Migraine ICYMI

Key clinical point: Interictal levels of plasma glutamate are elevated in patients with episodic migraine (EM) and chronic migraine (CM), thus qualifying it as a potential marker for both EM and CM.

Major finding: Plasma glutamate levels were significantly higher in patients with EM (49.73 μmol/L [95% CI 40.82-66.12] ) and CM (58.70 μmol/L [95% CI 44.64-72.46]) vs control participants (38.79 μmol/L [95% CI 29.50-53.60]; P < .001).

Study details: This single-center study included 240 women aged 19-65 years, of which 98 had EM, 92 had CM, and 50 were nonmigraine control participants.

Disclosures: The study was supported by a National Research Foundation of Korea (NRF) grant from the Korean government. MK Chu declared serving as a site investigator for a multicenter trial and an advisory member for and receiving lecture honoraria and grants from various organizations, including NRF.

Source: Park CG, Chu MK. Interictal plasma glutamate levels are elevated in individuals with episodic and chronic migraine. Sci Rep. 2022;12:6921 (Apr 28). Doi: 10.1038/s41598-022-10883-9

Key clinical point: Interictal levels of plasma glutamate are elevated in patients with episodic migraine (EM) and chronic migraine (CM), thus qualifying it as a potential marker for both EM and CM.

Major finding: Plasma glutamate levels were significantly higher in patients with EM (49.73 μmol/L [95% CI 40.82-66.12] ) and CM (58.70 μmol/L [95% CI 44.64-72.46]) vs control participants (38.79 μmol/L [95% CI 29.50-53.60]; P < .001).

Study details: This single-center study included 240 women aged 19-65 years, of which 98 had EM, 92 had CM, and 50 were nonmigraine control participants.

Disclosures: The study was supported by a National Research Foundation of Korea (NRF) grant from the Korean government. MK Chu declared serving as a site investigator for a multicenter trial and an advisory member for and receiving lecture honoraria and grants from various organizations, including NRF.

Source: Park CG, Chu MK. Interictal plasma glutamate levels are elevated in individuals with episodic and chronic migraine. Sci Rep. 2022;12:6921 (Apr 28). Doi: 10.1038/s41598-022-10883-9

Key clinical point: Interictal levels of plasma glutamate are elevated in patients with episodic migraine (EM) and chronic migraine (CM), thus qualifying it as a potential marker for both EM and CM.

Major finding: Plasma glutamate levels were significantly higher in patients with EM (49.73 μmol/L [95% CI 40.82-66.12] ) and CM (58.70 μmol/L [95% CI 44.64-72.46]) vs control participants (38.79 μmol/L [95% CI 29.50-53.60]; P < .001).

Study details: This single-center study included 240 women aged 19-65 years, of which 98 had EM, 92 had CM, and 50 were nonmigraine control participants.

Disclosures: The study was supported by a National Research Foundation of Korea (NRF) grant from the Korean government. MK Chu declared serving as a site investigator for a multicenter trial and an advisory member for and receiving lecture honoraria and grants from various organizations, including NRF.

Source: Park CG, Chu MK. Interictal plasma glutamate levels are elevated in individuals with episodic and chronic migraine. Sci Rep. 2022;12:6921 (Apr 28). Doi: 10.1038/s41598-022-10883-9

Key clinical point: Adherence and persistence to fremanezumab was high among patients with migraine, especially for quarterly vs monthly dosing.

Major finding: After 6 months of fremanezumab initiation, the mean proportion of days covered (PDC) and medication possession ratio (MPR) were 86.1% and 88.7% respectively, with 74.8% and 79.0% of patients being classified as higher adherers by PDC (≥80%) and MPR (≥80%), respectively. Quarterly vs monthly fremanezumab was associated with significantly higher adherence (P ≤ .006) and mean persistence rates (P = .011).

Study details: This was a retrospective study including 987 adult patients with ≥1 migraine diagnosis during the study period who received fremanezumab on or after diagnosis.

Disclosures: The study was sponsored by Teva Pharmaceuticals. Some authors reported being current orformer employees of Teva.

Source: Krasenbaum LJ et al. A real-world study of acute and preventive medication use, adherence, and persistence in patients prescribed fremanezumab in the United States. J Headache Pain. 2022;23:54 (May 4). Doi: 10.1186/s10194-022-01413-z

Key clinical point: Adherence and persistence to fremanezumab was high among patients with migraine, especially for quarterly vs monthly dosing.

Major finding: After 6 months of fremanezumab initiation, the mean proportion of days covered (PDC) and medication possession ratio (MPR) were 86.1% and 88.7% respectively, with 74.8% and 79.0% of patients being classified as higher adherers by PDC (≥80%) and MPR (≥80%), respectively. Quarterly vs monthly fremanezumab was associated with significantly higher adherence (P ≤ .006) and mean persistence rates (P = .011).

Study details: This was a retrospective study including 987 adult patients with ≥1 migraine diagnosis during the study period who received fremanezumab on or after diagnosis.

Disclosures: The study was sponsored by Teva Pharmaceuticals. Some authors reported being current orformer employees of Teva.

Source: Krasenbaum LJ et al. A real-world study of acute and preventive medication use, adherence, and persistence in patients prescribed fremanezumab in the United States. J Headache Pain. 2022;23:54 (May 4). Doi: 10.1186/s10194-022-01413-z

Key clinical point: Adherence and persistence to fremanezumab was high among patients with migraine, especially for quarterly vs monthly dosing.

Major finding: After 6 months of fremanezumab initiation, the mean proportion of days covered (PDC) and medication possession ratio (MPR) were 86.1% and 88.7% respectively, with 74.8% and 79.0% of patients being classified as higher adherers by PDC (≥80%) and MPR (≥80%), respectively. Quarterly vs monthly fremanezumab was associated with significantly higher adherence (P ≤ .006) and mean persistence rates (P = .011).

Study details: This was a retrospective study including 987 adult patients with ≥1 migraine diagnosis during the study period who received fremanezumab on or after diagnosis.

Disclosures: The study was sponsored by Teva Pharmaceuticals. Some authors reported being current orformer employees of Teva.

Source: Krasenbaum LJ et al. A real-world study of acute and preventive medication use, adherence, and persistence in patients prescribed fremanezumab in the United States. J Headache Pain. 2022;23:54 (May 4). Doi: 10.1186/s10194-022-01413-z

Key clinical point: With self-reported migraine being associated with 26% higher odds of adverse pregnancy outcomes (APO), it may be a significant risk factor for APO.

Major finding: After adjusting for confounding factors, women with migraine showed increased odds of any APO (adjusted odds ratio 1.26; 95% CI 1.12-1.41).

Study details: This was a multicenter prospective study, nuMoM2b, including 9450 nulliparous singleton pregnant women in early gestation, of which 1752 self-reported migraine at the first-trimester visit.

Disclosures: The nuMoM2b study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Case Western Reserve University, and Columbia University, among others. EC Miller and NA Bello declared receiving financial support from various sources.

