Migraine Drug Ubrogepant Tackles Debilitating Early Symptoms
Results from a phase 3 clinical trial suggest that taking ubrogepant at the first sign of an oncoming migraine can prevent preheadache fatigue and light sensitivity
Migraine symptoms that appear long before a headache can include fatigue, light sensitivity, neck pain and difficulty concentrating.
Scientists have shown that a drug approved to treat migraine headaches can also alleviate debilitating non-headache symptoms, such as fatigue, brain fog and blinding light sensitivity, that occur as the migraine is starting.
The drug — called ubrogepant — is already known to stop the onset of a full-blown migraine attack in some people if they take it when the headache begins. But a phase III clinical trial, described in Nature Medicine on 12 May, shows that it can also tackle the ‘prodrome’ symptoms that arrive hours or even days earlier.
The results suggest that ubrogepant could “free patients from a disabling part of migraine,” says study co-author Peter Goadsby, a neuroscientist at King’s College London.
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Early intervention
The process of a migraine starts long before the head pain, when brain circuits involving the hypothalamus — a region that regulates several vital bodily functions — become dysregulated. In the prodrome, or premonitory phase, people can experience various unpleasant symptoms, including fatigue, neck pain, an aversion to light (photophobia) or sound (phonophobia) and difficulty concentrating.
“Not enough attention has been given to prodrome symptoms,” says Goadsby. The trial aimed to “fill this gap” by investigating whether ubrogepant has an effect on the initial stages of a migraine.
The trial included 438 participants who could reliably identify incoming migraine attacks from their prodromal symptoms. During the 60 days of the trial, they took ubrogepant or a placebo whenever they felt any prodromal symptoms coming on, and reported whether doing this had any effect.
The results suggest that for some participants, the drug increased their ability to concentrate one hour after treatment, reduced their photophobia two hours after treatment and reduced their fatigue and neck pain after three hours.
But the “effect sizes were small” and never more than 15 percentage points compared with the placebo, points out Gregory Dussor, a neuroscientist and migraine specialist at the University of Texas at Dallas. For example, 27% of participants who took ubrogepant reported an absence of fatigue, compared with 17% who took the placebo. Dussor suggests this modest improvement is because the class of drugs to which ubrogepant belongs is a “life-changing therapeutic” for a minority of people — perhaps only one in five, according to some studies. It makes little difference to others, so its effect for that minority “gets diluted in the data”.
“Nevertheless, this study answers the question of whether ubrogepant works when you dose it early in the migraine, when people feel prodromal symptoms coming on,” he says.
Know your migraine
Ubrogepant is already known to stop migraine headaches, but Goadsby says the data show that it works substantially better if taken in the prodromal stage rather than once the attack starts. In the trial, it was crucial that participants could predict their preliminary symptoms. “People who know their migraine would benefit more from this medicine,” he says. The next challenge for the field, he adds, is to train people to understand their migraine symptoms so they can judge when to take ubrogepant.
Dussor thinks that once the prodrome has begun, it is probably still too late for ubrogepant to block the migraine entirely. He says research should explore another question: “Is there some way to alert people much earlier to take the drug, before they feel symptoms coming on?”
The study could also provide clues about the cause of prodromal symptoms. Ubrogepant works by blocking receptors that bind to calcitonin gene-related peptide (CGRP), a molecule that sensitizes the nerves in the head and skull during a migraine attack. “Knowing there’s some CGRP component earlier than the headache phase is important to know in our mechanistic understanding of migraine,” says Dussor.
This article is reproduced with permission and was first published on May 12, 2025.