Migraine ICYMI

Key clinical point: The efficacy and safety of eptinezumab in preventing migraine realized in the PROMISE-1 and PROMISE-2 trials remain unperturbed by the intrinsic baseline characteristics of the study participants, including sex, age, and body mass index (BMI).

Main finding: The ≥50% migraine responder rate (MRR) was ≥10% higher with eptinezumab relative to placebo for most demographic factors, except in the case of obesity; although patients with a BMI of 30-35 kg/m² receiving eptinezumab vs. placebo showed improved ≥50% MRR, the separation was <10%. Eptinezumab was generally safe, and no new treatment-emergent adverse events were identified.

Study details: This was a post hoc subgroup analysis of adult patients with episodic or chronic migraine from the phase 3 PROMISE-1 and PROMISE-2 trials, respectively, which included a total of 1,960 patients in the safety analysis and 1,737 patients (99.8%) in the efficacy analysis.

Disclosures: The study received financial support from H. Lundbeck A/S. The authors disclosed having no conflicts of interest.

Source: Martin V et al. Clin Ther. 2022 (Feb 9). Doi: 10.1016/j.clinthera.2022.01.006

Key clinical point: The efficacy and safety of eptinezumab in preventing migraine realized in the PROMISE-1 and PROMISE-2 trials remain unperturbed by the intrinsic baseline characteristics of the study participants, including sex, age, and body mass index (BMI).

Main finding: The ≥50% migraine responder rate (MRR) was ≥10% higher with eptinezumab relative to placebo for most demographic factors, except in the case of obesity; although patients with a BMI of 30-35 kg/m² receiving eptinezumab vs. placebo showed improved ≥50% MRR, the separation was <10%. Eptinezumab was generally safe, and no new treatment-emergent adverse events were identified.

Study details: This was a post hoc subgroup analysis of adult patients with episodic or chronic migraine from the phase 3 PROMISE-1 and PROMISE-2 trials, respectively, which included a total of 1,960 patients in the safety analysis and 1,737 patients (99.8%) in the efficacy analysis.

Disclosures: The study received financial support from H. Lundbeck A/S. The authors disclosed having no conflicts of interest.

Source: Martin V et al. Clin Ther. 2022 (Feb 9). Doi: 10.1016/j.clinthera.2022.01.006

Key clinical point: The efficacy and safety of eptinezumab in preventing migraine realized in the PROMISE-1 and PROMISE-2 trials remain unperturbed by the intrinsic baseline characteristics of the study participants, including sex, age, and body mass index (BMI).

Main finding: The ≥50% migraine responder rate (MRR) was ≥10% higher with eptinezumab relative to placebo for most demographic factors, except in the case of obesity; although patients with a BMI of 30-35 kg/m² receiving eptinezumab vs. placebo showed improved ≥50% MRR, the separation was <10%. Eptinezumab was generally safe, and no new treatment-emergent adverse events were identified.

Study details: This was a post hoc subgroup analysis of adult patients with episodic or chronic migraine from the phase 3 PROMISE-1 and PROMISE-2 trials, respectively, which included a total of 1,960 patients in the safety analysis and 1,737 patients (99.8%) in the efficacy analysis.

Disclosures: The study received financial support from H. Lundbeck A/S. The authors disclosed having no conflicts of interest.

Source: Martin V et al. Clin Ther. 2022 (Feb 9). Doi: 10.1016/j.clinthera.2022.01.006

Key clinical point: Patients with migraine present with a 20% higher risk of developing neovascular age-related macular degeneration (AMD) compared with individuals without migraine.

Main finding: A significantly higher proportion of patients with neovascular AMD vs. control individuals had migraine before the index date (6.1% vs. 4.9%; P < .001), with an adjusted (for age, sex, monthly income, geographic location, urbanization, hyperlipidemia, diabetes, coronary heart disease, hypertension, and cataract surgery) odds ratio of 1.201 (P < .001).

Study details: This nationwide, population-based study included 20,333 patients aged 40 years or older diagnosed with neovascular AMD in at least 2 claims, with the first diagnosis date defined as the index date. They were propensity score-matched (1:4) with 81,332 nonneovascular AMD control individuals.

Disclosures: No source of funding was declared. None of the authors identified any conflicts of interest.

Source: Kuang TM et al. Sci Rep. 2022;12:1792 (Feb 2). Doi: 10.1038/s41598-022-05638-5

Key clinical point: Patients with migraine present with a 20% higher risk of developing neovascular age-related macular degeneration (AMD) compared with individuals without migraine.

Main finding: A significantly higher proportion of patients with neovascular AMD vs. control individuals had migraine before the index date (6.1% vs. 4.9%; P < .001), with an adjusted (for age, sex, monthly income, geographic location, urbanization, hyperlipidemia, diabetes, coronary heart disease, hypertension, and cataract surgery) odds ratio of 1.201 (P < .001).

Study details: This nationwide, population-based study included 20,333 patients aged 40 years or older diagnosed with neovascular AMD in at least 2 claims, with the first diagnosis date defined as the index date. They were propensity score-matched (1:4) with 81,332 nonneovascular AMD control individuals.

Disclosures: No source of funding was declared. None of the authors identified any conflicts of interest.

Source: Kuang TM et al. Sci Rep. 2022;12:1792 (Feb 2). Doi: 10.1038/s41598-022-05638-5

Key clinical point: Patients with migraine present with a 20% higher risk of developing neovascular age-related macular degeneration (AMD) compared with individuals without migraine.

Main finding: A significantly higher proportion of patients with neovascular AMD vs. control individuals had migraine before the index date (6.1% vs. 4.9%; P < .001), with an adjusted (for age, sex, monthly income, geographic location, urbanization, hyperlipidemia, diabetes, coronary heart disease, hypertension, and cataract surgery) odds ratio of 1.201 (P < .001).

Study details: This nationwide, population-based study included 20,333 patients aged 40 years or older diagnosed with neovascular AMD in at least 2 claims, with the first diagnosis date defined as the index date. They were propensity score-matched (1:4) with 81,332 nonneovascular AMD control individuals.

Disclosures: No source of funding was declared. None of the authors identified any conflicts of interest.

Source: Kuang TM et al. Sci Rep. 2022;12:1792 (Feb 2). Doi: 10.1038/s41598-022-05638-5

Key clinical point: Clinical management of pain intensity and disability in patients with migraine would benefit from closely monitoring their dietary nutrient patterns.

Main finding: After adjusting for all confounders, higher consumption of vitamins B1 (thiamine), B3 (niacin), and B9 (folic acid). and carbohydrate, protein, and total fiber was positively associated with pain intensity as assessed using the Visual Analogue Scale (regression coefficient [β] 0.37; P < .001), whereas that of vitamins A, K, C, B6, B2 (riboflavin), and calcium and magnesium was negatively associated with migraine-related disability measured by Migraine Disability Assessment (β −3.14; P = .01).

Study details: Findings are from a cross-sectional study involving 266 adult women with migraine and no chronic disease.

Disclosures: The study was sponsored by the Tehran University of Medical Sciences, Iran. The authors reported having no conflicts of interest.

Source: Bahrampour N et al. Br J Nutr. 2022 (Jan 17). Doi: 10.1017/S0007114522000046

Key clinical point: Clinical management of pain intensity and disability in patients with migraine would benefit from closely monitoring their dietary nutrient patterns.

