Headache & Migraine

Key clinical point: Oral calcitonin gene-related peptide (CGRP) receptor antagonists appeared to be safer and better tolerated than triptans for the treatment of acute migraine and could be a viable option for patients who experience overall triptan-associated adverse events (AE).

Major finding: Oral CGRP receptor antagonists were safer than triptans in terms of any AE (risk ratio [RR] 0.78; P  =  .03) and treatment-related AE (RR 0.68; P < .00001), with the incidence of dizziness (RR 0.69; P  =  .01), dry mouth (RR 0.72; P  =  .02), fatigue (RR 0.52; P  =  .001), paresthesia (RR 0.34; P < .0001), and somnolence (RR 0.65; P  =  .004) being lower with oral CGRP receptor antagonists vs triptans.

Study details: The data come from a meta-analysis of 15 trials including 13,270 patients who received oral CGRP receptor antagonists (n = 8240), placebo (n = 4253), or triptans (n = 777) for the treatment of acute migraine.

Disclosures: This study was funded by a National Research Foundation of Korea grant funded by the Korea government. The authors declared no competing interests.

Source: Lee S et al. Safety evaluation of oral calcitonin-gene–related peptide receptor antagonists in patients with acute migraine: A systematic review and meta-analysis. Eur J Clin Pharmacol. 2022 (Jun 22). Doi: 10.1007/s00228-022-03347-6

Key clinical point: Oral calcitonin gene-related peptide (CGRP) receptor antagonists appeared to be safer and better tolerated than triptans for the treatment of acute migraine and could be a viable option for patients who experience overall triptan-associated adverse events (AE).

Major finding: Oral CGRP receptor antagonists were safer than triptans in terms of any AE (risk ratio [RR] 0.78; P  =  .03) and treatment-related AE (RR 0.68; P < .00001), with the incidence of dizziness (RR 0.69; P  =  .01), dry mouth (RR 0.72; P  =  .02), fatigue (RR 0.52; P  =  .001), paresthesia (RR 0.34; P < .0001), and somnolence (RR 0.65; P  =  .004) being lower with oral CGRP receptor antagonists vs triptans.

Study details: The data come from a meta-analysis of 15 trials including 13,270 patients who received oral CGRP receptor antagonists (n = 8240), placebo (n = 4253), or triptans (n = 777) for the treatment of acute migraine.

Disclosures: This study was funded by a National Research Foundation of Korea grant funded by the Korea government. The authors declared no competing interests.

Source: Lee S et al. Safety evaluation of oral calcitonin-gene–related peptide receptor antagonists in patients with acute migraine: A systematic review and meta-analysis. Eur J Clin Pharmacol. 2022 (Jun 22). Doi: 10.1007/s00228-022-03347-6

Key clinical point: Oral calcitonin gene-related peptide (CGRP) receptor antagonists appeared to be safer and better tolerated than triptans for the treatment of acute migraine and could be a viable option for patients who experience overall triptan-associated adverse events (AE).

Major finding: Oral CGRP receptor antagonists were safer than triptans in terms of any AE (risk ratio [RR] 0.78; P  =  .03) and treatment-related AE (RR 0.68; P < .00001), with the incidence of dizziness (RR 0.69; P  =  .01), dry mouth (RR 0.72; P  =  .02), fatigue (RR 0.52; P  =  .001), paresthesia (RR 0.34; P < .0001), and somnolence (RR 0.65; P  =  .004) being lower with oral CGRP receptor antagonists vs triptans.

Study details: The data come from a meta-analysis of 15 trials including 13,270 patients who received oral CGRP receptor antagonists (n = 8240), placebo (n = 4253), or triptans (n = 777) for the treatment of acute migraine.

Disclosures: This study was funded by a National Research Foundation of Korea grant funded by the Korea government. The authors declared no competing interests.

Source: Lee S et al. Safety evaluation of oral calcitonin-gene–related peptide receptor antagonists in patients with acute migraine: A systematic review and meta-analysis. Eur J Clin Pharmacol. 2022 (Jun 22). Doi: 10.1007/s00228-022-03347-6

Key clinical point: Levetiracetam reduced attack frequency, headache days, and days with acute drug intake as the prophylactic treatment for episodic migraine along with an overall tolerable safety profile.

Major finding: During the last 4 weeks of treatment, levetiracetam significantly reduced the number of migraine attacks (P < .001), days with migraine (P  =  .001), and use of acute drugs for migraine attack (P < .001), with 46.0% of patients showing at least 50% reduction in migraine attack frequency and the mean number of migraine attacks decreasing from 5.2 ± 2.1 to 3.4 ± 2.7.

Study details: The data come from a prospective, open-label study including 50 patients with episodic migraine who received 1000 mg levetiracetam (starting dose 500 mg) twice a day for 12 weeks.

Disclosures: This study was supported by UCB Chemie GmbH Germany. Some authors declared serving as consultants for various sources.

Source: Evers S et al. Levetiracetam in the prophylactic treatment of episodic migraine: A prospective open label study. Cephalalgia. 2022 (May 27). Doi: 10.1177/03331024221103815

Key clinical point: Levetiracetam reduced attack frequency, headache days, and days with acute drug intake as the prophylactic treatment for episodic migraine along with an overall tolerable safety profile.

Major finding: During the last 4 weeks of treatment, levetiracetam significantly reduced the number of migraine attacks (P < .001), days with migraine (P  =  .001), and use of acute drugs for migraine attack (P < .001), with 46.0% of patients showing at least 50% reduction in migraine attack frequency and the mean number of migraine attacks decreasing from 5.2 ± 2.1 to 3.4 ± 2.7.

Study details: The data come from a prospective, open-label study including 50 patients with episodic migraine who received 1000 mg levetiracetam (starting dose 500 mg) twice a day for 12 weeks.

Disclosures: This study was supported by UCB Chemie GmbH Germany. Some authors declared serving as consultants for various sources.

Source: Evers S et al. Levetiracetam in the prophylactic treatment of episodic migraine: A prospective open label study. Cephalalgia. 2022 (May 27). Doi: 10.1177/03331024221103815

Key clinical point: Levetiracetam reduced attack frequency, headache days, and days with acute drug intake as the prophylactic treatment for episodic migraine along with an overall tolerable safety profile.

Major finding: During the last 4 weeks of treatment, levetiracetam significantly reduced the number of migraine attacks (P < .001), days with migraine (P  =  .001), and use of acute drugs for migraine attack (P < .001), with 46.0% of patients showing at least 50% reduction in migraine attack frequency and the mean number of migraine attacks decreasing from 5.2 ± 2.1 to 3.4 ± 2.7.

Study details: The data come from a prospective, open-label study including 50 patients with episodic migraine who received 1000 mg levetiracetam (starting dose 500 mg) twice a day for 12 weeks.

Disclosures: This study was supported by UCB Chemie GmbH Germany. Some authors declared serving as consultants for various sources.

Source: Evers S et al. Levetiracetam in the prophylactic treatment of episodic migraine: A prospective open label study. Cephalalgia. 2022 (May 27). Doi: 10.1177/03331024221103815

Key clinical point: Once-daily oral atogepant was overall safe and effective for the prevention of episodic migraine in adults.

Major finding: The reduction in the mean number of migraine days across the 12-week treatment period was significantly greater with 10 mg atogepant (mean difference [MD] −1.16; P < .001), 30 mg (MD −1.15; P < .001), or 60 mg (MD −1.20; P  =  .016) vs placebo. Overall, the relative risk for any adverse event with atogepant vs placebo treatment was 1.07 (P  =  .630).

Study details: The data come from a systematic review and meta-analysis of 2 randomized controlled trials including 1550 patients with episodic migraine who were randomly assigned to receive 10 mg atopegant (n = 314), 30 mg atogepant (n = 411), 60 mg atopegant (n = 417), or placebo (n = 408).

Disclosures: This study did not receive any funding. Some authors declared receiving grants or serving as speakers, consultants, or on advisory boards for various sources.

