Chronic migraine (CM) is a complex, neurological disease impacting ~1–2% of the global population (1). The International Classification of Headache Disorders, 3rd edition (ICHD-3) defines CM as ≥15 monthly headache days (MHD) for >3 months over a 12 month period, with at least 8 headaches per month fulfilling the criteria for migraine with or without aura (2). Individuals with CM experience frequent debilitating migraine attacks, which prevent them from performing daily activities and significantly impact their quality of life. As a result, CM is associated with substantial societal and familial burdens (3, 4); and CM is associated with significant direct and indirect costs, leading to an economic burden for patients and healthcare systems (5–7).

The successful management of CM requires a holistic approach, which includes lifestyle modifications, trigger management, appropriate acute and preventive pharmacological treatments, and management of comorbidities (8–11). The goals of preventive treatment for CM include reducing the frequency, severity, duration, and disability of a migraine attack. Additionally, preventive treatment may alleviate some of the burdens associated with CM by improving function, reducing disability, reducing overall costs associated with migraine treatment, improving health-related quality of life, and reducing headache-related distress and psychological symptoms (10, 12). OnabotulinumtoxinA was first approved as a preventive treatment for CM in 2010 and since then, a robust body of evidence from clinical and real-world studies has demonstrated its safety, tolerability, and efficacy for CM prevention (13–17). Direct inhibition of CGRP pathways has emerged as a new target of both acute and preventive migraine treatments (18). In 2018, three subcutaneously injected monoclonal antibodies (mAbs) directed against CGRP or its receptor were approved by the US Food and Drug Administration (FDA) for migraine prevention. Erenumab (19) targets the CGRP receptor, while fremanezumab (20) and galcanezumab (21) directly target CGRP, preventing ligand binding to the CGRP receptor. In 2020, the FDA also approved eptinezumab, an intravenously administered mAb that also binds to the CGRP ligand (22, 23).

The pathophysiology of CM is complex, involving multiple pathways and receptors. As a result, though patients with CM often benefit from preventive treatment with onabotulinumtoxinA, they may continue to experience migraine attacks frequently enough to meet the criteria for receiving additional preventive treatments. The AHS recently published an updated position statement emphasizing the importance of developing preventive treatment plans to meet the individual needs of patients with migraine, which may involve combining older and newer treatments as well as complex and non-traditional approaches (11). The position statement reports that combination treatment with onabotulinumtoxinA and a CGRP mAb is probably effective, and CGRP therapy may be added to one or more established treatments based on clinical judgment provided the risk of drug-antibody interactions is considered minimal or non-existent (10, 11). Preclinical and clinical data suggest that combination treatment with onabotulinumtoxinA and a CGRP mAb could be additive or synergistic in the prevention of migraine due to the distinct mechanisms of action of the treatments (24–30).

To date, no randomized controlled clinical trials have evaluated the safety and efficacy of combination treatment with onabotulinumtoxinA and a CGRP mAb for migraine prevention. The objective of this study was to improve the understanding of the safety, tolerability, and potential benefits of adding a CGRP mAb to onabotulinumtoxinA as a combination preventive treatment regimen in adults with CM. To accomplish this, we collected real-world data from the electronic medical records (EMR) of patients treated with up to 12 months of continuous combination treatment at a single clinical site. Treatment benefits were based on effectiveness assessments available in patients' charts that are widely used and recognized as being reliable, accurate, and relevant to migraine.

Chronic migraine is a debilitating disease with a complex pathophysiology, involving multiple pathways and receptors. As a result, though patients with CM often benefit from preventive treatment with onabotulinumtoxinA, they may continue to experience migraine attacks frequently enough to meet the criteria for receiving additional preventive treatments. AHS recently published an updated position statement emphasizing the importance of developing preventive treatment plans to meet the individual needs of patients with migraine, which may involve combining older and newer treatments as well as complex and non-traditional approaches (11).