Source: Miller EC et al. Migraine and adverse pregnancy outcomes: the nuMoM2b study. Am J Obstet Gynecol. 2022 (May 2). Doi: 10.1016/j.ajog.2022.04.049

Key clinical point: With self-reported migraine being associated with 26% higher odds of adverse pregnancy outcomes (APO), it may be a significant risk factor for APO.

Major finding: After adjusting for confounding factors, women with migraine showed increased odds of any APO (adjusted odds ratio 1.26; 95% CI 1.12-1.41).

Study details: This was a multicenter prospective study, nuMoM2b, including 9450 nulliparous singleton pregnant women in early gestation, of which 1752 self-reported migraine at the first-trimester visit.

Disclosures: The nuMoM2b study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Case Western Reserve University, and Columbia University, among others. EC Miller and NA Bello declared receiving financial support from various sources.

Source: Miller EC et al. Migraine and adverse pregnancy outcomes: the nuMoM2b study. Am J Obstet Gynecol. 2022 (May 2). Doi: 10.1016/j.ajog.2022.04.049

Key clinical point: With self-reported migraine being associated with 26% higher odds of adverse pregnancy outcomes (APO), it may be a significant risk factor for APO.

Major finding: After adjusting for confounding factors, women with migraine showed increased odds of any APO (adjusted odds ratio 1.26; 95% CI 1.12-1.41).

Study details: This was a multicenter prospective study, nuMoM2b, including 9450 nulliparous singleton pregnant women in early gestation, of which 1752 self-reported migraine at the first-trimester visit.

Disclosures: The nuMoM2b study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Case Western Reserve University, and Columbia University, among others. EC Miller and NA Bello declared receiving financial support from various sources.

Source: Miller EC et al. Migraine and adverse pregnancy outcomes: the nuMoM2b study. Am J Obstet Gynecol. 2022 (May 2). Doi: 10.1016/j.ajog.2022.04.049

Key clinical point: Self-administered single-dose subcutaneous (SC) injection of diclofenac sodium (50 mg/mL) complexed with hydroxypropyl-β-cyclodextrin (HPβCD) is safe and effective for the treatment of acute migraine attacks in patients with moderate-to-severe migraine pain.

Major finding: After 2 hours of injection, 46.7% of patients were pain-free in the 50 mg diclofenac/HPβCD group, with the percentage being significantly higher than that in the placebo group (16.1%; P = .01). Most treatment-emergent adverse events were mild.

Study details: The findings are from a multicenter, phase 2, dose-finding pilot study including 122 adult patients experiencing 2-8 migraine attacks/month with moderate-to-severe pain who were randomly assigned to receive diclofenac/HPβCD (25, 50, or 75 mg) or placebo.

Disclosures: The study was sponsored by IBSA Institut Biochimique S.A. (Switzerland). Some authors declared serving as advisory board members, consultants, or speakers, or receiving honoraria for clinical investigation studies, travel and research grants, or personal fees from various sources.

Source: Geppetti P et al. Self-administered subcutaneous diclofenac sodium in acute migraine attack: A randomized, double-blind, placebo-controlled dose-finding pilot study. Cephalalgia. 2022 (Apr 26). Doi: 10.1177/03331024221093712

Key clinical point: Self-administered single-dose subcutaneous (SC) injection of diclofenac sodium (50 mg/mL) complexed with hydroxypropyl-β-cyclodextrin (HPβCD) is safe and effective for the treatment of acute migraine attacks in patients with moderate-to-severe migraine pain.

Major finding: After 2 hours of injection, 46.7% of patients were pain-free in the 50 mg diclofenac/HPβCD group, with the percentage being significantly higher than that in the placebo group (16.1%; P = .01). Most treatment-emergent adverse events were mild.

Study details: The findings are from a multicenter, phase 2, dose-finding pilot study including 122 adult patients experiencing 2-8 migraine attacks/month with moderate-to-severe pain who were randomly assigned to receive diclofenac/HPβCD (25, 50, or 75 mg) or placebo.

Disclosures: The study was sponsored by IBSA Institut Biochimique S.A. (Switzerland). Some authors declared serving as advisory board members, consultants, or speakers, or receiving honoraria for clinical investigation studies, travel and research grants, or personal fees from various sources.

Source: Geppetti P et al. Self-administered subcutaneous diclofenac sodium in acute migraine attack: A randomized, double-blind, placebo-controlled dose-finding pilot study. Cephalalgia. 2022 (Apr 26). Doi: 10.1177/03331024221093712

Key clinical point: Self-administered single-dose subcutaneous (SC) injection of diclofenac sodium (50 mg/mL) complexed with hydroxypropyl-β-cyclodextrin (HPβCD) is safe and effective for the treatment of acute migraine attacks in patients with moderate-to-severe migraine pain.

Major finding: After 2 hours of injection, 46.7% of patients were pain-free in the 50 mg diclofenac/HPβCD group, with the percentage being significantly higher than that in the placebo group (16.1%; P = .01). Most treatment-emergent adverse events were mild.

Study details: The findings are from a multicenter, phase 2, dose-finding pilot study including 122 adult patients experiencing 2-8 migraine attacks/month with moderate-to-severe pain who were randomly assigned to receive diclofenac/HPβCD (25, 50, or 75 mg) or placebo.

Disclosures: The study was sponsored by IBSA Institut Biochimique S.A. (Switzerland). Some authors declared serving as advisory board members, consultants, or speakers, or receiving honoraria for clinical investigation studies, travel and research grants, or personal fees from various sources.

Source: Geppetti P et al. Self-administered subcutaneous diclofenac sodium in acute migraine attack: A randomized, double-blind, placebo-controlled dose-finding pilot study. Cephalalgia. 2022 (Apr 26). Doi: 10.1177/03331024221093712

Key clinical point: Compared with placebo, ubrogepant therapy provides favorable 2-hour outcomes, as measured by functional disability, medication satisfaction, and impression of overall change in migraine, in patients with migraine who are triptan insufficient responders (TIR).

Major finding: At 2 hours after initial dose of ubrogepant vs placebo, significantly greater proportion of patients reported no disability (38% vs 29%; odds ratio [OR] 1.5; P = .048), treatment satisfaction (33% vs 21%; OR 1.8; P = .006), and improvement in migraine (30% vs 18%; OR 2.0; P = .006).

Study details: This post hoc analysis included 1799 patients with migraine with or without aura from the phase 3 ACHIEVE I and ACHIEVE II trials who were self-reported TIR and received 50 mg ubrogepant (n = 887) or placebo (n = 912).

Disclosures: The study was funded by Allergan (before acquisition by AbbVie). Some authors declared serving as consultants or advisory board members and receiving research support, honoraria, or royalties from various sources, including AbbVie/Allergan. The other authors are current or former employees and stockholders of AbbVie.