Source: Lattanzi S et al. Atogepant for the prevention of episodic migraine in adults: A systematic review and meta-analysis of efficacy and safety. Neurol Ther. 2022 (Jun 15). Doi:  10.1007/s40120-022-00370-8

Key clinical point: Once-daily oral atogepant was overall safe and effective for the prevention of episodic migraine in adults.

Major finding: The reduction in the mean number of migraine days across the 12-week treatment period was significantly greater with 10 mg atogepant (mean difference [MD] −1.16; P < .001), 30 mg (MD −1.15; P < .001), or 60 mg (MD −1.20; P  =  .016) vs placebo. Overall, the relative risk for any adverse event with atogepant vs placebo treatment was 1.07 (P  =  .630).

Study details: The data come from a systematic review and meta-analysis of 2 randomized controlled trials including 1550 patients with episodic migraine who were randomly assigned to receive 10 mg atopegant (n = 314), 30 mg atogepant (n = 411), 60 mg atopegant (n = 417), or placebo (n = 408).

Disclosures: This study did not receive any funding. Some authors declared receiving grants or serving as speakers, consultants, or on advisory boards for various sources.

Source: Lattanzi S et al. Atogepant for the prevention of episodic migraine in adults: A systematic review and meta-analysis of efficacy and safety. Neurol Ther. 2022 (Jun 15). Doi:  10.1007/s40120-022-00370-8

Key clinical point: Once-daily oral atogepant was overall safe and effective for the prevention of episodic migraine in adults.

Major finding: The reduction in the mean number of migraine days across the 12-week treatment period was significantly greater with 10 mg atogepant (mean difference [MD] −1.16; P < .001), 30 mg (MD −1.15; P < .001), or 60 mg (MD −1.20; P  =  .016) vs placebo. Overall, the relative risk for any adverse event with atogepant vs placebo treatment was 1.07 (P  =  .630).

Study details: The data come from a systematic review and meta-analysis of 2 randomized controlled trials including 1550 patients with episodic migraine who were randomly assigned to receive 10 mg atopegant (n = 314), 30 mg atogepant (n = 411), 60 mg atopegant (n = 417), or placebo (n = 408).

Disclosures: This study did not receive any funding. Some authors declared receiving grants or serving as speakers, consultants, or on advisory boards for various sources.

Source: Lattanzi S et al. Atogepant for the prevention of episodic migraine in adults: A systematic review and meta-analysis of efficacy and safety. Neurol Ther. 2022 (Jun 15). Doi:  10.1007/s40120-022-00370-8

Key clinical point: Calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) could serve as effective diagnostic biomarkers for pediatric migraine.

Major finding: The plasma levels of CGRP and PACAP-38 were significantly higher in patients with migraine in the ictal and interictal periods and with and without aura compared with healthy controls (P < .001), with PACAP-38 (adjusted odds ratio [aOR] 1.331; P < .001) and CGRP (aOR 1.113; P < .001) being independent risk factors for the diagnosis of pediatric migraine.

Study details: This was a prospective study of 76 patients aged 4-18 years with migraine and 77 age-matched healthy controls.

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

Source: Liu J et al. CGRP and PACAP-38 play an important role in diagnosing pediatric migraine. J Headache Pain. 2022;23:68 (Jun 13). Doi: 10.1186/s10194-022-01435-7

Key clinical point: Calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) could serve as effective diagnostic biomarkers for pediatric migraine.

Major finding: The plasma levels of CGRP and PACAP-38 were significantly higher in patients with migraine in the ictal and interictal periods and with and without aura compared with healthy controls (P < .001), with PACAP-38 (adjusted odds ratio [aOR] 1.331; P < .001) and CGRP (aOR 1.113; P < .001) being independent risk factors for the diagnosis of pediatric migraine.

Study details: This was a prospective study of 76 patients aged 4-18 years with migraine and 77 age-matched healthy controls.

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

Source: Liu J et al. CGRP and PACAP-38 play an important role in diagnosing pediatric migraine. J Headache Pain. 2022;23:68 (Jun 13). Doi: 10.1186/s10194-022-01435-7

Key clinical point: Calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) could serve as effective diagnostic biomarkers for pediatric migraine.

Major finding: The plasma levels of CGRP and PACAP-38 were significantly higher in patients with migraine in the ictal and interictal periods and with and without aura compared with healthy controls (P < .001), with PACAP-38 (adjusted odds ratio [aOR] 1.331; P < .001) and CGRP (aOR 1.113; P < .001) being independent risk factors for the diagnosis of pediatric migraine.

Study details: This was a prospective study of 76 patients aged 4-18 years with migraine and 77 age-matched healthy controls.

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

Source: Liu J et al. CGRP and PACAP-38 play an important role in diagnosing pediatric migraine. J Headache Pain. 2022;23:68 (Jun 13). Doi: 10.1186/s10194-022-01435-7

Key clinical point: Migraine was significantly associated with the incidence of ocular motor cranial nerve palsy (OMCNP), with the risk being particularly high among patients with migraine who smoked or had diabetes mellitus.

Major finding: The incidence of OMCNP was significantly higher in patients with vs without migraine (adjusted hazard ratio [aHR] 1.166; 95% CI 1.013-1.343), with the association being strongest among those who smoked (aHR 1.426; 95% CI 1.127-1.803) and had diabetes mellitus (aHR 1.378; 95% CI 1.045-1.378).

Study details: This was a population-based, observational, retrospective cohort study including 4,053,824 medical beneficiaries; of which 5806 developed OMCNP and 4,048,018 did not develop OMCNP (control population). A subgroup of 111,853 patients had migraine.

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

Source: Rhiu S et al. Association between migraine and risk of ocular motor cranial nerve palsy. Sci Rep. 2022;12:10512 (Jun 22). Doi: 10.1038/s41598-022-14621-z

Key clinical point: Migraine was significantly associated with the incidence of ocular motor cranial nerve palsy (OMCNP), with the risk being particularly high among patients with migraine who smoked or had diabetes mellitus.

Major finding: The incidence of OMCNP was significantly higher in patients with vs without migraine (adjusted hazard ratio [aHR] 1.166; 95% CI 1.013-1.343), with the association being strongest among those who smoked (aHR 1.426; 95% CI 1.127-1.803) and had diabetes mellitus (aHR 1.378; 95% CI 1.045-1.378).

Study details: This was a population-based, observational, retrospective cohort study including 4,053,824 medical beneficiaries; of which 5806 developed OMCNP and 4,048,018 did not develop OMCNP (control population). A subgroup of 111,853 patients had migraine.

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

Source: Rhiu S et al. Association between migraine and risk of ocular motor cranial nerve palsy. Sci Rep. 2022;12:10512 (Jun 22). Doi: 10.1038/s41598-022-14621-z

Key clinical point: Migraine was significantly associated with the incidence of ocular motor cranial nerve palsy (OMCNP), with the risk being particularly high among patients with migraine who smoked or had diabetes mellitus.

Major finding: The incidence of OMCNP was significantly higher in patients with vs without migraine (adjusted hazard ratio [aHR] 1.166; 95% CI 1.013-1.343), with the association being strongest among those who smoked (aHR 1.426; 95% CI 1.127-1.803) and had diabetes mellitus (aHR 1.378; 95% CI 1.045-1.378).

Study details: This was a population-based, observational, retrospective cohort study including 4,053,824 medical beneficiaries; of which 5806 developed OMCNP and 4,048,018 did not develop OMCNP (control population). A subgroup of 111,853 patients had migraine.

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

Source: Rhiu S et al. Association between migraine and risk of ocular motor cranial nerve palsy. Sci Rep. 2022;12:10512 (Jun 22). Doi: 10.1038/s41598-022-14621-z

Key clinical point: Treatment of a single migraine attack with 200 mg lasmiditan demonstrated a strong association between achieving freedom from pain and central nervous system common treatment-emergent adverse events (CTEAE).

Major finding: Significantly higher proportion of patients treated with 200 mg lasmiditan who were pain-free vs those who experienced moderate-to-severe pain at 2 hours post-dose reported ≥1 CTEAE (48.2% vs 28.7%; P < .001). A significantly higher proportion of patients reporting ≥1 vs 0 CTEAE were pain-free at 2 hours (39.0% vs 30.2%; P < .001). However, the absence of CTAE did not translate to the lack of efficacy.

