medieval times to treat headache – “given sublingually. It helped the headache slightly but increased the nausea. DHE, or dihydroergotamine, was available only by injection and not used very much.”

DHE, a semi-synthetic molecule based on ergotamine, had FDA approval for migraine, but was complicated to administer. Like the opioids, it provoked vomiting when given intravenously, in patients already suffering migraine-induced nausea. But Dr. Rapoport, along with some of his colleagues, felt that there was a role for DHE for the most severe subtypes of patients, those with long histories of frequent migraines.

“We put people in the hospital and we gave them intravenous DHE. Eventually I got the idea to give it intramuscularly or subcutaneously in the emergency room or my office. When you give it that way, it doesn’t work as quickly but has fewer side effects.” Dr. Rapoport designed a cocktail by coadministering promethazine for nausea, and eventually added a steroid, dexamethasone. The triple shots worked on most patients experiencing severe daily or near-daily migraine attacks, Dr. Rapoport saw, and he began administering the drug combination at The New England Center for Headache in Stamford and Greenwich, Conn., which he opened with Dr. Fred D. Sheftell in 1979.

“The triple shots really worked,” Dr. Rapoport recalled. “There was no need to keep patients in the office or emergency room for intravenous therapy. The patients never called to complain or came back the next day,” he said, as often occurred with opioid treatment.

Dr. Rapoport had learned early in his residency, in the late 1960s, from Dr. David R. Coddon, a neurologist at Mount Sinai hospital in New York, that a tricyclic antidepressant, imipramine, could be helpful in some patients with frequent migraine attacks. As evidence trickled in that other antidepressants, beta-blockers, and antiepileptic drugs might have preventive properties, Dr. Rapoport and others prescribed them for certain patients. But of all the drugs in the headache specialists’ repertoire, few were approved for either treatment or prevention. “And this continued until the triptans,” Dr. Rapoport said.
 

The triptan era

Sumatriptan was developed by Glaxo for the acute treatment of migraine. The medication, first available only as self-administered subcutaneous injections, was originally designed to bind to vascular serotonin receptors to allow selective constriction of cranial vessels that dilate, causing pain, during a migraine attack. (Years later it was discovered that triptans also worked as anti-inflammatory agents that decreased the release of the neurotransmitter calcitonin gene-related peptide, or CGRP.)

Triptans “changed the world for migraine patients and for me,” Dr. Rapoport said. “I could now prescribe a medication that people could take at home to decrease or stop the migraine process in an hour or two.” The success of the triptans prompted pharmaceutical companies to search for new, more effective ways to treat migraine attacks, with better tolerability.

Seven different triptans were developed, some as injections or tablets and others as nasal sprays. “If one triptan didn’t work, we’d give a second and rarely a third,” Dr. Rapoport said. “We learned that if oral triptans did not work, the most likely issue was that it was not rapidly absorbed from the small intestine, as migraine patients have nausea, poor GI absorption, and slow transit times. This prompted the greater use of injections and nasal sprays.” Headache specialists began combining triptan treatment with nonsteroidal anti-inflammatory drugs, offering further relief for the acute care of migraine.
 

Medication overuse headache

The years between 1993 and 2000, which saw all the current triptan drugs come onto the market, was an exhilarating one for headache specialists. But even those who were thrilled by the possibilities of the triptans, like Dr. Rapoport, soon came to recognize their limitations, in terms of side effects and poor tolerability for some patients.

Specialists also noticed something unsettling about the triptans: that patients’ headaches seemed to recur within a day, or occur more frequently over time, with higher medication use.

Medication overuse headache (MOH) was known to occur when patients treated migraine too often with acute care medications, especially over-the-counter analgesics and prescription opioids and barbiturates. Dr. Rapoport began warning at conferences and in seminars that MOH seemed to occur with the triptans as well. “In the beginning other doctors didn’t think the triptans could cause MOH, but I observed that patients who were taking triptans daily or almost daily were having increased headache frequency and the triptans stopped being effective. If they didn’t take the drug they were overusing, they were going to get much worse, almost like a withdrawal.”

