BERLIN – People never treated for their chronic migraines and those who failed a previous first-line medication reported similar reductions in frequency of headache days after treatment with onabotulinumtoxinA in a post hoc comparison study of the two phase III studies that Allergan used to gain approval for the new indication.

Some migraine medications work better in treatment-naïve patients, compared with those with a past marred by partial responses or one or more failures to first-line prophylactic therapies.

For this reason, Dr. Sheena K. Aurora and her associates assessed data from the two Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) studies (Headache 2010;50:921-36) determine if onabotulinumtoxinA treatment works the same way. They compared 575 participants with a history of migraine prophylaxis use to another 809 participants who never tried such a first-line medication, as defined by the British Association for the Study of Headache (BASH). Amitriptyline and propranolol were the most common previous medications.

There was no significant difference in the reduction of frequency of headache days with onabotulinumtoxinA between previously-treated and untreated patients, Dr. Aurora said at the International Headache Congress, which was sponsored by the International Headache Society and the American Headache Society. A total 45% of patients with a history of first-line medication use versus 50% of those with no such history had a significant reduction in frequency of headache days.

"OnabotulinumtoxinA is an effective treatment of chronic migraine patients who previously failed BASH first-line migraine prophylactic meds and those naïve to BASH first-line migraine prophylactic treatment," said Dr. Aurora, a neurologist specializing in headache, migraine, and movement disorders at the Swedish Pain and Headache Center in Seattle.

Patients also experienced significant improvements in several secondary outcome measures that did not differ significantly between groups. These outcomes included frequency of migraine days, number of moderate to severe headache days, total cumulative hours of headache on headache days, and percentage of participants who reported severe migraines with a 60 or higher on the Headache Impact Test (HIT-6).

patient reports of improvements in health-related quality of life and disability did not differ significantly between groups, Dr. Aurora said.

The BASH guidelines assign medications to first-, second-, and third-line categories for prophylaxis against episodic migraines. However, many physicians use the same medicines to help chronic migraine sufferers, Dr. Aurora said, so the study answers a clinically relevant question.

Chronic migraine affects approximately 2% of the global population. Chronic migraine sufferers also report greater disability than patients with episodic migraine, according to Dr. Andrew Blumenfeld, who spoke during a separate session at the congress. "Chronic migraineurs experience a higher percentage of severe disability on more headache days than episodic migraineurs."

The burden of illness could be an additional criterion to define chronic migraine beyond the traditional cutoff of 15 or more affected days per month, said Dr. Blumenfeld, who was the lead author on a study comparing disability status and migraine frequency (Cephalalgia 2011;31:301-15). He is a neurologist in private practice in Encinitas, Calif.

The PREEMPT studies included 1,384 highly disabled migraine patients who reported 15 or more days per month with a headache lasting at least 4 hours per day. The 24-week, multicenter, double-blind study researchers randomized 688 of these men and women ages 18 to 65 years old to onabotulinumtoxinA and another 696 to placebo. A 32-week, open-label phase followed the acute treatment study. "There was a cumulative benefit over time – most patients continued to receive treatment benefit after five treatment cycles," Dr. David Dodick, one of the PREEMPT investigators, said in a separate presentation at the congress. "In clinical practice, patients should be administered at least two treatment cycles. If they have absolutely no response, do not proceed."

"You can tell patients that almost 70% of patients treated with [onabotulinumtoxinA] had 50% or more reduction in headache days at 56 weeks," said Dr. Dodick, professor of neurology at the Mayo Clinic in Phoenix, Ariz.

The mechanism of action of onabotulinumtoxinA in chronic migraine remains to be elucidated, Dr. Dodick said. "I don’t think any of us know how the prophylactic medications work in practice." In animal models, peripheral injections of the toxin reduced pain and c-fos protein expression in the spinal dorsal horn and inhibited central sensitization of spinal and medullary dorsal horn neurons, he said. "Clearly, injecting botulinum toxin peripherally has an effect on neurons centrally. Is it trans-synaptic spread or reduction in afferent drive or a combination of the two?"

A recommended injection method for chronic migraine based on the PREEMPT studies is explained, including a diagram of onabotulinumtoxinA injection sites, was published last year (Headache 2010;50:1406-18).

Allergan funded the post hoc analysis. Dr. Aurora said she is a member of the Allergan medical advisory board. Dr. Blumenfeld and Dr. Dodick have received funding from Allergan.

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