Study details: This was a post hoc analysis of 4 randomized phase 2/3 trials including 6602 patients with migraine with or without aura who received lasmiditan (50, 100, or 200 mg) or placebo.

Disclosures: This study was funded by Eli Lilly and Company. Six authors reported being employees and minor stockholders of Eli Lilly. RB Lipton reported ties with Eli Lilly and other sources and owning stock or stock options in 3 companies.

Source: Doty EG et al. The association between the occurrence of common treatment-emergent adverse events and efficacy outcomes after lasmiditan treatment of a single migraine attack: Secondary analyses from four pooled randomized clinical trials. CNS Drugs. 2022;36:771–783 (Jul 2). Doi: 10.1007/s40263-022-00928-y

Key clinical point: Treatment of a single migraine attack with 200 mg lasmiditan demonstrated a strong association between achieving freedom from pain and central nervous system common treatment-emergent adverse events (CTEAE).

Major finding: Significantly higher proportion of patients treated with 200 mg lasmiditan who were pain-free vs those who experienced moderate-to-severe pain at 2 hours post-dose reported ≥1 CTEAE (48.2% vs 28.7%; P < .001). A significantly higher proportion of patients reporting ≥1 vs 0 CTEAE were pain-free at 2 hours (39.0% vs 30.2%; P < .001). However, the absence of CTAE did not translate to the lack of efficacy.

Study details: This was a post hoc analysis of 4 randomized phase 2/3 trials including 6602 patients with migraine with or without aura who received lasmiditan (50, 100, or 200 mg) or placebo.

Disclosures: This study was funded by Eli Lilly and Company. Six authors reported being employees and minor stockholders of Eli Lilly. RB Lipton reported ties with Eli Lilly and other sources and owning stock or stock options in 3 companies.

Source: Doty EG et al. The association between the occurrence of common treatment-emergent adverse events and efficacy outcomes after lasmiditan treatment of a single migraine attack: Secondary analyses from four pooled randomized clinical trials. CNS Drugs. 2022;36:771–783 (Jul 2). Doi: 10.1007/s40263-022-00928-y

Key clinical point: Treatment of a single migraine attack with 200 mg lasmiditan demonstrated a strong association between achieving freedom from pain and central nervous system common treatment-emergent adverse events (CTEAE).

Major finding: Significantly higher proportion of patients treated with 200 mg lasmiditan who were pain-free vs those who experienced moderate-to-severe pain at 2 hours post-dose reported ≥1 CTEAE (48.2% vs 28.7%; P < .001). A significantly higher proportion of patients reporting ≥1 vs 0 CTEAE were pain-free at 2 hours (39.0% vs 30.2%; P < .001). However, the absence of CTAE did not translate to the lack of efficacy.

Study details: This was a post hoc analysis of 4 randomized phase 2/3 trials including 6602 patients with migraine with or without aura who received lasmiditan (50, 100, or 200 mg) or placebo.

Disclosures: This study was funded by Eli Lilly and Company. Six authors reported being employees and minor stockholders of Eli Lilly. RB Lipton reported ties with Eli Lilly and other sources and owning stock or stock options in 3 companies.

Source: Doty EG et al. The association between the occurrence of common treatment-emergent adverse events and efficacy outcomes after lasmiditan treatment of a single migraine attack: Secondary analyses from four pooled randomized clinical trials. CNS Drugs. 2022;36:771–783 (Jul 2). Doi: 10.1007/s40263-022-00928-y

Key clinical point: Long-term treatment with galcanezumab led to three-quarters of patients with chronic migraine (CM) reverting to episodic migraine (EM), with more than half persistently reverting to episodic migraine (EM) under real-life conditions.

Major finding: Over 1 year, approximately ≥75% of patients reverted from CM to EM at each visit, with persistent reversion from CM to EM and medium-to-low frequency EM being reported by 52.3% and 20.6% of patients, respectively. Older age at onset (P  =  .01) and less frequent baseline monthly migraine days (P  =  .005) significantly increased the reversion frequency to EM.

Study details: Findings are from a 12-month observational, longitudinal cohort study, GARLIT, including 155 patients with CM who received galcanezumab.

Disclosures: This study did not receive any specific funding. Several authors reported receiving grants or honoraria from various sources.

Source: Altamura C et al for the GARLIT Study Group. Conversion from chronic to episodic migraine in patients treated with galcanezumab in real life in Italy: The 12-month observational, longitudinal, cohort multicenter GARLIT experience. J Neurol. 2022 (Jun 28). Doi: 10.1007/s00415-022-11226-4

Key clinical point: Long-term treatment with galcanezumab led to three-quarters of patients with chronic migraine (CM) reverting to episodic migraine (EM), with more than half persistently reverting to episodic migraine (EM) under real-life conditions.

Major finding: Over 1 year, approximately ≥75% of patients reverted from CM to EM at each visit, with persistent reversion from CM to EM and medium-to-low frequency EM being reported by 52.3% and 20.6% of patients, respectively. Older age at onset (P  =  .01) and less frequent baseline monthly migraine days (P  =  .005) significantly increased the reversion frequency to EM.

Study details: Findings are from a 12-month observational, longitudinal cohort study, GARLIT, including 155 patients with CM who received galcanezumab.

Disclosures: This study did not receive any specific funding. Several authors reported receiving grants or honoraria from various sources.

Source: Altamura C et al for the GARLIT Study Group. Conversion from chronic to episodic migraine in patients treated with galcanezumab in real life in Italy: The 12-month observational, longitudinal, cohort multicenter GARLIT experience. J Neurol. 2022 (Jun 28). Doi: 10.1007/s00415-022-11226-4

Key clinical point: Long-term treatment with galcanezumab led to three-quarters of patients with chronic migraine (CM) reverting to episodic migraine (EM), with more than half persistently reverting to episodic migraine (EM) under real-life conditions.

Major finding: Over 1 year, approximately ≥75% of patients reverted from CM to EM at each visit, with persistent reversion from CM to EM and medium-to-low frequency EM being reported by 52.3% and 20.6% of patients, respectively. Older age at onset (P  =  .01) and less frequent baseline monthly migraine days (P  =  .005) significantly increased the reversion frequency to EM.

Study details: Findings are from a 12-month observational, longitudinal cohort study, GARLIT, including 155 patients with CM who received galcanezumab.

Disclosures: This study did not receive any specific funding. Several authors reported receiving grants or honoraria from various sources.

Source: Altamura C et al for the GARLIT Study Group. Conversion from chronic to episodic migraine in patients treated with galcanezumab in real life in Italy: The 12-month observational, longitudinal, cohort multicenter GARLIT experience. J Neurol. 2022 (Jun 28). Doi: 10.1007/s00415-022-11226-4

Key clinical point: Eptinezumab (100 and 300 mg) was efficacious compared with placebo with an acceptable safety and tolerability profile in patients with episodic and chronic migraine and 2-4 previous unsuccessful preventive treatments.

Major finding: In 1-12 weeks, 100 and 300 mg eptinezumab vs placebo led to a significantly higher reduction in mean monthly migraine days (difference from placebo −2.7 and −3.2, respectively; both P < .0001) and higher odds of ≥75% migraine responder rates (odds ratio 9.2 and 11.4, respectively; both P < .0001), with comparable treatment-emergent adverse events.

Study details: Findings are from the phase 3b DELIVER trial including 892 patients with episodic and chronic migraine and 2-4 previous unsuccessful preventive treatments who were randomly assigned to receive eptinezumab (100 or 300 mg) or placebo.

Disclosures: This study was supported by H Lundbeck. Five authors reported being full-time employees or owning stock or stock options in H Lundbeck or its subsidiaries. Several authors reported ties with various sources and scientific journals.

Source: Ashina M et al. Safety and efficacy of eptinezumab for migraine prevention in patients with two-to-four previous preventive treatment failures (DELIVER): A multi-arm, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 2022;21(7):597-607 (Jul 1). Doi: 10.1016/S1474-4422(22)00185-5

Key clinical point: Eptinezumab (100 and 300 mg) was efficacious compared with placebo with an acceptable safety and tolerability profile in patients with episodic and chronic migraine and 2-4 previous unsuccessful preventive treatments.

