Mind over migraine: Disease burden, innovative therapies, and managed care trends in treating migraine disease

Abstract

Migraine is a genetically influenced complex neurological disease characterized by attacks of moderate to severe headaches and a variety of concomitant symptoms. Migraine disease can significantly impact individuals’ daily activities and quality of life. It is a major cause of disability and loss of productivity, which can be exacerbated by migraine-related stigma. Recent advances in migraine treatment and ongoing research may offer additional options for patients; however, treatment barriers still exist, resulting in underdiagnosis and undertreatment of migraine disease, especially in some minority and vulnerable groups. Primary care and emergency department providers are often the first point of contact for patients with migraine disease, so there is opportunity for them to assist in addressing these barriers, particularly with strategies to make care more patient-centered. Managed care organizations can also play a role in overcoming these barriers and supporting equitable access.

Plain language summary

Migraine is a disorder of the brain and is influenced by a person’s genetics. It causes attacks of moderate to severe headaches and other symptoms. Migraine disease can be very disruptive to people’s lives both at home and at work. New migraine treatments have become available, and others are being studied, but some people still have difficulty getting treatment. Front-line providers and managed care organizations can help overcome some of these difficulties.

Implications for managed care pharmacy

Migraine is a genetically influenced complex neurological disease that can significantly impact individuals’ daily activities and quality of life. It is a major cause of disability and loss of productivity. Managed care organizations can play a role in overcoming barriers to diagnosis and appropriate treatment of migraine disease and help to support equitable access.

Overview of Migraine Disease

Migraine is a genetically influenced complex neurological disorder. It is characterized by attacks of moderate to severe headaches and a variety of concomitant symptoms including but not limited to nausea, vomiting, photophobia, phonophobia, and osmophobia. ¹ The migraine headache phase may be preceded by a prodrome phase and followed by a postdrome phase. Aura may precede or accompany the headache phase (Figure 1). ¹

FIGURE 1.

Phases of Migraine Attack ^{1 , 61 , 62}

The migraine headache phase may be preceded by a prodrome phase and followed by a postdrome phase. Aura, when present, may precede or accompany the headache phase.

Although the pathophysiology of migraine disease is not completely understood, the trigeminovascular system, which relays head pain signals to the brain, plays a key role. ¹ Activated trigeminovascular neurons relay the migraine pain signal from the periphery to the central nervous system, and repeated activation over time results in a state of nervous system hypersensitivity and sustained pain. ¹

Several molecules have been associated with the pathophysiology of migraine disease and represent both current and future pharmacologic treatment targets. ^{1 , 2} For example, activation of serotonin receptors causes vasoconstriction and inhibition of peptides such as calcitonin gene–related peptide (CGRP), which results in pain relief. ³ Additionally, pituitary adenylate cyclase–activating polypeptide (PACAP) is being studied as a potential therapy based on proposed mechanisms including vasodilatation, effects on the parasympathetic nervous system, mast cell degranulation, activation of sensory afferents, and central effects. ^{1 , 2 , 4}

DIAGNOSIS

Migraine is a primary headache disorder that includes migraine with and without aura, and chronic migraine, which may also be with or without aura. ⁵ The International Classification of Headache Disorders, 3rd edition (ICHD-3), developed by the International Headache Society, provides diagnostic criteria for migraine disease and other headache disorders. Criteria specific to migraine diagnoses are listed in Table 1. Also listed in Table 1 are the ICHD-3 diagnostic criteria for migraine-related conditions including probable migraine and medication overuse headache, which can result from overuse of acute treatment for migraine attacks. ⁵

TABLE 1.