Main finding: After adjusting for all confounders, higher consumption of vitamins B1 (thiamine), B3 (niacin), and B9 (folic acid). and carbohydrate, protein, and total fiber was positively associated with pain intensity as assessed using the Visual Analogue Scale (regression coefficient [β] 0.37; P < .001), whereas that of vitamins A, K, C, B6, B2 (riboflavin), and calcium and magnesium was negatively associated with migraine-related disability measured by Migraine Disability Assessment (β −3.14; P = .01).

Study details: Findings are from a cross-sectional study involving 266 adult women with migraine and no chronic disease.

Disclosures: The study was sponsored by the Tehran University of Medical Sciences, Iran. The authors reported having no conflicts of interest.

Source: Bahrampour N et al. Br J Nutr. 2022 (Jan 17). Doi: 10.1017/S0007114522000046

Key clinical point: Clinical management of pain intensity and disability in patients with migraine would benefit from closely monitoring their dietary nutrient patterns.

Main finding: After adjusting for all confounders, higher consumption of vitamins B1 (thiamine), B3 (niacin), and B9 (folic acid). and carbohydrate, protein, and total fiber was positively associated with pain intensity as assessed using the Visual Analogue Scale (regression coefficient [β] 0.37; P < .001), whereas that of vitamins A, K, C, B6, B2 (riboflavin), and calcium and magnesium was negatively associated with migraine-related disability measured by Migraine Disability Assessment (β −3.14; P = .01).

Study details: Findings are from a cross-sectional study involving 266 adult women with migraine and no chronic disease.

Disclosures: The study was sponsored by the Tehran University of Medical Sciences, Iran. The authors reported having no conflicts of interest.

Source: Bahrampour N et al. Br J Nutr. 2022 (Jan 17). Doi: 10.1017/S0007114522000046

Key clinical point: Migraine, migraine with aura (MWA), and migraine without aura (MWoA) are negatively associated with large artery atherosclerosis (LAA) in young patients with ischemic stroke, irrespective of traditional vascular risk factors.

Major finding: LAA of any grade was significantly less frequent in patients with migraine (P < .001), MWA (P < .001), and MWoA (P = .005) vs. those without migraine. Migraine (adjusted odds ratio [aOR] 0.44; P = .005), MWoA (aOR 0.42; P = .020), and MWA (aOR 0.47; P = .037) vs. no migraine showed a negative association with LAA of any grade.

Study details: Findings are from a cross-sectional study including 415 patients aged 18-54 years with first-ever acute ischemic stroke, of which 144 had migraine (MWA, n = 76; MWoA, n = 68).

Disclosures: No funding was received for this study. The authors declared no conflicts of interest.

Source: Gollion C et al. Headache. 2022;62(2):191-7 (Feb 5). Doi: 10.1111/head.14265

Key clinical point: Migraine, migraine with aura (MWA), and migraine without aura (MWoA) are negatively associated with large artery atherosclerosis (LAA) in young patients with ischemic stroke, irrespective of traditional vascular risk factors.

Major finding: LAA of any grade was significantly less frequent in patients with migraine (P < .001), MWA (P < .001), and MWoA (P = .005) vs. those without migraine. Migraine (adjusted odds ratio [aOR] 0.44; P = .005), MWoA (aOR 0.42; P = .020), and MWA (aOR 0.47; P = .037) vs. no migraine showed a negative association with LAA of any grade.

Study details: Findings are from a cross-sectional study including 415 patients aged 18-54 years with first-ever acute ischemic stroke, of which 144 had migraine (MWA, n = 76; MWoA, n = 68).

Disclosures: No funding was received for this study. The authors declared no conflicts of interest.

Source: Gollion C et al. Headache. 2022;62(2):191-7 (Feb 5). Doi: 10.1111/head.14265

Key clinical point: Migraine, migraine with aura (MWA), and migraine without aura (MWoA) are negatively associated with large artery atherosclerosis (LAA) in young patients with ischemic stroke, irrespective of traditional vascular risk factors.

Major finding: LAA of any grade was significantly less frequent in patients with migraine (P < .001), MWA (P < .001), and MWoA (P = .005) vs. those without migraine. Migraine (adjusted odds ratio [aOR] 0.44; P = .005), MWoA (aOR 0.42; P = .020), and MWA (aOR 0.47; P = .037) vs. no migraine showed a negative association with LAA of any grade.

Study details: Findings are from a cross-sectional study including 415 patients aged 18-54 years with first-ever acute ischemic stroke, of which 144 had migraine (MWA, n = 76; MWoA, n = 68).

Disclosures: No funding was received for this study. The authors declared no conflicts of interest.

Source: Gollion C et al. Headache. 2022;62(2):191-7 (Feb 5). Doi: 10.1111/head.14265

Key clinical point: Chronic caffeine use is associated with a reduced cerebrovascular reactivity (CVR) in the posterior circulation of patients with episodic migraine, whereas caffeine cessation is associated with a significantly improved CVR.

Major finding: The breath-holding index (BHI) of the posterior cerebral arteries (PCA) was lower in caffeine users vs. nonusers (median 1.1 vs. 1.3; P = .03), with caffeine cessation being associated with a significant improvement in PCA-BHI (median 1.1 at baseline vs. 1.3 at 3 months of follow-up; P = .03) and independently associated with changes in PCA-BHI (adjusted unstandardized β 0.27; P = .04).

Study details: Findings are from a prospective, longitudinal, observational study of 84 adult patients with episodic migraine and no vascular risk factors, of whom 56 were caffeine users and were instructed to discontinue caffeine use.

Disclosures: The study was supported by the Dong-A ST and National Research Foundation of Korea grant funded by the Korean government. The authors declared no conflicts of interest.

Source: Gil Y-E et al. Headache. 2022;62(2):169-75 (Feb 3). Doi: 10.1111/head.14263

Key clinical point: Chronic caffeine use is associated with a reduced cerebrovascular reactivity (CVR) in the posterior circulation of patients with episodic migraine, whereas caffeine cessation is associated with a significantly improved CVR.

Major finding: The breath-holding index (BHI) of the posterior cerebral arteries (PCA) was lower in caffeine users vs. nonusers (median 1.1 vs. 1.3; P = .03), with caffeine cessation being associated with a significant improvement in PCA-BHI (median 1.1 at baseline vs. 1.3 at 3 months of follow-up; P = .03) and independently associated with changes in PCA-BHI (adjusted unstandardized β 0.27; P = .04).

Study details: Findings are from a prospective, longitudinal, observational study of 84 adult patients with episodic migraine and no vascular risk factors, of whom 56 were caffeine users and were instructed to discontinue caffeine use.

Disclosures: The study was supported by the Dong-A ST and National Research Foundation of Korea grant funded by the Korean government. The authors declared no conflicts of interest.

Source: Gil Y-E et al. Headache. 2022;62(2):169-75 (Feb 3). Doi: 10.1111/head.14263

Key clinical point: Chronic caffeine use is associated with a reduced cerebrovascular reactivity (CVR) in the posterior circulation of patients with episodic migraine, whereas caffeine cessation is associated with a significantly improved CVR.

Major finding: The breath-holding index (BHI) of the posterior cerebral arteries (PCA) was lower in caffeine users vs. nonusers (median 1.1 vs. 1.3; P = .03), with caffeine cessation being associated with a significant improvement in PCA-BHI (median 1.1 at baseline vs. 1.3 at 3 months of follow-up; P = .03) and independently associated with changes in PCA-BHI (adjusted unstandardized β 0.27; P = .04).

Study details: Findings are from a prospective, longitudinal, observational study of 84 adult patients with episodic migraine and no vascular risk factors, of whom 56 were caffeine users and were instructed to discontinue caffeine use.

