Migraine management is shifting from the use of nonspecific preventive treatments toward migraine-specific therapies that target CGRP and other pathways that are implicated in the pathophysiology of migraine. Amaal J. Starling, MD, FAAN, FAHS, and Stewart J. Tepper, MD, FAHS, discuss current treatment selection, emerging therapeutic targets, neuromodulation, and patient-centered goals for migraine freedom.

In terms of treatment evolution in migraine, we began with nonspecific preventive treatments that were developed for other therapeutic areas, including antidepressants, antihypertensives, and antiseizure drugs. These agents had modest benefit but were limited by side effects, titration requirements, and poor adherence. In a retrospective claims database study of more than 8600 people, more than 80% had stopped these types of preventive medicines by the end of 1 year. That is the definition of clinical futility.

The first of the migraine-specific treatments were triptans. These were serotonin agonists specifically developed as acute treatments for migraine, and they made a huge difference in terms of how we could treat patients. The next big wave of preventive and acute treatments targeted the CGRP pathway outside the brain, and those included monoclonal antibodies targeting the CGRP ligand or receptor and small-molecule CGRP receptor antagonists (collectively known as gepants), which block the CGRP receptor. OnabotulinumtoxinA was also discovered fortuitously to prevent chronic migraine, and, while it is not technically a migraine-specific medication, it is very important because of its low number of side effects and high efficacy.

A number of receptors that are implicated in the pathophysiology of migraine are currently being studied, most predominantly PACAP. PACAP is released very similarly to CGRP, and it has more parasympathetic effect than CGRP. With respect to PACAP, a phase 2a trial published in The New England Journal of Medicine showed that a single infusion of an anti-PACAP ligand monoclonal antibody called bocunebart worked to reduce migraine days over 4 weeks, with reasonably low adverse events. Another emerging treatment target is the MRGPRX2 receptor; blocking this receptor may affect multiple sensory neuropeptides associated with migraine, including PACAP. TRP channels are also being studied. These evolving targets suggest that migraine care is still early in the migraine-specific medication era.

In current practice, individualizing therapies sometimes comes down to patient preference. We do not yet have sufficiently reliable clinical data to predict which patient will respond to which medication based on their individual profile, so selection often depends on whether a patient prefers oral medications, monthly or quarterly injections, infusions, or medications that can be used for both preventive and acute treatment, such as gepants.

Many current treatment approaches target migraine pathophysiology downstream in the attack, but the prodrome phase involves central activation in the hypothalamus. Future approaches, including orexin modulation or other hypothalamic targeting, may be able to treat migraine at the anatomical onset of the attack rather than blocking a single downstream pathway involving CGRP, PACAP, or TRP.

GLP-1 receptor agonists have also been a popular topic in medicine, including in migraine research. We know that obesity and visceral fat can create a proinflammatory environment, and a proinflammatory environment can reduce the threshold for a migraine attack and promote migraine chronification. A recent small pilot study showed a decrease in migraine frequency with the GLP-1 receptor agonist liraglutide. Larger randomized controlled studies are ongoing to see whether GLP-1 receptor agonists might be a mechanism-based treatment option.

Moreover, we have had an explosion of noninvasive neuromodulation devices, and other noninvasive and implantable techniques are being studied. Neuromodulation gives us the opportunity to modulate peripherally in a way that may also affect centrally mediated migraine mechanisms. Clinical data show not only benefit at 3 or 6 months but also sustained benefit with continued use over time. This may reflect neuromodulation normalizing function in the moment, with neuroplastic potential to change the disease process over the longer-term.

Patients can feel hopeful that the treatment armamentarium is continuing to grow and is supported by clinicians, researchers, and scientists who are working to advance migraine care. We should measure what matters to the patient, treat to a defined target, and aim for migraine freedom or fewer than 4 migraine days per month and a return to normal function within 2 hours of each attack.