ICHD-3 Diagnostic Criteria ⁵

Diagnosis	ICHD-3 criteria
Migraine without aura	A.At least 5 attacks fulfilling criteria B-D. B.Headache attacks lasting 4-72 h (when untreated or unsuccessfully treated). C.Headache has ≥2 of the following 4 characteristics: 1.Unilateral location 2. Pulsating quality 3.Moderate or severe pain intensity 4. Aggravation by or causing avoidance of routine physical activity D.During headache, ≥1 of the following: 1.Nausea and/or vomiting 2.Photophobia and phonophobia E.Not better accounted for by another diagnosis.
Migraine with aura	A. At least 2 attacks fulfilling criteria B and C. B. One or more of the following fully reversible aura symptoms: 1. Visual 2. Sensory 3. Speech and/or language 4. Motor 5. Brainstem 6. Retinal C. At least 3 of the following 6 characteristics: 1. At least 1 aura symptom spreads gradually over 5 min 2. Two or more aura symptoms occur in succession 3. Each individual aura symptom lasts 5-60 min 4. At least 1 aura symptom is unilateral 5. At least 1 aura symptom is positive 6. The aura is accompanied, or followed within 60 min, by headache D. Not better accounted for by another diagnosis.
Chronic migraine	A. Migraine- or tension-type-like headache on ≥15 d/mo for >3 mo that fulfill criteria B and C. B.Occurring in a patient who has had ≥5 attacks fulfilling criteria for migraine with or without aura. C. On ≥8 d/mo for >3 mo, fulfilling any of the following: 1.Criteria C and D for migraine without aura 2. Criteria B and C for migraine with aura 3. Believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative D. Not better accounted for by another diagnosis.
Probable migraine	A. Attacks fulfilling all but 1 of criteria for migraine with or without aura. B. Not fulfilling ICHD-3 criteria for any other headache disorder. C. Not better accounted for by another ICHD-3 diagnosis.
Medication overuse headache	A. Headache occurring on ≥15 d/mo with a preexisting headache disorder. B. Regular overuse for >3 mo of 1 or more drugs taken for acute and/or symptomatic treatment of headache, with medication overuse defined as 1.10 or more d/mo for ergot derivatives, triptans, opioids, combination analgesics, or a combination of drugs from different classes that are not individually overused 2. 15 or more d/mo for nonopioid analgesics, acetaminophen, or NSAIDs C. Not better accounted for by another diagnosis.

Adapted from the International Headache Society ICHD-3.

d = day; h = hour; ICHD = International Classification of Headache Disorders; mo = month; NSAID = nonsteroidal anti-inflammatory drug.

Although not included in the ICHD-3 criteria, the term episodic migraine is also commonly used to differentiate from chronic migraine. ⁶ Episodic migraine describes fewer than 15 headache days per month, some of which are migraine days, whereas chronic migraine is 15 or more headache days per month, at least 8 of which are migraine days. ^{5 , 6}

CONDITION PROGRESSION

Migraine attacks in some patients may increase in frequency over time from episodic to chronic. ^{7 , 8} This process is referred to as transformation or chronification. Although the exact mechanisms underlying this process are not fully understood, numerous risk factors have been identified. These include disease characteristics (eg, headache frequency, frequent and persistent nausea, presence of cutaneous allodynia), treatment-related factors (eg, suboptimal acute treatment, acute medication overuse, barbiturate-containing or opioid medications), comorbidities (eg, psychiatric disorders, metabolism-related conditions, traumatic head injury), lifestyle factors (eg, frequent exposure to stressful events, adverse childhood experiences), and demographic factors (eg, being female, hormonal status). ^{7 , 8} The actions with the best evidence for protection against chronification are to optimize acute and preventive medications. ⁸

CONDITION BURDEN

Approximately 2.81 billion individuals globally had migraine disease or tension-type headache in 2021, with female individuals aged 15 to 49 years being the most affected. ⁹ The global burden of migraine disease increased from 1990 to 2021 based on both prevalence (increased by 1.6% to a prevalence of 14,246.5/100,000) and years lived with disability (increased by 0.6% to 532.7/100,000 years lived with disability). ¹⁰ Among disorders affecting the nervous system in 2021, it was the third highest globally and the second highest in North America based on disability-adjusted life-years. In the same year, it was the leading cause of nervous system disability-adjusted life-years for children and adolescents aged 5 to 19 years (380.0/100,000) and the second highest for adults aged 20 to 59 years (750.8/100,000). It is significantly more prevalent in female individuals, with a female to male ratio in 2021 of 1.69. ¹⁰

Patients with migraine disease experience significant burden during migraine attacks, with common symptoms including head pain, aura, affected vision, photophobia, phonophobia, nausea, vomiting, dizziness, and cognitive effects. ^{1 , 11} They also experience burden due to treatment side effects and between attacks during the interictal phase. ¹¹ Interictal burden includes decreased health-related quality of life, lifestyle modifications in anticipation of an attack, and impacts on work, career, daily activities, and relationships. Emotional impacts such as anger, depression, anxiety, and hopelessness are also common. Preventive treatments improve health-related quality of life and functioning for many patients, but breakthrough attacks are common, and with some treatments, patients have reported varying efficacy between doses. ¹¹