Disclosures: The study was supported by the Dong-A ST and National Research Foundation of Korea grant funded by the Korean government. The authors declared no conflicts of interest.

Source: Gil Y-E et al. Headache. 2022;62(2):169-75 (Feb 3). Doi: 10.1111/head.14263

Key clinical point: Compared with nortriptyline alone, its combination with atorvastatin significantly reduces the frequency of headache and improves the quality of life (QOL) in patients with migraine; however, the effect on migraine intensity is nonsignificant.

Major finding: Atorvastatin plus nortriptyline vs. nortriptyline alone led to a significantly lower headache frequency (P = .004) at week 24 in addition to a significant improvement in the QOL at weeks 14 and 24 (both P = .001); however, no significant difference was observed in the headache intensity over 24 weeks.

Study details: This prospective, triple-blind, randomized controlled trial included 68 adult patients with migraine who were randomly assigned to receive atorvastatin plus nortriptyline (n = 34) or placebo plus nortriptyline (n = 34) for 24 weeks.

Disclosures: The study was supported by a grant from the Research and Technology Department of Shahid Sadoughi University of Medical Sciences, Yazd, Iran. The authors reported having no conflicts of interest.

Source: Sherafat M et al. Neurol Res. 2022 (Jan 17). Doi: 10.1080/01616412.2021

Key clinical point: Compared with nortriptyline alone, its combination with atorvastatin significantly reduces the frequency of headache and improves the quality of life (QOL) in patients with migraine; however, the effect on migraine intensity is nonsignificant.

Major finding: Atorvastatin plus nortriptyline vs. nortriptyline alone led to a significantly lower headache frequency (P = .004) at week 24 in addition to a significant improvement in the QOL at weeks 14 and 24 (both P = .001); however, no significant difference was observed in the headache intensity over 24 weeks.

Study details: This prospective, triple-blind, randomized controlled trial included 68 adult patients with migraine who were randomly assigned to receive atorvastatin plus nortriptyline (n = 34) or placebo plus nortriptyline (n = 34) for 24 weeks.

Disclosures: The study was supported by a grant from the Research and Technology Department of Shahid Sadoughi University of Medical Sciences, Yazd, Iran. The authors reported having no conflicts of interest.

Source: Sherafat M et al. Neurol Res. 2022 (Jan 17). Doi: 10.1080/01616412.2021

Key clinical point: Compared with nortriptyline alone, its combination with atorvastatin significantly reduces the frequency of headache and improves the quality of life (QOL) in patients with migraine; however, the effect on migraine intensity is nonsignificant.

Major finding: Atorvastatin plus nortriptyline vs. nortriptyline alone led to a significantly lower headache frequency (P = .004) at week 24 in addition to a significant improvement in the QOL at weeks 14 and 24 (both P = .001); however, no significant difference was observed in the headache intensity over 24 weeks.

Study details: This prospective, triple-blind, randomized controlled trial included 68 adult patients with migraine who were randomly assigned to receive atorvastatin plus nortriptyline (n = 34) or placebo plus nortriptyline (n = 34) for 24 weeks.

Disclosures: The study was supported by a grant from the Research and Technology Department of Shahid Sadoughi University of Medical Sciences, Yazd, Iran. The authors reported having no conflicts of interest.

Source: Sherafat M et al. Neurol Res. 2022 (Jan 17). Doi: 10.1080/01616412.2021

Key clinical point: Rimegepant on a patient treated as needed (PRN) basis reduces monthly migraine days (MMD) without increasing the monthly tablet use and improves health-related quality of life (HRQoL) in patients with acute migraine.

Major finding: Rimegepant reduced the mean MMD from 10.9 days at baseline to 8.9 days by week 52 and led to an increase of 0.08 quality-adjusted life years. The mean monthly tablet use decreased from 7.9 tablets to 7.3 tablets between weeks 4-8 and 48-52.

Study details: This was a post hoc analysis of the phase 2/3 safety BHV3000-201 study including 1,044 patients with a ≥1-year history of migraine and ≥6 MMD who received 75 mg rimegepant up to once daily PRN for up to 52 weeks.

Disclosures: The study was sponsored by Biohaven Pharmaceuticals. CP Schreiber reported being a speaker for various organizations, including Biohaven. The rest of the authors are employees and stock/stock option owners of Biohaven or Broadstreet HEOR (funded by the former).

Source: Johnston K et al. J Headache Pain. 2022;23:10 (Jan 17). Doi: 10.1186/s10194-021-01378-5

Key clinical point: Rimegepant on a patient treated as needed (PRN) basis reduces monthly migraine days (MMD) without increasing the monthly tablet use and improves health-related quality of life (HRQoL) in patients with acute migraine.

Major finding: Rimegepant reduced the mean MMD from 10.9 days at baseline to 8.9 days by week 52 and led to an increase of 0.08 quality-adjusted life years. The mean monthly tablet use decreased from 7.9 tablets to 7.3 tablets between weeks 4-8 and 48-52.

Study details: This was a post hoc analysis of the phase 2/3 safety BHV3000-201 study including 1,044 patients with a ≥1-year history of migraine and ≥6 MMD who received 75 mg rimegepant up to once daily PRN for up to 52 weeks.

Disclosures: The study was sponsored by Biohaven Pharmaceuticals. CP Schreiber reported being a speaker for various organizations, including Biohaven. The rest of the authors are employees and stock/stock option owners of Biohaven or Broadstreet HEOR (funded by the former).

Source: Johnston K et al. J Headache Pain. 2022;23:10 (Jan 17). Doi: 10.1186/s10194-021-01378-5

Key clinical point: Rimegepant on a patient treated as needed (PRN) basis reduces monthly migraine days (MMD) without increasing the monthly tablet use and improves health-related quality of life (HRQoL) in patients with acute migraine.

Major finding: Rimegepant reduced the mean MMD from 10.9 days at baseline to 8.9 days by week 52 and led to an increase of 0.08 quality-adjusted life years. The mean monthly tablet use decreased from 7.9 tablets to 7.3 tablets between weeks 4-8 and 48-52.

Study details: This was a post hoc analysis of the phase 2/3 safety BHV3000-201 study including 1,044 patients with a ≥1-year history of migraine and ≥6 MMD who received 75 mg rimegepant up to once daily PRN for up to 52 weeks.

Disclosures: The study was sponsored by Biohaven Pharmaceuticals. CP Schreiber reported being a speaker for various organizations, including Biohaven. The rest of the authors are employees and stock/stock option owners of Biohaven or Broadstreet HEOR (funded by the former).

Source: Johnston K et al. J Headache Pain. 2022;23:10 (Jan 17). Doi: 10.1186/s10194-021-01378-5

Key clinical point: Galcanezumab improves functioning and decreases disability in patients with treatment-resistant migraine.

Main finding: At month 3, galcanezumab vs. placebo caused a greater improvement in the Migraine-Specific Quality of Life Questionnaire (version 2.1 Role Function-Restrictive) (least-squares mean [LSM] change 23.19 vs. 10.66; P ≤ .0001] and European Quality of Life-5 Dimensions-5 Level Visual Analog Scale (LSM change 3.38 vs. −0.086; P = .0277) scores and a greater reduction in Migraine Disability Assessment total scores (LSM chang, −21.10 vs. −3.30; P ≤ .0001).

Study details: Findings are from the phase 3b CONQUER trial including 462 adult patients with episodic or chronic migraine and no response to previous 2-4 migraine preventive treatment categories who were randomly assigned to double-blind treatment with galcanezumab (n = 232) or placebo (n = 230) for 3 months followed by 3-month open-label treatment with galcanezumab.

