Drug may stop migraines before headache starts

When taken at the first signs of a migraine, before headache pain begins, a drug called ubrogepant may be effective in helping people with migraine go about their daily lives with little or no symptoms, according to a new study published in the August 28, 2024, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study focused on people with migraine who could tell when an attack was about to happen, due to early symptoms such as sensitivity to light and sound, fatigue, neck pain or stiffness, or dizziness.

Ubrogepant is a calcitonin gene-related peptide receptor antagonist, or CGRP inhibitor. CGRP is a protein that plays a key role in the migraine process.

"Migraine is one of the most prevalent diseases worldwide, yet so many people who suffer from this condition do not receive treatment or report that they are not satisfied with their treatment," said study author Richard B. Lipton, MD, of Albert Einstein College of Medicine in Bronx, New York, and Fellow of the American Academy of Neurology. "Improving care at the first signs of migraine, even before headache pain begins, can be a key to improved outcomes. Our findings are encouraging, suggesting that ubrogepant may help people with migraine function normally and go about their day."

The study involved 518 participants who had migraine for at least one year and two to eight migraine attacks per month in the three months before the study. All of the participants regularly experienced signs that a migraine would be starting within the next few hours. Participants were asked to treat two attacks during a two-month period.

Researchers divided participants into two groups. The first group received a placebo for their first set of pre-headache symptoms of migraine, followed by taking 100 milligrams (mg) of ubrogepant for their second instance of symptoms. The second group took ubrogepant for the first instance and placebo for the second instance.

Participants evaluated limitations on their activity in their diary using a scale ranging from zero to five, with 0 meaning "not at all limited -- I could do everything"; 1, "a little limited"; 2, "somewhat limited"; 3, "very limited"; or 4, "extremely limited."

Twenty-four hours after taking the drug or a placebo, 65% of people who took ubrogepant reported themselves as "not at all limited -- I could do everything," or "a little limited," compared to 48% of those who took the placebo.

Researchers found that as early as two hours post-medication, people who took the drug were 73% more likely to report that they had "no disability, able to function normally," than those who took the placebo.

"Based on our findings, treatment with ubrogepant may allow people with migraine who experience early warning signs before a migraine occurs to quickly treat migraine attacks in their earliest stages and go about their daily lives with little discomfort and disruption," said Lipton. "This could lead to an improved quality of life for those living with migraine."

Lipton noted that participants showed that based on their headache warning symptoms, they could reliably predict impending migraine headaches. These findings apply only to those with reliable warning symptoms.

A limitation of the study was that participants recorded their symptoms and medication use in electronic diaries, so it is possible some people may not have recorded all information accurately.

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Whether physical exertion feels 'easy' or 'hard' may be due to dopamine levels, study suggests

Dopamine, a brain chemical long associated with pleasure, motivation and reward-seeking, also appears to play an important role in why exercise and other physical efforts feel "easy" to some people and exhausting to others, according to results of a study of people with Parkinson's disease led by Johns Hopkins Medicine researchers. Parkinson's disease is marked by a loss of dopamine-producing cells in the brain over time.

The findings, published online April 1 in NPG Parkinson's Disease, could, the researchers say, eventually lead to more effective ways to help people establish and stick with exercise regimens, new treatments for fatigue associated with depression and many other conditions, and a better understanding of Parkinson's disease.

"Researchers have long been trying to understand why some people find physical effort easier than others," says study leader Vikram Chib, Ph.D., associate professor in the Department of Biomedical Engineering at the Johns Hopkins University School of Medicine and research scientist at the Kennedy Krieger Institute. "This study's results suggest that the amount of dopamine availability in the brain is a key factor."

Chib explains that after a bout of physical activity, people's perception and self-reports of the effort they expended varies, and also guides their decisions about undertaking future exertions. Previous studies have shown that people with increased dopamine are more willing to exert physical effort for rewards, but the current study focuses on dopamine's role in people's self-assessment of effort needed for a physical task, without the promise of a reward.

For the study, Chib and his colleagues from Johns Hopkins Medicine and the Kennedy Krieger Institute recruited 19 adults diagnosed with Parkinson's disease, a condition in which neurons in the brain that produce dopamine gradually die off, causing unintended and uncontrollable movements such as tremors, fatigue, stiffness and trouble with balance or coordination.

In Chib's lab, 10 male volunteers and nine female volunteers with an average age of 67 were asked to perform the same physical task -- squeezing a hand grip equipped with a sensor -- on two different days within four weeks of each other. On one of the days, the patients were asked to take their standard, daily synthetic dopamine medication as they normally would. On the other, they were asked not to take their medication for at least 12 hours prior to performing the squeeze test.

On both days, the patients were initially taught to squeeze a grip sensor at various levels of defined effort, and then were asked to squeeze and report how many units of effort they put forth.

When the participants had taken their regular synthetic dopamine medication, their self-assessments of units of effort expended were more accurate than when they hadn't taken the drug. They also had less variability in their efforts, showing accurate squeezes when the researchers cued them to squeeze at different levels of effort.

In contrast, when the patients hadn't taken the medication, they consistently over-reported their efforts -- meaning they perceived the task to be physically harder -- and had significantly more variability among grips after being cued.

In another experiment, the patients were given a choice between a sure option of squeezing with a relatively low amount of effort on the grip sensor or flipping a coin and taking a chance on having to perform either no effort or a very high level of effort. When these volunteers had taken their medication, they were more willing to take a chance on having to perform a higher amount of effort than when they didn't take their medication.

A third experiment offered participants the choice between getting a small amount of guaranteed money or, with the flip of a coin, getting either nothing or a higher amount of money. Results showed no difference in the subjects on days when they took their medication and when they did not. This result, researchers say, suggests that dopamine's influence on risk-taking preferences is specific to physical effort-based decision-making.

Together, Chib says, these findings suggest that dopamine level is a critical factor in helping people accurately assess how much effort a physical task requires, which can significantly affect how much effort they're willing to put forth for future tasks. For example, if someone perceives that a physical task will take an extraordinary amount of effort, they may be less motivated to do it.

Understanding more about the chemistry and biology of motivation could advance ways to motivate exercise and physical therapy regimens, Chib says. In addition, inefficient dopamine signaling could help explain the pervasive fatigue present in conditions such as depression and long COVID, and during cancer treatments. Currently, he and his colleagues are studying dopamine's role in clinical fatigue.

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