Like other invisible or concealable conditions, migraine disease is stigmatized, and migraine disease–related stigma is associated with more disability, greater interictal burden, and reduced quality of life. ¹² Stigma may result, for example, when individuals appear well between attacks. They are often expected to function normally and, if unable, may be viewed as avoiding responsibility or participation because of laziness or poor work ethic. Additionally, instead of recognizing migraine as a neurological disorder, it gets incorrectly attributed to factors like stress, mood disorders, poor sleep, diet, and hydration. This may lead to patients blaming themselves or being blamed by others for their condition. There is also evidence that migraine is not considered a significant neurological disorder among physicians, which could lead them to devalue the treatment needs of patients with migraine disease. ¹² Minimal headache education in medical school for many physicians may further compound this bias. ¹³

MANAGEMENT

Management of migraine disease is focused on alleviating the symptoms of acute attacks, reducing the frequency and severity of attacks, and improving individual quality of life. ^{1 , 14} Treatment plans for migraine disease should include acute treatment for all patients and preventive treatment when indicated. ¹⁴ Patients also benefit from discussing optimization of lifestyle, maintaining a headache diary, and counseling on available nonpharmacologic treatments. ¹⁴

Acute Pharmacologic Treatment.

All patients should be offered acute treatment for migraine disease and education to decrease their risk of medication overuse headache. ¹⁴ Principles of acute pharmacologic treatment selection and acute pharmacologic treatments with established and probable efficacy in migraine disease as listed by the American Headache Society (AHS) are detailed in Table 2. These include but are not limited to nonsteroidal anti-inflammatory drugs, acetaminophen and caffeine combinations medications, ergot derivatives, selective serotonin 1F receptor agonists (ditans), selective serotonin 1B/1D receptor agonists (triptans), and small molecule CGRP receptor antagonists (gepants). Peripheral nerve block may also be used particularly when patients require rescue treatment when initial acute medication does not provide pain relief. ¹⁴

TABLE 2.

Pharmacologic Treatment Selection in Migraine Disease ^{14 , 39}

Acute	Preventive
Principles of treatment selection
Use evidence-based treatments • A treatment not specific to migraine disease for mild to moderate attacks • A treatment specific to migraine disease for severe attacks Choose a nonoral route when there is severe nausea/vomiting Assess benefit vs risk Consider a self-administered rescue treatment Avoid medication overuse Criteria for initiating acute treatment with gepants, ditans, or neuromodulatory devices: • Contraindications to or inability to tolerate triptans, or • Inadequate response to 2 or more oral triptans	Use evidence-based treatments Start low and titrate When reaching a therapeutic dose, give an adequate trial of at least 3 mo Establish realistic expectations Consider factors to optimize treatment and maximize adherence, such as: • Tolerability • Episodic vs chronic • Concomitant medications • Body habitus • Ease of use • Contraindications/allergies • Patient preference • Comorbid illnesses • Physiological factors (eg, blood pressure) • Pregnancy/potential pregnancy • Response to previous treatments • Cost/insurance coverage
Pharmacologic treatments with established efficacy in migraine disease
Nonspecific to migraine disease • Acetaminophen/aspirin/caffeine •NSAIDs: aspirin, celecoxib oral solution, diclofenac, ibuprofen, naproxen Specific to migraine disease • Ergotamine derivatives • Lasmiditan (ditans) • Selective serotonin 1B/1D receptor agonists (triptans) • Small molecule CGRP receptor antagonists (gepants)	CGRP receptor antagonists • mAbs • Gepants: atogepant, rimegapant Candesartan Divalproex sodium Frovatriptan Metoprolol OnabotulinumtoxinA Propranolol Timolol Topiramate Valproate sodium
Pharmacologic treatments with probable efficacy in migraine disease
Nonspecific to migraine disease • NSAIDs: flurbiprofen, ketoprofen, IV/IM ketorolac •IV magnesium • Isometheptene-containing compounds • Antiemetics: chlorpromazine, droperidol, metoclopramide, prochlorperazine, promethazine Specific to migraine disease • Ergotamine • Other forms of dihydroergotamine	Amitriptyline Atenolol Lisinopril Memantine Nadolol OnabotulinumtoxinA + CGRP mAb Venlafaxine

Adapted from The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice.