Disclosures: Eli Lilly and Company sponsored the study. SJ Tepper and J Ailani declared receiving research grants, speaker's/advisory board member's honoraria, or institutional research funding for clinical trials from various sources, including Eli Lilly. The rest of the authors are employees and stockholders of Eli Lilly.

Source: Tepper SJ et al. Clin Drug Investig. 2022 (Jan 18). Doi: 10.1007/s40261-021-01115-5

Key clinical point: Galcanezumab improves functioning and decreases disability in patients with treatment-resistant migraine.

Main finding: At month 3, galcanezumab vs. placebo caused a greater improvement in the Migraine-Specific Quality of Life Questionnaire (version 2.1 Role Function-Restrictive) (least-squares mean [LSM] change 23.19 vs. 10.66; P ≤ .0001] and European Quality of Life-5 Dimensions-5 Level Visual Analog Scale (LSM change 3.38 vs. −0.086; P = .0277) scores and a greater reduction in Migraine Disability Assessment total scores (LSM chang, −21.10 vs. −3.30; P ≤ .0001).

Study details: Findings are from the phase 3b CONQUER trial including 462 adult patients with episodic or chronic migraine and no response to previous 2-4 migraine preventive treatment categories who were randomly assigned to double-blind treatment with galcanezumab (n = 232) or placebo (n = 230) for 3 months followed by 3-month open-label treatment with galcanezumab.

Disclosures: Eli Lilly and Company sponsored the study. SJ Tepper and J Ailani declared receiving research grants, speaker's/advisory board member's honoraria, or institutional research funding for clinical trials from various sources, including Eli Lilly. The rest of the authors are employees and stockholders of Eli Lilly.

Source: Tepper SJ et al. Clin Drug Investig. 2022 (Jan 18). Doi: 10.1007/s40261-021-01115-5

Key clinical point: Galcanezumab improves functioning and decreases disability in patients with treatment-resistant migraine.

Main finding: At month 3, galcanezumab vs. placebo caused a greater improvement in the Migraine-Specific Quality of Life Questionnaire (version 2.1 Role Function-Restrictive) (least-squares mean [LSM] change 23.19 vs. 10.66; P ≤ .0001] and European Quality of Life-5 Dimensions-5 Level Visual Analog Scale (LSM change 3.38 vs. −0.086; P = .0277) scores and a greater reduction in Migraine Disability Assessment total scores (LSM chang, −21.10 vs. −3.30; P ≤ .0001).

Study details: Findings are from the phase 3b CONQUER trial including 462 adult patients with episodic or chronic migraine and no response to previous 2-4 migraine preventive treatment categories who were randomly assigned to double-blind treatment with galcanezumab (n = 232) or placebo (n = 230) for 3 months followed by 3-month open-label treatment with galcanezumab.

Disclosures: Eli Lilly and Company sponsored the study. SJ Tepper and J Ailani declared receiving research grants, speaker's/advisory board member's honoraria, or institutional research funding for clinical trials from various sources, including Eli Lilly. The rest of the authors are employees and stockholders of Eli Lilly.

Source: Tepper SJ et al. Clin Drug Investig. 2022 (Jan 18). Doi: 10.1007/s40261-021-01115-5

Edoardo Caronna, MD and Patricia Pozo-Rosich, MD, PhD,  Neurology Department, Hospital Universitari Vall d’Hebron, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; and Headache and Neurological Pain Research Group, Vall d’Hebron Research Institute, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. Dr. Pozo-Rosich also serves on the boards of the International Headache Society and Council of the European Headache Federation and is an editor for various peer-reviewed journals, including Cephalalgia and Headache.

Headache is a symptom of the coronavirus disease 2019 (Covid-19), caused by the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the pandemic began, researchers have tried to describe, understand, and help clinicians manage headache in the setting of Covid-19.

The reason is simple: Headache is common, often debilitating, and difficult to treat.¹

Moreover, headache could manifest both in the acute phase of the infection and, once the infection has resolved, in the post-acute phase.¹ Therefore, it is critical for clinicians to know more about headache, as headache can be a common reason that patients seek help, both in the specialized and non-specialized medical care setting.

Definitions and manifestations

While the first step in such a communication would be to define headache attributed to Covid-19, no specific definition exists, as this is a new disease. Therefore, headache attributed to Covid-19 should be defined under the diagnostic criteria, as contained in the International Classification of Headache Disorders-3, as headache attributed to a systemic viral infection.² As this is a secondary headache appearing with an infection, the treating physician needs to rule out possible underlying meningitis and/or encephalitis in the diagnosis. Moreover, other secondary headaches (eg, cerebral venous thrombosis) may appear, so clinicians need to carefully evaluate patients with headache during Covid-19 to detect signs or symptoms that point to other etiologies.

It is also advisable to know the clinical manifestations of headache attributed to Covid-19. Studies published so far have observed two main phenotypes of headache in the acute phase of the infection: one resembles migraine, the other, a tension-type headache.^1,3 Although patients with history of migraine who contract Covid-19 report headache that is more similar to primary headache disorder,⁴ two relevant aspects should be considered. Namely, migraine-like features can be observed in patients without personal migraine history; and Covid-19 patients with such history may perceive that headache they experience in the infection’s acute phase differs from their usual experience, especially regarding increased severity or duration.^5,6 Of note, headache can be a prodromal symptom of the SARS-CoV-2 infection.¹

Evolution of a headache

 Because headache appearing after the acute phase of the infection can persist, often manifesting migraine-like features, it is inordinately helpful for clinicians to know its evolution.¹ This persistent headache, sometimes referred to as post-covid headache, is not aptly named because the post-covid headache is not just one type of headache, but instead can manifest as different headache types.

 A recently published case series in Headache discussed three Covid patients who all experienced persistent headache during the infection’s post-acute phase.⁷ These patients experienced a migraine-like phenotype as have others with mild Covid-19, but their personal history of migraine, as well as their experience with Covid-19 related headache, were substantially different. Some patients had personal migraine history while others did not; some patients experienced no headache in the acute phase but did so in the post-acute phase; and the concomitant symptoms of the post-acute phase, such as insomnia, memory loss, dizziness, fatigue, and brain fog, were differentially expressed by patients.⁷ 

 This case series introduces the concept that patients with no prior history of migraine or any other primary headache disorder can develop a de novo headache because of their SARS-CoV-2 infection. Moreover, it could manifest as a new daily persistent headache. And patients with personal history of migraine may experience sudden chronification in their headache’s characteristics, rather than develop a new type of headache.⁷

 In another study, soon to be published in Cephalalgia, researchers observed that the median duration of headache in the acute phase is 2 weeks. This multicenter Spanish study, in which data on headache duration were available for 874 patients, found that 16% of these particular patients had persistent headache after 9 months. According to this study, headache that does not resolve within the first 3 months is less likely to do so later on.

Treatment

For clinicians, the significance of these findings is straightforward: Patients with headache experienced in the infection’s acute phase that does not seem to resolve post-infection requires continued medical attention. Patients should be monitored, carefully managed, and treated to avoid the onset of a persisting headache. This applies to patients with or without personal migraine history.

But which treatments should be prescribed? As there are no specific therapies for headache attributed to Covid-19, either in the acute or post-acute phase of the infection, clinicians must turn to existing therapies.

As with patients with migraine, patients with persistent headache post-Covid infection need a headache prevention strategy.

The strategy should be based on the following principles:

• treat headache
• treat comorbidities including mood disorders,  insomnia, and so on
• avoid complications such as medication overuse, which may be very common in these patients.

