Migraine Preventive Medications Research Articles

Effects of Circadian Rhythm on Migraine Therapy

Circadian rhythms are 24-hour cycles of physical, mental, and behavioral changes regulated and maintained by the internal primary circadian clock, however modifiable by a number of external cues or “zeitgebers”, the most powerful one being light. Core set of clock genes regulate the whole-body metabolism and transcription of over 40% of mammalian RNA, including that for drug transporters, binding and metabolizing proteins responsible for regulation of pharmacokinetics of vast array of medications. Growing amount of evidence also shows circadian rhythmicity of a number of patho-physiological processes, such as are migraine, chronic pain, and epilepsy, suggesting amenability to chronotherapy. Chronotherapy involves behavioral and pharmacological strategies to restore or correct ill-functioning circadian rhythm as well as manipulation of standardized treatments throughout the day to maximize therapeutic and minimize side effects, termed chronopharmacology. Chronotherapy for chronic migraines and headache variants using synchronization techniques as well as chronopharmacology of abortive and preventive migraine medications is being actively researched. In this review, we summarize current state of chronotherapy for headache variants and discuss future prospects in circadian optimization of migraine headaches treatment.

Reduction in the severity and duration of headache following fremanezumab treatment in patients with episodic and chronic migraine.

ObjectiveTo evaluate the impact of fremanezumab on the severity and duration of remaining migraine attacks in patients with chronic migraine (CM) or episodic migraine (EM).BackgroundFremanezumab is a fully humanized monoclonal antibody (IgGΔa) that selectively targets calcitonin gene‐related peptide and is efficacious in reducing migraine frequency.MethodsThis exploratory post hoc analysis included data from three randomized, double‐blind, 12‐week, phase 3 studies (HALO CM, HALO EM, and FOCUS). In all three studies, patients with CM or EM were randomized 1:1:1 to receive subcutaneous quarterly fremanezumab (month 1/2/3: 675 mg/placebo/placebo), monthly fremanezumab (month 1/2/3: 675 mg [CM], 225 mg [EM]/225 mg/225 mg), or matched monthly placebo. Changes from baseline were evaluated in the proportion of headache days of at least moderate severity, peak severity of headache days, mean monthly headache hours (of any severity and at least moderate severity), and mean headache hours per headache day of any severity.ResultsA total of 2843 patients were randomized with 2823 patients included in the efficacy analyses across all studies (HALO CM, N = 1121; HALO EM, N = 865; FOCUS, N = 837). At study baseline, mean (standard deviation [SD]) monthly number of headache days rated moderate or severe in the quarterly fremanezumab, monthly fremanezumab, and placebo groups, respectively, were 13.2 (5.5), 12.8 (5.8), and 13.3 (5.8) in HALO CM; 7.2 (3.1), 6.8 (2.9), and 6.9 (3.1) in HALO EM; and 12.4 (5.8), 12.7 (5.8), and 12.8 (5.9) in FOCUS. Patients experienced significant least‐squares mean (LSM; 95% confidence interval) percent reductions from baseline in monthly number of headache days rated moderate or severe during the 12 weeks: HALO CM, quarterly fremanezumab, 34.5% (−39.8, −29.2) and monthly fremanezumab, 36.2% (−41.4, −31.0) vs. placebo, 19.6% (−20.0, −14.3); HALO EM, quarterly fremanezumab, 40.7% (−47.8, −33.5) and monthly fremanezumab, 43.4% (−50.4, −36.3) vs. placebo, 17.9% (−24.9, −11.0); and FOCUS, quarterly fremanezumab, 36.5% (−41.9, −31.1) and monthly fremanezumab, 38.6% (−44.0, −33.3) vs. placebo, 3.5% (−8.9, 1.8); all p < 0.0001. At study baseline, mean (SD) number of monthly headache hours rated moderate or severe in the quarterly fremanezumab, monthly fremanezumab, and placebo groups, respectively, were 66.4 (58.8), 68.0 (53.9), and 68.5 (57.0) in HALO CM; 33.3 (25.4), 31.7 (23.7), and 31.6 (23.2) in HALO EM; and 59.2 (54.7), 64.3 (65.2), and 65.9 (70.2) in FOCUS. Significant reductions were observed in LSM (standard error) number of monthly headache hours of at least moderate severity: HALO CM, quarterly fremanezumab, 24.4 (2.5) and monthly fremanezumab, 26.4 (2.3) vs. placebo, 14.1 (2.5); HALO EM, quarterly fremanezumab, 14.5 (1.4) and monthly fremanezumab, 15.5 (1.3) vs. placebo, 8.1 (1.3); and FOCUS, quarterly fremanezumab, 16.8 (3.0) and monthly fremanezumab, 18.3 (3.0) vs. placebo, 2.3 (3.0); all p < 0.001.ConclusionThese analyses demonstrated that quarterly or monthly treatment with fremanezumab significantly reduced headache severity and duration in patients with CM or EM, including in patients with documented inadequate response to two to four prior migraine preventive medication classes.