CGRP = calcitonin gene–related peptide; IM = intramuscular; IV = intravenous; mAb = monoclonal antibody; mo = month; NSAID = nonsteroidal anti-inflammatory drug.

It should be noted that gepants are not associated with medication overuse headache. ¹⁴ In contrast, neither butalbital nor opioids are recommended in the treatment of migraine disease except as a last resort because of significant risk of medication overuse headache. ^{14 , 15}

The goals of acute treatment are to (1) achieve rapid and consistent freedom from pain and associated symptoms, (2) restore ability to function, (3) minimize need for repeat dosing or rescue medications, (4) avoid or minimize adverse events, (5) optimize self-care and reduce health care resource utilization (eg, emergency department [ED] visits, diagnostic imaging, outpatient services), and (6) maintain affordability to patients. ¹⁴

Patient-oriented, validated outcome measures of acute treatment success can help determine whether patients have experienced a meaningful response and identify the need for adjustments to a treatment plan. ¹⁴ The AHS recommends several tools of varying lengths, with questions evaluating, for example, patient satisfaction with their acute treatment based on efficacy (eg, 2-hour pain freedom, pain relief), function, ease of use, cost, and tolerability. ^{14 , 16 – 18}

Preventive Pharmacologic Treatment.

Preventive treat­ment is indicated for frequent attacks, severe disability despite acute treatment, acute treatment contraindication or side effects, medication overuse headache risk, or patient preference. ¹⁴ Principles of preventive pharmacologic treatment selection and preventive pharmacologic treatments with established and probable efficacy in migraine disease as listed by the AHS are detailed in Table 2. These include but are not limited to CGRP receptor antagonist monoclonal antibodies (CGRP mAbs), the gepants atogepant and rimegepant, candesartan, divalproex sodium, metoprolol, onabotulinumtoxinA, propranolol, timolol, topiramate, and valproate sodium. ¹⁴

The goals of preventive treatment are to (1) reduce attack frequency, severity, and duration, (2) improve function and reduce disability, (3) improve responsiveness to and avoid escalation in use of acute treatment, (4) reduce reliance on poorly tolerated, ineffective, or unwanted acute treatments, (5) improve health-related quality of life, (6) reduce headache-related distress and psychological symptoms, (7) enable patients to manage their own disease to enhance a sense of personal control, and (8) reduce overall cost associated with migraine disease treatment. ¹⁴

Determining the efficacy and tolerability of preventive treatment should be patient driven. ¹⁴ Outcome measures that may be important to patients include a reduction in days with headache or migraine (eg, 50% reduction in days per month with headache or migraine), a significant decrease in migraine attack severity and duration, improved response to acute treatment, reduction in migraine-related disability and improvement in functioning, and improvement in health-related quality of life and reduction in psychological distress due to migraine. ¹⁴

Nonpharmacologic Treatment

Lifestyle.

The mnemonic SEEDS (sleep, exercise, eat, diary, and stress) can assist with lifestyle management for patients with migraine disease. ¹⁹ It includes standard sleep hygiene to maximize sleep quantity and quality, exercise for 30 to 60 minutes 3 to 5 times a week, regular healthy meals and adequate hydration, and low or stable caffeine intake. Additionally, it emphasizes patients should keep a migraine attack diary to establish a baseline pattern, assess response to treatment, and monitor analgesia. The importance of coping with condition-related and other stress is also highlighted and can be done, for example, through cognitive behavioral therapy, mindfulness, relaxation, biofeedback, and developing health care provider (HCP)–patient trust to minimize anxiety. ¹⁹

Neuromodulation.

All patients with a confirmed diagnosis of migraine disease may be offered treatment with a neuromodulatory device, which modulates pain mechanisms involved in headache by stimulating the nervous system with an electric current or a magnetic field. ^{14 , 20} They can be used for both acute and preventive treatment alone or in combination with pharmacologic therapy. Neuromodulatory devices can especially be considered in patients who prefer to avoid medication; those with a history of poor medication tolerability, significant medication contraindications, or inadequate response to medication; those at risk of medication overuse headache or migraine chronification; and those who are indicated for preventive treatment. ^{14 , 21}

Biobehavioral therapies.