Source: Lipton RB et al. Functionality, satisfaction, and global impression of change with ubrogepant for the acute treatment of migraine in triptan insufficient responders: A post hoc analysis of the ACHIEVE I and ACHIEVE II randomized trials. J Headache Pain. 2022;23:50 (Apr 25). Doi: 10.1186/s10194-022-01419-7

Key clinical point: Compared with placebo, ubrogepant therapy provides favorable 2-hour outcomes, as measured by functional disability, medication satisfaction, and impression of overall change in migraine, in patients with migraine who are triptan insufficient responders (TIR).

Major finding: At 2 hours after initial dose of ubrogepant vs placebo, significantly greater proportion of patients reported no disability (38% vs 29%; odds ratio [OR] 1.5; P = .048), treatment satisfaction (33% vs 21%; OR 1.8; P = .006), and improvement in migraine (30% vs 18%; OR 2.0; P = .006).

Study details: This post hoc analysis included 1799 patients with migraine with or without aura from the phase 3 ACHIEVE I and ACHIEVE II trials who were self-reported TIR and received 50 mg ubrogepant (n = 887) or placebo (n = 912).

Disclosures: The study was funded by Allergan (before acquisition by AbbVie). Some authors declared serving as consultants or advisory board members and receiving research support, honoraria, or royalties from various sources, including AbbVie/Allergan. The other authors are current or former employees and stockholders of AbbVie.

Source: Lipton RB et al. Functionality, satisfaction, and global impression of change with ubrogepant for the acute treatment of migraine in triptan insufficient responders: A post hoc analysis of the ACHIEVE I and ACHIEVE II randomized trials. J Headache Pain. 2022;23:50 (Apr 25). Doi: 10.1186/s10194-022-01419-7

Key clinical point: Compared with placebo, ubrogepant therapy provides favorable 2-hour outcomes, as measured by functional disability, medication satisfaction, and impression of overall change in migraine, in patients with migraine who are triptan insufficient responders (TIR).

Major finding: At 2 hours after initial dose of ubrogepant vs placebo, significantly greater proportion of patients reported no disability (38% vs 29%; odds ratio [OR] 1.5; P = .048), treatment satisfaction (33% vs 21%; OR 1.8; P = .006), and improvement in migraine (30% vs 18%; OR 2.0; P = .006).

Study details: This post hoc analysis included 1799 patients with migraine with or without aura from the phase 3 ACHIEVE I and ACHIEVE II trials who were self-reported TIR and received 50 mg ubrogepant (n = 887) or placebo (n = 912).

Disclosures: The study was funded by Allergan (before acquisition by AbbVie). Some authors declared serving as consultants or advisory board members and receiving research support, honoraria, or royalties from various sources, including AbbVie/Allergan. The other authors are current or former employees and stockholders of AbbVie.

Source: Lipton RB et al. Functionality, satisfaction, and global impression of change with ubrogepant for the acute treatment of migraine in triptan insufficient responders: A post hoc analysis of the ACHIEVE I and ACHIEVE II randomized trials. J Headache Pain. 2022;23:50 (Apr 25). Doi: 10.1186/s10194-022-01419-7

Key clinical point: In treatment-resistant episodic or chronic migraine, galcanezumab therapy can help achieve a clinically meaningful reduction in monthly acute headache medication use.

Major finding: Galcanezumab vs. placebo led to a significantly greater least-squares mean reduction in monthly acute headache medication use from 1 to 3 months (4.2 vs 0.8 days; P < .0001). At 6 months, the monthly acute headache medication use was similar between the groups.

Study details: The data come from the phase 3 CONQUER study including 462 patients with treatment-resistant episodic or chronic migraine who were randomly assigned to receive galcanezumab (n = 232) or placebo (n = 230) in the double-blind phase (months 1-3), followed by galcanezumab in the open-label phase (months 4-6).

Disclosures: The study was sponsored by Eli Lilly and Company. Some authors declared being on the advisory board or speakers’ bureau for and receiving consulting fees, speaker fees, honoraria, or travel support from various sources, including Eli Lilly. The other authors are employees or stockholders of Eli Lilly or one of its subsidiaries.

Source: Ambrosini A et al. Changes in acute headache medication use and health care resource utilization: Results from a randomized, double-blind, placebo-controlled clinical trial evaluating galcanezumab in adults with treatment-resistant migraine (CONQUER). J Manag Care Spec Pharm. 2022 (Apr 22). Doi: 10.18553/jmcp.2022.21375

Key clinical point: In treatment-resistant episodic or chronic migraine, galcanezumab therapy can help achieve a clinically meaningful reduction in monthly acute headache medication use.

Major finding: Galcanezumab vs. placebo led to a significantly greater least-squares mean reduction in monthly acute headache medication use from 1 to 3 months (4.2 vs 0.8 days; P < .0001). At 6 months, the monthly acute headache medication use was similar between the groups.

Study details: The data come from the phase 3 CONQUER study including 462 patients with treatment-resistant episodic or chronic migraine who were randomly assigned to receive galcanezumab (n = 232) or placebo (n = 230) in the double-blind phase (months 1-3), followed by galcanezumab in the open-label phase (months 4-6).

Disclosures: The study was sponsored by Eli Lilly and Company. Some authors declared being on the advisory board or speakers’ bureau for and receiving consulting fees, speaker fees, honoraria, or travel support from various sources, including Eli Lilly. The other authors are employees or stockholders of Eli Lilly or one of its subsidiaries.

Source: Ambrosini A et al. Changes in acute headache medication use and health care resource utilization: Results from a randomized, double-blind, placebo-controlled clinical trial evaluating galcanezumab in adults with treatment-resistant migraine (CONQUER). J Manag Care Spec Pharm. 2022 (Apr 22). Doi: 10.18553/jmcp.2022.21375

Key clinical point: In treatment-resistant episodic or chronic migraine, galcanezumab therapy can help achieve a clinically meaningful reduction in monthly acute headache medication use.

Major finding: Galcanezumab vs. placebo led to a significantly greater least-squares mean reduction in monthly acute headache medication use from 1 to 3 months (4.2 vs 0.8 days; P < .0001). At 6 months, the monthly acute headache medication use was similar between the groups.

Study details: The data come from the phase 3 CONQUER study including 462 patients with treatment-resistant episodic or chronic migraine who were randomly assigned to receive galcanezumab (n = 232) or placebo (n = 230) in the double-blind phase (months 1-3), followed by galcanezumab in the open-label phase (months 4-6).

Disclosures: The study was sponsored by Eli Lilly and Company. Some authors declared being on the advisory board or speakers’ bureau for and receiving consulting fees, speaker fees, honoraria, or travel support from various sources, including Eli Lilly. The other authors are employees or stockholders of Eli Lilly or one of its subsidiaries.

Source: Ambrosini A et al. Changes in acute headache medication use and health care resource utilization: Results from a randomized, double-blind, placebo-controlled clinical trial evaluating galcanezumab in adults with treatment-resistant migraine (CONQUER). J Manag Care Spec Pharm. 2022 (Apr 22). Doi: 10.18553/jmcp.2022.21375

Key clinical point: A second dose of eptinezumab may be beneficial in patients with migraine who exhibit a suboptimal first-dose response.