Efficacy of galcanezumab in patients with migraine who did not benefit from commonly prescribed preventive treatments

BackgroundGalcanezumab is a calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) indicated for the preventive treatment of migraine. While galcanezumab has demonstrated efficacy in patients who did not respond to prior preventive medications in general, its efficacy in patients who did not benefit from individual, commonly prescribed preventive treatments due to inadequate efficacy or safety/tolerability remains unknown.MethodsCONQUER was a 3-month, randomized, double-blind, placebo-controlled, phase 3b study that enrolled patients with episodic or chronic migraine who had 2 to 4 migraine preventive medication category failures in the past 10 years. Patients were randomly assigned 1:1 to receive placebo (N = 230) or galcanezumab 120 mg/month (240 mg loading dose; N = 232). Post hoc analyses were conducted to determine the efficacy of galcanezumab in patients who had not benefited from six of the most commonly prescribed migraine preventive medications. The mean change from baseline in monthly migraine headache days and ≥ 50 % response rates were assessed over months 1–3. Improvement in Migraine-Specific Questionnaire Role Function-Restrictive (MSQ-RFR) scores were assessed at month 3. The endpoints were estimated via mixed model with repeated measures.ResultsThe most common treatment failures due to inadequate efficacy or safety/tolerability, which at least 20 % of patients reported trying without benefit, included topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and metoprolol. Patients who had not previously benefited from these treatments had a greater mean reduction in monthly migraine headache days across months 1–3 in the galcanezumab group compared to placebo (all p < 0.01). More patients treated with galcanezumab experienced a ≥ 50 % reduction from baseline in monthly migraine headache days across months 1–3 compared to placebo (all p < 0.05). Galcanezumab-treated patients had a greater improvement in mean MSQ-RFR scores at month 3 compared to placebo (all p < 0.01).ConclusionsIn this population, galcanezumab was effective in reducing monthly migraine headache days, improving response rates, and enhancing quality of life in patients who had not previously benefited from topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and/or metoprolol due to inadequate efficacy or safety/tolerability.Trial registrationClinicalTrials.gov NCT03559257 (CONQUER).

Efficacy and safety of fremanezumab in patients with migraine and inadequate response to prior preventive treatment: subgroup analyses by country of a randomized, placebo-controlled trial

BackgroundThe FOCUS study evaluated the efficacy of migraine preventive medications across different countries within the same patient population, particularly for patients with difficult-to-treat migraine. These prespecified subgroup analyses evaluated efficacy by country in the FOCUS study of fremanezumab in adults with episodic migraine or chronic migraine and documented inadequate response to 2 to 4 migraine preventive medication classes.MethodsOverall, 838 participants were enrolled in the FOCUS study, a randomized, double-blind, placebo-controlled, parallel-group, phase 3b study performed at 104 sites. For 12 weeks of double-blind treatment, patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab, or matched placebo. The primary efficacy endpoint was the mean change from baseline in monthly average migraine days over 12 weeks of double-blind treatment, evaluated by country in these subgroup analyses.ResultsOf 14 countries contributing data, the Czech Republic (n = 188/838; 22%), the United States (n = 120/838; 14%), and Finland (n = 85/838; 10%) enrolled the most patients. Changes from baseline in monthly average migraine days over 12 weeks were significantly greater with fremanezumab versus placebo for patients in these countries: Czech Republic (least-squares mean difference versus placebo [95% confidence interval]: quarterly fremanezumab, − 1.9 [− 3.25, − 0.47]; P = 0.009; monthly fremanezumab, − 3.0 [− 4.39, − 1.59]; P < 0.001), the United States (quarterly fremanezumab, − 3.7 [− 5.77, − 1.58]; P < 0.001; monthly fremanezumab, − 4.2 [− 6.23, − 2.13]; P < 0.001), and Finland (quarterly fremanezumab, − 3.0 [− 5.32, − 0.63]; P = 0.014; monthly fremanezumab, − 3.9 [− 6.27, − 1.44]; P = 0.002). Results were comparable for the remaining 9 countries, with the least-squares mean difference versus placebo ranging from – 5.6 to – 2.4 with quarterly fremanezumab and from − 5.3 to − 1.5 with monthly fremanezumab. Incidences of serious adverse events and adverse events leading to discontinuation were low and comparable across countries and treatment groups.ConclusionsMonthly and quarterly fremanezumab significantly reduced the monthly average number of migraine days versus placebo regardless of country and continent (North America versus Europe) in migraine patients with documented inadequate response to 2 to 4 migraine preventive medication classes.Trial registrationClinicalTrials.gov Identifier: NCT03308968.