Today, all seven triptans are now generic, and they remain a mainstay of migraine treatment: “Almost all of my patients are using, or have used a triptan,” Dr. Rapoport said. Yet researchers came to recognize the need for treatments targeting different pathways, both for prevention and acute care.
 

The next revolution: CGRP and gepants

Studies in the early 2000s began to show a link between the release of one ubiquitous nervous system neurotransmitter, calcitonin gene-related peptide, or CGRP, and migraine. They also noticed that blocking meningeal inflammation could lead to improvement in headache. Two new drug classes emerged from this science: monoclonal antibodies against CGRP or its receptor that had to be given by injection, and oral CGRP receptor blockers that could be used both as a preventive or as an acute care medication.

In 2018 the first monoclonal antibody against the CGRP receptor, erenumab (Aimovig, marketed by Amgen), delivered by injection, was approved for migraine prevention. Three others followed, most given by autoinjector, and one by IV infusion in office or hospital settings. “Those drugs are great,” Dr. Rapoport said. “You take one shot a month or every 3 months, and your headaches drop by 50% or more with very few side effects. Some patients actually see their migraines disappear.”

The following year ubrogepant (Ubrelvy, marketed by AbbVie), the first of a novel class of oral CGRP receptor blockers known as “gepants,” was approved to treat acute migraine. The FDA soon approved another gepant, rimegepant (Nurtec, marketed by Pfizer), which received indications both for prevention and for stopping a migraine attack acutely.

Both classes of therapies – the antibodies and the gepants – are far costlier than the triptans, which are all generic, and may not be needed for every migraine patient. With the gepants, for example, insurers may restrict use to people who have not responded to triptans or for whom triptans are contraindicated or cause too many adverse events. But the CGRP-targeted therapies as a whole “have been every bit as revolutionary” as the triptans, Dr. Rapoport said. The treatments work quickly to resolve headache and disability and get the patient functioning within an hour or two, and there are fewer side effects.

In a review article published in CNS Drugs in 2021, Dr. Rapoport and his colleagues reported that the anti-CGRP treatment with gepants did not appear linked to medication overuse headache, as virtually all previous acute care medication classes did, and could be used in patients who had previously reported MOH. “I am confident that over the next few years, more people will be using them as insurance coverage will improve for patients living with migraine,” he said.
 

Headache treatment today

Migraine specialists and patients now have a staggering range of therapeutic options. Approved treatments now include prevention of migraine with onabotulinumtoxinA (Botox, marketed by the Allergan division of AbbVie) injections, which work alone and with other medicines; acute care treatment with ditans like lasmiditan (Reyvow, marketed by Lilly*), a category of acute care medicines that work like triptans but target different serotonin receptors. Five devices have been cleared for migraine and other types of headache by the FDA. These work alone or along with medication and can be used acutely or preventively. The devices “should be used more,” Dr. Rapoport said, but are not yet well covered by insurance.

Thirty years after the triptans, scientists and researchers continue to explore the pathophysiology of headache disorders, finding new pathways and identifying new potential targets.

“There are many parts of the brain and brain stem that are involved, as well as the thalamus and hypothalamus,” Dr. Rapoport said. “It’s interesting that the newer medications, and some of the older ones, work in the peripheral nervous system, outside the brain stem in the trigeminovascular system, to modulate the central nervous system. We also know that the CGRP system is involved with cellular second-order messengers. Stimulating and blocking this chain of reactions with newer drugs may become treatments in the future.”

Recent research has focused on a blood vessel dilating neurotransmitter, pituitary adenylate-cyclase-activating polypeptide, or PACAP-38, as a potential therapeutic target. Psychedelic medications such as psilocybin, strong pain medications such as ketamine, and even cannabinoids such as marijuana have all been investigated in migraine. Biofeedback therapies, mindfulness, and other behavioral interventions also have proved effective.