Major finding: In 1-12 weeks, 100 and 300 mg eptinezumab vs placebo led to a significantly higher reduction in mean monthly migraine days (difference from placebo −2.7 and −3.2, respectively; both P < .0001) and higher odds of ≥75% migraine responder rates (odds ratio 9.2 and 11.4, respectively; both P < .0001), with comparable treatment-emergent adverse events.

Study details: Findings are from the phase 3b DELIVER trial including 892 patients with episodic and chronic migraine and 2-4 previous unsuccessful preventive treatments who were randomly assigned to receive eptinezumab (100 or 300 mg) or placebo.

Disclosures: This study was supported by H Lundbeck. Five authors reported being full-time employees or owning stock or stock options in H Lundbeck or its subsidiaries. Several authors reported ties with various sources and scientific journals.

Source: Ashina M et al. Safety and efficacy of eptinezumab for migraine prevention in patients with two-to-four previous preventive treatment failures (DELIVER): A multi-arm, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 2022;21(7):597-607 (Jul 1). Doi: 10.1016/S1474-4422(22)00185-5

Key clinical point: Eptinezumab (100 and 300 mg) was efficacious compared with placebo with an acceptable safety and tolerability profile in patients with episodic and chronic migraine and 2-4 previous unsuccessful preventive treatments.

Major finding: In 1-12 weeks, 100 and 300 mg eptinezumab vs placebo led to a significantly higher reduction in mean monthly migraine days (difference from placebo −2.7 and −3.2, respectively; both P < .0001) and higher odds of ≥75% migraine responder rates (odds ratio 9.2 and 11.4, respectively; both P < .0001), with comparable treatment-emergent adverse events.

Study details: Findings are from the phase 3b DELIVER trial including 892 patients with episodic and chronic migraine and 2-4 previous unsuccessful preventive treatments who were randomly assigned to receive eptinezumab (100 or 300 mg) or placebo.

Disclosures: This study was supported by H Lundbeck. Five authors reported being full-time employees or owning stock or stock options in H Lundbeck or its subsidiaries. Several authors reported ties with various sources and scientific journals.

Source: Ashina M et al. Safety and efficacy of eptinezumab for migraine prevention in patients with two-to-four previous preventive treatment failures (DELIVER): A multi-arm, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 2022;21(7):597-607 (Jul 1). Doi: 10.1016/S1474-4422(22)00185-5

Many of our patients with refractory migraine do not respond to first-line acute or preventive treatments, and, almost by definition, first- and second-line treatments have failed in the majority of patients on calcitonin gene-related peptide (CGRP) antagonist medications. Three studies this month highlight the efficacy of CGRP monoclonal antibody (mAb) and small-molecule medications in this population specifically.

Most headache specialists are familiar with the "standard" or PREEMPT onabotulinumtoxinA (Botox) paradigm used preventively for migraine. This protocol uses 155 units of onabotulinumtoxinA over 31 sites in seven muscle groups. OnabotulinumtoxinA vials typically come in 100 or 200 units, and when preparing onabotulinumtoxinA for patients who are being injected most providers are forced to discard most or all of the remaining 45 units. Anecdotally, some providers do inject the entire 200-unit vial, and the additional injection sites are either given in another standard protocol or in a follow-the-pain manner.

The study by Zandieh and colleagues followed 175 patients with chronic migraine who first received three injections of 150 units of onabotulinumtoxinA, then three injections of 200 units of this agent. The additional 50 units were injected into the temporalis and occipitalis muscles — the standard sites were used, but additional units were injected into each of the sites. The majority of patients experienced primarily frontal pain; the injections were not given in specific areas where more pain was manifesting.

The average number of headache days per month decreased significantly when the onabotulinumtoxinA dose was increased; patients tolerated the medication over the 3-month period as well. In practice, many providers use the additional units of onabotulinumtoxinA. This study argues that there is a minimal risk, and probably a potential significant benefit, when using up to 200 units every 3 months. Providers should, however, be aware that in rare instances, some insurances will only cover a 155-unit injection, and the use of additional units may jeopardize reimbursement for those plans.

Many patients anecdotally will use cold or heat as a treatment for acute migraine pain; however, the topical use of temperature has not been well studied for this purpose. Cold stimulus has, importantly, been known to be a trigger of migraine as well as other headache disorders classified in the International Classification of Headache Disorders, third edition (ICHD-3), including external cold stimulus headache and "brain freeze" or internal cold stimulus headache. Hsu and colleagues produced a meta-analysis and systematic review on the use of cold for acute treatment of migraine.

Six studies were found to be eligible for this review. The cold stimulus could be placed anywhere on the head, and the studies could have considered its use for any migraine-associated symptom. This includes headache, eye pain, nausea, or vomiting. The interventions used cold somewhat differently, including as ice packing, cooling compression, soaking, and as a rinse. Both randomized and nonrandomized trials were included in the systematic review; however, only randomized controlled trials were used for the meta-analysis.

The primary outcome evaluated by the authors was pain intensity; secondary outcomes were duration of migraine pain as well as associated symptoms (eg, nausea, vomiting). The meta-analysis revealed that cold interventions reduce migraine pain by 3.21 points on an analog scale, and this was found to be effective within 30 minutes. At 1-2 hours after the intervention, the effect was not seen to be significant. At 24 hours, the effect of cold intervention was marginal. Cold was not seen to significantly reduce nausea or vomiting at 2 hours after intervention.

Although cold treatments are commonly used by patients, there appears to be benefit only early in the onset of a migraine attack. Headache specialists typically recommend early treatment with a migraine-specific acute medication; however, the medication may take minutes to hours before taking effect. Cold can be recommended to patients during that intervening period, and it may help until the time that their acute medications take effect.

Chronic refractory migraine remains one of the most debilitating neurologic disorders and is a challenge even for the best trained neurologist or headache specialist. There are few headache centers with inpatient headache units around the United States, and those that remain use treatments that most neurologists are not familiar with. Schwenk and colleagues retrospectively reviewed the data of a major academic headache center and revealed impressive outcomes in this very difficult-to-treat population.

This study reviewed the outcomes of 609 consecutive patients admitted to the Thomas Jefferson University inpatient headache unit from 2017 to 2021. These patients all received continuous lidocaine infusions that were titrated according to an internal protocol that balanced daily plasma lidocaine levels, tolerability, and pain relief. Hospital discharge occurred when patients were pain-free for 12-24 hours or had a minimal response after 5 days of treatment. All patients had at least eight severe headaches per month for at least 6 consecutive months and had tried one to seven preventive medications, with the result of either intolerance or ineffectiveness.

The primary outcome was change from baseline to discharge pain level. Patients were admitted with an average score of 7.0 of 10 on admission and were discharged at a score of 1.0 of 10. Secondary outcomes were average pain at post-discharge appointment vs baseline (5.5 vs 7.0), number of monthly headache days at post-discharge appointment (22.5 vs 26.8), and current and average pain levels at the post-discharge appointment, which were both significantly lower as well. The most common adverse effect was nausea; others noted were cardiovascular changes, hallucinations or nightmares, sedation, anxiety, and chest pain.

This is an important retrospective on the effectiveness of an inpatient lidocaine protocol for refractory chronic migraine. When considering this population, especially if multiple lines of preventive and acute medications are not effective, referral to an academic inpatient headache center should definitely be considered. This patient population does not respond effectively to most treatment modalities, and this is cause to give them hope.

Many of our patients with refractory migraine do not respond to first-line acute or preventive treatments, and, almost by definition, first- and second-line treatments have failed in the majority of patients on calcitonin gene-related peptide (CGRP) antagonist medications. Three studies this month highlight the efficacy of CGRP monoclonal antibody (mAb) and small-molecule medications in this population specifically.

Most headache specialists are familiar with the "standard" or PREEMPT onabotulinumtoxinA (Botox) paradigm used preventively for migraine. This protocol uses 155 units of onabotulinumtoxinA over 31 sites in seven muscle groups. OnabotulinumtoxinA vials typically come in 100 or 200 units, and when preparing onabotulinumtoxinA for patients who are being injected most providers are forced to discard most or all of the remaining 45 units. Anecdotally, some providers do inject the entire 200-unit vial, and the additional injection sites are either given in another standard protocol or in a follow-the-pain manner.

