Our results demonstrate that concurrent anti-CGRP and onabot therapy significantly reduces MMDs in chronic migraine patients treated at the Cleveland Clinic, when compared with monotherapy alone. These results were consistent when comparing the first therapy and dual therapy within a single group of patients who experienced both treatment conditions, as well as when comparing patients who received dual treatment with a separate group of patients who received consecutive monotherapy.

The prophylactic treatment of migraine has evolved dramatically with the addition of onabot in 2010, followed by the anti-CGRP mAbs beginning in 2018. Although concurrent use has been largely limited by insurance approval, there is surmounting evidence that their combined use leads to reduced headache frequency and disability. Our study is a retrospective chart review analyzing the concomitant use of onabot and anti-CGRP mAbs performed at one of the largest headache centers in the United States.

To date, the two largest real-world studies on combined use of anti-CGRP mAbs and onabot performed at private practice headache centers showed a reduction in monthly headache days (MHDs) [34, 35]. The study performed by Blumenfeld et al. (October 2018–November 2019 study timeline) demonstrated 25.7% (n = 218) of patients and 36.7% (n = 180) of patients experienced a ≥ 50% reduction in MHDs after approximately 3 and 6 months of dual therapy, respectively [34]. Similarly, the retrospective chart review (n = 148) performed by Mechtler et al. (June 2018–March 2020 study timeline) demonstrated that 21.2% of patients had a ≥ 50% reduction in MHD and 4.4% had a ≥ 75% reduction in MHD after 3 months of combined treatment with anti-CGRP mAbs and onabot [35]. In our study, we found that 68.0% (132/194) of patients had a ≥ 50% reduction in MMDs and 46.4% (90/194) had a ≥ 75% reduction in MMDs after a minimum of 3 months of dual therapy (Table 2). These studies may demonstrate a lower benefit of combined use of anti-CGRP mAbs and onabot, as our study focused on MMDs rather than MHDs, to better target and observe the impact on migraines specifically. Additionally, these studies looked specifically at anti-CGRP mAbs being added to onabot and did not include patients with anti-CGRP mAbs adding onabot; however, we included both routes of dual therapy. A retrospective cohort study by Nandyala et al. examining combined treatment of onabot and erenumab (n = 50) demonstrated that combined treatment presented a significantly lower number of MMDs than onabot treatment alone (11.3 ± 9.3 vs. 14.9 ± 9.4; p < 0.001) as well as a significantly lower number of MHDs than onabot treatment alone (18.2 ± 10.3 vs. 20.7 ± 9.1; p = 0.042) [36]; however, that study only looked at 1 month of combined use.

In our study, 58.8% (114/194) of the dual-therapy patients were prescribed erenumab, 22.2% (43/194) were prescribed galcanezumab, and 19.1% (37/194) were prescribed fremanezumab. In the aforementioned studies, 77.8% (200/257) of patients were prescribed erenumab, 16.3% (42/257) were prescribed galcanezumab, and 5.8% (15/257) were prescribed fremanezumab, while in the second study, 56.7% (84/148) of patients were prescribed erenumab, 0.7% were prescribed galcanezumab (1/148), and 42.6% were prescribed fremanezumab (63/148) [34, 35]. Therefore, our study has a higher percentage of patients receiving galcanezumab and fremanezumab, which bind the CGRP ligand, whereas erenumab binds to the receptor, which may reflect differences in outcomes.

Unlike the previous studies, we compared the dual-therapy dataset with a separate consecutive monotherapy group. There was a significant difference in the MMD reductions between monotherapy of onabot, anti-CGRP mAb monotherapy, and the dual-therapy groups (p < 0.0001). The MMD reduction comparison of onabot monotherapy and dual therapy proved significantly different (p < 0.0001) and anti-CGRP mAb and dual therapy were found to be significantly different (p < 0.0001). Overall, dual therapy shows improvement in MMDs compared with monotherapy of either treatment. In addition, we found a significant difference (p = 0.04) between anti-CGRP mAb monotherapy and onabot monotherapy, which may be because the onabot group is skewed towards people who took onabot for a longer time, which is more indicative of a strong positive response. Although, there is a larger median reduction of MMD from onabot monotherapy (10 [1–18] onabot vs. 7 [0–15.5]), we see a slightly higher percentage of anti-CGRP mAb monotherapy patients who experienced a ≥ 75% (16.6% onabot vs. 19.7% anti-CGRP mAb) improvement in MMD frequency. This may suggest that patients respond better to onabot generally, but those who benefit from anti-CGRP mAbs have larger margins of improvement.

Onabot is administered every 12 weeks according to the PREEMPT paradigm. However, a wear-off phenomenon has been demonstrated as early as week 8, prior to the next treatment session, resulting in increased moderate to severe migraine days, number of rescue medications used, and number of emergency room visits [37,38,39]. A retrospective chart review by Masters-Irailov and Robbins demonstrated wear-off in 62.9% (90/143) of patients receiving onabot for chronic migraine, most commonly 2–4 weeks prior to the next injection (43.3%) and after the very first injection (40.0%) [37]. Our study found 50.5% of patients experiencing wear-off at 2 (2–4) weeks prior to the next onabot injection. A retrospective chart review performed by Ozudogru et al. (n = 36) demonstrated that there is a potential benefit of anti-CGRP mAbs in delaying the wearing-off of onabot by an average of 2 weeks when used in combination, thus extending the therapeutic benefit of onabot [40].

Our study shows further evidence that concomitant use of anti-CGRP mAbs and onabot leads to improved migraine frequency. Due to the differences in administration and eptinezumab’s later FDA approval date, the anti-CGRP mAb intravenous infusion was not included in our patient population. Limitations of this study include the limited follow-up period (post-prescription follow-up appointments have predetermined timelines generally); the standard follow-up for both onabot and anti-CGRP mAbs is approximately every 3 months initially. However in practice, scheduling conflicts and availability of appointments may adjust or delay the follow-ups. In the chart review, the appointment timelines were noted and confirmed to have met the inclusion criteria. Additionally, there is variation of onabot administration among providers (ranging from 155 to 200 units within the muscle groups included in the PREEMPT protocol) that can introduce some noise into the dataset. Furthermore, the nature of a real-world retrospective chart review can be inaccurate or inconsistent. A thorough manual check of each individual patients’ charts was conducted to ensure the most accurate data were extracted, and the templated notes provided further consistency. The resulting datasets for the dual-therapy and consecutive monotherapy groups had no missing data. Of note, we also sought to evaluate whether sequence of therapy made a difference. Since anti-CGRP mAbs first gained FDA approval in 2018, the majority of patients were started on onabot first, and therefore the results in the anti-CGRP mAb-first group were likely limited by lack of power. Future randomized controlled trials should be considered to further assess their combined use.