“I expect the next 2-5 years to bring us many important clinical trials on new types of pharmacological treatments,” Dr. Rapoport said. “This is a wonderful time to be a doctor or nurse treating patients living with migraine. When I started out treating headache, 51 years ago, we had only ergotamine tartrate. Today we have so many therapies and combinations of therapies that I hardly know where to start.”

Dr. Rapoport has served as a consultant to or speaker for AbbVie, Amgen, Biohaven, Cala Health, Lundbeck, Satsuma, and Teva, among others.

*Correction, 3/30/23: An earlier version of this article misstated the name of the company that markets Reyvow.

Children who experience migraine headaches in the aftermath of a concussion are more likely to experience prolonged symptoms of the head injury than are those with other forms of headache or no headaches at all, researchers have found.

“Early assessment of headache – and whether it has migraine features – after concussion can be helpful in predicting which children are at risk for poor outcomes and identifying children who require targeted intervention,” said senior author Keith Owen Yeates, PhD, the Ronald and Irene Ward Chair in Pediatric Brain Injury Professor and head of the department of psychology at the University of Calgary (Alta.). “Posttraumatic headache, especially when it involves migraine features, is a strong predictor of persisting symptoms and poorer quality of life after childhood concussion.”

Approximately 840,000 children per year visit an emergency department in the United States after having a traumatic brain injury. As many as 90% of those visits are considered to involve a concussion, according to the investigators. Although most children recover quickly, approximately one-third continue to report symptoms a month after the event.

Posttraumatic headache occurs in up to 90% of children, most commonly with features of migraine.

The new study, published in JAMA Network Open, was a secondary analysis of the Advancing Concussion Assessment in Pediatrics (A-CAP) prospective cohort study. The study was conducted at five emergency departments in Canada from September 2016 to July 2019 and included children and adolescents aged 8-17 years who presented with acute concussion or an orthopedic injury.

Children were included in the concussion group if they had a history of blunt head trauma resulting in at least one of three criteria consistent with the World Health Organization definition of mild traumatic brain injury. The criteria include loss of consciousness for less than 30 minutes, a Glasgow Coma Scale score of 13 or 14, or at least one acute sign or symptom of concussion, as noted by emergency clinicians.

Patients were excluded from the concussion group if they had deteriorating neurologic status, underwent neurosurgical intervention, had posttraumatic amnesia that lasted more than 24 hours, or had a score higher than 4 on the Abbreviated Injury Scale (AIS). The orthopedic injury group included patients without symptoms of concussion and with blunt trauma associated with an AIS 13 score of 4 or less. Patients were excluded from both groups if they had an overnight hospitalization for traumatic brain injury, a concussion within the past 3 months, or a neurodevelopmental disorder.

The researchers analyzed data from 928 children of 967 enrolled in the study. The median age was 12.2 years, and 41.3% were female. The final study cohort included 239 children with orthopedic injuries but no headache, 160 with a concussion and no headache, 134 with a concussion and nonmigraine headaches, and 254 with a concussion and migraine headaches.

Children with posttraumatic migraines 10 days after a concussion had the most severe symptoms and worst quality of life 3 months following their head trauma, the researchers found. Children without headaches within 10 days after concussion had the best 3-month outcomes, comparable to those with orthopedic injuries alone.

The researchers said the strengths of their study included its large population and its inclusion of various causes of head trauma, not just sports-related concussions. Limitations included self-reports of headaches instead of a physician diagnosis and lack of control for clinical interventions that might have affected the outcomes.

Charles Tator, MD, PhD, director of the Canadian Concussion Centre at Toronto Western Hospital, said the findings were unsurprising.

“Headaches are the most common symptom after concussion,” Dr. Tator, who was not involved in the latest research, told this news organization. “In my practice and research with concussed kids 11 and up and with adults, those with preconcussion history of migraine are the most difficult to treat because their headaches don’t improve unless specific measures are taken.”

Dr. Tator, who also is a professor of neurosurgery at the University of Toronto, said clinicians who treat concussions must determine which type of headaches children are experiencing – and refer as early as possible for migraine prevention or treatment and medication, as warranted.

“Early recognition after concussion that migraine headaches are occurring will save kids a lot of suffering,” he said.