Major finding: Percent change in monthly migraine days (MMD) over weeks 1-12 (PROMISE-1: odds ratio [OR] 0.97; P = .0001; PROMISE-2: OR 0.94; P < .0001) and change in 6-item Headache Impact Test total score (only PROMISE-2: OR 0.92; P = .027) were observed to be significant first-dose predictors of second-dose response.

Study details: This post hoc analysis included patients with migraine (episodic [n = 416; PROMISE-1] and chronic [n = 479; PROMISE-2]), suboptimal response (<50% reduction from baseline in MMD across weeks 1-12), and patient-reported outcome data at weeks 12 and 24.

Disclosures: The study was sponsored by Lundbeck LLC, USA. Some authors declared serving as consultants, advisory board members, or speakers for and receiving speaker honoraria from various sources, including Lundbeck. The other authors are current orformer employees of H. Lundbeck A/S or its subsidiary/contracted service provider.

Source: Schim JD et al. Likelihood of response with subsequent dosing for patients with migraine and initial suboptimal response with eptinezumab: A post hoc analysis of two placebo-controlled randomized clinical trials. Headache. 2022 (May 6). Doi: 10.1111/head.14302

Key clinical point: A second dose of eptinezumab may be beneficial in patients with migraine who exhibit a suboptimal first-dose response.

Major finding: Percent change in monthly migraine days (MMD) over weeks 1-12 (PROMISE-1: odds ratio [OR] 0.97; P = .0001; PROMISE-2: OR 0.94; P < .0001) and change in 6-item Headache Impact Test total score (only PROMISE-2: OR 0.92; P = .027) were observed to be significant first-dose predictors of second-dose response.

Study details: This post hoc analysis included patients with migraine (episodic [n = 416; PROMISE-1] and chronic [n = 479; PROMISE-2]), suboptimal response (<50% reduction from baseline in MMD across weeks 1-12), and patient-reported outcome data at weeks 12 and 24.

Disclosures: The study was sponsored by Lundbeck LLC, USA. Some authors declared serving as consultants, advisory board members, or speakers for and receiving speaker honoraria from various sources, including Lundbeck. The other authors are current orformer employees of H. Lundbeck A/S or its subsidiary/contracted service provider.

Source: Schim JD et al. Likelihood of response with subsequent dosing for patients with migraine and initial suboptimal response with eptinezumab: A post hoc analysis of two placebo-controlled randomized clinical trials. Headache. 2022 (May 6). Doi: 10.1111/head.14302

Key clinical point: A second dose of eptinezumab may be beneficial in patients with migraine who exhibit a suboptimal first-dose response.

Major finding: Percent change in monthly migraine days (MMD) over weeks 1-12 (PROMISE-1: odds ratio [OR] 0.97; P = .0001; PROMISE-2: OR 0.94; P < .0001) and change in 6-item Headache Impact Test total score (only PROMISE-2: OR 0.92; P = .027) were observed to be significant first-dose predictors of second-dose response.

Study details: This post hoc analysis included patients with migraine (episodic [n = 416; PROMISE-1] and chronic [n = 479; PROMISE-2]), suboptimal response (<50% reduction from baseline in MMD across weeks 1-12), and patient-reported outcome data at weeks 12 and 24.

Disclosures: The study was sponsored by Lundbeck LLC, USA. Some authors declared serving as consultants, advisory board members, or speakers for and receiving speaker honoraria from various sources, including Lundbeck. The other authors are current orformer employees of H. Lundbeck A/S or its subsidiary/contracted service provider.

Source: Schim JD et al. Likelihood of response with subsequent dosing for patients with migraine and initial suboptimal response with eptinezumab: A post hoc analysis of two placebo-controlled randomized clinical trials. Headache. 2022 (May 6). Doi: 10.1111/head.14302

Key clinical point: Erenumab is effective in managing patients with treatment-resistant chronic migraine in a tertiary care setting without causing any serious adverse effects.

Major finding: At 3 and 6 months, erenumab significantly reduced the median monthly migraine days (MMD; −4 and −9 days, respectively; P < .001), with the MMD 50% responder rate at 3 months being 36%. No serious adverse events were observed.

Study details: This was a prospective study including 92 patients aged >18 years with chronic migraine and ≥3 prior migraine preventive treatment failures who received monthly 70 mg erenumab for 3 months.

Disclosures: The authors did not report any source of funding or conflict of interests.

Source: Khalil M et al. Erenumab in chronic migraine: Experience from a UK tertiary centre and comparison with other real-world evidence. Eur J Neurol. 2022 (Apr 21). Doi: 10.1111/ene.15364

Key clinical point: Erenumab is effective in managing patients with treatment-resistant chronic migraine in a tertiary care setting without causing any serious adverse effects.

Major finding: At 3 and 6 months, erenumab significantly reduced the median monthly migraine days (MMD; −4 and −9 days, respectively; P < .001), with the MMD 50% responder rate at 3 months being 36%. No serious adverse events were observed.

Study details: This was a prospective study including 92 patients aged >18 years with chronic migraine and ≥3 prior migraine preventive treatment failures who received monthly 70 mg erenumab for 3 months.

Disclosures: The authors did not report any source of funding or conflict of interests.

Source: Khalil M et al. Erenumab in chronic migraine: Experience from a UK tertiary centre and comparison with other real-world evidence. Eur J Neurol. 2022 (Apr 21). Doi: 10.1111/ene.15364

Key clinical point: Erenumab is effective in managing patients with treatment-resistant chronic migraine in a tertiary care setting without causing any serious adverse effects.

Major finding: At 3 and 6 months, erenumab significantly reduced the median monthly migraine days (MMD; −4 and −9 days, respectively; P < .001), with the MMD 50% responder rate at 3 months being 36%. No serious adverse events were observed.

Study details: This was a prospective study including 92 patients aged >18 years with chronic migraine and ≥3 prior migraine preventive treatment failures who received monthly 70 mg erenumab for 3 months.

Disclosures: The authors did not report any source of funding or conflict of interests.

Source: Khalil M et al. Erenumab in chronic migraine: Experience from a UK tertiary centre and comparison with other real-world evidence. Eur J Neurol. 2022 (Apr 21). Doi: 10.1111/ene.15364

Key clinical point: Fremanezumab treatment leads to clinically meaningful improvement in patients with migraine for up to 6 months, regardless of the dosing regimen or number of prior migraine preventive treatment failures.

Major finding: At 6 months, mean percentage reductions from baseline in monthly migraine days, monthly headache days, Migraine Disability Assessment score, and 6-item Headache Impact Test score were 72.4% (−9.2 days), 70.0% (−9.8 days), 63.1% (−18.1 days), and 27.0% (−16.2 days), respectively. Subgroups formed according to the dosing schedule and number of prior migraine preventive treatment failures showed similar improvements.

Study details: This was a retrospective, online physician chart review study that included data from 421 clinicians and 1003 patients with migraine who had initiated fremanezumab treatment at ≥18 years of age and received ≥1 fremanezumab dose.