Rimegepant is Safe and Tolerable for the Acute Treatment of Migraine in Patients Using Preventive Migraine Medications: Results from a Long-Term Open-Label Safety Study (2370)

Rimegepant is Safe and Tolerable for the Acute Treatment of Migraine in Patients Using Preventive Migraine Medications: Results from a Long-Term Open-Label Safety Study (2370)

Number Needed to Treat/Harm for Fremanezumab in Patients Who Had Inadequate Response to 2–4 Prior Migraine Preventive Medication Classes (2055)

Number Needed to Treat/Harm for Fremanezumab in Patients Who Had Inadequate Response to 2–4 Prior Migraine Preventive Medication Classes (2055)

Early onset of effect following galcanezumab treatment in patients with previous preventive medication failures

BackgroundGalcanezumab is a monoclonal antibody (mAb) that binds calcitonin gene-related peptide (CGRP) and is indicated for the preventive treatment of migraine. Galcanezumab demonstrated early onset of effect in patients with migraine but it is unknown whether the same holds true for patients who have not benefited from multiple prior migraine preventives.MethodsPatients with episodic or chronic migraine from a 3-month, randomized, double-blind, placebo-controlled, phase 3b study (CONQUER) who had 2 to 4 migraine preventive medication category failures in the past 10 years were randomized 1:1 to placebo (N = 230) or galcanezumab 120 mg/month (240 mg loading dose; N = 232). In this post-hoc analysis, change from baseline in number of monthly and weekly migraine headache days was assessed. Monthly onset of effect was the earliest month at which significant improvement with galcanezumab compared to placebo was achieved and maintained at all subsequent months. Weekly onset was the initial week at which statistical separation was achieved and maintained at all subsequent weeks during that month. Proportion of patients with migraine headache days in the first week of treatment, and patients achieving ≥50%, ≥75%, and 100% response by month and week were also assessed.ResultsGalcanezumab-treated patients had a significantly greater reduction in monthly migraine headache days starting at month 1, which remained significant for all subsequent months compared to placebo (all p ≤ 0.0001, month 1 mean change from baseline: placebo − 0.7; galcanezumab − 4.0). Weekly migraine headache days was significantly reduced in galcanezumab-treated patients starting at week 1 and continued for each subsequent week of month 1 compared to placebo (all p < 0.01, week 1 mean change from baseline: placebo − 0.2; galcanezumab − 1.1). A significantly smaller percentage of patients had a migraine headache on the first day after galcanezumab treatment compared to placebo (28.4% vs 39.2%) and at each subsequent day during week 1 (all p < 0.05). A greater proportion of galcanezumab-treated patients achieved ≥50%, ≥75%, and 100% response at months 1–3 (all p < 0.05) and at weeks 1–4 of month 1 compared to placebo (all p < 0.01).ConclusionGalcanezumab showed early onset of effect beginning the day after treatment initiation in patients who had not previously benefited from migraine preventive treatments.Trial registrationClinicalTrials.gov, NCT03559257. Registered 18 June 2018.

Psychological Considerations in the Etiology and Pathophysiology of Migraines

Although studies to understand the pathogenesis of migraines are in progress, no theory has adequately explained the etiology and pathophysiology of migraines to date. This has affected the development of treatment strategies for migraineurs. Currently, the pharmacological treatment for migraines provides both acute and prophylactic options to patients based on a biomedical model of pain. However, patients’ adherence to oral migraine preventive medication (OMPM) is poor, and their persistence is even lower when they cycle through a variety of OMPMs [1]. Although our understanding of the pathophysiology of migraines within the context of the current biopsychosocial model of pain has advanced in recent years, there is a need to better understand the role of social and psychological factors in the pathophysiology of this debilitating disease, which would pave the way for the development and acceptance of more diverse and inclusive treatments. In this review, we provide an overview of the various theories that purport to explain the pathogenesis of the headache phase of migraines, examine the usefulness and shortcomings of these theories, and investigate how psychological considerations may help develop treatments to assist migraine sufferers in managing their headaches better.

Understanding the migraine treatment landscape prior to the introduction of calcitonin gene-related peptide inhibitors: Results from the Assessment of TolerabiliTy and Effectiveness in MigrAINe Patients using Preventive Treatment (ATTAIN) study.

