Targeting the CGRP System: A New Treatment Option for Medication Overuse Headache

A recent phase 4 trial shows that erenumab, an anti-CGRP receptor antibody, led to MOH remission in patients with chronic migraine and MOH.

Medications for the acute treatment of migraine are a lifeline to many people who have this condition. However – paradoxically – using these drugs can sometimes make a migraine worse, or even lead to the development of a new kind of headache. This phenomenon is known as medication overuse headache (MOH) and, to date, effective treatment options for it are limited.

A new study led by Stewart Tepper, from the New England Institute for Neurology and Headache, Stamford, US, now offers hope for people with MOH, showing that the calcitonin gene-related peptide (CGRP) receptor-blocking antibody erenumab, which is already approved for the preventive treatment of migraine, yielded high rates of MOH remission in those with chronic migraine (CM) and MOH. This phase 4 randomized, placebo-controlled trial also showed promising results on a number of secondary measures considered in the study.

“This is a well-conducted study, [and] the first phase 4 randomized controlled trial that evaluated the efficacy and safety of a CGRP monoclonal antibody for nonopioid medication overuse headache in patients with chronic migraine,” according to Sait Ashina, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, US, in an email to Migraine Science Collaborative. Ashina, a headache specialist and researcher, was not involved in the current study.

The research appeared online ahead of print in JAMA Neurology on September 16, 2024.

Building the case for a clinical trial of a CGRP drug for MOH
People with migraine have several options for acute treatment, including triptans and analgesic medications. But if these drugs are not given at the right time and in the right way, MOH can become a problem.

“Acute medications work best when taken early. So we, as practitioners, tell our patients to treat early, but we also stress to not treat too often, or you may transform into medication overuse headache and chronic migraine,” Tepper told MSC in an interview.

MOH is a secondary headache disorder defined by the International Classification of Headache Disorders (ICHD-3) as 15 or more headache days per month, for more than 3 months, in a patient with a pre-existing primary headache disorder who regularly overuses (more than 10 times per month) acute rescue medication. Once a patient develops MOH, it’s difficult to treat. From a historical perspective, withdrawing the overused medication to alleviate MOH has received a lot of attention, but that approach has drawbacks, including the potential for relapse and stigmatization of patients. Currently, no consensus exists on the best way to handle MOH.

That a CGRP-targeted treatment might be an effective MOH therapy for those who also have migraine became clear after evidence began to emerge from the phase 3 trials of the four currently approved anti-CGRP monoclonal antibodies for prevention of chronic migraine.

“Forty to 60% of chronic migraine individuals who were studied in the pivotal trials for these medications had MOH, and in all four trials these patients moved from chronic to episodic migraine and from acute medication overuse to below the level of use that the ICHD characterizes as MOH,” Tepper said.

One key missing piece of evidence was a placebo-controlled trial designed specifically to investigate whether blocking CGRP signaling with erenumab could improve MOH, setting the stage for the current work.

A successful trial
As MOH is most common in CM, the study authors enrolled CM patients with accompanying MOH, who had a history of at least one preventative treatment failure, into a phase 4 trial. The goal was to test whether erenumab could produce MOH remission, and sustained remission, in patients with non-opioid CM-MOH (the authors are planning a separate analysis of those with CM and MOH caused by opioids).

A total of 584 patients (with an average age of 44 years; 82.5% were female) from North America, Europe, and Australia were assigned to one of three different treatment groups: Placebo, 70 mg erenumab, or 140 mg erenumab. Participants received the treatment once a month for 6 months. The trial’s primary endpoint was remission of MOH at month 6. More specifically, this was defined as less than an average of 10 days per month of acute headache medication use.

There were also a number of secondary outcomes, including change from baseline in average monthly acute headache medication days, at month 6; sustained MOH remission throughout the trial’s treatment period; and change from baseline in physical impairment and impact on everyday activities.

By the end of the 6-month treatment period, approximately 69% of patients in the high-dose (140 mg) erenumab group and 60% in the low-dose (70 mg) group achieved MOH remission, compared to 52% in the placebo-controlled group. Those in the high-dose group were twice as likely to achieve remission compared to placebo, a statistically significant result. Those in the low-dose group were 37% more likely to achieve remission compared to placebo, but that result was not statistically significant.

Further, patients reduced their consumption of acute headache medication by almost 9.5 days in the 140-mg erenumab group, and by roughly 8 days in the 70-mg treatment group, compared to just 6 days in the placebo group. These differences, statistically significant in the high-dose group but nominally significant in the low-dose group, were from an average of 18 to 19 days of headache medication use per month at baseline.

With regard to sustained MOH remission throughout the 6 months of treatment, approximately 61% of participants achieved sustained remission in the 140-mg erenumab group compared to 50% in the 70-mg group, and 38% in the placebo group. Sustained remission was defined as the absence of MOH over months 1, 2, and 3, and over months 4, 5, and 6, of the 6-month treatment period.

Further, the number of monthly migraine days reported by trial participants was significantly lower in the high-dose erenumab group compared to placebo, though only nominally significant in the low-dose group. Further, erenumab-treated patients also reported less physical impairment and a reduced impact of migraine on everyday activities, though the results were not always significant compared to placebo.

Finally, in terms of safety, the profile of adverse events in the trial was similar to that of previous studies of CGRP-targeted therapies, with constipation and COVID-19 being the most common.

A good result, with room for improvement
The study was not without its limitations, such as the 6-month placebo treatment period, which may have dissuaded the most severe CM-MOH patients from enrolling, since that represents a long time to go without receiving a drug treatment. As another example, the beneficial effect of erenumab was specific to CM patients and cannot be extrapolated to MOH more broadly.

In future studies, “stratifying patients according to those with and without non-pharmacological treatments, as well as with and without medication withdrawal, would provide additional insights and improve treatment recommendations for MOH,” according to Ashina.

Nevertheless, the findings, in combination with a recent report of the effectiveness of the small-molecule CGRP blocker atogepant for CM-MOH, point to the promise of targeting the CGRP system as an effective and safe way to treat CM-MOH.

Encouraging as the current findings are, Tepper believes there is scope for even greater impact on the clinical care of MOH patients.

“Clinically, I don’t think a reduction from 24 to 12 headache days per month, with the associated reduction in acute medication use, is good enough. Ultimately, we need to get the migraine frequency so low and the intensity so mild that the patients forget they have migraine,” he explained.

As the arsenal of anti-migraine treatments has grown in the past decade, combination therapies could be a viable approach to achieve these goals.

As an example, “starting with erenumab, you could move patients from chronic to episodic migraine frequency and have them no longer be in medication overuse. Then you could add onabotulinumtoxin A to drive headache frequency to no more than once a week,” Tepper hypothesized.

In the meantime, in addition to drugs, behavioral approaches as well as education should remain an important part of current MOH treatment.

“Patient education is a critical component in the treatment of MOH, as many individuals are unaware that frequent use of acute headache medications can exacerbate their headache patterns,” Ashina said.

Dara Bree, PhD, is a freelance science writer based in Ireland.

Image credit: 123RF Stock Photo.

Reference
Efficacy and safety of erenumab for nonopioid medication overuse headache in chronic migraine: A phase 4, randomized, placebo-controlled trial.
Tepper et al.
JAMA Neurol. 2024 Sep 16:e243043. Online ahead of print.