Disclosures: The study was sponsored by Teva Pharmaceuticals. Some authors declared being current or former employees of Teva. The other authors are employees of an organization funded by Teva.

Source: Driessen MT et al. Real-world effectiveness of fremanezumab in migraine patients initiating treatment in the United States: results from a retrospective chart study. J Headache Pain. 2022;23:47 (Apr 11). Doi: 10.1186/s10194-022-01411-1

Key clinical point: Fremanezumab treatment leads to clinically meaningful improvement in patients with migraine for up to 6 months, regardless of the dosing regimen or number of prior migraine preventive treatment failures.

Major finding: At 6 months, mean percentage reductions from baseline in monthly migraine days, monthly headache days, Migraine Disability Assessment score, and 6-item Headache Impact Test score were 72.4% (−9.2 days), 70.0% (−9.8 days), 63.1% (−18.1 days), and 27.0% (−16.2 days), respectively. Subgroups formed according to the dosing schedule and number of prior migraine preventive treatment failures showed similar improvements.

Study details: This was a retrospective, online physician chart review study that included data from 421 clinicians and 1003 patients with migraine who had initiated fremanezumab treatment at ≥18 years of age and received ≥1 fremanezumab dose.

Disclosures: The study was sponsored by Teva Pharmaceuticals. Some authors declared being current or former employees of Teva. The other authors are employees of an organization funded by Teva.

Source: Driessen MT et al. Real-world effectiveness of fremanezumab in migraine patients initiating treatment in the United States: results from a retrospective chart study. J Headache Pain. 2022;23:47 (Apr 11). Doi: 10.1186/s10194-022-01411-1

Key clinical point: Fremanezumab treatment leads to clinically meaningful improvement in patients with migraine for up to 6 months, regardless of the dosing regimen or number of prior migraine preventive treatment failures.

Major finding: At 6 months, mean percentage reductions from baseline in monthly migraine days, monthly headache days, Migraine Disability Assessment score, and 6-item Headache Impact Test score were 72.4% (−9.2 days), 70.0% (−9.8 days), 63.1% (−18.1 days), and 27.0% (−16.2 days), respectively. Subgroups formed according to the dosing schedule and number of prior migraine preventive treatment failures showed similar improvements.

Study details: This was a retrospective, online physician chart review study that included data from 421 clinicians and 1003 patients with migraine who had initiated fremanezumab treatment at ≥18 years of age and received ≥1 fremanezumab dose.

Disclosures: The study was sponsored by Teva Pharmaceuticals. Some authors declared being current or former employees of Teva. The other authors are employees of an organization funded by Teva.

Source: Driessen MT et al. Real-world effectiveness of fremanezumab in migraine patients initiating treatment in the United States: results from a retrospective chart study. J Headache Pain. 2022;23:47 (Apr 11). Doi: 10.1186/s10194-022-01411-1

Editors’ note: For the April edition of Expert Perspectives, we asked 2 leading neurologists to present differing views on the use of calcitonin gene-related peptide  (CGRP) monoclonal antibodies (mAbs) for the treatment of migraine. Here, Lawrence Robbins, MD, of the Robbins Headache Clinic in Riverwoods, IL, discusses potential safety concerns associated with this drug class. To read a counterargument in which Jack D. Schim, MD, of the Neurology Center of Southern California, discusses the observed benefits of CGRP mAbs, click here. 

Lawrence Robbins, MD is an associate professor of neurology at Chicago Medical School and is in private practice in Riverwoods, IL. 
Dr. Robbins discloses speaker’s bureau remuneration from AbbVie, Amgen, Biohaven, Impel NeuroPharma, Lundbeck, and Teva.

 
The calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) were introduced in 2018 as efficacious with few adverse effects. Unfortunately, the phase 3 trials failed to indicate the considerable number of adverse effects that have since been identified. This is a common occurrence with new drugs and mAbs. 
 
There are few adverse events identified in the package insert (PI) for any of the 4 CGRP mAbs, but again that is not restricted to this class. Post-approval, it frequently takes time to piece together the true adverse effect profile. Reasons that phase 3 studies may miss adverse effects include 1) The studies are powered for efficacy but are not powered for adverse effects in terms of both the number of patients and the length of the study; 2) Studies do not use a checklist of likely adverse effects; and 3) Adverse effects become “disaggregated” (for example, 1 person states they have malaise, another tiredness, and another fatigue).                                                                
 
In the ensuing years since the launch of the CGRP mAbs, various lines of evidence pointed to the adverse effects attributed to these mAbs. These include the US Food and Drug Administration (FDA)/FDA Adverse Event Reporting System (FAERS) website, published studies, the collective experience of high prescribers, and filtered comments from patient chat boards. In addition, I have received hundreds of letters from providers and patients regarding serious adverse effects, which are detailed further in this article. 
 
As of March 2022, the FDA/FAERS website has listed approximately 50,000 adverse events in connection with the CGRP mAbs. The number of serious events (hospitalization or life-threatening issues) was about 7000. These large numbers, just 3.75 years after launch, are like those listed for onabotulinumtoxin A after 30 years! Most of the reports involve erenumab. This is because erenumab was approved first and is the most prescribed drug in this class. I do not believe it is more dangerous than the others. Considering that the vast majority of adverse events go unreported, these are staggering numbers. Regarding serious adverse events, only 1% to 10% are actually reported to the FDA. Nobody knows the true percentage of milder adverse events that are actually reported, but in my experience, it is extremely low.
 
Unfortunately, the FDA/FAERS website lists on only adverse events, not adverse effects, which are just as important to discuss. In my small practice I have observed 4 serious adverse effects in women I believe are attributable to CGRP mAbs. These include a cerebrovascular accident in a 21-year-old patient, a case of reversible cerebral vasoconstrictive syndrome in a 61-year-old patient, severe joint pain in a 66-year-old patient, and a constellation of symptoms that resembled multiple sclerosis in a 30-year-old patient. I have administered onabotulinumtoxinA to thousands of patients for 25 years, with no serious adverse effects.
 
There have been a number of post-approval articles, studies, and case reports published since the launch of the CGRP mAbs. Many “review” or “meta-analysis” articles tend to repeat the results of the pharma-sponsored studies. They typically characterize the CGRP mAbs as safe, with few adverse events. Long-term safety extension studies almost always conclude that the drug is safe. In my opinion, the results from these studies are not reliable because of their possible ties to phrama. 
 
Other studies tell a different tale. One observational study of erenumab concluded that adverse effects contributed to 33% of the discontinuations. Another study reported that 63.3% of patients taking mAbs described at least 1 adverse effect. A study of patients who had been prescribed erenumab indicated that 48% reported a non-serious adverse event after 3 months.  
 