BackgroundCalcitonin gene‐related peptide (CGRP) inhibitors were introduced in the United States (US) in 2018. To understand the changing patterns of preventive treatment following the introduction of these new agents, we must first characterize the patterns which preceded their introduction.ObjectiveTo characterize the burden, unmet need, and treatment patterns in patients with migraine initiating preventive migraine medications before the introduction of CGRP inhibitors in the US.MethodsBetween March 2016 and October 2017, we enrolled episodic (EM) and chronic migraine (CM) patients initiating or changing preventive treatment at primary care or neurology clinic visits in the US, in a real‐world observational study using a prospective cohort design. At baseline and monthly thereafter for 6 months, we collected data from study sites and patients on migraine frequency, treatment modifications, migraine impact on functioning, and work productivity for a descriptive analysis of migraine patient experience and treatment patterns.ResultsFrom the sample of 234 completers, 118 had EM (50.4%) and 116 had CM (49.6%). Mean age at enrollment was 41 years (SD = 12) and mean age at first migraine diagnosis was 22 years (SD = 11). Most participants were females (n = 204/234; 87.2%) and white (n = 178/234; 76.1%). The majority (n = 164/234; 70.1%) had not used preventive migraine treatment in the 5 years prior to enrollment (treatment naïve). At baseline, mean monthly migraine days were 9.6 days (SD = 5.0) for the preventive treatment naïve group and 12.4 days (SD = 7.0) for treatment experienced patients. The majority had severe Migraine Disability Assessment (Grade IV, total score ≥21), including 67.1% (n = 110/164) of the preventive treatment naïve and 77.1% (n = 54/70) of the preventive treatment experienced patients. Headache Impact Test total scores indicating severe impairment (score >59) occurred in 88.4% (n = 145/164) of the treatment naïve and 88.6% (n = 62/70) of treatment experienced patients. Mean work productivity loss as measured by the Work Productivity and Activity Impairment questionnaire in the subsample of employed patients was 53.3% loss. The most used acute medications at baseline were nonsteroidal anti‐inflammatory agents (n = 124/234; 53.0%), acetaminophen‐based products (n = 112/234; 47.9%), and triptans (n = 105/234; 44.9%). The most commonly initiated preventive treatments were topiramate (n = 100/234; 42.7%), tricyclic antidepressants (n = 39/234; 16.7%), beta‐blockers (n = 26/234; 11.1%), and onabotulinumtoxinA (n = 24/234; 10.3%). Over the 6‐month follow‐up period, almost half of patients (n = 116/234, 49.6%) modified their preventive treatment and discontinued treatment (n = 88/312 total modifications; 28.2%) or modified their pattern of use by increasing, decreasing, or skipping doses (n = 224/312 total modifications; 71.8%), often without seeking medical advice. Avoiding side effects was the main reason reported among patients who discontinued (n = 52/88; 59.1%), decreased frequency or dose (n = 37/89; 41.6%), and skipped doses (n = 29/86; 33.7%). Perceived lack of efficacy was another frequent reason reported among those who discontinued (n = 20/88; 22.7%), decreased frequency or dose (n = 15/89; 16.9%), and skipped doses (n = 18/86; 20.9%). Despite initiation of preventive treatment and improvements observed in number of headache and migraine days, migraine patients continued to experience substantial disability, headache impact, and reduced productivity throughout the 6‐month follow‐up period.ConclusionsPrior to 2018, the burden of migraine was high for patients initiating preventive treatments. Despite having more than 9 days of migraine per month on average, the majority (70.1%) of patients initiating prevention had been treatment naïve, indicating underuse of preventive treatments. The preventive treatments used in this study were poorly tolerated and were reported by patients to lack efficacy, resulting in suboptimal adherence. The high discontinuation rates suggest that the preventive medications being offered during the period of the study did not meet the treatment needs of patients. In addition, the decisions by about half of patients to alter their prescribed treatment plan without consulting their provider can pose substantial health risks. These findings pertain to the broad set of preventive treatments initiated in this study and do not support inferences about individual preventive treatments, due to limitations in sample size. These findings suggest the need for more effective and better tolerated preventive treatment options.

Underuse of Behavioral Treatments for Headache: a Narrative Review Examining Societal and Cultural Factors.

Migraine affects over 40 million Americans and is the world’s second most disabling condition. As the majority of medical care for migraine occurs in primary care settings, not in neurology nor headache subspecialty practices, healthcare system interventions should focus on primary care. Though there is grade A evidence for behavioral treatment (e.g., biofeedback, cognitive behavioral therapy (CBT), and relaxation techniques) for migraine, these treatments are underutilized. Behavioral treatments may be a valuable alternative to opioids, which remain widely used for migraine, despite the US opioid epidemic and guidelines that recommend against them. Identifying and removing barriers to the use of headache behavioral therapy could help reduce the disability as well as the personal and social costs of migraine. These techniques will have their greatest impact if offered in primary care settings to the lower socioeconomic status groups at greatest risk for migraine. We review the societal and cultural challenges that impose barriers to optimal use of non-pharmacological treatment services. These barriers include insufficient knowledge of migraine/headache behavioral treatments and insufficient availability of clinicians trained in non-pharmacological treatment delivery; limited access in underserved communities; financial burden; and stigma associated with both headache and mental health diagnoses and treatment. For each barrier, we discuss potential approaches to minimizing its effect and thus enhancing non-pharmacological treatment utilization.Case ExampleA 25-year-old graduate student with a prior history of headaches in college is attending school in the evenings while working a full-time job. Now, his headaches have significant nausea and photophobia. They are twice weekly and are disabling enough that he is unable to complete homework assignments. He does not understand why the headaches occur on Saturdays when he pushes through all week to get through his examinations that take place on Friday evenings. He tried two different migraine preventive medications, but neither led to the 50% reduction in headache days his doctor had hoped for. His doctor had suggested cognitive behavioral therapy (CBT) before initiating the medications, but he had been too busy to attend the appointments, and the challenges in finding an in-network provider proved difficult. Now with the worsening headaches, he opted for the CBT and by the fifth week had already noted improvements in his headache frequency and intensity.