Cognitive behavioral therapy, biofeedback, and relaxation therapies have good evidence for their use as preventive therapies. ¹⁴ Limited evidence and clinical experience also support their use as acute therapies. Additionally, mindfulness-based therapies and acceptance and commitment therapy are active topics of research and have a growing evidence base for use in migraine disease. ¹⁴

Complementary/alternative therapies. 

Physical therapy, massage therapy, and acupuncture may be used as complementary or alternative therapies in migraine disease. ²¹ Meta-analyses of evidence for acupuncture, for example, indicates reduction in the frequency of migraine attacks and is less likely than medication to result in adverse effects. ²¹

Dietary/herbal supplementation. 

Dietary and herbal supplements can be used as part of a migraine disease treatment plan. Magnesium, Coenzyme Q10, and riboflavin have evidence for their use in migraine disease. ^{21 , 22}

EMERGING TREATMENTS

The discussion below provides brief summaries of selected treatments for migraine disease that are in advanced stages of development.

Lu AG09222.

Lu AG09222 is a monoclonal antibody, which targets PACAP and inhibits its effects. ² In a phase 2, double-blind, randomized, placebo-controlled trial, the safety and efficacy of Lu AG09222 were evaluated in a total of 237 participants (Lu AG09222 750 mg n = 97, Lu AG09222 100 mg n = 46, placebo n = 94). ²³ The primary endpoint was the mean change from baseline in the number of migraine days per month in the Lu AG09222 750 mg group as compared with the placebo group. The mean number of baseline migraine days per month was 16.7, and the mean change from baseline was −6.2 days in the Lu AG09222 750 mg group and −4.2 days in the placebo group (difference, −2.0 days; 95% CI, −3.8 to −0.3; P = 0.02). Adverse events with a higher incidence in the Lu AG09222 750 mg group than in the placebo group during the 12-week observation period included COVID-19, nasopharyngitis, and fatigue. ²³

Digital Therapeutics.

Digital therapeutics used in migraine disease are primarily smartphone applications. ²⁴ These may, for instance, link patients with headache experts online to diagnose migraine disease or provide treatment options, offer digital diaries and other tools to diagnose and track migraine attacks, and support nonpharmacologic treatment including providing digital cognitive behavioral therapy. The evidence for digital therapeutics is still evolving, and much of it is focused on the use of digital diaries. ²⁴ However, one published protocol describes a new study to assess the efficacy of several interdisciplinary digital interventions compared with conventional treatment options. ²⁵ Digital interventions will include headache nurse counseling, cognitive behavioral therapy, and physical therapy in addition to a headache diary. The primary outcome measure will be the number of headache days at 3 months compared with baseline, with secondary objectives of evaluating components such as adherence, credibility, clinical contact, and cost-effectiveness in comparison with conventional treatment delivery. ²⁵

Optimal Management in Various Practice Settings

Primary barriers to optimal management in migraine disease include patient reluctance to initiate a discussion about their migraine disease symptoms with their HCP, delays in receiving a correct diagnosis of migraine disease, and being offered a minimally appropriate standard-of-care treatment once a diagnosis is established. ^{26 , 27} Because primary care providers (PCPs) and ED providers are often the first point of contact for patients with migraine disease within the health care system, there is opportunity for them to assist in addressing these barriers. ²⁷ For instance, acknowledging that migraine disease is underdiagnosed, especially among women, and proactively asking patients about headaches or number of days they are headache-free. Also, using empowering, nonstigmatizing language such as migraine attacks vs migraines, which helps to acknowledge there is a wide range of symptoms other than head pain that may be experienced during an attack and may encourage patients to discuss them. ²⁷

Additionally, owing to the limited number of headache specialists, it is important for these front-line HCPs to be comfortable treating migraine disease as well as knowing when to refer patients to another HCP. ²⁷ Knowing how to recognize a likely patient with migraine disease (ie, if the patient mentions head pain plus 2 of photophobia, nausea, or inability to focus) is a key first step. ^{27 , 28} Once identified, a trial of at least 2 acute migraine disease treatments and 2 preventive migraine disease treatments is suggested before referring the patient to a neurologist or a headache specialist. ²⁷

