Headache Horizons: Key Updates in Headache and Migraine Care

Headache and migraine care are evolving rapidly, advancing along with our understanding of the pathophysiology and etiology of these conditions, from the important role of social determinants of health to the development of novel therapeutic targets and technologies. This review article highlights some of the recent updates and developments in the field, including important clinical trials, holistic strategies for improving outcomes, and promising horizons in headache therapy. 

Recent Updates from Clinical Trials and Studies in Headache

Advancements in headache and migraine treatment may reshape traditional approaches to care by focusing on early intervention and improving quality of life (QoL). New therapies, such as gepants (oral calcitonin gene-related peptide [CGRP] receptor antagonists), have the potential to reduce migraine severity before the headache develops, which may improve outcomes considerably. Innovations in combination therapies and neuroimaging are also expanding treatment options, as well as the field’s developing understanding of the beneficial effects of treatment with glucagon-like peptide-1 (GLP-1) agonists.

Gepants: Shifting the Paradigm Toward Early Intervention and Improving Quality of Life

The 2023 results of the landmark UBR Prodrome study (Study to Evaluate Oral Ubrogepant in the Acute Treatment of Migraine During the Prodrome in Adult Participants; NCT04492020),¹ which evaluated the initiation of ubrogepant (Ubrelvy; AbbVie, North Chicago, IL) treatment during the prodromal phase of migraine, have critical implications that may challenge the field’s longstanding focus on preventing migraine through the avoidance of triggers. Instead, treatment with the CGRP receptor antagonist ubrogepant at the onset of prodromal migraine symptoms (eg, irritability, mood changes, fatigue, sensory disturbances) was shown to reduce the chance of developing migraine headache hours later by half. Applying these study findings in clinical practice by educating and instructing patients to use ubrogepant as a prodromal intervention may have an empowering effect, helping them feel more in control of their symptoms as opposed to a prevention-oriented approach focused on the avoidance of triggers: advice that runs counter to basic principles of psychology (stimulus avoidance actually enhances the power of triggers rather than reducing it) and may be associated with increased stigmatization. As discussed later in this article, migraine stigma can have a substantial effect on outcomes and QoL.

Studies evaluating atogepant (Qulipta; AbbVie, Lake Bluff, IL), such as those by Lipton et al² in 2023, Lipton et al³ in 2024, and Rizzoli et al⁴ in 2024, may have similar, potentially paradigm-shifting implications. In secondary analyses of these trials, atogepant treatment was associated with fewer headache days as well as significant reductions in migraine severity and duration. In terms of QoL, these findings reinforce other study findings as well as clinical experience that reducing the severity or duration of migraine is at least as impactful as reducing migraine days overall. Even without a reduction in the number of migraine attacks, people who experience a reduction in migraine severity are likely to have reduced anxiety and increased success in accomplishing personal and professional goals—both of which are important factors for QoL. In addition, the reduction of migraine severity may enable treatment with fewer medications, which has implications for medication overuse headache.

Central Sensitization

Central sensitization, a hallmark of chronic migraine, describes the increased responsiveness of nociceptive neurons in the central nervous system, which can cause hyperalgesia and allodynia. Most people with chronic migraine show some degree of central sensitization, but most migraine treatments do not target this underlying pathophysiologic mechanism. In one study from 2024 by Danno et al,⁵ participants treated for 6 months with galcanezumab (Emgality; Eli Lilly, Indianapolis, IN), a CGRP-targeting monoclonal antibody, reported significant improvements in central sensitization–associated symptoms as measured using validated rating scales.

Vestibular Migraine

Treatment with galcanezumab was also shown to produce some improvement in patients diagnosed with vestibular migraine, according to a pilot study by Sharon et al.⁶ This study is a significant advance given that vestibular migraine appears to be the most common cause of dizziness and vertigo in the general population.

Combination Therapy

Earlier this year, the Food and Drug Administration announced the approval of single-dose combination therapy with meloxicam and rizatriptan (Symbravo; Axsome Therapeutics, New York, NY]) for the acute treatment of migraine. The approval was based on clinical trial data from the MOMENTUM clinical trial (Maximizing Outcomes in Treating Acute Migraine; NCT03896009) suggesting that the absorption rate for meloxicam and rizatriptan when combined using molecular solubility enhanced inclusion complex technology is faster than for each drug by itself. For clinicians, this research highlights the importance of using multiple drug classes instead of limiting acute treatment to a single drug type.⁷

Triptans vs Gepants

A large meta-analysis published in the British Medical Journal in 2024⁸ demonstrated that triptans may be more effective than gepants for the acute treatment of migraine. However, treatment with gepants is associated with some unique benefits, such as fewer adverse events, but the results of this meta-analysis remind us that older-generation triptans remain a useful tool in the physician’s armamentarium. 

CSF Pressure Disorders: GLP-1 Agonists and New Diagnostic Neuroimaging Options 

A landmark 2024 trial⁹ evaluated the use of exenatide, a GLP-1 agonist, as a treatment for individuals with idiopathic intracranial hypertension (IIH), demonstrating unprecedented dual benefits. Unlike traditional IIH therapies like acetazolamide, exenatide not only reduced cerebrospinal fluid (CSF) production and intracranial pressure but also significantly decreased headache frequency, addressing an important gap in care. The mechanisms of GLP-1 agonists extend beyond satiety induction to include fat metabolism modulation and reduced CSF production, making them ideal for IIH, particularly in patients with obesity.