Acute medications

Despite the lack of specific literature on this matter, migraine-like phenotypes may respond to triptans and probably, where available, lasmiditan and gepants. These medications probably represent a therapeutic option for Covid patients with headache, but before prescribing them clinicians should carefully evaluate their use.

Before deciding on the prescription, clinicians should consider not only the medications’ most common contraindications, but also those that are related to Covid-19: the phase of the infection (acute/post-acute); the infection’s severity; and the presence of other Covid-related health problems. The concerns over the use of nonsteroidal anti-inflammatory medications (NSAIDs) and corticosteroids, raised when the pandemic first struck, have greatly dissipated.^8,9 Some patients with prolonged headache may benefit from a brief cycle of corticosteroids, similar to the treatment given to those patients with status migrainosus. Nerve blocks could also be considered.

Preventive medications

Drugs can be prescribed according to the headache phenotype too, but there are no published studies that specifically evaluate headache prevention treatments in patients with persistent headache post-infection. The case series mentioned earlier in this article recorded that patients whose headaches were treated with amitriptyline and onabotulinumtoxinA had reported variable treatment responses to this regimen, according to the patients’ characteristics.⁷

However, one important question regarding the safety of Covid patients with migraine – specifically patients on preventive treatments during the infection’s acute phase – has been somewhat resolved.

Medications such as renin-angiotensin system (RAS) blockers, suspected of possible involvement in the SARs-CoV-2 pathogenicity, seem to be safe.^8,10 And, in another multicenter Spanish study, researchers found that the use of anti-CGRP monoclonal antibodies did not seem to be associated with worse Covid-19 outcomes despite the possible implication of CGRP in modulating inflammatory responses during a viral infection.¹¹

The study of anti-CGRP monoclonal antibodies could be important in the future for another reason: To see whether these medications could be effective as a preventive treatment in patients with persistent headache after Covid-19, regardless of whether these patients have personal migraine history.

An interesting and important message to close this article. Although headache experienced in the infection’s acute phase could be extremely disabling for patients, the evidence points to the presence of headache as a marker of a better Covid-19 prognosis, in terms of a shorter infection period and a lower risk of mortality among hospitalized patients.^1,3,12  

This brief communication contains current information to help clinicians treat and inform their patients with Covid-sourced headache. Yet, we must keep in mind that the majority of the data reported here and published in the literature refer to studies conducted during the first wave of the pandemic. The emergence of new SARS-CoV-2 variants and vaccines have enormously changed the disease’s clinical presentation and course, so future studies are warranted to re-assess the validity of these findings under new conditions.

Edoardo Caronna, MD and Patricia Pozo-Rosich, MD, PhD,  Neurology Department, Hospital Universitari Vall d’Hebron, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; and Headache and Neurological Pain Research Group, Vall d’Hebron Research Institute, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. Dr. Pozo-Rosich also serves on the boards of the International Headache Society and Council of the European Headache Federation and is an editor for various peer-reviewed journals, including Cephalalgia and Headache.

Headache is a symptom of the coronavirus disease 2019 (Covid-19), caused by the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the pandemic began, researchers have tried to describe, understand, and help clinicians manage headache in the setting of Covid-19.

The reason is simple: Headache is common, often debilitating, and difficult to treat.¹

Moreover, headache could manifest both in the acute phase of the infection and, once the infection has resolved, in the post-acute phase.¹ Therefore, it is critical for clinicians to know more about headache, as headache can be a common reason that patients seek help, both in the specialized and non-specialized medical care setting.

Definitions and manifestations

While the first step in such a communication would be to define headache attributed to Covid-19, no specific definition exists, as this is a new disease. Therefore, headache attributed to Covid-19 should be defined under the diagnostic criteria, as contained in the International Classification of Headache Disorders-3, as headache attributed to a systemic viral infection.² As this is a secondary headache appearing with an infection, the treating physician needs to rule out possible underlying meningitis and/or encephalitis in the diagnosis. Moreover, other secondary headaches (eg, cerebral venous thrombosis) may appear, so clinicians need to carefully evaluate patients with headache during Covid-19 to detect signs or symptoms that point to other etiologies.

It is also advisable to know the clinical manifestations of headache attributed to Covid-19. Studies published so far have observed two main phenotypes of headache in the acute phase of the infection: one resembles migraine, the other, a tension-type headache.^1,3 Although patients with history of migraine who contract Covid-19 report headache that is more similar to primary headache disorder,⁴ two relevant aspects should be considered. Namely, migraine-like features can be observed in patients without personal migraine history; and Covid-19 patients with such history may perceive that headache they experience in the infection’s acute phase differs from their usual experience, especially regarding increased severity or duration.^5,6 Of note, headache can be a prodromal symptom of the SARS-CoV-2 infection.¹

Evolution of a headache

 Because headache appearing after the acute phase of the infection can persist, often manifesting migraine-like features, it is inordinately helpful for clinicians to know its evolution.¹ This persistent headache, sometimes referred to as post-covid headache, is not aptly named because the post-covid headache is not just one type of headache, but instead can manifest as different headache types.

 A recently published case series in Headache discussed three Covid patients who all experienced persistent headache during the infection’s post-acute phase.⁷ These patients experienced a migraine-like phenotype as have others with mild Covid-19, but their personal history of migraine, as well as their experience with Covid-19 related headache, were substantially different. Some patients had personal migraine history while others did not; some patients experienced no headache in the acute phase but did so in the post-acute phase; and the concomitant symptoms of the post-acute phase, such as insomnia, memory loss, dizziness, fatigue, and brain fog, were differentially expressed by patients.⁷ 

 This case series introduces the concept that patients with no prior history of migraine or any other primary headache disorder can develop a de novo headache because of their SARS-CoV-2 infection. Moreover, it could manifest as a new daily persistent headache. And patients with personal history of migraine may experience sudden chronification in their headache’s characteristics, rather than develop a new type of headache.⁷

 In another study, soon to be published in Cephalalgia, researchers observed that the median duration of headache in the acute phase is 2 weeks. This multicenter Spanish study, in which data on headache duration were available for 874 patients, found that 16% of these particular patients had persistent headache after 9 months. According to this study, headache that does not resolve within the first 3 months is less likely to do so later on.

Treatment

For clinicians, the significance of these findings is straightforward: Patients with headache experienced in the infection’s acute phase that does not seem to resolve post-infection requires continued medical attention. Patients should be monitored, carefully managed, and treated to avoid the onset of a persisting headache. This applies to patients with or without personal migraine history.

But which treatments should be prescribed? As there are no specific therapies for headache attributed to Covid-19, either in the acute or post-acute phase of the infection, clinicians must turn to existing therapies.

As with patients with migraine, patients with persistent headache post-Covid infection need a headache prevention strategy.

The strategy should be based on the following principles:

• treat headache
• treat comorbidities including mood disorders,  insomnia, and so on
• avoid complications such as medication overuse, which may be very common in these patients.

Acute medications

Despite the lack of specific literature on this matter, migraine-like phenotypes may respond to triptans and probably, where available, lasmiditan and gepants. These medications probably represent a therapeutic option for Covid patients with headache, but before prescribing them clinicians should carefully evaluate their use.

Before deciding on the prescription, clinicians should consider not only the medications’ most common contraindications, but also those that are related to Covid-19: the phase of the infection (acute/post-acute); the infection’s severity; and the presence of other Covid-related health problems. The concerns over the use of nonsteroidal anti-inflammatory medications (NSAIDs) and corticosteroids, raised when the pandemic first struck, have greatly dissipated.^8,9 Some patients with prolonged headache may benefit from a brief cycle of corticosteroids, similar to the treatment given to those patients with status migrainosus. Nerve blocks could also be considered.