Early use of erenumab in US real-world practice

Background: Erenumab, a monoclonal antibody (mAb) developed to block the calcitonin gene-related peptide (CGRP) receptor, is approved for the prevention of migraine in adults. This retrospective observational study sought to describe early real-world use of erenumab. Methods: This study used the Practice Fusion ambulatory Electronic Health Record database, which represents approximately 6% of ambulatory care among primary care and specialist practices in the United States. Among migraine patients initiating erenumab, demographics, migraine type, comorbidities, and prior treatments were assessed during the 12-month baseline period. Treatment patterns including changes in acute and preventive medications, switches to other CGRP mAbs (fremanezumab and galcanezumab), and for erenumab, changes in dose and adherence were examined among patients with 6 months of follow-up. Results: Of 3,336 patients identified (85.9% female; mean age = 49.1 years), approximately 40% had documentation of chronic migraine. Common comorbidities included non-migraine headache, anxiety, depression, and hypertension. Most patients (76.3%) initiated on the 70 mg dose of erenumab. Among 1,638 patients included in the treatment pattern analysis, 53.1% used acute medications and 55.7% used other non-specific preventive migraine medications during follow-up, reductions of 9.8% and 10.2%, respectively, over the same period of time before index. Switching to fremanezumab and galcanezumab were observed in 12.2% and 13.8% of patients, respectively. The mean proportion of days covered by erenumab at 6 months was 79%. Dosage of erenumab increased (from 70 mg to 140 mg) in 13.0% and decreased (from 140 mg to 70 mg) in 24.9% of patients. Conclusion: This early real-world study showed high adherence among erenumab users. This combined with observed reductions in previously used acute and preventive medications are suggestive of erenumab’s benefit.

Comparative effectiveness of erenumab versus oral preventive medications among migraine patients: A US claims database study

Background:Erenumab, a fully human monoclonal antibody targeting the calcitonin gene-related peptide pathway, was developed specifically for preventive treatment of migraine.Objective:To compare the real-world effectiveness of erenumab and non-specific oral migraine preventive medication (OMPM) on acute medication usage and healthcare resource utilization (HCRU) among migraine patients.Methods:This retrospective US claims analysis included patients (≥18 years) diagnosed with migraine who initiated erenumab (May 01, 2018 and September 30, 2019) or OMPM (May 01, 2016 and October 31, 2017). Cohorts were matched 1:1 using the propensity score (PS) method with stratification. Acute medication usage, HCRU, and a composite endpoint of 1) outpatient visit with a migraine diagnosis and associated acute medication claim, 2) hospital admission with a primary migraine diagnosis, or 3) emergency room visit with a primary migraine diagnosis were assessed 6 months post-treatment initiation.Results:Following PS matching, both cohorts included 2,343 patients. At 6 months, erenumab was associated with significantly less acute medication usage versus OMPM, including number of types of acute medications used, number of claims per person, and proportion of patients using acute medication. HCRU and number of composite events were also significantly lower among erenumab users.Conclusion:Erenumab is more effective than OMPM at reducing acute medication usage and HCRU among migraine patients.Trial registration:N/A.

The migraine signature study: Methods and baseline results.

ObjectiveTo characterize patients who utilize services for migraine in a large integrated health care network, and describe patterns of care and utilization.BackgroundWithin health care systems, migraine is a common reason for seeking primary and neurology care, but relatively little is documented about who seeks care and the factors that explain variation in utilization.MethodsWe conducted a retrospective cohort study using electronic health record (EHR) data from Sutter Health primary care (PC) patients who had at least one office visit to a PC clinic between 2013 and 2017. Migraine status was ascertained from diagnosis codes and medication orders. Control status was assigned to those with no evidence of care for any type of headache. We divided the primary care migraine cohort into two groups: those who received all their care for migraine from PC (denoted PC‐M) and those who had ≥1 encounter with a neurologist for migraine (denoted N‐M). Migraine cases were also designated as having preexisting migraine if they had an encounter with a migraine diagnosis within (±) 6 months of their first study period PC visit and, otherwise, designated as first migraine consult. Two levels of contrasts included: patients with migraine and controls; and within the group of patients with migraine, PC‐M and N‐M groups. Comorbid conditions were determined from EHR encounter diagnosis codes.ResultsWe identified 94,149 patients with migraine (including 21,525 N‐M and 72,624 PC‐M) and 1,248,763 controls. Comorbidities: Proportions of psychiatric [29.8% (n = 28,054) vs. 11.8% (n = 147,043)], autoimmune [(4.4% (n = 4162) vs. 2.6% (n = 31,981)], pain [13.2% (n = 12,439) vs. 5.8% (n = 72,049)], respiratory [24.6% (n = 23,186) vs. 12.3% (n = 153,692)], neurologic [2.9% (n = 2688) vs. 0.9% (n = 11,321)], and cerebrovascular [1.0% (n = 945) vs. 0.6% (n = 7500)] conditions were higher in the migraine group compared to controls, all p < 0.001. Among patients with migraine, the N‐M group was similar to the PC‐M group in sex, age, ethnicity, and marital status, but were more likely to have preexisting migraine (49.9% (n = 10,734) vs. 36.2% (n = 26,317), p < 0.001). Proportions of comorbid conditions were higher among the N‐M group than the PC‐M group {psychiatric [38.5% (n = 8291) vs. 27.2% (n = 19,763)], autoimmune [6.3% (n = 1365) vs. 3.9% (n = 2797)], pain [19.6% (n = 4218) vs. 11.3% (n = 8211)], respiratory [30.3% (n = 6516) vs. 23.0% (n = 16,670)], neurologic [6.0% (n = 1288) vs. 1.9% (n = 1400)], cardiovascular [9.7% (n = 2091) vs. 7.0% (n = 5076)], and cerebrovascular [2.3% (n = 500) vs. 0.6% (n = 445)], all p < 0.001}. Medications: During the study period, 82.6% (n = 77,762) of patients with migraine received ≥1 prescription order for an acute migraine medication [89.4% (n = 19,250) of N‐M vs. 80.6% (n = 58,512) of PC]. Opioids were prescribed to 52.9% (n = 49,837) of patients with migraine [63.5% (n = 13,669) for N‐M and 49.8% (n = 36,168) for PC‐M patients). During the study period, 61.4% (n = 57,810) of patients received ≥1 prescription for a migraine preventive medication [81.4% (n = 17,521) of N‐M and 55.5% (n = 40,289) of PC‐M patients]. The most commonly prescribed classes of preventive medications were antidepressants.ConclusionsAmong patients with migraine in a large health system, those who were also cared for in neurology were more likely to receive both acute and preventive medication migraine orders than those patients who did not see a neurologist, with triptans and antidepressants the most commonly prescribed classes of acute and preventive pharmacotherapies, respectively. Opioids were prescribed to approximately half of the total sample and more common in the N‐M group. Adjusting for demographics, patients with migraine had higher rates of nearly every comorbidity we assessed and were more likely to utilize services compared to those without migraine. Overall, patients with migraine also cared for in neurology practices used more of all health care resource types under consideration and had more medical issues, which may be due in some part to a more severe, frequent and disabling disease state compared to those who sought care exclusively from PC practices.