The study by Zandieh and colleagues followed 175 patients with chronic migraine who first received three injections of 150 units of onabotulinumtoxinA, then three injections of 200 units of this agent. The additional 50 units were injected into the temporalis and occipitalis muscles — the standard sites were used, but additional units were injected into each of the sites. The majority of patients experienced primarily frontal pain; the injections were not given in specific areas where more pain was manifesting.

The average number of headache days per month decreased significantly when the onabotulinumtoxinA dose was increased; patients tolerated the medication over the 3-month period as well. In practice, many providers use the additional units of onabotulinumtoxinA. This study argues that there is a minimal risk, and probably a potential significant benefit, when using up to 200 units every 3 months. Providers should, however, be aware that in rare instances, some insurances will only cover a 155-unit injection, and the use of additional units may jeopardize reimbursement for those plans.

Many patients anecdotally will use cold or heat as a treatment for acute migraine pain; however, the topical use of temperature has not been well studied for this purpose. Cold stimulus has, importantly, been known to be a trigger of migraine as well as other headache disorders classified in the International Classification of Headache Disorders, third edition (ICHD-3), including external cold stimulus headache and "brain freeze" or internal cold stimulus headache. Hsu and colleagues produced a meta-analysis and systematic review on the use of cold for acute treatment of migraine.

Six studies were found to be eligible for this review. The cold stimulus could be placed anywhere on the head, and the studies could have considered its use for any migraine-associated symptom. This includes headache, eye pain, nausea, or vomiting. The interventions used cold somewhat differently, including as ice packing, cooling compression, soaking, and as a rinse. Both randomized and nonrandomized trials were included in the systematic review; however, only randomized controlled trials were used for the meta-analysis.

The primary outcome evaluated by the authors was pain intensity; secondary outcomes were duration of migraine pain as well as associated symptoms (eg, nausea, vomiting). The meta-analysis revealed that cold interventions reduce migraine pain by 3.21 points on an analog scale, and this was found to be effective within 30 minutes. At 1-2 hours after the intervention, the effect was not seen to be significant. At 24 hours, the effect of cold intervention was marginal. Cold was not seen to significantly reduce nausea or vomiting at 2 hours after intervention.

Although cold treatments are commonly used by patients, there appears to be benefit only early in the onset of a migraine attack. Headache specialists typically recommend early treatment with a migraine-specific acute medication; however, the medication may take minutes to hours before taking effect. Cold can be recommended to patients during that intervening period, and it may help until the time that their acute medications take effect.

Chronic refractory migraine remains one of the most debilitating neurologic disorders and is a challenge even for the best trained neurologist or headache specialist. There are few headache centers with inpatient headache units around the United States, and those that remain use treatments that most neurologists are not familiar with. Schwenk and colleagues retrospectively reviewed the data of a major academic headache center and revealed impressive outcomes in this very difficult-to-treat population.

This study reviewed the outcomes of 609 consecutive patients admitted to the Thomas Jefferson University inpatient headache unit from 2017 to 2021. These patients all received continuous lidocaine infusions that were titrated according to an internal protocol that balanced daily plasma lidocaine levels, tolerability, and pain relief. Hospital discharge occurred when patients were pain-free for 12-24 hours or had a minimal response after 5 days of treatment. All patients had at least eight severe headaches per month for at least 6 consecutive months and had tried one to seven preventive medications, with the result of either intolerance or ineffectiveness.

The primary outcome was change from baseline to discharge pain level. Patients were admitted with an average score of 7.0 of 10 on admission and were discharged at a score of 1.0 of 10. Secondary outcomes were average pain at post-discharge appointment vs baseline (5.5 vs 7.0), number of monthly headache days at post-discharge appointment (22.5 vs 26.8), and current and average pain levels at the post-discharge appointment, which were both significantly lower as well. The most common adverse effect was nausea; others noted were cardiovascular changes, hallucinations or nightmares, sedation, anxiety, and chest pain.

This is an important retrospective on the effectiveness of an inpatient lidocaine protocol for refractory chronic migraine. When considering this population, especially if multiple lines of preventive and acute medications are not effective, referral to an academic inpatient headache center should definitely be considered. This patient population does not respond effectively to most treatment modalities, and this is cause to give them hope.

Many of our patients with refractory migraine do not respond to first-line acute or preventive treatments, and, almost by definition, first- and second-line treatments have failed in the majority of patients on calcitonin gene-related peptide (CGRP) antagonist medications. Three studies this month highlight the efficacy of CGRP monoclonal antibody (mAb) and small-molecule medications in this population specifically.

Most headache specialists are familiar with the "standard" or PREEMPT onabotulinumtoxinA (Botox) paradigm used preventively for migraine. This protocol uses 155 units of onabotulinumtoxinA over 31 sites in seven muscle groups. OnabotulinumtoxinA vials typically come in 100 or 200 units, and when preparing onabotulinumtoxinA for patients who are being injected most providers are forced to discard most or all of the remaining 45 units. Anecdotally, some providers do inject the entire 200-unit vial, and the additional injection sites are either given in another standard protocol or in a follow-the-pain manner.

The study by Zandieh and colleagues followed 175 patients with chronic migraine who first received three injections of 150 units of onabotulinumtoxinA, then three injections of 200 units of this agent. The additional 50 units were injected into the temporalis and occipitalis muscles — the standard sites were used, but additional units were injected into each of the sites. The majority of patients experienced primarily frontal pain; the injections were not given in specific areas where more pain was manifesting.

The average number of headache days per month decreased significantly when the onabotulinumtoxinA dose was increased; patients tolerated the medication over the 3-month period as well. In practice, many providers use the additional units of onabotulinumtoxinA. This study argues that there is a minimal risk, and probably a potential significant benefit, when using up to 200 units every 3 months. Providers should, however, be aware that in rare instances, some insurances will only cover a 155-unit injection, and the use of additional units may jeopardize reimbursement for those plans.

Many patients anecdotally will use cold or heat as a treatment for acute migraine pain; however, the topical use of temperature has not been well studied for this purpose. Cold stimulus has, importantly, been known to be a trigger of migraine as well as other headache disorders classified in the International Classification of Headache Disorders, third edition (ICHD-3), including external cold stimulus headache and "brain freeze" or internal cold stimulus headache. Hsu and colleagues produced a meta-analysis and systematic review on the use of cold for acute treatment of migraine.

Six studies were found to be eligible for this review. The cold stimulus could be placed anywhere on the head, and the studies could have considered its use for any migraine-associated symptom. This includes headache, eye pain, nausea, or vomiting. The interventions used cold somewhat differently, including as ice packing, cooling compression, soaking, and as a rinse. Both randomized and nonrandomized trials were included in the systematic review; however, only randomized controlled trials were used for the meta-analysis.

The primary outcome evaluated by the authors was pain intensity; secondary outcomes were duration of migraine pain as well as associated symptoms (eg, nausea, vomiting). The meta-analysis revealed that cold interventions reduce migraine pain by 3.21 points on an analog scale, and this was found to be effective within 30 minutes. At 1-2 hours after the intervention, the effect was not seen to be significant. At 24 hours, the effect of cold intervention was marginal. Cold was not seen to significantly reduce nausea or vomiting at 2 hours after intervention.

Although cold treatments are commonly used by patients, there appears to be benefit only early in the onset of a migraine attack. Headache specialists typically recommend early treatment with a migraine-specific acute medication; however, the medication may take minutes to hours before taking effect. Cold can be recommended to patients during that intervening period, and it may help until the time that their acute medications take effect.

Chronic refractory migraine remains one of the most debilitating neurologic disorders and is a challenge even for the best trained neurologist or headache specialist. There are few headache centers with inpatient headache units around the United States, and those that remain use treatments that most neurologists are not familiar with. Schwenk and colleagues retrospectively reviewed the data of a major academic headache center and revealed impressive outcomes in this very difficult-to-treat population.