Preventive medications

Drugs can be prescribed according to the headache phenotype too, but there are no published studies that specifically evaluate headache prevention treatments in patients with persistent headache post-infection. The case series mentioned earlier in this article recorded that patients whose headaches were treated with amitriptyline and onabotulinumtoxinA had reported variable treatment responses to this regimen, according to the patients’ characteristics.⁷

However, one important question regarding the safety of Covid patients with migraine – specifically patients on preventive treatments during the infection’s acute phase – has been somewhat resolved.

Medications such as renin-angiotensin system (RAS) blockers, suspected of possible involvement in the SARs-CoV-2 pathogenicity, seem to be safe.^8,10 And, in another multicenter Spanish study, researchers found that the use of anti-CGRP monoclonal antibodies did not seem to be associated with worse Covid-19 outcomes despite the possible implication of CGRP in modulating inflammatory responses during a viral infection.¹¹

The study of anti-CGRP monoclonal antibodies could be important in the future for another reason: To see whether these medications could be effective as a preventive treatment in patients with persistent headache after Covid-19, regardless of whether these patients have personal migraine history.

An interesting and important message to close this article. Although headache experienced in the infection’s acute phase could be extremely disabling for patients, the evidence points to the presence of headache as a marker of a better Covid-19 prognosis, in terms of a shorter infection period and a lower risk of mortality among hospitalized patients.^1,3,12  

This brief communication contains current information to help clinicians treat and inform their patients with Covid-sourced headache. Yet, we must keep in mind that the majority of the data reported here and published in the literature refer to studies conducted during the first wave of the pandemic. The emergence of new SARS-CoV-2 variants and vaccines have enormously changed the disease’s clinical presentation and course, so future studies are warranted to re-assess the validity of these findings under new conditions.

Edoardo Caronna, MD and Patricia Pozo-Rosich, MD, PhD,  Neurology Department, Hospital Universitari Vall d’Hebron, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; and Headache and Neurological Pain Research Group, Vall d’Hebron Research Institute, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. Dr. Pozo-Rosich also serves on the boards of the International Headache Society and Council of the European Headache Federation and is an editor for various peer-reviewed journals, including Cephalalgia and Headache.

Headache is a symptom of the coronavirus disease 2019 (Covid-19), caused by the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the pandemic began, researchers have tried to describe, understand, and help clinicians manage headache in the setting of Covid-19.

The reason is simple: Headache is common, often debilitating, and difficult to treat.¹

Moreover, headache could manifest both in the acute phase of the infection and, once the infection has resolved, in the post-acute phase.¹ Therefore, it is critical for clinicians to know more about headache, as headache can be a common reason that patients seek help, both in the specialized and non-specialized medical care setting.

Definitions and manifestations

While the first step in such a communication would be to define headache attributed to Covid-19, no specific definition exists, as this is a new disease. Therefore, headache attributed to Covid-19 should be defined under the diagnostic criteria, as contained in the International Classification of Headache Disorders-3, as headache attributed to a systemic viral infection.² As this is a secondary headache appearing with an infection, the treating physician needs to rule out possible underlying meningitis and/or encephalitis in the diagnosis. Moreover, other secondary headaches (eg, cerebral venous thrombosis) may appear, so clinicians need to carefully evaluate patients with headache during Covid-19 to detect signs or symptoms that point to other etiologies.

It is also advisable to know the clinical manifestations of headache attributed to Covid-19. Studies published so far have observed two main phenotypes of headache in the acute phase of the infection: one resembles migraine, the other, a tension-type headache.^1,3 Although patients with history of migraine who contract Covid-19 report headache that is more similar to primary headache disorder,⁴ two relevant aspects should be considered. Namely, migraine-like features can be observed in patients without personal migraine history; and Covid-19 patients with such history may perceive that headache they experience in the infection’s acute phase differs from their usual experience, especially regarding increased severity or duration.^5,6 Of note, headache can be a prodromal symptom of the SARS-CoV-2 infection.¹

Evolution of a headache

 Because headache appearing after the acute phase of the infection can persist, often manifesting migraine-like features, it is inordinately helpful for clinicians to know its evolution.¹ This persistent headache, sometimes referred to as post-covid headache, is not aptly named because the post-covid headache is not just one type of headache, but instead can manifest as different headache types.

 A recently published case series in Headache discussed three Covid patients who all experienced persistent headache during the infection’s post-acute phase.⁷ These patients experienced a migraine-like phenotype as have others with mild Covid-19, but their personal history of migraine, as well as their experience with Covid-19 related headache, were substantially different. Some patients had personal migraine history while others did not; some patients experienced no headache in the acute phase but did so in the post-acute phase; and the concomitant symptoms of the post-acute phase, such as insomnia, memory loss, dizziness, fatigue, and brain fog, were differentially expressed by patients.⁷ 

 This case series introduces the concept that patients with no prior history of migraine or any other primary headache disorder can develop a de novo headache because of their SARS-CoV-2 infection. Moreover, it could manifest as a new daily persistent headache. And patients with personal history of migraine may experience sudden chronification in their headache’s characteristics, rather than develop a new type of headache.⁷

 In another study, soon to be published in Cephalalgia, researchers observed that the median duration of headache in the acute phase is 2 weeks. This multicenter Spanish study, in which data on headache duration were available for 874 patients, found that 16% of these particular patients had persistent headache after 9 months. According to this study, headache that does not resolve within the first 3 months is less likely to do so later on.

Treatment

For clinicians, the significance of these findings is straightforward: Patients with headache experienced in the infection’s acute phase that does not seem to resolve post-infection requires continued medical attention. Patients should be monitored, carefully managed, and treated to avoid the onset of a persisting headache. This applies to patients with or without personal migraine history.

But which treatments should be prescribed? As there are no specific therapies for headache attributed to Covid-19, either in the acute or post-acute phase of the infection, clinicians must turn to existing therapies.

As with patients with migraine, patients with persistent headache post-Covid infection need a headache prevention strategy.

The strategy should be based on the following principles:

• treat headache
• treat comorbidities including mood disorders,  insomnia, and so on
• avoid complications such as medication overuse, which may be very common in these patients.

Acute medications

Despite the lack of specific literature on this matter, migraine-like phenotypes may respond to triptans and probably, where available, lasmiditan and gepants. These medications probably represent a therapeutic option for Covid patients with headache, but before prescribing them clinicians should carefully evaluate their use.

Before deciding on the prescription, clinicians should consider not only the medications’ most common contraindications, but also those that are related to Covid-19: the phase of the infection (acute/post-acute); the infection’s severity; and the presence of other Covid-related health problems. The concerns over the use of nonsteroidal anti-inflammatory medications (NSAIDs) and corticosteroids, raised when the pandemic first struck, have greatly dissipated.^8,9 Some patients with prolonged headache may benefit from a brief cycle of corticosteroids, similar to the treatment given to those patients with status migrainosus. Nerve blocks could also be considered.

Preventive medications

Drugs can be prescribed according to the headache phenotype too, but there are no published studies that specifically evaluate headache prevention treatments in patients with persistent headache post-infection. The case series mentioned earlier in this article recorded that patients whose headaches were treated with amitriptyline and onabotulinumtoxinA had reported variable treatment responses to this regimen, according to the patients’ characteristics.⁷

However, one important question regarding the safety of Covid patients with migraine – specifically patients on preventive treatments during the infection’s acute phase – has been somewhat resolved.