Headache research in 2020: disrupting and improving practice

Primary headache disorders are, perhaps unsurprisingly, a continued source of medical shame as a major cause of disability globally, with so little time given to the subject in the medical curriculum and little investment in research. Advances in understanding and care of patients with headache disorders thus can have a potentially broad impact. Here, I comment on five clinical papers, published in 2020, that advance thinking about headache disorders, 1 Mulleners WM Kim B-K Lainez MJA et al. Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 2020; 19: 814-825 Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar , 2 Goadsby PJ Dodick DW Ailani J et al. Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial. Lancet Neurol. 2020; 19: 727-737 Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar , 3 Ziegeler C Mehnert J Asmussen K May A Central effects of erenumab in migraine patients: an event-related functional imaging study. Neurology. 2020; 95: e2794-e2802 Crossref PubMed Scopus (5) Google Scholar , 4 Knievel K Buchanan AS Lombard L et al. Lasmiditan for the acute treatment of migraine: subgroup analyses by prior response to triptans. Cephalalgia. 2020; 40: 19-27 Crossref PubMed Scopus (17) Google Scholar , 5 Porta-Etessam J Matias-Guiu JA Gonzalez-Garcia N et al. Spectrum of headaches associated with SARS-CoV-2 infection: study of healthcare professionals. Headache. 2020; 60: 1697-1704 Crossref PubMed Scopus (23) Google Scholar and will most likely have implications well into the 2020s.

Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial

Many patients who require migraine preventive treatment have not been able to tolerate or have not responded to multiple previous preventive medications. We aimed to assess the safety and efficacy of galcanezumab, an antibody to calcitonin gene-related peptide, in patients with migraine who had not benefited from preventive medications from two to four categories. CONQUER was a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial done at 64 sites (hospitals, clinics, or research centres) in 12 countries (Belgium, Canada, Czech Republic, France, Germany, Hungary, Japan, the Netherlands, South Korea, Spain, the UK, and the USA). Patients were 18-75 years of age, with episodic or chronic migraine, with migraine onset before the age of 50 years, who had a documented failure of preventive medications from two to four drug categories in the past 10 years owing to lack of efficacy or tolerability, or both. Patients were randomised 1:1 to receive subcutaneous placebo or galcanezumab 120 mg per month (with a 240 mg loading dose administered as two 120 mg injections) for 3 months. For masking purposes, patients receiving placebo also received two injections during the first dosing visit. Randomisation was done by a computer-generated random sequence by means of an interactive web-response system stratified by country and migraine frequency (low frequency episodic migraine, four to fewer than eight migraine headache days per month; high frequency episodic migraine, eight to 14 migraine headache days per month and fewer than 15 headache days per month; chronic migraine, at least eight migraine headache days per month and at least 15 headache days per month). The primary endpoint was the overall mean change from baseline in number of monthly migraine headache days during the 3-month treatment period in all patients who were randomly assigned and received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03559257, and is now completed. Between Sept 10, 2018, and March 21, 2019, 462 participants with episodic (269 [58%]) or chronic (193 [42%]) migraine were randomly assigned and received at least one injection with placebo (n=230) or galcanezumab (n=232). Galcanezumab-treated patients had significantly greater reduction in migraine headache days versus placebo across months 1-3. The galcanezumab group had on average 4·1 fewer monthly migraine headache days compared with baseline (13·4), while the placebo group had on average 1·0 fewer than at baseline (13·0; between-group difference -3·1 [95% CI -3·9 to -2·3]; p<0·0001; effect size=0·72). Types and number of treatment-emergent adverse events were similar between galcanezumab and placebo. Treatment-emergent adverse events were reported in 122 (53%) of 230 patients in the placebo group and 119 (51%) of 232 patients in the galcanezumab group. There were four serious adverse events during the study, two (1%) reported in the placebo group and two (1%) reported in the galcanezumab group. Galcanezumab was superior to placebo in the preventive treatment of migraine and was safe and well tolerated in patients for whom multiple previous standard-of-care preventive treatments had failed. Galcanezumab might represent an important treatment option for patients who have not benefited from or tolerated previous standard-of-care treatments. Eli Lilly.