This study reviewed the outcomes of 609 consecutive patients admitted to the Thomas Jefferson University inpatient headache unit from 2017 to 2021. These patients all received continuous lidocaine infusions that were titrated according to an internal protocol that balanced daily plasma lidocaine levels, tolerability, and pain relief. Hospital discharge occurred when patients were pain-free for 12-24 hours or had a minimal response after 5 days of treatment. All patients had at least eight severe headaches per month for at least 6 consecutive months and had tried one to seven preventive medications, with the result of either intolerance or ineffectiveness.

The primary outcome was change from baseline to discharge pain level. Patients were admitted with an average score of 7.0 of 10 on admission and were discharged at a score of 1.0 of 10. Secondary outcomes were average pain at post-discharge appointment vs baseline (5.5 vs 7.0), number of monthly headache days at post-discharge appointment (22.5 vs 26.8), and current and average pain levels at the post-discharge appointment, which were both significantly lower as well. The most common adverse effect was nausea; others noted were cardiovascular changes, hallucinations or nightmares, sedation, anxiety, and chest pain.

This is an important retrospective on the effectiveness of an inpatient lidocaine protocol for refractory chronic migraine. When considering this population, especially if multiple lines of preventive and acute medications are not effective, referral to an academic inpatient headache center should definitely be considered. This patient population does not respond effectively to most treatment modalities, and this is cause to give them hope.

The Health Terminology/Ontology Portal (HeTOP), on which the curious can discover information about off-label use, lists 645 medications prescribed for migraine worldwide. Treatments ranging from blood pressure medications to antidepressants, and anticonvulsants to antiepileptics, along with their doses and administrations, are all listed. The number of migraine-indicated medications is 114.  Dominated by triptans and topiramate, the list also includes erenumab, the calcitonin gene-related peptide CGRP agonist. The difference in figures between the predominately off label and migraine-approved lists is a good indicator of the struggle that health care providers have had through the years to help their patients.

 The idea now is to make that list even longer by finding biomarkers that lead to new therapies.

But first, a conversation about the trigeminal ganglia.

The trigeminal ganglia

The trigeminal ganglia sit on either side of the head, in front of the ears. Their primary role is to receive stimuli and convey it to the brain. The humantrigeminal ganglia contain 20,000 to 35,000 neurons and express an array of neuropeptides, including CGRP. Some neuropeptides, like CGRP and pituitary adenylate cyclase–activating peptide 38 (PACAP38) are vasodilators. Others, like substance P, are vasoconstrictors. Edvinsson and Goadsby discussed in 1994 how CGRP was released simultaneously in those with “spontaneous attacks of migraine.”

Over the past 30 years, researchers in our institution  and elsewhere have shown repeatedly that migraine develops in individuals who are exposed to certain signaling molecules, namely nitroglycerin, CGRP, cyclic guanosine monophosphate (cGMP), intracellular cyclic adenosine monophosphate (cAMP), potassium, and PACAP38, among others. Such exposure reinforces the notion that peripheral sensitization of trigeminal sensory neurons brings on headache. The attack could occur due to vasodilation, mast cell degranulation, involvement of the parasympathetic system, or activation of nerve fibers.

Some examples from the literature:

• In our research, results from a small study of patients under spontaneous migraine attack, who underwent a 3-Tesla MRI scan, showed that cortical thickness diminishes in the prefrontal and pericalcarine cortices. The analysis we performed involving individuals with migraine without aura revealed that these patients experience reduced cortical thickness and volume when migraine attacks come on, suggesting that cortical thickness and volume may serve as a potential biomarker.
• A comparison of 20 individuals with chronic migraine and 20 healthy controls by way of 3-Tesla magnetic resonance imaging scans revealed that those with headache appeared to have substantially increased neural connectivity between the hypothalamus and certain brain areas – yet there appeared to be no connectivity irregularities between the hypothalamus and brainstem, which as the authors noted, is the “migraine generator.”

In other words, vasodilation might be  a secondary symptom of migraine but likely isn’t its source.

Other migraine makers

Neurochemicals and nucleotides play a role in migraine formation, too:

• Nitric oxide. Can open blood vessels in the head and brain and has been shown to set migraine in motion. It leads to peak headache intensity 5.5 hours after infusion and causes migraine without aura.

• GRP. Gastrin-releasing peptide receptors cause delayed headache, including what qualifies as an induced migraine attack. Researchers also note that similar pathways trigger migraine with and without aura. 

• Intracellular cGMP and intracellular cAMP. These 2 cyclic nucleotides are found extensively in the trigeminovascular system and have a role in the pathogenesis of migraine.  Studies demonstrate that cGMP levels increase after nitroglycerin administration and cAMP increases after CGRP and PACAP38 exposure.

• Levcromakalim. This potassium channel opener is sensitive to ATP. In a trial published in 2019, researchers showed that modulating potassium channels could cause some headache pain, even in those without migraine. They infused 20 healthy volunteers with levcromakalim; over the next 5-plus hours, the middle meningeal artery of all 20 became and remained dilated. Later research showed that this dilation is linked to substance P. 

Identifying migraine types

Diagnosing migraine is 1 step; determining its type is another.

Consider that a person with a posttraumatic headache can have migraine-like symptoms. To find objective separate characteristics, researchers at Mayo Clinic designed a headache classification model using questionnaires, which were then paired with the patient’s MRI data. The questionnaires delved into headache characteristics, sensory hypersensitivities, cognitive functioning, and mood. The system worked well with primary migraine, with 97% accuracy. But with posttraumatic headache, the system was 65% accurate. What proved to differentiate persistent posttraumatic headache were questions regarding decision making and anxiety. These patients had severe symptoms of anxiety, depression, physical issues, and mild brain injury attributed to blasts.

All of which explains why we and others are actively looking for biomarkers.

The biomarkers

A look at clinicaltrials.gov shows that 15 trials are recruiting patients (including us) in the search for biomarkers. One wants to identify a computational algorithm using AI, based on 9 types of markers in hopes of identifying those predictive elements that will respond to CGRP-targeting monoclonal antibodies (mABs). The factors range from the clinical to epigenetic to structural and functional brain imaging. Another registered study is using ocular coherence tomography, among other technologies, to identify photophobia.

Our interests are in identifying CGRP as a definitive biomarker; finding structural and functional cerebral changes, using MRI, in study subjects before and after they are given erenumab. We also want to create a registry for migraine based on the structural and functional MRI findings.

Another significant reason for finding biomarkers is to identify the alteration that accompany progression from episodic to chronic migraine. Pozo-Rosich et al write that these imaging, neurophysiological, and biochemical changes that occur with this progression could be used “for developing chronic migraine biomarkers that might assist with diagnosis, prognosticating individual patient outcomes, and predicting responses to migraine therapies.” And, ultimately, in practicing precision medicine to improve care of patients.

Significant barriers still exist in declaring a molecule is a biomarker. For example, a meta-analysis points to the replication challenge observed in neuroimaging research. Additionally, several genetic variants produce small effect sizes, which also might be impacted by environmental factors. This makes it difficult to map genetic biomarkers. Large prospective studies are needed to bring this area of research out of infancy to a place where treatment response can be clinically assessed. Additionally, while research evaluating provocation biomarkers has already contributed to the treatment landscape, large-scale registry studies may help uncover a predictive biomarker of treatment response. Blood biomarker research still needs a standardized protocol. Imaging-based biomarkers show much potential, but standardized imaging protocols and improved characterization and data integration are necessary going forward.

The patients

The discovery of the CGRPs couldn’t have been more timely.

Those of us who have been treating patients with migraine for years have seen the prevalence of this disease slowly rise. In 2018, the age-adjusted prevalence was 15.9% for all adults in the United States; in 2010, it was 13.2%. Worldwide, in 2019, it was 14%. In 2015, it was 11.6%.

In the past few years, journal articles have appeared regarding the connection between obesity, diabetes, hypertension, and migraine severity. Numerous other comorbidities affect our patients – not just the well-known psychiatric disorders – but also the respiratory, digestive, and central nervous system illnesses.

In other words, many of our patients come to us sicker than in years past.

