A groundbreaking phase III clinical trial has demonstrated that ubrogepant, a drug already approved for treating migraine headaches, can effectively alleviate the debilitating non-headache symptoms that occur during the early stages of a migraine attack. The study, published in Nature Medicine on May 12, marks the first investigation into whether migraine can be effectively interrupted during its prodromal phase.
Researchers found that ubrogepant not only helps prevent the onset of full-blown migraine attacks but also tackles prodromal symptoms such as fatigue, brain fog, neck pain, and sensitivity to light and sound that can appear hours or even days before the headache begins.
"Not enough attention has been given to prodrome symptoms," says study co-author Peter Goadsby, a neuroscientist at King's College London. The trial aimed to "fill this gap" by investigating whether ubrogepant has an effect on the initial stages of a migraine, potentially "freeing patients from a disabling part of migraine."
Understanding the Prodromal Phase
The migraine process begins long before head pain manifests, when brain circuits involving the hypothalamus become dysregulated. During the prodromal phase, patients experience various unpleasant symptoms that significantly impact daily functioning.
Prodromal symptoms should not be confused with migraine aura. While aura involves specific neurological symptoms like scintillating scotoma (visual disturbances with flickering lights), prodromal symptoms include cognitive impairment, fatigue, sensitivity to light and sound, neck pain, and difficulty concentrating.
These early symptoms originate in the hypothalamus, supporting the hypothesis that migraines have a central nervous system origin. The ability to treat migraine during this early phase represents a significant advancement in migraine management.
The PRODROME Study Design and Results
The trial included 438 participants who could reliably identify incoming migraine attacks from their prodromal symptoms. During the 60-day study period, participants took either 100mg of ubrogepant or a placebo whenever they felt prodromal symptoms developing, then reported the effects.
Results showed that ubrogepant was more effective than placebo in eliminating bothersome prodromal symptoms:
- Two hours after treatment: Light sensitivity was absent in 19.5% of ubrogepant-treated attacks versus 12.5% with placebo
- Three hours after treatment: Fatigue was absent in 27.3% of ubrogepant-treated attacks versus 16.8% with placebo
- Three hours after treatment: Neck pain was absent in 28.9% of ubrogepant-treated attacks versus 15.9% with placebo
- Four hours after treatment: Noise sensitivity was absent in 50.7% of ubrogepant-treated attacks versus 35.8% with placebo
Additionally, improvements were observed in concentration difficulties and drowsiness. Most significantly, within 24 hours, moderate or severe headaches were prevented in 46% of participants taking ubrogepant compared to 29% taking placebo.
Mechanism and Significance
Ubrogepant belongs to a class of drugs called gepants, which block the calcitonin gene-related peptide (CGRP) receptor. CGRP is a neuropeptide that plays a central role in migraine development.
The study's findings suggest that the pathophysiological causes of migraine likely originate in the central nervous system, as evidenced by ubrogepant's effectiveness in the early stages of migraine and its influence on symptoms associated with central nervous system function.
Gregory Dussor, a neuroscientist and migraine specialist at the University of Texas at Dallas, notes that while "effect sizes were small" and never more than 15 percentage points compared with placebo, this modest improvement may be because gepants are "life-changing therapeutics" for a minority of people—perhaps only one in five, according to some studies.
Clinical Implications
Current practice for acute migraine treatment primarily involves medication use once the headache has begun. The ability to intervene during the prodromal phase represents a significant paradigm shift in migraine management.
Unlike triptans, which should only be taken once headache has started, gepants like ubrogepant could potentially be used preventatively when patients recognize early warning signs. Additionally, gepants are not thought to be associated with medication overuse headache, making early intervention even more appealing.
The good tolerability profile of ubrogepant makes it particularly valuable for patients who cannot tolerate triptans or for whom triptans are ineffective. While the efficacy of ubrogepant regarding pain freedom two hours after administration (approximately 20% versus 10% with placebo) may be inferior to some triptans in indirect comparisons, its tolerability and effectiveness in treating prodromal symptoms offer unique advantages.
Future Perspectives
While ubrogepant is not yet approved in Europe, similar effects may potentially be achieved with rimegepant, which is expected to become available in Europe in summer 2025, and atogepant, which is currently being investigated as an acute medication for migraine attacks.
The effect on prodromal symptoms when taken in the early phase represents significant progress for migraine patients. As one expert noted, "Any additional treatment option improves the situation for those affected."
Further specifically designed studies are needed to scientifically confirm this promising approach. However, the available data provide initial indications that ubrogepant may be effective in the prodromal phase of migraine, supporting an interesting hypothesis that could transform migraine treatment strategies.