Fremanezumab: a disease-specific option for the preventive treatment of migraine, including difficult-to-treat migraine.

Fremanezumab is a fully humanized monoclonal antibody (IgG2Δa) that targets calcitonin gene-related peptide (CGRP), a key neuropeptide involved in the pathophysiology of migraine. Fremanezumab is approved for quarterly and monthly subcutaneous dosing for the preventive treatment of migraine in adults. The phase 3 clinical development program for fremanezumab aimed to evaluate the efficacy of this preventive treatment across different patient populations, including those with difficult-to-treat migraine. Two pivotal 12-week, phase 3, placebo-controlled studies investigated quarterly and monthly dosing of fremanezumab in participants with chronic migraine (HALO CM) and episodic migraine (HALO EM). The efficacy of fremanezumab was further explored in individuals with difficult-to-treat chronic or episodic migraine in the 12-week FOCUS study, which enrolled participants who had previously experienced an inadequate response to 2–4 pharmacological classes of migraine preventive medications. The long-term efficacy of fremanezumab was assessed in a 12-month long-term study (HALO LTS), which enrolled participants completing the 12-week HALO studies and new participants. Across these studies, treatment with fremanezumab dosed quarterly or monthly provided significant reductions in the frequency of migraine days, headache days of at least moderate severity, and migraine- and headache-related disability compared with placebo. Sustained improvements were seen with long-term fremanezumab treatment. Subgroup analyses of participants with difficult-to-treat migraine (those with comorbid depression, overuse of acute headache medications, and concomitant use of other migraine preventive medications) demonstrated the effectiveness of quarterly or monthly fremanezumab in these populations. Ongoing studies are further exploring the potential benefits of fremanezumab in difficult-to-treat migraine and other headache and pain disorders.

Burden of Illness Among People with Migraine and ≥ 4 Monthly Headache Days While Using Acute and/or Preventive Prescription Medications for Migraine.

Migraine is a chronic disease that reduces health-related quality of life. Little is known about the burden of migraine in individuals who are potential candidates for preventive treatment with ≥ 4 monthly headache days currently using migraine medications. To characterize the burden of migraine among patients reporting ≥ 4 monthly headache days while taking acute and/or preventive migraine medications. In this retrospective, cross-sectional study, data from the 2016 U.S. National Health and Wellness Survey (N = 97,503) compared the burden of migraine among individuals self-reporting a diagnosis of migraine by a health care professional and ≥ 4 monthly headache days while using acute and/or preventive prescription migraine medications to matched nonmigraine controls. Propensity score matching across different variables (e.g., age, gender, and body mass index) was used to identify matched controls from respondents who did not self-report a diagnosis of migraine. Migraine-associated burden was measured by impairment in work productivity and daily activities (Work Productivity and Activity Impairment questionnaire), all-cause health care resource utilization (HRU), and all-cause direct and indirect costs. This analysis included 197 treated migraine patients with ≥ 4 monthly headache days and 197 matched nonmigraine controls. Greater proportions of treated migraine patients reported comorbid depression (58.4% vs. 27.9%, P < 0.001) or generalized anxiety disorder (15.2% vs. 8.6%, P = 0.043) and were on long-term disability (13.7% vs. 5.6%, P = 0.003). Absenteeism (11.8% vs. 6.3%, P = 0.030); presenteeism (36.0% vs. 17.5%, P < 0.001); overall work impairment (41.0% vs. 20.9%, P < 0.001); and activity impairment (45.4% vs. 25.4%, P < 0.001) were greater in treated migraine patients versus nonmigraine controls. Treated migraine patients had higher all-cause HRU and higher all-cause direct ($24,499.90 vs. $15,318.91, P = 0.013) and indirect ($14,770.57 vs. $5,764.93, P < 0.001) costs than nonmigraine controls. Treated migraine patients with ≥ 4 monthly headache days reported significantly reduced work productivity and increased all-cause HRU and cost despite migraine treatment compared with nonmigraine controls. These findings highlight unmet needs in the treatment and management of migraine. This study was funded by Teva Pharmaceutical Industries (Petach Tikva, Israel). Cohen is an employee of Teva Branded Pharmaceutical Products R&D (USA); Bell was an employee of Teva Pharmaceutical Industries at the time of this study and holds stock/stock options in Teva Pharmaceutical Industries. Lee is an employee of Kantar, which received funding from Teva Pharmaceutical Industries for data analyses performed for this study. Buse has served as a paid consultant to Amgen/Novartis, Allergan, Biohaven, Eli Lilly, Promius/Dr. Reddy's, and Teva Pharmaceuticals, but she was not compensated financially for work on this study. Yugrakh has received research support from Teva Pharmaceuticals and Cefaly Technology. Lipton has received research support from the NIH, the Migraine Research Foundation, and the National Headache Foundation; holds stock options in eNeura Therapeutics and Biohaven Holdings; serves as consultant, advisory board member, or has received honoraria from the American Academy of Neurology, Alder, Allergan, the American Headache Society, Amgen, Autonomic Technologies, Avanir, Biohaven, BioVision, Boston Scientific, Dr. Reddy's, electroCore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Pernix, Pfizer, Supernus, Teva, Trigemina, Vector, and Vedanta. This study was presented as a poster at the American Academy of Neurology 2018 Annual Meeting, April 21-27, 2018, in Los Angeles, CA; PAINWeek 2018, September 4-8, 2018, in Las Vegas, NV; and the 2017 European Headache Federation (EHF) Congress, December 1-3, 2017, in Rome, Italy.