The study was supported by a Canadian Institute of Health Research Foundation Grant and by funds from the Alberta Children’s Hospital Foundation and the Alberta Children’s Hospital Research Institute. Dr. Tator has disclosed no relevant financial relationships.
 

A version of this article first appeared on Medscape.com.

Children who experience migraine headaches in the aftermath of a concussion are more likely to experience prolonged symptoms of the head injury than are those with other forms of headache or no headaches at all, researchers have found.

“Early assessment of headache – and whether it has migraine features – after concussion can be helpful in predicting which children are at risk for poor outcomes and identifying children who require targeted intervention,” said senior author Keith Owen Yeates, PhD, the Ronald and Irene Ward Chair in Pediatric Brain Injury Professor and head of the department of psychology at the University of Calgary (Alta.). “Posttraumatic headache, especially when it involves migraine features, is a strong predictor of persisting symptoms and poorer quality of life after childhood concussion.”

Approximately 840,000 children per year visit an emergency department in the United States after having a traumatic brain injury. As many as 90% of those visits are considered to involve a concussion, according to the investigators. Although most children recover quickly, approximately one-third continue to report symptoms a month after the event.

Posttraumatic headache occurs in up to 90% of children, most commonly with features of migraine.

The new study, published in JAMA Network Open, was a secondary analysis of the Advancing Concussion Assessment in Pediatrics (A-CAP) prospective cohort study. The study was conducted at five emergency departments in Canada from September 2016 to July 2019 and included children and adolescents aged 8-17 years who presented with acute concussion or an orthopedic injury.

Children were included in the concussion group if they had a history of blunt head trauma resulting in at least one of three criteria consistent with the World Health Organization definition of mild traumatic brain injury. The criteria include loss of consciousness for less than 30 minutes, a Glasgow Coma Scale score of 13 or 14, or at least one acute sign or symptom of concussion, as noted by emergency clinicians.

Patients were excluded from the concussion group if they had deteriorating neurologic status, underwent neurosurgical intervention, had posttraumatic amnesia that lasted more than 24 hours, or had a score higher than 4 on the Abbreviated Injury Scale (AIS). The orthopedic injury group included patients without symptoms of concussion and with blunt trauma associated with an AIS 13 score of 4 or less. Patients were excluded from both groups if they had an overnight hospitalization for traumatic brain injury, a concussion within the past 3 months, or a neurodevelopmental disorder.

The researchers analyzed data from 928 children of 967 enrolled in the study. The median age was 12.2 years, and 41.3% were female. The final study cohort included 239 children with orthopedic injuries but no headache, 160 with a concussion and no headache, 134 with a concussion and nonmigraine headaches, and 254 with a concussion and migraine headaches.

Children with posttraumatic migraines 10 days after a concussion had the most severe symptoms and worst quality of life 3 months following their head trauma, the researchers found. Children without headaches within 10 days after concussion had the best 3-month outcomes, comparable to those with orthopedic injuries alone.

The researchers said the strengths of their study included its large population and its inclusion of various causes of head trauma, not just sports-related concussions. Limitations included self-reports of headaches instead of a physician diagnosis and lack of control for clinical interventions that might have affected the outcomes.

Charles Tator, MD, PhD, director of the Canadian Concussion Centre at Toronto Western Hospital, said the findings were unsurprising.

“Headaches are the most common symptom after concussion,” Dr. Tator, who was not involved in the latest research, told this news organization. “In my practice and research with concussed kids 11 and up and with adults, those with preconcussion history of migraine are the most difficult to treat because their headaches don’t improve unless specific measures are taken.”

Dr. Tator, who also is a professor of neurosurgery at the University of Toronto, said clinicians who treat concussions must determine which type of headaches children are experiencing – and refer as early as possible for migraine prevention or treatment and medication, as warranted.

“Early recognition after concussion that migraine headaches are occurring will save kids a lot of suffering,” he said.

The study was supported by a Canadian Institute of Health Research Foundation Grant and by funds from the Alberta Children’s Hospital Foundation and the Alberta Children’s Hospital Research Institute. Dr. Tator has disclosed no relevant financial relationships.
 

