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SAN FRANCISCO -- People with migraine can be classified into eight clinically meaningful subgroups according to comorbidities, which may offer clues about headache causes and lead to individualized treatment, researchers reported here.

A modeling analysis showed that comorbidity patterns were correlated with a range of headache features. For example, people with respiratory and psychiatric comorbidities were most likely to experience photophobia and phonophobia, while those with cardiovascular comorbidities were least likely to experience nausea in conjunction with their headaches, according to Richard Lipton, MD, of Albert Einstein College of Medicine in New York City, and colleagues.

"We started with a set of questions," Lipton said during the Harold G. Wolff award lecture at the American Headache Society (AHS) annual meeting. "Why is migraine so common? Why are the clinical features of migraine so variable from person to person? Why do some people respond well to one preventive treatment but not another? Why do we have to work so hard to find the right treatment for our patients? Why can't we find genes that account for most people with common forms of migraine?"

"The answer to all these questions is that migraine is really more than one thing," Lipton continued. "It becomes quite important to understand the heterogeneous nature of migraine and to find approaches for identifying natural subgroups of people with migraine -- groups that are characterized by common risk factors, common biology, and if we're lucky common treatment response."

Lipton's group used a statistical technique called latent class analysis to identify subgroups of migraine patients with shared features, focusing on comorbidities and concomitant conditions.

The analysis was based on data from , a prospective web-based survey that has collected data on symptoms, treatment, and quality of life from thousands of people with migraines in the U.S.

Out of a total population of nearly 13,000 respondents, those with no self-reported comorbidities were excluded, leaving a sample of 11,837 patients. The researchers initially looked at 62 comorbidities, but excluded those that were not useful in discriminating between groups, leaving 22.

After exploring a series of models, they found that a model with eight subgroups best fit the data. The researchers then determined whether various comorbidities, symptoms, and other headache features were more or less common than average in each subgroup.

• Class 1: high on many comorbidities
• Class 2: highest on respiratory and psychiatric symptoms
• Class 3: highest on respiratory and pain symptoms
• Class 4: highest on respiratory comorbidities
• Class 5: highest on psychiatric comorbidities
• Class 6: highest on cardiovascular comorbidities
• Class 7: highest on joint pain
• Class 8: low on comorbidities

Each natural subgroup had a distinct profile of demographic characteristics and clinical characteristic varied across classes, Lipton reported. For example, the respiratory/psychiatric group included a higher proportion of women, the cardiovascular group included more men and the psychiatric group was the youngest.

Patients who had many comorbidities were over four times more likely to have chronic migraine compared with people in the low comorbidities group (23.1% vs 4.8%). This group was also most likely to experience aura, allodynia, moderate to severe intensity pain, nausea, and worsening of pain with routine activities.

Those in the respiratory/psychiatric group were most likely to report pounding or throbbing headaches and were most likely to be bothered by light and sound. In contrast, the cardiovascular group was least likely to experience any of these symptoms.

Patients with many comorbidities were most likely to say they had severe migraine-related disability, or MIDAS grade IV (48.1%), followed by the respiratory/psychiatric (31.9%), respiratory/pain (28.6%), and psychiatric (26.1%) subgroups. Again, the cardiovascular group reported the least severe disability (14.1%).

The researchers then asked whether these comorbidity subgroups could be used to identify which patients were at greatest risk for progression from episodic migraine to chronic migraine.

"If you want to understand the mechanism of something, it's very often useful to understand what it co-localizes with," AHS scientific program committee chair Peter Goadsby, MD, PhD, told reporters during a media briefing ahead of the meeting.

"Those of you with family members with migraine, if I tell you people with more comorbidities are more likely to progress, maybe you're not going to be surprised. If you start to understand the mechanisms of that interaction, you start to understand better how people with infrequent migraine develop frequent migraine," he continued. "If you understand how they get there, you can understand how to lead them back."

After excluding people who already had chronic migraine at baseline, Lipton's group looked at an analysis sample of 8,658 patients.

Compared with the low comorbidities subgroup, those in the high comorbidities group were 5.3 times more likely to develop new onset chronic migraine over the course of a year after, adjusting for demographic factors only, Lipton reported. When other migraine features such as symptom severity and medication overuse were added to the model, the effect was attenuated (3.0 times more likely), but comorbidity subgroup still predicted the risk of progression.

"The hope is that as we identify biologically homogeneous groups, we'll be able to do for a larger fraction of people with migraine what's been done for familial hemiplegic migraine -- that this work can help us predict prognosis and treatment response and ultimately perhaps lead to more powerful clinical trials," Lipton said.

"At the moment, the drugs we discover are the ones that are effective for large subgroups of migraine," he added. "If there were a treatment that works for 10% or 15% of migraine, the way we do our trials right now, we'd completely miss those effects."

These results represent a step toward more individualized treatment for people with migraine.

"We can see how this work can lead us into an era of precision medicine for migraine," said AHS session moderator Todd Schwedt, MD, of the Mayo Clinic in Phoenix.

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