However, there are differences in barriers to diagnosis and treatment options among PCPs. ²⁹ Lack of diagnosis may be due to factors such as unclear patient histories, prioritizing other comorbidities, insufficient time, or lack of education. ^{13 , 29} Diagnosis and treatment may also be impacted by length of time in clinical practice. ²⁹ It is important, therefore, that training programs, health systems, and professional societies and others that provide clinician continuing education contribute to increasing familiarity with migraine disease and its treatments and decreasing barriers to migraine care. ^{13 , 29}

A more detailed description regarding the patient journey with migraine disease and how these barriers may affect it can be found in Figure 2.

FIGURE 2.

Migraine Disease Patient Journey ^{38 , 63 , 64}

Health Disparities Among a Diverse Migraine Disease Population

Disparities exist in the diagnosis, treatment, and outcomes of underserved patients with migraine disease and other headache disorders. ³⁰ These disparities are based on race, sexual orientation, socioeconomic status, and geography, among other factors. For example, although the prevalence of severe headache and migraine disease is reportedly similar among Black, Hispanic, and White individuals in the United States, Black and Hispanic patients are 25% and 50% less likely, respectively, to receive a migraine disease diagnosis compared with White patients, and Black men receive the least care for migraine disease. Additionally, Black patients report more headache days per month, higher pain intensity, and poorer quality of life than White patients, indicating potentially more severe disease or a greater extent of undertreatment, or both. ³⁰ Undertreatment may be at least in part due to a persistent incorrect stereotype that Black patients are more pain tolerant. ^{30 , 31}

There are few data on potential disparities among native/indigenous people in America despite them having the highest prevalence of migraine (19.2%); however, they are more likely to experience allodynia, which is associated with poor treatment outcomes. ³⁰ There are also limited data on potential disparities and the experience of migraine among Asian Americans. ³⁰

Among sexual minority groups, the prevalence of migraine disease is higher compared with those who are heterosexual, which may in part be due to sexual minority stress consisting of prejudice, stigma, and discrimination and may also be influenced by gender-affirming hormone therapy. ^{32 , 33} Although data specific to biases in migraine disease or other headache disorders are lacking, biases among health care professions students and HCPs toward sexual and gender minority patients have been documented in the health care literature. ³⁰ These patients also report discrimination from HCPs and are more likely to delay or avoid necessary medical treatment compared with nonminority patients. ³⁰

Lower-income groups have a 60% higher rate of migraine disease compared with higher-income groups, and they are less likely to receive acute migraine disease treatment, putting them at higher risk for migraine disease progression. ³⁰ It has been proposed that this disparity may be due to social selection, a situation in which individuals may be unable to perform their regular educational and occupational responsibilities, leading to a decline in social status because of migraine disease disability, or social causation, a situation in which low socioeconomic status is linked to increased stress, which causes an increased duration or incidence of disability. ³⁰

Geographic disparities also exist, as the density of headache specialists is lower in rural states and there are limited or no training programs in some areas. ³⁰ Additionally, social stigma and privacy concerns act as even greater barriers to health care access in rural communities where there is little anonymity. Transportation, travel time, longer wait times, and greater income loss because of additional time off work for health care visits also pose challenges for rural patients. Technology such as telehealth may provide a solution for some but can compound disparity for rural patients if they do not have access to sufficient technological infrastructure or knowledge, for example. ³⁰

Fostering Patient-Centered Care

A primary need expressed by patients is to have their opinions heard, validated, and respected by their HCP because despite its significant associated disability, many patients feel they and migraine disease as a disorder are not taken seriously. ³⁴ A more patient-centered approach can be achieved through HCP awareness of and work to mitigate their biases and, as previously discussed, through the use of empowering, nonjudgmental language. ^{27 , 34} Care can also be more patient-centered by using a shared decision-making process, which requires HCPs to have the most current knowledge regarding migraine disease and its treatment and to use it to discuss varying treatment characteristics and help patients weigh the pros and cons of each option. ³⁴ Additionally, asking patients to keep a headache diary and reviewing it at each visit includes patients as active participants in their care and allows for improved monitoring of symptoms, function, and treatment effect. ^{19 , 27 , 34}