Some cannot take one or more medications designed for acute migraine attacks due to comorbidities, including cardiovascular disease or related risk factors, and gastrointestinal bleeding.

A large survey of 15,133 people with migraine confirmed the findings on these numerous comorbidities; they reported that they have more insomnia, depression, and anxiety. As the authors point out, identifying these comorbidities can help with accurate diagnosis, treatment and its adherence, and prognosis. The authors also noted that as migraine days increase per month, so do the rates of comorbidities.

But the CGRPs are showing how beneficial they can be. One study assessing medication overuse showed how 60% of the enrolled patients no longer fit that description 6 months after receiving erenumab or galcanezumab. Some patients who contend with episodic migraine showed a complete response after receiving eptinezumab and galcanezumab. They also have helped patients with menstrual migraine and refractory migraine.

But they are not complete responses to these medications, which is an excellent reason to continue viewing, recording, and assessing the migraine brain, for all it can tell us.

The Health Terminology/Ontology Portal (HeTOP), on which the curious can discover information about off-label use, lists 645 medications prescribed for migraine worldwide. Treatments ranging from blood pressure medications to antidepressants, and anticonvulsants to antiepileptics, along with their doses and administrations, are all listed. The number of migraine-indicated medications is 114.  Dominated by triptans and topiramate, the list also includes erenumab, the calcitonin gene-related peptide CGRP agonist. The difference in figures between the predominately off label and migraine-approved lists is a good indicator of the struggle that health care providers have had through the years to help their patients.

 The idea now is to make that list even longer by finding biomarkers that lead to new therapies.

But first, a conversation about the trigeminal ganglia.

The trigeminal ganglia

The trigeminal ganglia sit on either side of the head, in front of the ears. Their primary role is to receive stimuli and convey it to the brain. The humantrigeminal ganglia contain 20,000 to 35,000 neurons and express an array of neuropeptides, including CGRP. Some neuropeptides, like CGRP and pituitary adenylate cyclase–activating peptide 38 (PACAP38) are vasodilators. Others, like substance P, are vasoconstrictors. Edvinsson and Goadsby discussed in 1994 how CGRP was released simultaneously in those with “spontaneous attacks of migraine.”

Over the past 30 years, researchers in our institution  and elsewhere have shown repeatedly that migraine develops in individuals who are exposed to certain signaling molecules, namely nitroglycerin, CGRP, cyclic guanosine monophosphate (cGMP), intracellular cyclic adenosine monophosphate (cAMP), potassium, and PACAP38, among others. Such exposure reinforces the notion that peripheral sensitization of trigeminal sensory neurons brings on headache. The attack could occur due to vasodilation, mast cell degranulation, involvement of the parasympathetic system, or activation of nerve fibers.

Some examples from the literature:

• In our research, results from a small study of patients under spontaneous migraine attack, who underwent a 3-Tesla MRI scan, showed that cortical thickness diminishes in the prefrontal and pericalcarine cortices. The analysis we performed involving individuals with migraine without aura revealed that these patients experience reduced cortical thickness and volume when migraine attacks come on, suggesting that cortical thickness and volume may serve as a potential biomarker.
• A comparison of 20 individuals with chronic migraine and 20 healthy controls by way of 3-Tesla magnetic resonance imaging scans revealed that those with headache appeared to have substantially increased neural connectivity between the hypothalamus and certain brain areas – yet there appeared to be no connectivity irregularities between the hypothalamus and brainstem, which as the authors noted, is the “migraine generator.”

In other words, vasodilation might be  a secondary symptom of migraine but likely isn’t its source.

Other migraine makers

Neurochemicals and nucleotides play a role in migraine formation, too:

• Nitric oxide. Can open blood vessels in the head and brain and has been shown to set migraine in motion. It leads to peak headache intensity 5.5 hours after infusion and causes migraine without aura.

• GRP. Gastrin-releasing peptide receptors cause delayed headache, including what qualifies as an induced migraine attack. Researchers also note that similar pathways trigger migraine with and without aura. 

• Intracellular cGMP and intracellular cAMP. These 2 cyclic nucleotides are found extensively in the trigeminovascular system and have a role in the pathogenesis of migraine.  Studies demonstrate that cGMP levels increase after nitroglycerin administration and cAMP increases after CGRP and PACAP38 exposure.

• Levcromakalim. This potassium channel opener is sensitive to ATP. In a trial published in 2019, researchers showed that modulating potassium channels could cause some headache pain, even in those without migraine. They infused 20 healthy volunteers with levcromakalim; over the next 5-plus hours, the middle meningeal artery of all 20 became and remained dilated. Later research showed that this dilation is linked to substance P. 

Identifying migraine types

Diagnosing migraine is 1 step; determining its type is another.

Consider that a person with a posttraumatic headache can have migraine-like symptoms. To find objective separate characteristics, researchers at Mayo Clinic designed a headache classification model using questionnaires, which were then paired with the patient’s MRI data. The questionnaires delved into headache characteristics, sensory hypersensitivities, cognitive functioning, and mood. The system worked well with primary migraine, with 97% accuracy. But with posttraumatic headache, the system was 65% accurate. What proved to differentiate persistent posttraumatic headache were questions regarding decision making and anxiety. These patients had severe symptoms of anxiety, depression, physical issues, and mild brain injury attributed to blasts.

All of which explains why we and others are actively looking for biomarkers.

The biomarkers

A look at clinicaltrials.gov shows that 15 trials are recruiting patients (including us) in the search for biomarkers. One wants to identify a computational algorithm using AI, based on 9 types of markers in hopes of identifying those predictive elements that will respond to CGRP-targeting monoclonal antibodies (mABs). The factors range from the clinical to epigenetic to structural and functional brain imaging. Another registered study is using ocular coherence tomography, among other technologies, to identify photophobia.

Our interests are in identifying CGRP as a definitive biomarker; finding structural and functional cerebral changes, using MRI, in study subjects before and after they are given erenumab. We also want to create a registry for migraine based on the structural and functional MRI findings.

Another significant reason for finding biomarkers is to identify the alteration that accompany progression from episodic to chronic migraine. Pozo-Rosich et al write that these imaging, neurophysiological, and biochemical changes that occur with this progression could be used “for developing chronic migraine biomarkers that might assist with diagnosis, prognosticating individual patient outcomes, and predicting responses to migraine therapies.” And, ultimately, in practicing precision medicine to improve care of patients.

Significant barriers still exist in declaring a molecule is a biomarker. For example, a meta-analysis points to the replication challenge observed in neuroimaging research. Additionally, several genetic variants produce small effect sizes, which also might be impacted by environmental factors. This makes it difficult to map genetic biomarkers. Large prospective studies are needed to bring this area of research out of infancy to a place where treatment response can be clinically assessed. Additionally, while research evaluating provocation biomarkers has already contributed to the treatment landscape, large-scale registry studies may help uncover a predictive biomarker of treatment response. Blood biomarker research still needs a standardized protocol. Imaging-based biomarkers show much potential, but standardized imaging protocols and improved characterization and data integration are necessary going forward.

The patients

The discovery of the CGRPs couldn’t have been more timely.

Those of us who have been treating patients with migraine for years have seen the prevalence of this disease slowly rise. In 2018, the age-adjusted prevalence was 15.9% for all adults in the United States; in 2010, it was 13.2%. Worldwide, in 2019, it was 14%. In 2015, it was 11.6%.

In the past few years, journal articles have appeared regarding the connection between obesity, diabetes, hypertension, and migraine severity. Numerous other comorbidities affect our patients – not just the well-known psychiatric disorders – but also the respiratory, digestive, and central nervous system illnesses.

In other words, many of our patients come to us sicker than in years past.

Some cannot take one or more medications designed for acute migraine attacks due to comorbidities, including cardiovascular disease or related risk factors, and gastrointestinal bleeding.

A large survey of 15,133 people with migraine confirmed the findings on these numerous comorbidities; they reported that they have more insomnia, depression, and anxiety. As the authors point out, identifying these comorbidities can help with accurate diagnosis, treatment and its adherence, and prognosis. The authors also noted that as migraine days increase per month, so do the rates of comorbidities.