Neurologists are generally unaware of the dangers posed by CGRP mAbs. In September 2021, I engaged in a debate on this topic during the International 15th World Congress on Controversies in Neurology (CONy). Prior to the debate, the audience members were polled. 94% believed the CGRP mAbs to be safe. After our debate, only 40% felt that these mAbs were safe. I think that the audience, primarily consisting of neurologists, was not informed as to the potential dangers of the CGRP mAbs.                                                        

                            
In our practice

For refractory patients, I do prescribe these CGRP mAbs. However, I feel they should only be prescribed after several other, safer options have failed. These include the natural approaches (butterbur, magnesium, riboflavin), several of the standard medications (amitriptyline, beta blockers, topiramate, valproate, angiotensin II receptor blockers), and onabotulinumtoxinA. Additionally, the newer gepants for prevention (rimegepant and atogepant) appear to be safer options than the CGRP mAbs, although we cannot say this definitively at this time.

In 2018, our clinic began a retrospective study that lasted until January 2020. We assessed 119 patients with chronic migraine who had been prescribed one of the CGRP mAbs. This study incorporated the use of a checklist of possible adverse effects. Each of these adverse effects had created a “signal.” We initially asked the patients, “Have you experienced any issues, problems, or side effects due to the CGRP monoclonal antibody?” The patients subsequently were interviewed and asked about each possible adverse effect included on the checklist. The patient and physician determined whether any adverse effect mentioned by the patient was due to the CGRP mAb. After discussing the checklist, 66% of the patients concluded they had experienced 1 additional adverse effect that they attributed to the CGRP mAb and had not originally disclosed in response to the initial question. Most of these patients identified more than 1 additional adverse effect through use of the checklist.  
 

Gathering data

To determine the true adverse event profile post-approval, we rely upon the input of high prescribers, who often can provide this necessary feedback. I have assessed input from headache provider chat boards, private correspondence with many providers, and discussions with colleagues at conferences. The opinions do vary, with some headache providers arguing that there are not that many adverse effects arising from the CGRP mAbs. Many others believe, as I do, that there are a large number of adverse events. In my observations, there is not a consensus among headache providers. 
 
The CGRP patient chat boards are another valuable line of evidence. I have screened 2800 comments from patients regarding adverse events. I filtered these down into 490 “highly believable” comments. Among those, the adverse events described align very well with our other lines of evidence. 
 
If we put all the post-approval lines of evidence together, we come up with the following list of “adverse effect signals” attribututed  to the CGRP mAbs. These include constipation (it may be severe; hence the warning in the erenumab PI), injection site reactions, joint pain, anxiety, muscle pain or cramps, hypertension or worsening hypertension (there is a warning in the erenumab PI), nausea (it may be severe; “area postrema syndrome” has occurred), rash, increased headache, fatigue, depression, insomnia, hair loss, tachycardia (and other cardiac arrhythmias), stroke, angina and myocardial infarction, weight gain or loss, irritability, and sexual dysfunction. There are also other adverse events. In his review of the CGRP mAbs, Thomas Moore, a leading expert in adverse events, cited the “sheer number of case reports, and it is likely that AEs of this migraine preventive were underestimated in the clinical trials.”   
 
This discussion has focused on short-term adverse events. We have no idea regarding long-term effects, but I suspect that we will encounter serious ones. Evolution has deemed CGRP to be vital for 450 million years. We ignore evolution at our peril. 
  
CGRP is a powerful vasodilator and protects our cardiovascular and cerebrovascular systems. CGRP resists the onset of hypertension. Wound and burn healing, as well as tissue repair, require CGRP. Bony metabolism and bone healing are partly dependent upon CGRP. CGRP protects from gastrointestinal (GI) ulcers and aids GI motility. CGRP mitigates the effects of sepsis. 
 
CGRP is also involved with flushing, thermoregulation, cold hypersensitivity, protecting the kidneys when under stress, helping regulate insulin release, and mediating the adrenal glucocorticoid response to acute stress (particularly in the mature fetus). Effects on the hypothalamic-pituitary-adrenal axis are worrisome but unknown. CGRP is important as a vasodilator during stress, and the CGRP mAbs have not yet been tested under stress.  

The CGRP mAbs have been terrific for many patients, and their efficacy is on par with onabotulinumtoxinA. However, in a short period of time we have witnessed a plethora of serious (and non-serious) adverse effects from short-term use. CGRP plays an important role in many physiologic processes. We have no idea as to the long-term consequences of blocking CGRP and we should proceed with caution.
 

Editors’ note: For the April edition of Expert Perspectives, we asked 2 leading neurologists to present differing views on the use of calcitonin gene-related peptide  (CGRP) monoclonal antibodies (mAbs) for the treatment of migraine. Here, Lawrence Robbins, MD, of the Robbins Headache Clinic in Riverwoods, IL, discusses potential safety concerns associated with this drug class. To read a counterargument in which Jack D. Schim, MD, of the Neurology Center of Southern California, discusses the observed benefits of CGRP mAbs, click here. 

Lawrence Robbins, MD is an associate professor of neurology at Chicago Medical School and is in private practice in Riverwoods, IL. 
Dr. Robbins discloses speaker’s bureau remuneration from AbbVie, Amgen, Biohaven, Impel NeuroPharma, Lundbeck, and Teva.

 
The calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) were introduced in 2018 as efficacious with few adverse effects. Unfortunately, the phase 3 trials failed to indicate the considerable number of adverse effects that have since been identified. This is a common occurrence with new drugs and mAbs. 
 
There are few adverse events identified in the package insert (PI) for any of the 4 CGRP mAbs, but again that is not restricted to this class. Post-approval, it frequently takes time to piece together the true adverse effect profile. Reasons that phase 3 studies may miss adverse effects include 1) The studies are powered for efficacy but are not powered for adverse effects in terms of both the number of patients and the length of the study; 2) Studies do not use a checklist of likely adverse effects; and 3) Adverse effects become “disaggregated” (for example, 1 person states they have malaise, another tiredness, and another fatigue).                                                                
 
In the ensuing years since the launch of the CGRP mAbs, various lines of evidence pointed to the adverse effects attributed to these mAbs. These include the US Food and Drug Administration (FDA)/FDA Adverse Event Reporting System (FAERS) website, published studies, the collective experience of high prescribers, and filtered comments from patient chat boards. In addition, I have received hundreds of letters from providers and patients regarding serious adverse effects, which are detailed further in this article. 
 
As of March 2022, the FDA/FAERS website has listed approximately 50,000 adverse events in connection with the CGRP mAbs. The number of serious events (hospitalization or life-threatening issues) was about 7000. These large numbers, just 3.75 years after launch, are like those listed for onabotulinumtoxin A after 30 years! Most of the reports involve erenumab. This is because erenumab was approved first and is the most prescribed drug in this class. I do not believe it is more dangerous than the others. Considering that the vast majority of adverse events go unreported, these are staggering numbers. Regarding serious adverse events, only 1% to 10% are actually reported to the FDA. Nobody knows the true percentage of milder adverse events that are actually reported, but in my experience, it is extremely low.
 