Regarding treatments, patient preferences include nonpharmacologic options, long-lasting effect, high effectiveness, rapidity of action, lower cost and improved access, and having a self-management/self-delivery option. ³⁴ Treatment outcomes important to patients include side effects, addiction potential, function, pain reoccurrence, and nonheadache symptoms. This highlights the value of HCPs being mindful of migraine symptoms beyond headache, such as aura, nausea/vomiting, photophobia, and phonophobia, and how migraine disease may affect functioning. ³⁴ It also reinforces the AHS recommendation to use patient-oriented, validated tools to evaluate treatment effectiveness. ^{14 , 31}

Managed Care Considerations in Migraine Disease

SUPPORTING EQUITABLE ACCESS TO CARE

Equity in access to migraine disease care can be supported clinically, in terms of clinician education and training, and by addressing systemic disparities in research. ³⁰ Suggested clinical strategies include using telemedicine and encouraging migraine disease care in primary and secondary settings to mitigate geographic disparities and limited specialist availability, promoting screenings to determine and help address unmet needs, and proactively considering accessibility issues to optimize care once initiated. ³⁰

Managed care organizations (MCOs) can play a role in these strategies, for example, by allowing coverage of telehealth visits in accordance with relevant laws, advocating for expansion of legislation related to telehealth, providing resources to their members to address challenges with use of technology, and ensuring the availability of translating services for telehealth visits on platforms they promote. ³⁰ Additionally, they can continuously review and improve HCP networks when possible, and work with relevant stakeholders such as HCPs and employer groups, to increase migraine disease screenings and improve quality of care. ³⁰

MCOs can also work with their HCP partners to provide education on migraine disease and its treatments when appropriate, and work with their drug development partners through education or joint forums like those facilitated by AMCP, for example, to improve representation of minority and vulnerable groups in research and evidence generation. ³⁰

These considerations for supporting equitable access to care in migraine disease are listed in Table 3.

TABLE 3 .

Managed Care Considerations in Migraine Disease ^{30 , 35 , 38 – 41 , 44}

Focus	Considerations
Supporting equitable access to care	• Allow coverage of telehealth visits in accordance with relevant laws. • Advocate for expansion of legislation related to telehealth. • Provide resources to members to address challenges with use of technology. • Ensure the availability of translating services for telehealth visits on promoted platforms. • Continuously review and improve provider networks when possible. • Work with relevant stakeholders such as health care providers and employer groups to increase migraine disease screenings and improve quality of care. • Work with health care provider partners to provide education on migraine disease and its treatments when appropriate • Work with drug development partners to improve representation of minority and vulnerable groups in research and evidence generation.
Managing treatments for migraine disease	Coverage policy—The coverage determination process should be clear and efficient. The following criteria elements may be considered: • Appropriate patient population • Diagnosis • Ability to use other treatment options (eg, drug-drug interactions) • Other patient-specific factors (eg, route of administration needs, impact of tolerability on adherence) • Specialist consultation requirement • Allowing concomitant use • Coverage renewal parameters • Align pharmacy and medical policies (eg, onabotulinumtoxinA) Preferred medications/step therapy—Consider guideline recommendations such as from the American Headache Society and American College of Physicians. Quantity limits—Consider prescribing information maximum dosages and risks of medication overuse headache and chronification with acute treatments. Value-based arrangement—Consider outcomes-based contracts for newer or more costly medications to ensure cost-effective use. Nonpharmacologic treatments—Consider strategies to encourage appropriate use including coverage when applicable.

MANAGING TREATMENTS FOR MIGRAINE DISEASE

In a 2020 review of the acute migraine disease treatments lasmiditan—a serotonin agonist—and the gepants, rimegepant and ubrogepant, the Institute for Clinical and Economic Review (ICER) concluded that the evidence does not demonstrate superiority of these newer agents vs existing less-expensive treatment options (eg, triptans), nor does it show major differences in the safety and efficacy between rimegepant and ubrogepant. ³⁵ As a result, in the final policy recommendations, they state it is reasonable for payers to develop coverage criteria based on clinical evidence, clinical practice guidelines, and input from clinical experts and patients for these therapies to ensure their prudent use. They also indicate it is reasonable for payers to prefer certain products, provided there is a path to appeal for coverage of nonpreferred products when clinically appropriate. ³⁵ This might be in the case of triptan nonresponse, which reportedly occurs in approximately 30% of patients, or contraindications to triptans, for example. ¹⁴

