This study assessed interictal burden and impact of migraine attacks in a sample of people with variable migraine disease burden and a subset of patients with CGRP mAb treatment experience. The study highlighted the severe disease burden people affected by migraine experience even when not having an acute migraine episode.
Two-thirds of the overall study sample had severe interictal burden, as measured by the MIBS-4. Furthermore, over half reported severe interictal burden irrespective of whether they had or did not have a chronic migraine diagnosis or whether they had or had not been treated with CGRP mAb. Following the recommendations of the MIBS-4 instrument developers , 81% of the total study sample should be considered for preventive treatment. The prevalence of moderate to severe interictal burden in the current study was higher than in a previous international study exploring migraine burden in patients (81% vs. 28%) . Differences in prevalence of interictal burden may have been a result of the current study including patients with a medical diagnosis of migraine only, while the previous study included both patients with and without a medical diagnosis.
Our findings show that impact of migraine attacks, as measured by the HIT-6, migraine frequency and headache frequency were each uniquely associated with interictal burden. Previous studies have also shown a positive, albeit weaker, association between interictal burden and migraine/headache frequency [27, 28]. This study showed a positive association between ictal disability (HIT-6) and interictal burden (MIBS-4) but did not explore specific biological or clinical drivers of interictal burden. Future studies could investigate the impact of ictal symptoms, for example nausea or photo−/phonophobia, and pre- and postictal symptoms of the pro- and postdrome phase on interictal burden, on interictal burden. This may help better understand patients’ unmet need for acute and/or preventive migraine treatment and optimize treatment plans.
Our study also explored the unique association between interictal burden and more distal demographic, clinical and treatment factors. First, depression was associated with worse interictal burden. Qualitative evidence suggests that feelings of depression due to secondary impacts of migraine (e.g., being unreliable, unable to plan, having to abandon social activities) are how the migraine interictal burden can manifest . Consistent with this hypothesis, the item-level results of the MIBS-4 also showed that worry about social and leisure activity was where most patients experienced impairment.
Second, patients who were treated with a CGRP mAb in the last 3 months had lower interictal burden than patients treated with CGRP mAbs in the past. However, patients who were treated with a CGRP mAb in the last 3 months had more severe interictal burden than patients who had never received a CGRP mAb, even after adjusting for migraine frequency and impact of migraine attacks. Patients who are treated with CGRP mAb are commonly thought to be more severely impacted than other patients, as they need to qualify for CGRP mAb treatment, for example by having refractory disease [40, 41]. To our knowledge, interictal burden is not regularly considered when treatment benefits are assessed, and the relationship between treatment and interictal burden is not well understood. One recent galcanezumab clinical trial included the MIBS-4 as a secondary outcome measure and was able to show a treatment benefit . Our study results add to this by showing that patients who were taking CGRP mAb in the last 3 months still have higher interictal burden than patients who have never taken CGRP mAb. Further research investigating the effect of CGRP mAb and other treatments on interictal burden is necessary to fully understand how treatments may relieve interictal burden. Considering the high levels of interictal burden found in this study, these findings indicate that many patients on CGRP mAb have a remaining unmet need.
The study results showed a tentative unique association between being employed and more severe interictal burden, with retired patients being the least affected. This might be due to the unpredictable nature of migraine and being employed may cause additional worry associated with migraine, in line with qualitative findings  and item 1 of the MIBS-4, which specifically explores the interictal effect of migraine on work. The impact of migraine attacks on work and productivity is well established [42, 43]. Our study findings suggest that the impact of migraine may go beyond the immediate productivity loss due to migraine days, as interictal burden may also be associated with reduced productivity and absenteeism [23, 44].
Our results also indicate a tentative unique association between satisfaction with the overall treatment regimen and less interictal burden. Having no control over migraine has been described as an important aspect of interictal burden , and having access to reliable treatment could give patients more control over their migraine, thus reducing their interictal burden.
Strengths and limitations
The study recruited a large sample of people with a self-reported diagnosis of migraine in the US and Germany. The minimum quota set for patients treated with CGRP mAb resulted in a study sample with relatively severe disease burden and the sample may underrepresent those with milder migraine. Due to the cross-sectional and exploratory study design, no a priori hypotheses on relationships between interictal burden and patient characteristics were tested, and it was not possible to determine causality. Given the study design and recruitment from patient panels, the results of the study may not be representative of the population of people affected by migraine.
While the HIT-6 is validated in German and US people with migraine, the German translation of the MIBS-4 was not validated and the psychometric properties of the MIBS-4 across countries have not been studied. The translated study materials were reviewed and checked for accuracy by a native German speaker fluent in English. Further, the MIBS-4 has a recall period of 4 weeks, while other explanatory variables specified different time periods, leading to unprecise estimates.
This study relies on self-reports of participants which can bias the findings. Participants may have had difficulty recalling their number of migraine or headache days and provided inaccurate estimates. Due to the study design, it was not possible to verify participant responses; in particular use of CGRP mAb treatments and diagnosis of reported conditions (i.e. migraine, depression and anxiety) were not verified by a clinician.
For these reasons, the results of the multivariable regression analysis are presented to generate hypotheses and support further research in examining factors contributing to or alleviating interictal burden .