This contrasts with the results of the 2014 international Idiopathic Intracranial Hypertension Treatment Trial,¹⁰ which found that treatment with acetazolamide, weight loss, or both in combination preserved vision but had no effect on headaches. The evidenced ability of GLP-1 agonists to concurrently mitigate CSF pressure and headache burden would represent a major development in the treatment landscape, offering a single agent to target both IIH pathophysiology and symptom burden.

Advances in neuroimaging have further refined our understanding of IIH and related disorders. In individuals with IIH, MRI findings of perioptic nerve sheath distension and tortuosity (due to elevated CSF pressure) remain diagnostic cornerstones. A new study from the Cedars-Sinai group shows that spontaneous intracranial hypotension (SIH) from spinal CSF leaks is now identifiable by reduced perioptic CSF volume on coronal orbital MRI—a simple yet highly predictive marker of an underling CSF-venous fistula.¹¹ These imaging nuances underscore the importance of tailored protocols for CSF pressure disorders, enabling precise diagnosis and monitoring.

Migraine Stigma and Prodromal Treatment

Migraine stigma remains a pervasive and underrecognized barrier to effective care, profoundly affecting QoL. A recent analysis from the OVERCOME study published in Neurology demonstrated the significant negative effects of stigma,¹² which increased migraine burden regardless of headache frequency. People who experience stigma—including dismissive attitudes or accusations of dishonesty—report significantly worse QoL than those with more frequent headaches but less stigma. For example, a patient with 20 headache days per month but minimal stigma may have better outcomes than someone with only 2 headache days per month who experiences frequent stigmatization.

Another recent study, published in 2023 in the American Sociological Review,¹³ investigated how various diseases are framed in the lay press by analyzing ~5 million documents mentioning 106 diseases over 40 years. The researchers assessed whether the surrounding language conveyed a pejorative or positive framing. They measured stigma based on “judgment” and “disgust” scores; judgment was defined as the extent to which a disease is associated with negative character traits or moral failings; disgust was defined as the degree to which the disease is viewed as repulsive or shameful. The study revealed that migraine is among the most judged chronic illnesses, surpassing human immunodeficiency virus infection, tuberculosis, Lyme disease, some sexually transmitted infections, anxiety or depression. Conditions such as Parkinson disease and multiple sclerosis were shown to be viewed more favorably.¹³

The knowledge that migraine remains so highly stigmatized along with new insight into the powerful impact of experienced stigma on the burden of migraine compel us to find ways to mitigate migraine stigma. One opportunity lies in reframing the idea of “triggers”, which we now understand are actually symptoms of migraine prodrome (eg, becoming irritable or sensitive to light due to impending migraine does not mean that “stress” or bright lights “caused my migraine”). Yet reinforcing the concept of triggers also perpetuates the idea that migraine patients have negative character traits—the basis of “judgement”—by implying that they have weak character traits and “cannot handle” everyday life. Reframing the relationship of environment to migraine symptom severity as one mediated by prodromal sensitization and/or cognitive impairment is an empowering conversation—as opposed to instructing patients to avoid exposure to triggering stimuli by avoiding situations of everyday life.

Shifting the migraine treatment paradigm away from prevention and toward early intervention—such as through ubrogepant treatment initiation at the onset of prodromal symptoms—may provide one strategy for reducing migraine stigma. Treatments that reduce the severity of migraine attack, initiated before the onset of the most painful symptoms, may enable patients to reframe their understanding of migraine as a treatable neurologic condition, rather than a perceived personal failing or weakness.

Implementing Insights from Research Into Practice: Key Takeaways

By incorporating the following recommendations into clinical practice, physicians may be able to improve the care provided to their patients with migraine:

Recognize migraine prevalence: multiple lines of research indicate that ~95% of patients presenting with recurring headaches should be diagnosed with migraine. Early recognition improves treatment outcomes. Physicians should avoid the misdiagnosis of migraine as other disorders, such as sinus or tension headache.¹⁴

Simplify diagnosis: it may be more effective to avoid overlapping diagnoses and to treat the majority of headache conditions as migraine.

Focus on optimal acute care: prioritize effective acute treatments to fully resolve attacks within the first few hours. Combining multiple drug classes may be necessary depending on severity.

Partner with patients: communicate with patients to emphasize the importance of recognizing prodromal symptoms to permit early treatment vs trigger avoidance and discuss pathways to achieve their treatment goals.

CNS Lymphatic System Dysregulation: A New Frontier in Headache

In terms of the future of headache practice, one developing area of research is the role of the meningeal lymphatic system in headache. In recent studies, CGRP has been shown to directly affect the brain’s lymphatic drainage system: application or release of CGRP lead to reduced lymphatic flow in rodent models.¹⁵ This finding connects our understanding of the brain lymphatic system with migraine pathophysiology, offering new insights into the mechanisms that may underlie migraine symptoms in humans. However, studies with human participants will be necessary to confirm the role of the CNS lymphatic and glymphatic systems in headache and to identify potential strategies for treatment.

Conclusion

The evolving landscape of headache medicine is characterized by promising developments in clinical research and a growing appreciation for the potent psychosocial dimensions of migraine. Embracing early intervention strategies, such as prodromal ubrogepant treatment, and addressing migraine stigma are important steps toward empowering patients. At the same time, rapid developments in the diagnosis and treatment of CSF pressure disorders amplify our ability to address correctable causes of chronic headache. As research unveils novel mechanisms and therapeutic targets, a comprehensive approach that integrates pharmacologic advancements with patient-centered care will be imperative for improved outcomes and enhanced QoL for people with headache disorders.