Since this review, rimegepant has gained an indication for preventive treatment of episodic migraine, and the new gepant, zavegepant (intranasal spray), has been approved for the acute treatment of migraine attacks (details of all the most recently approved novel pharmacologic treatments in migraine disease can be found in Table 4). ^{36 , 37} MCOs should consider these and other ongoing developments along with the currently available clinical and value evidence in their management strategy for acute migraine disease treatments.

TABLE 4 .

Recently Approved Novel Pharmacologic Treatments in Migraine Disease ^{36 , 37 , 42 , 43 , 45 – 60}

Product	Dosage form	Indications	Approval date
CGRP receptor antagonist monoclonal antibodies (CGRP mAbs)
Eptinezumab	Intravenous injection	Preventive treatment of migraine attacks in adults	February 2020
Erenumab	Subcutaneous injection	Preventive treatment of migraine attacks in adults	May 2018
Fremanezumab	Subcutaneous injection	Preventive treatment of migraine attacks in adults	September 2018
Galcanezumab	Subcutaneous injection	Preventive treatment of migraine attacks in adults	September 2018
		Treatment of episodic cluster headache	June 2019
Small molecule CGRP receptor antagonists (gepants)
Atogepant	Oral tablet	Preventive treatment of migraine attacks in adults	April 2023
Rimegepant	Oral disintegrating tablet	Acute treatment of migraine attacks with/without aura	February 2020
		Preventive treatment of episodic migraine disease	May 2021
Ubrogepant	Oral tablet	Acute treatment of migraine attacks with/without aura	December 2019
Zavegepant	Nasal spray	Acute treatment of migraine attacks with/without aura	March 2023
Selective serotonin 1F receptor agonists (ditans)
Lasmiditan	Oral tablet	Acute treatment of migraine attacks with/without aura	October 2019

CGRP = calcitonin gene–related peptide.

ICER also conducted a review of the preventive CGRP mAbs erenumab, fremanezumab, and galcanezumab in 2018, acknowledging their then-new mechanism of action and lack of long-term safety and efficacy data. ³⁸ Like acute treatments, their recommendations for these medications stated it was reasonable for payers to implement coverage criteria to ensure prudent use and to prefer certain products, with nonpreferred products accessible by appeal. ³⁸

Since this review, a more robust body of evidence for all CGRP receptor antagonists is available and the AHS has provided a consensus statement indicating that CGRP receptor antagonists may be a first-line option for preventive treatment of migraine disease. ³⁹ This recommendation is based on their assessment that the efficacy and tolerability of CGRP receptor antagonists are equal to or greater than those of older first-line treatments and that serious adverse events with CGRP receptor antagonists are rare. ³⁹

An even more recent comparative effectiveness analysis performed by the American College of Physicians, however, led to the recommendation that a trial of metoprolol, propranolol, valproate, venlafaxine, or amitriptyline is appropriate prior to initiation of a CGRP receptor antagonist. ⁴⁰ Other groups encourage caution when using these results owing to limitations with the data used in the analysis. ⁴¹ For example, many of the studies use outdated methods and definitions of migraine and often included patients with mild disease. ⁴¹

Also since the ICER review, the CGRP mAb eptinezumab (intravenous injection) and the gepant atogepant (oral tablet) have been approved for the preventive treatment of migraine attacks (details of all the most recently approved novel pharmacologic treatments in migraine disease can be found in Table 4). ^{42 , 43} MCOs should consider these and other ongoing developments along with the currently available clinical and value evidence in their management strategy for preventive migraine disease treatments.

A detailed list of managed care considerations in migraine disease can be found in Table 3.

Conclusions

Migraine disease is a complex neurological condition with significant burden globally, as well as to individual patients. Recent advances in migraine disease treatment and ongoing research may offer additional options for patients; however, treatment barriers still exist and result in underdiagnosis and undertreatment of migraine disease, especially in some minority and vulnerable groups. There is opportunity for front-line providers and MCOs to address these barriers, particularly with strategies to make care more patient-centered, and to support equitable access.