Unfortunately, the FDA/FAERS website lists on only adverse events, not adverse effects, which are just as important to discuss. In my small practice I have observed 4 serious adverse effects in women I believe are attributable to CGRP mAbs. These include a cerebrovascular accident in a 21-year-old patient, a case of reversible cerebral vasoconstrictive syndrome in a 61-year-old patient, severe joint pain in a 66-year-old patient, and a constellation of symptoms that resembled multiple sclerosis in a 30-year-old patient. I have administered onabotulinumtoxinA to thousands of patients for 25 years, with no serious adverse effects.
 
There have been a number of post-approval articles, studies, and case reports published since the launch of the CGRP mAbs. Many “review” or “meta-analysis” articles tend to repeat the results of the pharma-sponsored studies. They typically characterize the CGRP mAbs as safe, with few adverse events. Long-term safety extension studies almost always conclude that the drug is safe. In my opinion, the results from these studies are not reliable because of their possible ties to phrama. 
 
Other studies tell a different tale. One observational study of erenumab concluded that adverse effects contributed to 33% of the discontinuations. Another study reported that 63.3% of patients taking mAbs described at least 1 adverse effect. A study of patients who had been prescribed erenumab indicated that 48% reported a non-serious adverse event after 3 months.  
 
Neurologists are generally unaware of the dangers posed by CGRP mAbs. In September 2021, I engaged in a debate on this topic during the International 15th World Congress on Controversies in Neurology (CONy). Prior to the debate, the audience members were polled. 94% believed the CGRP mAbs to be safe. After our debate, only 40% felt that these mAbs were safe. I think that the audience, primarily consisting of neurologists, was not informed as to the potential dangers of the CGRP mAbs.                                                        

                            
In our practice

For refractory patients, I do prescribe these CGRP mAbs. However, I feel they should only be prescribed after several other, safer options have failed. These include the natural approaches (butterbur, magnesium, riboflavin), several of the standard medications (amitriptyline, beta blockers, topiramate, valproate, angiotensin II receptor blockers), and onabotulinumtoxinA. Additionally, the newer gepants for prevention (rimegepant and atogepant) appear to be safer options than the CGRP mAbs, although we cannot say this definitively at this time.

In 2018, our clinic began a retrospective study that lasted until January 2020. We assessed 119 patients with chronic migraine who had been prescribed one of the CGRP mAbs. This study incorporated the use of a checklist of possible adverse effects. Each of these adverse effects had created a “signal.” We initially asked the patients, “Have you experienced any issues, problems, or side effects due to the CGRP monoclonal antibody?” The patients subsequently were interviewed and asked about each possible adverse effect included on the checklist. The patient and physician determined whether any adverse effect mentioned by the patient was due to the CGRP mAb. After discussing the checklist, 66% of the patients concluded they had experienced 1 additional adverse effect that they attributed to the CGRP mAb and had not originally disclosed in response to the initial question. Most of these patients identified more than 1 additional adverse effect through use of the checklist.  
 

Gathering data

To determine the true adverse event profile post-approval, we rely upon the input of high prescribers, who often can provide this necessary feedback. I have assessed input from headache provider chat boards, private correspondence with many providers, and discussions with colleagues at conferences. The opinions do vary, with some headache providers arguing that there are not that many adverse effects arising from the CGRP mAbs. Many others believe, as I do, that there are a large number of adverse events. In my observations, there is not a consensus among headache providers. 
 
The CGRP patient chat boards are another valuable line of evidence. I have screened 2800 comments from patients regarding adverse events. I filtered these down into 490 “highly believable” comments. Among those, the adverse events described align very well with our other lines of evidence. 
 
If we put all the post-approval lines of evidence together, we come up with the following list of “adverse effect signals” attribututed  to the CGRP mAbs. These include constipation (it may be severe; hence the warning in the erenumab PI), injection site reactions, joint pain, anxiety, muscle pain or cramps, hypertension or worsening hypertension (there is a warning in the erenumab PI), nausea (it may be severe; “area postrema syndrome” has occurred), rash, increased headache, fatigue, depression, insomnia, hair loss, tachycardia (and other cardiac arrhythmias), stroke, angina and myocardial infarction, weight gain or loss, irritability, and sexual dysfunction. There are also other adverse events. In his review of the CGRP mAbs, Thomas Moore, a leading expert in adverse events, cited the “sheer number of case reports, and it is likely that AEs of this migraine preventive were underestimated in the clinical trials.”   
 
This discussion has focused on short-term adverse events. We have no idea regarding long-term effects, but I suspect that we will encounter serious ones. Evolution has deemed CGRP to be vital for 450 million years. We ignore evolution at our peril. 
  
CGRP is a powerful vasodilator and protects our cardiovascular and cerebrovascular systems. CGRP resists the onset of hypertension. Wound and burn healing, as well as tissue repair, require CGRP. Bony metabolism and bone healing are partly dependent upon CGRP. CGRP protects from gastrointestinal (GI) ulcers and aids GI motility. CGRP mitigates the effects of sepsis. 
 
CGRP is also involved with flushing, thermoregulation, cold hypersensitivity, protecting the kidneys when under stress, helping regulate insulin release, and mediating the adrenal glucocorticoid response to acute stress (particularly in the mature fetus). Effects on the hypothalamic-pituitary-adrenal axis are worrisome but unknown. CGRP is important as a vasodilator during stress, and the CGRP mAbs have not yet been tested under stress.  

The CGRP mAbs have been terrific for many patients, and their efficacy is on par with onabotulinumtoxinA. However, in a short period of time we have witnessed a plethora of serious (and non-serious) adverse effects from short-term use. CGRP plays an important role in many physiologic processes. We have no idea as to the long-term consequences of blocking CGRP and we should proceed with caution.
 

Editors’ note: For the April edition of Expert Perspectives, we asked 2 leading neurologists to present differing views on the use of calcitonin gene-related peptide  (CGRP) monoclonal antibodies (mAbs) for the treatment of migraine. Here, Lawrence Robbins, MD, of the Robbins Headache Clinic in Riverwoods, IL, discusses potential safety concerns associated with this drug class. To read a counterargument in which Jack D. Schim, MD, of the Neurology Center of Southern California, discusses the observed benefits of CGRP mAbs, click here. 

Lawrence Robbins, MD is an associate professor of neurology at Chicago Medical School and is in private practice in Riverwoods, IL. 
Dr. Robbins discloses speaker’s bureau remuneration from AbbVie, Amgen, Biohaven, Impel NeuroPharma, Lundbeck, and Teva.

 
The calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) were introduced in 2018 as efficacious with few adverse effects. Unfortunately, the phase 3 trials failed to indicate the considerable number of adverse effects that have since been identified. This is a common occurrence with new drugs and mAbs. 
 