Profile of Migraine Patients in a Developing Country: a Multicentre Study

Migraine is a common headache disorder with significant impact on quality of life. Despite the significant progress in treatment and understanding of migraine, the care of sufferers is inadequate in low resource settings. Studies on characteristics of migraine patients receiving care in sub-Saharan Africa are limited. We aim to determine the effect of demographic characteristics on migraine diagnosis, and the adequacy of treatment offered in tertiary hospitals. This was a multi-centre, hospital-based, cross-sectional study conducted over 4 months in Northeast Nigeria. Participants were patients with known migraine on follow up at the neurology outpatient clinics. The sociodemographic, clinical records, and treatment outcome of each subject was documented. Of the 112 migraineurs who fulfilled the inclusion criteria, 104 consented to participate in the study. The mean age of the participants was 30.8 ± 10.4 years. Females constituted 74% of subjects, with a female to male ratio of 2.9:1. The difference between the mean age of migraine onset and the mean age at diagnosis was 4.6 years. On multivariate logistic regression analysis, age at headache onset (p = 0.001) and lower level of education (p = 0.03) independently predicted a delay in diagnosis of migraine. At first specialist clinic visit, 69.2% of the subjects had only a diagnosis of chronic migraine, 25% was additionally diagnosed with medication overuse headache, and about 92% was not placed on migraine preventive medication for their headaches despite meeting the criteria. Fifty-five (52.9%) patients had clinic visits in the past 12 months, among which prophylactic medications were used by 26 (45.1%) patients, while 13 (23.6%) were not adherent to preventive drug treatment, and 16 (29%) patients used their preventive medications as acute treatment. The significant delay from headache onset to migraine diagnosis has resulted in a more prevalent presentation with chronic migraine headache. Younger age at migraine onset and low educational attainment may affect diagnosis and treatment. The low prescription rate of migraine prophylactic medications by practitioners in this region may be affecting the quality of life of migraineurs.

Lasmiditan Is a New Option for Acute Migraine Treatment

Lasmiditan is a new oral medication for treatment of acute migraine. It was approved by the U.S. Food and Drug Administration in October 2019 and is marketed under the brand name Reyvow (Eli Lilly and Company, Indianapolis, IN). It is the first of its kind in a new drug class called ditans. Lasmiditan has been studied as monotherapy for acute migraine treatment and as an abortive therapy for adults taking chronic migraine preventive medication. Lasmiditan may be an option for individuals who have had no relief with triptans or other acute migraine treatment agents or who are unable to use other migraine treatments because of contraindications.

Multidimensional assessment of the effects of erenumab in chronic migraine patients with previous unsuccessful preventive treatments: a comprehensive real-world experience

Backgrounderenumab was safe and effective in clinical trials for the prevention of migraine. However, real-life data are still lacking. Here we report the clinical experience from an Italian real-world setting using erenumab in patients with chronic migraine experiencing previous unsuccessful preventive treatments.MethodsSeventy patients with chronic migraine and failure to ≥4 migraine preventive medication classes initially received monthly erenumab 70 mg s.c. Patients without a clinically meaningful improvement, considered as a > 30% reduction in headache days per month, after ≥3 months of therapy switched to monthly erenumab 140 mg. At the first administration and after 3 and 6 months, patients underwent extensive interviews to assess clinical parameters of disease severity and migraine-related disability and impact, and validated questionnaires to explore depression/anxiety, sleep, and quality of life (QoL). Finally, the Pain Catastrophizing Scale, Allodynia Symptom Checklist-12 and MIGraine attacks-Subjective COGnitive impairments scale (MIG-SCOG) were administered.Results70% of patients were “responders” after the third administration of erenumab 70 mg, whereas 30% switched to erenumab 140 mg; 29% (6 pts) responded after the sixth administration. The headache-day frequency was reduced from 21.1 ± 0.7 to 11.4 ± 0.9 days after the third administration (p < 0.001) and to 8.9 ± 0.7 days after the sixth administration (p < 0.001). 53% and 70% of patients, respectively, showed a reduction of ≥50% of headache days/month after the third and the sixth administrations.Also improved were headache pain severity, migraine-related disability, and impact on daily living, QoL, pain catastrophizing and allodynia (all p < 0.001), quality of sleep, symptoms of depression or anxiety (p < 0.05) but not MIG-SCOG. There were no new adverse event signals.ConclusionThese real-world data support monthly erenumab 70 or 140 mg s.c. as a safe and effective preventive treatment to reduce headache frequency and severity in chronic migraine patients experiencing previous unsuccessful preventive treatments.