Chronic migraine sufferers know an attack rarely emerges out of the blue. Aura, disruptions to cognition and sight, often appears just before the painful pressure and headache. But even prior to aura — during the earliest phase of an upcoming migraine, which is called the prodrome — people can experience unpleasant symptoms such as light and sound sensitivity, fatigue, and neck pain (1). A new analysis published in Nature Medicine  suggests that a drug approved to suppress the onset of migraine may also reduce these prodromal effects (2). The study authors said that the data may also help answer a long-running debate about how migraine begins. 

Researchers collected the new data during PRODROME, a Phase 3 placebo-controlled and double-blinded trial that assessed the migraine-suppressing ability of the small-molecule drug ubrogepant when administered during prodrome (3). Ubrogepant is part of a drug class called the gepants (4). These are antagonists of calcitonin gene-related peptide (CGRP), a molecule released during migraine that transmits pain signals (4). 

PRODROME validated urogepant’s effectiveness in treating migraines, but the trial also recorded the drug’s effect on prodrome symptoms as a secondary endpoint, said Peter Goadsby, a neurologist and director at the National Institute for Health Research (NIHR) King’s Clinical Research Facility. 

Goadsby and his colleagues recruited 477 patients for a final efficacy analysis. Participants took an oral dose of ubrogepant or placebo when they felt symptoms that they believed would develop into migraine. Under the study’s crossover design, all volunteers took both ubrogepant and placebo at different stages of the research study and acted as their own controls. The researchers asked the volunteers to record when their symptoms abated. Ubrogepant consistently produced faster symptom relief than placebo. After two hours, 19.5 percent of patients taking ubrogepant experiencing photophobia reported no symptoms compared with 12.5 percent of the placebo group. Patients experiencing fatigue or neck pain first reported greater relief after three hours, and those with sound sensitivity after four hours. 

“You can actually treat these premonitory symptoms during this premonitory phase before there's any headache altogether,” said Goadsby.

You can actually treat these premonitory symptoms during this premonitory phase before there's any headache altogether. 
- Peter Goadsby, NIHR King’s Clinical Research Facility

These findings offer an important new treatment option for migraine patients. The most effective migraine drug class, the triptans, abort head pain but can only be taken in limited doses (5). That’s because overuse can cause a rebound condition called medication-overuse headache (6). It’s hard to predict if prodromal symptoms will always turn into a full-blown migraine, said Goadsby, which meant that prescribing triptans for prodrome is considered a non-starter. No such issues are present with gepant drugs, he added. “You don't get this medication-overuse headache problem with them because they're actually preventive if you take them more frequently,” he said. 

The study team also gleaned further insight into an ongoing debate around the pathophysiology of migraine. Some researchers — Goadsby included — say that migraine is a condition that begins in the central nervous system (CNS). Others argue that it starts in the periphery, in a process involving the meninges and trigeminal nerve (7). This has not been an easy discussion to settle. “It's been going on for 30 or 40 years, if not more,” said Martin Kaag Rasmussen, a headache researcher at the University of Copenhagen who was unaffiliated with the study. Goadsby said that the study’s finding that anti-migraine drugs like ubrogepant can relieve cognitive prodrome symptoms, which are often collectively termed “brain fog,” shows that they must affect the brain itself.

Kaag Rasmussen also leans towards a CNS origin for migraine but points out many migraine drugs struggle to penetrate the blood-brain barrier (BBB). He added that injections of CGRP, which also struggles to break the BBB, can induce migraine. “It’s a very complex picture,” said Kaag Rasmussen. 

Andrew Russo, a neuroscientist at the University of Iowa, who was unaffiliated with the study, said that a paper coauthored by Kaag Rasmussen last year suggested that both sides of the debate may be correct. The article showed that cortical spreading depression — a wave of brain activity that is thought to stimulate a headache by activating pain pathways — could induce changes to proteins in cerebrospinal fluid (8). These proteins went on to activate the trigeminal nerve through a previously undetected gap in the BBB. 

The research findings clearly offer those living with unpleasant prodrome symptoms a new treatment option. Whether they settle the debate around migraine’s origin is less obvious. “We should not limit our thinking of being one or the other. It can be both central and peripheral-mediated,” said Russo.

References

1. Maniyar, F.H. et al.  The premonitory phase of migraine – what can we learn from it? Headache  55, 609–620 (2015).
2. Goadsby, P.J. et al.  Ubrogepant for the treatment of migraine prodromal symptoms: An exploratory analysis from the randomized phase 3 PRODROME trial. Nat Med, 1–7 (2025).
3. Dodick, D.W. et al.  Ubrogepant for the treatment of migraine attacks during the prodrome: A phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial in the USA. Lancet  402, 2307–2316 (2023).
4. Li, D. et al.  A brief review of gepants. Curr Pain Headache Rep  27, 479–488 (2023).
5. Chiang, C.-C. et al.  Simultaneous comparisons of 25 acute migraine medications based on 10 million users’ self-reported records from a smartphone application. Neurology  101, e2560-e2570 (2023).
6. Gosalia, H. et al.  Medication-overuse headache: A narrative review. J Headache Pain  25, 89 (2024).
7. Do, T.P. et al.  Migraine attacks are of peripheral origin: The debate goes on. J Headache Pain  24, 3 (2023).
8. Kaag Rasmussen, M. et al.  Trigeminal ganglion neurons are directly activated by influx of CSF solutes in a migraine model. Science  385, 80–86 (2024).