A version of this article first appeared on Medscape.com.

Children who experience migraine headaches in the aftermath of a concussion are more likely to experience prolonged symptoms of the head injury than are those with other forms of headache or no headaches at all, researchers have found.

“Early assessment of headache – and whether it has migraine features – after concussion can be helpful in predicting which children are at risk for poor outcomes and identifying children who require targeted intervention,” said senior author Keith Owen Yeates, PhD, the Ronald and Irene Ward Chair in Pediatric Brain Injury Professor and head of the department of psychology at the University of Calgary (Alta.). “Posttraumatic headache, especially when it involves migraine features, is a strong predictor of persisting symptoms and poorer quality of life after childhood concussion.”

Approximately 840,000 children per year visit an emergency department in the United States after having a traumatic brain injury. As many as 90% of those visits are considered to involve a concussion, according to the investigators. Although most children recover quickly, approximately one-third continue to report symptoms a month after the event.

Posttraumatic headache occurs in up to 90% of children, most commonly with features of migraine.

The new study, published in JAMA Network Open, was a secondary analysis of the Advancing Concussion Assessment in Pediatrics (A-CAP) prospective cohort study. The study was conducted at five emergency departments in Canada from September 2016 to July 2019 and included children and adolescents aged 8-17 years who presented with acute concussion or an orthopedic injury.

Children were included in the concussion group if they had a history of blunt head trauma resulting in at least one of three criteria consistent with the World Health Organization definition of mild traumatic brain injury. The criteria include loss of consciousness for less than 30 minutes, a Glasgow Coma Scale score of 13 or 14, or at least one acute sign or symptom of concussion, as noted by emergency clinicians.

Patients were excluded from the concussion group if they had deteriorating neurologic status, underwent neurosurgical intervention, had posttraumatic amnesia that lasted more than 24 hours, or had a score higher than 4 on the Abbreviated Injury Scale (AIS). The orthopedic injury group included patients without symptoms of concussion and with blunt trauma associated with an AIS 13 score of 4 or less. Patients were excluded from both groups if they had an overnight hospitalization for traumatic brain injury, a concussion within the past 3 months, or a neurodevelopmental disorder.

The researchers analyzed data from 928 children of 967 enrolled in the study. The median age was 12.2 years, and 41.3% were female. The final study cohort included 239 children with orthopedic injuries but no headache, 160 with a concussion and no headache, 134 with a concussion and nonmigraine headaches, and 254 with a concussion and migraine headaches.

Children with posttraumatic migraines 10 days after a concussion had the most severe symptoms and worst quality of life 3 months following their head trauma, the researchers found. Children without headaches within 10 days after concussion had the best 3-month outcomes, comparable to those with orthopedic injuries alone.

The researchers said the strengths of their study included its large population and its inclusion of various causes of head trauma, not just sports-related concussions. Limitations included self-reports of headaches instead of a physician diagnosis and lack of control for clinical interventions that might have affected the outcomes.

Charles Tator, MD, PhD, director of the Canadian Concussion Centre at Toronto Western Hospital, said the findings were unsurprising.

“Headaches are the most common symptom after concussion,” Dr. Tator, who was not involved in the latest research, told this news organization. “In my practice and research with concussed kids 11 and up and with adults, those with preconcussion history of migraine are the most difficult to treat because their headaches don’t improve unless specific measures are taken.”

Dr. Tator, who also is a professor of neurosurgery at the University of Toronto, said clinicians who treat concussions must determine which type of headaches children are experiencing – and refer as early as possible for migraine prevention or treatment and medication, as warranted.

“Early recognition after concussion that migraine headaches are occurring will save kids a lot of suffering,” he said.

The study was supported by a Canadian Institute of Health Research Foundation Grant and by funds from the Alberta Children’s Hospital Foundation and the Alberta Children’s Hospital Research Institute. Dr. Tator has disclosed no relevant financial relationships.
 

A version of this article first appeared on Medscape.com.