But the CGRPs are showing how beneficial they can be. One study assessing medication overuse showed how 60% of the enrolled patients no longer fit that description 6 months after receiving erenumab or galcanezumab. Some patients who contend with episodic migraine showed a complete response after receiving eptinezumab and galcanezumab. They also have helped patients with menstrual migraine and refractory migraine.

But they are not complete responses to these medications, which is an excellent reason to continue viewing, recording, and assessing the migraine brain, for all it can tell us.

The Health Terminology/Ontology Portal (HeTOP), on which the curious can discover information about off-label use, lists 645 medications prescribed for migraine worldwide. Treatments ranging from blood pressure medications to antidepressants, and anticonvulsants to antiepileptics, along with their doses and administrations, are all listed. The number of migraine-indicated medications is 114.  Dominated by triptans and topiramate, the list also includes erenumab, the calcitonin gene-related peptide CGRP agonist. The difference in figures between the predominately off label and migraine-approved lists is a good indicator of the struggle that health care providers have had through the years to help their patients.

 The idea now is to make that list even longer by finding biomarkers that lead to new therapies.

But first, a conversation about the trigeminal ganglia.

The trigeminal ganglia

The trigeminal ganglia sit on either side of the head, in front of the ears. Their primary role is to receive stimuli and convey it to the brain. The humantrigeminal ganglia contain 20,000 to 35,000 neurons and express an array of neuropeptides, including CGRP. Some neuropeptides, like CGRP and pituitary adenylate cyclase–activating peptide 38 (PACAP38) are vasodilators. Others, like substance P, are vasoconstrictors. Edvinsson and Goadsby discussed in 1994 how CGRP was released simultaneously in those with “spontaneous attacks of migraine.”

Over the past 30 years, researchers in our institution  and elsewhere have shown repeatedly that migraine develops in individuals who are exposed to certain signaling molecules, namely nitroglycerin, CGRP, cyclic guanosine monophosphate (cGMP), intracellular cyclic adenosine monophosphate (cAMP), potassium, and PACAP38, among others. Such exposure reinforces the notion that peripheral sensitization of trigeminal sensory neurons brings on headache. The attack could occur due to vasodilation, mast cell degranulation, involvement of the parasympathetic system, or activation of nerve fibers.

Some examples from the literature:

• In our research, results from a small study of patients under spontaneous migraine attack, who underwent a 3-Tesla MRI scan, showed that cortical thickness diminishes in the prefrontal and pericalcarine cortices. The analysis we performed involving individuals with migraine without aura revealed that these patients experience reduced cortical thickness and volume when migraine attacks come on, suggesting that cortical thickness and volume may serve as a potential biomarker.
• A comparison of 20 individuals with chronic migraine and 20 healthy controls by way of 3-Tesla magnetic resonance imaging scans revealed that those with headache appeared to have substantially increased neural connectivity between the hypothalamus and certain brain areas – yet there appeared to be no connectivity irregularities between the hypothalamus and brainstem, which as the authors noted, is the “migraine generator.”

In other words, vasodilation might be  a secondary symptom of migraine but likely isn’t its source.

Other migraine makers

Neurochemicals and nucleotides play a role in migraine formation, too:

• Nitric oxide. Can open blood vessels in the head and brain and has been shown to set migraine in motion. It leads to peak headache intensity 5.5 hours after infusion and causes migraine without aura.

• GRP. Gastrin-releasing peptide receptors cause delayed headache, including what qualifies as an induced migraine attack. Researchers also note that similar pathways trigger migraine with and without aura. 

• Intracellular cGMP and intracellular cAMP. These 2 cyclic nucleotides are found extensively in the trigeminovascular system and have a role in the pathogenesis of migraine.  Studies demonstrate that cGMP levels increase after nitroglycerin administration and cAMP increases after CGRP and PACAP38 exposure.

• Levcromakalim. This potassium channel opener is sensitive to ATP. In a trial published in 2019, researchers showed that modulating potassium channels could cause some headache pain, even in those without migraine. They infused 20 healthy volunteers with levcromakalim; over the next 5-plus hours, the middle meningeal artery of all 20 became and remained dilated. Later research showed that this dilation is linked to substance P. 

Identifying migraine types

Diagnosing migraine is 1 step; determining its type is another.

Consider that a person with a posttraumatic headache can have migraine-like symptoms. To find objective separate characteristics, researchers at Mayo Clinic designed a headache classification model using questionnaires, which were then paired with the patient’s MRI data. The questionnaires delved into headache characteristics, sensory hypersensitivities, cognitive functioning, and mood. The system worked well with primary migraine, with 97% accuracy. But with posttraumatic headache, the system was 65% accurate. What proved to differentiate persistent posttraumatic headache were questions regarding decision making and anxiety. These patients had severe symptoms of anxiety, depression, physical issues, and mild brain injury attributed to blasts.

All of which explains why we and others are actively looking for biomarkers.

The biomarkers

A look at clinicaltrials.gov shows that 15 trials are recruiting patients (including us) in the search for biomarkers. One wants to identify a computational algorithm using AI, based on 9 types of markers in hopes of identifying those predictive elements that will respond to CGRP-targeting monoclonal antibodies (mABs). The factors range from the clinical to epigenetic to structural and functional brain imaging. Another registered study is using ocular coherence tomography, among other technologies, to identify photophobia.

Our interests are in identifying CGRP as a definitive biomarker; finding structural and functional cerebral changes, using MRI, in study subjects before and after they are given erenumab. We also want to create a registry for migraine based on the structural and functional MRI findings.

Another significant reason for finding biomarkers is to identify the alteration that accompany progression from episodic to chronic migraine. Pozo-Rosich et al write that these imaging, neurophysiological, and biochemical changes that occur with this progression could be used “for developing chronic migraine biomarkers that might assist with diagnosis, prognosticating individual patient outcomes, and predicting responses to migraine therapies.” And, ultimately, in practicing precision medicine to improve care of patients.

Significant barriers still exist in declaring a molecule is a biomarker. For example, a meta-analysis points to the replication challenge observed in neuroimaging research. Additionally, several genetic variants produce small effect sizes, which also might be impacted by environmental factors. This makes it difficult to map genetic biomarkers. Large prospective studies are needed to bring this area of research out of infancy to a place where treatment response can be clinically assessed. Additionally, while research evaluating provocation biomarkers has already contributed to the treatment landscape, large-scale registry studies may help uncover a predictive biomarker of treatment response. Blood biomarker research still needs a standardized protocol. Imaging-based biomarkers show much potential, but standardized imaging protocols and improved characterization and data integration are necessary going forward.

The patients

The discovery of the CGRPs couldn’t have been more timely.

Those of us who have been treating patients with migraine for years have seen the prevalence of this disease slowly rise. In 2018, the age-adjusted prevalence was 15.9% for all adults in the United States; in 2010, it was 13.2%. Worldwide, in 2019, it was 14%. In 2015, it was 11.6%.

In the past few years, journal articles have appeared regarding the connection between obesity, diabetes, hypertension, and migraine severity. Numerous other comorbidities affect our patients – not just the well-known psychiatric disorders – but also the respiratory, digestive, and central nervous system illnesses.

In other words, many of our patients come to us sicker than in years past.

Some cannot take one or more medications designed for acute migraine attacks due to comorbidities, including cardiovascular disease or related risk factors, and gastrointestinal bleeding.

A large survey of 15,133 people with migraine confirmed the findings on these numerous comorbidities; they reported that they have more insomnia, depression, and anxiety. As the authors point out, identifying these comorbidities can help with accurate diagnosis, treatment and its adherence, and prognosis. The authors also noted that as migraine days increase per month, so do the rates of comorbidities.

But the CGRPs are showing how beneficial they can be. One study assessing medication overuse showed how 60% of the enrolled patients no longer fit that description 6 months after receiving erenumab or galcanezumab. Some patients who contend with episodic migraine showed a complete response after receiving eptinezumab and galcanezumab. They also have helped patients with menstrual migraine and refractory migraine.

But they are not complete responses to these medications, which is an excellent reason to continue viewing, recording, and assessing the migraine brain, for all it can tell us.