Medications such as renin-angiotensin system (RAS) blockers, suspected of possible involvement in the SARs-CoV-2 pathogenicity, seem to be safe.^8,10 And, in another multicenter Spanish study, researchers found that the use of anti-CGRP monoclonal antibodies did not seem to be associated with worse Covid-19 outcomes despite the possible implication of CGRP in modulating inflammatory responses during a viral infection.¹¹

The study of anti-CGRP monoclonal antibodies could be important in the future for another reason: To see whether these medications could be effective as a preventive treatment in patients with persistent headache after Covid-19, regardless of whether these patients have personal migraine history.

An interesting and important message to close this article. Although headache experienced in the infection’s acute phase could be extremely disabling for patients, the evidence points to the presence of headache as a marker of a better Covid-19 prognosis, in terms of a shorter infection period and a lower risk of mortality among hospitalized patients.^1,3,12  

This brief communication contains current information to help clinicians treat and inform their patients with Covid-sourced headache. Yet, we must keep in mind that the majority of the data reported here and published in the literature refer to studies conducted during the first wave of the pandemic. The emergence of new SARS-CoV-2 variants and vaccines have enormously changed the disease’s clinical presentation and course, so future studies are warranted to re-assess the validity of these findings under new conditions.

Cluster headache attacks induced by either pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) or vasoactive intestinal polypeptide (VIP) do not lead to changes in plasma levels of calcitonin gene-related peptide (CGRP) or markers of mast cell activation such as tryptase and histamine, a new study has found.

“Whether cluster headache attacks provoked by CGRP and PACAP38/VIP are mediated by distinct signaling pathways will be worth investigating in forthcoming studies,” wrote Lanfranco Pellesi, MD, of the Danish Headache Center at the University of Copenhagen, and his coauthors. The study was published in Cephalalgia.

To assess how these biochemical variables might contribute to cluster headache attacks, the researchers launched a randomized, double-blind trial of data from 44 Danish participants with cluster headache. The average age of the patients was 38 years; 14 had active episodic cluster headache, 15 had episodic cluster headache in remission, and 15 had chronic cluster headache.

All patients received a continuous infusion of either PACAP38 (10 pmol/kg per minute) or VIP (8 pmol/kg per minute) over a 20-minute period, using a time- and volume-controlled infusion pump. Blood was collected for analysis at fixed time points, including at baseline, at the end of the infusion, 10 minutes after the infusion, and 70 minutes after the infusion. Technical problems led to missing values in 285 out of 1,144 planned plasma samples.

PACAP38 infusion resulted in a cluster headache attack in 13 of the 44 participants and VIP induced an attack in 12 of the 44. No differences in plasma CGRP (P = .7074), tryptase (P = .6673), and histamine (P = .4792) levels were found between patients who developed attacks and those who did not, and the plasma concentrations did not differ among the various blood-drawing time points.

There was also no difference in plasma CGRP levels between patients with active episodic cluster headache, those with episodic cluster headache in remission, and those with chronic cluster headache. After post hoc analysis, plasma tryptase and plasma histamine levels were similar among the three cluster headache patient groups.

The final link to the cluster headache puzzle has not yet been found

“We know a lot about cluster headache: how it presents, how we can stop it acutely, and how we can stop it preventively. But we don’t know everything about all the neurotransmitters involved, the triggers that start an attack, or the causes of pain,” Alan Rapoport, MD, professor of neurology at the University of California, Los Angeles (UCLA), and past president of the International Headache Society, said in an interview. “This study was performed to find the answer to a small piece of the puzzle. Is CGRP the missing link for patients who begin a cluster attack, or should we be looking elsewhere?

“I would be cautious and say it appears that it doesn’t seem to be related, but further studies may show something different,” he added. “The reason for my qualification: There is a monoclonal antibody [galcanezumab], which grabs CGRP and prevents it from docking on its receptor, that has been approved for preventive treatment of episodic cluster headache. When you have episodic cluster, go into a cluster period, and take galcanezumab, it could and should decrease the number of attacks that you would ordinarily have had. That means it is related somewhat. But it certainly doesn’t work for everyone, so more investigations like this are needed.”

“What’s important about this study is that it opens up the possibility that there is another way into the cluster attack that could be operationalized for therapeutic purposes,” Peter Goadsby, MD, PhD, professor of neurology at UCLA and president of the American Headache Society, said in an interview.

When asked about the authors’ stated interest in investigating “if monoclonal antibodies targeting the CGRP pathway prevent PACAP38- or VIP-induced cluster headache attacks” as a follow-up, Dr. Goadsby strongly backed the idea. “If I sound excited about actually exploring whether that was a useful treatment or not, it’s because cluster headache is a dreadful condition. And the sooner you could work out whether it was useful or put the money into something else, well, that’s where I’d go.

“I think the principle here of doing experimental medicine, getting into human work with targets like this at the earliest possible time, is something that is not done as often as would be appropriate,” he added. “There is not enough investment, in my view, in early phase experimental work, which really just gets to that next step. Broadly speaking, the encouragement and support of experimental medicine is crucial to developing new therapies.”

The authors recognized their study’s potential limitations, including it’s being an exploratory study with results that should be interpreted cautiously. They acknowledged discrepancies with previous studies of plasma CGRP during cluster headache attacks, offering “different methodologies, including intra-assay differences and the location of blood sampling” as a possible reason. They also explained that some of the data are missing “completely at random” due to their policy of discarding all observations with incomplete laboratory measurements, adding that the impact on their sample size was “only modest.”

“In spite of these limitations,” Dr. Rapoport said, “this is an excellent study that shows us that PACAP38- and VIP-induced cluster headache attacks are not associated with alterations in plasma CGRP or in histamine and tryptase.”

Regarding potential conflicts of interest, one author reported being employed at the testing lab where the histamine measurements were conducted, as did another author who serves as the lab’s scientific adviser. A third author reported receiving personal fees from various pharmaceutical companies.

Cluster headache attacks induced by either pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) or vasoactive intestinal polypeptide (VIP) do not lead to changes in plasma levels of calcitonin gene-related peptide (CGRP) or markers of mast cell activation such as tryptase and histamine, a new study has found.

“Whether cluster headache attacks provoked by CGRP and PACAP38/VIP are mediated by distinct signaling pathways will be worth investigating in forthcoming studies,” wrote Lanfranco Pellesi, MD, of the Danish Headache Center at the University of Copenhagen, and his coauthors. The study was published in Cephalalgia.

To assess how these biochemical variables might contribute to cluster headache attacks, the researchers launched a randomized, double-blind trial of data from 44 Danish participants with cluster headache. The average age of the patients was 38 years; 14 had active episodic cluster headache, 15 had episodic cluster headache in remission, and 15 had chronic cluster headache.

All patients received a continuous infusion of either PACAP38 (10 pmol/kg per minute) or VIP (8 pmol/kg per minute) over a 20-minute period, using a time- and volume-controlled infusion pump. Blood was collected for analysis at fixed time points, including at baseline, at the end of the infusion, 10 minutes after the infusion, and 70 minutes after the infusion. Technical problems led to missing values in 285 out of 1,144 planned plasma samples.

PACAP38 infusion resulted in a cluster headache attack in 13 of the 44 participants and VIP induced an attack in 12 of the 44. No differences in plasma CGRP (P = .7074), tryptase (P = .6673), and histamine (P = .4792) levels were found between patients who developed attacks and those who did not, and the plasma concentrations did not differ among the various blood-drawing time points.

There was also no difference in plasma CGRP levels between patients with active episodic cluster headache, those with episodic cluster headache in remission, and those with chronic cluster headache. After post hoc analysis, plasma tryptase and plasma histamine levels were similar among the three cluster headache patient groups.