There are few adverse events identified in the package insert (PI) for any of the 4 CGRP mAbs, but again that is not restricted to this class. Post-approval, it frequently takes time to piece together the true adverse effect profile. Reasons that phase 3 studies may miss adverse effects include 1) The studies are powered for efficacy but are not powered for adverse effects in terms of both the number of patients and the length of the study; 2) Studies do not use a checklist of likely adverse effects; and 3) Adverse effects become “disaggregated” (for example, 1 person states they have malaise, another tiredness, and another fatigue).                                                                
 
In the ensuing years since the launch of the CGRP mAbs, various lines of evidence pointed to the adverse effects attributed to these mAbs. These include the US Food and Drug Administration (FDA)/FDA Adverse Event Reporting System (FAERS) website, published studies, the collective experience of high prescribers, and filtered comments from patient chat boards. In addition, I have received hundreds of letters from providers and patients regarding serious adverse effects, which are detailed further in this article. 
 
As of March 2022, the FDA/FAERS website has listed approximately 50,000 adverse events in connection with the CGRP mAbs. The number of serious events (hospitalization or life-threatening issues) was about 7000. These large numbers, just 3.75 years after launch, are like those listed for onabotulinumtoxin A after 30 years! Most of the reports involve erenumab. This is because erenumab was approved first and is the most prescribed drug in this class. I do not believe it is more dangerous than the others. Considering that the vast majority of adverse events go unreported, these are staggering numbers. Regarding serious adverse events, only 1% to 10% are actually reported to the FDA. Nobody knows the true percentage of milder adverse events that are actually reported, but in my experience, it is extremely low.
 
Unfortunately, the FDA/FAERS website lists on only adverse events, not adverse effects, which are just as important to discuss. In my small practice I have observed 4 serious adverse effects in women I believe are attributable to CGRP mAbs. These include a cerebrovascular accident in a 21-year-old patient, a case of reversible cerebral vasoconstrictive syndrome in a 61-year-old patient, severe joint pain in a 66-year-old patient, and a constellation of symptoms that resembled multiple sclerosis in a 30-year-old patient. I have administered onabotulinumtoxinA to thousands of patients for 25 years, with no serious adverse effects.
 
There have been a number of post-approval articles, studies, and case reports published since the launch of the CGRP mAbs. Many “review” or “meta-analysis” articles tend to repeat the results of the pharma-sponsored studies. They typically characterize the CGRP mAbs as safe, with few adverse events. Long-term safety extension studies almost always conclude that the drug is safe. In my opinion, the results from these studies are not reliable because of their possible ties to phrama. 
 
Other studies tell a different tale. One observational study of erenumab concluded that adverse effects contributed to 33% of the discontinuations. Another study reported that 63.3% of patients taking mAbs described at least 1 adverse effect. A study of patients who had been prescribed erenumab indicated that 48% reported a non-serious adverse event after 3 months.  
 
Neurologists are generally unaware of the dangers posed by CGRP mAbs. In September 2021, I engaged in a debate on this topic during the International 15th World Congress on Controversies in Neurology (CONy). Prior to the debate, the audience members were polled. 94% believed the CGRP mAbs to be safe. After our debate, only 40% felt that these mAbs were safe. I think that the audience, primarily consisting of neurologists, was not informed as to the potential dangers of the CGRP mAbs.                                                        

                            
In our practice

For refractory patients, I do prescribe these CGRP mAbs. However, I feel they should only be prescribed after several other, safer options have failed. These include the natural approaches (butterbur, magnesium, riboflavin), several of the standard medications (amitriptyline, beta blockers, topiramate, valproate, angiotensin II receptor blockers), and onabotulinumtoxinA. Additionally, the newer gepants for prevention (rimegepant and atogepant) appear to be safer options than the CGRP mAbs, although we cannot say this definitively at this time.

In 2018, our clinic began a retrospective study that lasted until January 2020. We assessed 119 patients with chronic migraine who had been prescribed one of the CGRP mAbs. This study incorporated the use of a checklist of possible adverse effects. Each of these adverse effects had created a “signal.” We initially asked the patients, “Have you experienced any issues, problems, or side effects due to the CGRP monoclonal antibody?” The patients subsequently were interviewed and asked about each possible adverse effect included on the checklist. The patient and physician determined whether any adverse effect mentioned by the patient was due to the CGRP mAb. After discussing the checklist, 66% of the patients concluded they had experienced 1 additional adverse effect that they attributed to the CGRP mAb and had not originally disclosed in response to the initial question. Most of these patients identified more than 1 additional adverse effect through use of the checklist.  
 

Gathering data

To determine the true adverse event profile post-approval, we rely upon the input of high prescribers, who often can provide this necessary feedback. I have assessed input from headache provider chat boards, private correspondence with many providers, and discussions with colleagues at conferences. The opinions do vary, with some headache providers arguing that there are not that many adverse effects arising from the CGRP mAbs. Many others believe, as I do, that there are a large number of adverse events. In my observations, there is not a consensus among headache providers. 
 
The CGRP patient chat boards are another valuable line of evidence. I have screened 2800 comments from patients regarding adverse events. I filtered these down into 490 “highly believable” comments. Among those, the adverse events described align very well with our other lines of evidence. 
 
If we put all the post-approval lines of evidence together, we come up with the following list of “adverse effect signals” attribututed  to the CGRP mAbs. These include constipation (it may be severe; hence the warning in the erenumab PI), injection site reactions, joint pain, anxiety, muscle pain or cramps, hypertension or worsening hypertension (there is a warning in the erenumab PI), nausea (it may be severe; “area postrema syndrome” has occurred), rash, increased headache, fatigue, depression, insomnia, hair loss, tachycardia (and other cardiac arrhythmias), stroke, angina and myocardial infarction, weight gain or loss, irritability, and sexual dysfunction. There are also other adverse events. In his review of the CGRP mAbs, Thomas Moore, a leading expert in adverse events, cited the “sheer number of case reports, and it is likely that AEs of this migraine preventive were underestimated in the clinical trials.”   
 
This discussion has focused on short-term adverse events. We have no idea regarding long-term effects, but I suspect that we will encounter serious ones. Evolution has deemed CGRP to be vital for 450 million years. We ignore evolution at our peril. 
  
CGRP is a powerful vasodilator and protects our cardiovascular and cerebrovascular systems. CGRP resists the onset of hypertension. Wound and burn healing, as well as tissue repair, require CGRP. Bony metabolism and bone healing are partly dependent upon CGRP. CGRP protects from gastrointestinal (GI) ulcers and aids GI motility. CGRP mitigates the effects of sepsis. 
 
CGRP is also involved with flushing, thermoregulation, cold hypersensitivity, protecting the kidneys when under stress, helping regulate insulin release, and mediating the adrenal glucocorticoid response to acute stress (particularly in the mature fetus). Effects on the hypothalamic-pituitary-adrenal axis are worrisome but unknown. CGRP is important as a vasodilator during stress, and the CGRP mAbs have not yet been tested under stress.  

The CGRP mAbs have been terrific for many patients, and their efficacy is on par with onabotulinumtoxinA. However, in a short period of time we have witnessed a plethora of serious (and non-serious) adverse effects from short-term use. CGRP plays an important role in many physiologic processes. We have no idea as to the long-term consequences of blocking CGRP and we should proceed with caution.