The final link to the cluster headache puzzle has not yet been found

“We know a lot about cluster headache: how it presents, how we can stop it acutely, and how we can stop it preventively. But we don’t know everything about all the neurotransmitters involved, the triggers that start an attack, or the causes of pain,” Alan Rapoport, MD, professor of neurology at the University of California, Los Angeles (UCLA), and past president of the International Headache Society, said in an interview. “This study was performed to find the answer to a small piece of the puzzle. Is CGRP the missing link for patients who begin a cluster attack, or should we be looking elsewhere?

“I would be cautious and say it appears that it doesn’t seem to be related, but further studies may show something different,” he added. “The reason for my qualification: There is a monoclonal antibody [galcanezumab], which grabs CGRP and prevents it from docking on its receptor, that has been approved for preventive treatment of episodic cluster headache. When you have episodic cluster, go into a cluster period, and take galcanezumab, it could and should decrease the number of attacks that you would ordinarily have had. That means it is related somewhat. But it certainly doesn’t work for everyone, so more investigations like this are needed.”

“What’s important about this study is that it opens up the possibility that there is another way into the cluster attack that could be operationalized for therapeutic purposes,” Peter Goadsby, MD, PhD, professor of neurology at UCLA and president of the American Headache Society, said in an interview.

When asked about the authors’ stated interest in investigating “if monoclonal antibodies targeting the CGRP pathway prevent PACAP38- or VIP-induced cluster headache attacks” as a follow-up, Dr. Goadsby strongly backed the idea. “If I sound excited about actually exploring whether that was a useful treatment or not, it’s because cluster headache is a dreadful condition. And the sooner you could work out whether it was useful or put the money into something else, well, that’s where I’d go.

“I think the principle here of doing experimental medicine, getting into human work with targets like this at the earliest possible time, is something that is not done as often as would be appropriate,” he added. “There is not enough investment, in my view, in early phase experimental work, which really just gets to that next step. Broadly speaking, the encouragement and support of experimental medicine is crucial to developing new therapies.”

The authors recognized their study’s potential limitations, including it’s being an exploratory study with results that should be interpreted cautiously. They acknowledged discrepancies with previous studies of plasma CGRP during cluster headache attacks, offering “different methodologies, including intra-assay differences and the location of blood sampling” as a possible reason. They also explained that some of the data are missing “completely at random” due to their policy of discarding all observations with incomplete laboratory measurements, adding that the impact on their sample size was “only modest.”

“In spite of these limitations,” Dr. Rapoport said, “this is an excellent study that shows us that PACAP38- and VIP-induced cluster headache attacks are not associated with alterations in plasma CGRP or in histamine and tryptase.”

Regarding potential conflicts of interest, one author reported being employed at the testing lab where the histamine measurements were conducted, as did another author who serves as the lab’s scientific adviser. A third author reported receiving personal fees from various pharmaceutical companies.

Cluster headache attacks induced by either pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) or vasoactive intestinal polypeptide (VIP) do not lead to changes in plasma levels of calcitonin gene-related peptide (CGRP) or markers of mast cell activation such as tryptase and histamine, a new study has found.

“Whether cluster headache attacks provoked by CGRP and PACAP38/VIP are mediated by distinct signaling pathways will be worth investigating in forthcoming studies,” wrote Lanfranco Pellesi, MD, of the Danish Headache Center at the University of Copenhagen, and his coauthors. The study was published in Cephalalgia.

To assess how these biochemical variables might contribute to cluster headache attacks, the researchers launched a randomized, double-blind trial of data from 44 Danish participants with cluster headache. The average age of the patients was 38 years; 14 had active episodic cluster headache, 15 had episodic cluster headache in remission, and 15 had chronic cluster headache.

All patients received a continuous infusion of either PACAP38 (10 pmol/kg per minute) or VIP (8 pmol/kg per minute) over a 20-minute period, using a time- and volume-controlled infusion pump. Blood was collected for analysis at fixed time points, including at baseline, at the end of the infusion, 10 minutes after the infusion, and 70 minutes after the infusion. Technical problems led to missing values in 285 out of 1,144 planned plasma samples.

PACAP38 infusion resulted in a cluster headache attack in 13 of the 44 participants and VIP induced an attack in 12 of the 44. No differences in plasma CGRP (P = .7074), tryptase (P = .6673), and histamine (P = .4792) levels were found between patients who developed attacks and those who did not, and the plasma concentrations did not differ among the various blood-drawing time points.

There was also no difference in plasma CGRP levels between patients with active episodic cluster headache, those with episodic cluster headache in remission, and those with chronic cluster headache. After post hoc analysis, plasma tryptase and plasma histamine levels were similar among the three cluster headache patient groups.

The final link to the cluster headache puzzle has not yet been found

“We know a lot about cluster headache: how it presents, how we can stop it acutely, and how we can stop it preventively. But we don’t know everything about all the neurotransmitters involved, the triggers that start an attack, or the causes of pain,” Alan Rapoport, MD, professor of neurology at the University of California, Los Angeles (UCLA), and past president of the International Headache Society, said in an interview. “This study was performed to find the answer to a small piece of the puzzle. Is CGRP the missing link for patients who begin a cluster attack, or should we be looking elsewhere?

“I would be cautious and say it appears that it doesn’t seem to be related, but further studies may show something different,” he added. “The reason for my qualification: There is a monoclonal antibody [galcanezumab], which grabs CGRP and prevents it from docking on its receptor, that has been approved for preventive treatment of episodic cluster headache. When you have episodic cluster, go into a cluster period, and take galcanezumab, it could and should decrease the number of attacks that you would ordinarily have had. That means it is related somewhat. But it certainly doesn’t work for everyone, so more investigations like this are needed.”

“What’s important about this study is that it opens up the possibility that there is another way into the cluster attack that could be operationalized for therapeutic purposes,” Peter Goadsby, MD, PhD, professor of neurology at UCLA and president of the American Headache Society, said in an interview.

When asked about the authors’ stated interest in investigating “if monoclonal antibodies targeting the CGRP pathway prevent PACAP38- or VIP-induced cluster headache attacks” as a follow-up, Dr. Goadsby strongly backed the idea. “If I sound excited about actually exploring whether that was a useful treatment or not, it’s because cluster headache is a dreadful condition. And the sooner you could work out whether it was useful or put the money into something else, well, that’s where I’d go.

“I think the principle here of doing experimental medicine, getting into human work with targets like this at the earliest possible time, is something that is not done as often as would be appropriate,” he added. “There is not enough investment, in my view, in early phase experimental work, which really just gets to that next step. Broadly speaking, the encouragement and support of experimental medicine is crucial to developing new therapies.”

The authors recognized their study’s potential limitations, including it’s being an exploratory study with results that should be interpreted cautiously. They acknowledged discrepancies with previous studies of plasma CGRP during cluster headache attacks, offering “different methodologies, including intra-assay differences and the location of blood sampling” as a possible reason. They also explained that some of the data are missing “completely at random” due to their policy of discarding all observations with incomplete laboratory measurements, adding that the impact on their sample size was “only modest.”

“In spite of these limitations,” Dr. Rapoport said, “this is an excellent study that shows us that PACAP38- and VIP-induced cluster headache attacks are not associated with alterations in plasma CGRP or in histamine and tryptase.”

Regarding potential conflicts of interest, one author reported being employed at the testing lab where the histamine measurements were conducted, as did another author who serves as the lab’s scientific adviser. A third author reported receiving personal fees from various pharmaceutical companies.