The addition of a CGRP mAb to onabotulinumtoxinA treatment for CM is routinely done in clinical practice among neurologist and headache specialists, however, data on the safety and efficacy of this treatment paradigm is limited. To date, no prospective clinical trials and only a limited number of real-world studies have examined this treatment approach (33–38). The AHS position statement reports that combination treatment with onabotulinumtoxinA and a CGRP mAb is probably effective, and CGRP therapy may be added to one or more established treatments based on clinical judgment provided the risk of drug-antibody interactions is considered minimal or non-existent (10, 11). Preclinical and clinical studies suggest that combination treatment with mechanistically distinct preventive treatments could have additive or synergistic effects in migraine prevention (26). Preclinical data show that onabotulinumtoxinA and CGRP mAbs prevent the activation of different types of pain fibers involved in migraine: onabotulinumtoxinA primarily prevents the activation of unmyelinated C-fibers (30) and CGRP mAbs mainly prevent the activation of thinly myelinated Aδ-fibers (29). Real-world studies have provided initial evidence of clinical benefit with the addition of a CGRP mAb to onabotulinumtoxinA treatment for CM (33–38).

In this retrospective, real-world study of 148 patients, the addition of a CGRP mAb (erenumab, galcanezumab, or fremanezumab) to onabotulinumtoxinA treatment as a combination preventive treatment for CM was generally well-tolerated and no new safety signals were identified. Patients discontinued CGRP mAb therapy more frequently than onabotulinumtoxinA (33 vs. 28%), though all patients included in this study received at least two onabotulinumtoxinA treatments before initiating combination treatment, which may partially explain this difference as patients not tolerating onabotulinumtoxinA were likely precluded from the study. The primary drivers of discontinuation of either treatment were lack of insurance coverage (40%) and lack of effect (34%). Only seven patients (14%) discontinued a CGRP mAb due to safety/tolerability and none discontinued onabotulinumtoxinA for this reason. Throughout follow up, only 12% of patients changed CGRP mAb brand and 7% changed CGRP mAb dose. While on combination preventive treatment, 12% of patients experienced one or more AE. The most common AE reported was constipation, experienced by 9.5% of patients prescribed erenumab at index. Injection site reactions were the next most common AE, experienced by 3.4% of total patients. No SAE were reported, and no new safety signals were identified.

The safety profile of combination treatment in this real-world study is consistent with that observed in prior analyses of each treatment alone and other real-world studies of CGRP mAbs added to onabotulinumtoxinA treatment for CM. In a similar study of combination preventive treatment of CM with onabotulinumtoxinA and a CGRP mAb by Blumenfeld et al. (36) 28% of patients experienced an AE; the only one reported by ≥5% of patients was constipation. Another retrospective chart review of patients prescribed a CGRP mAb while receiving onabotulinumtoxinA for CM by Cohen et al. (34) reported that AEs occurred in 8.5% of patients and included constipation, injection site reaction, and/or fatigue. The incidence of constipation was higher (34%) in a real-world observational study of 158 patients with CM treated with erenumab with or without other preventives or onabotulinumtoxinA (37). Constipation is a known adverse event associated with erenumab (19). Gastrointestinal and other AE are less common with the other CGRP mAbs prescribed in this study, occurring at rates similar to those observed with placebo in clinical trials (39–41). The most common AE reported with onabotulinumtoxinA for the treatment of CM in clinical trials were neck pain (9%) and headache (5%) (13, 14).

Clinically meaningful treatment benefits were observed with onabotulinumtoxinA prior to mAbs initiation and additional statistically significant benefits were observed after adding a CGRP mAb in patients who remained on combination treatment. Prior to the addition of a CGRP mAb, patients experienced a mean reduction of 6.4 MHD with onabotulinumtoxinA treatment alone. This mean is slightly lower than the average decrease in the PREEMPT trials, though it is important to note that mean baseline MHD were slightly higher in the PREEMPT trials than the present analysis (13, 14). Real-world CM patients are often more complicated than those enrolled in clinical trials due to the severity of disease and comorbidities. In particular, those identified for combination treatment may represent a severe and refractory subset of CM patients. Due to the nature and severity of CM, the patients in this study still experienced an average of 14 MHD at the initiation of combination treatment. The addition of a CGRP mAb to onabotulinumtoxinA treatment for CM resulted in significant and clinically meaningful reductions in MHD at each post-index assessment compared to baseline. Mean reductions of 3.8–4.6 days per month after 6–12 months of combination treatment were observed. After ~12 months of combination treatment, the proportion of patients who achieved controlled CM status (<15 MHD) was 27.9% higher than baseline, and over 30% of patients achieved at least a 50% reduction in MHD.

These findings are consistent with the results of other real-world studies evaluating the safety and efficacy of combination treatment with onabotulinumtoxinA and a CGRP mAb. The recent publication of a similar study by Blumenfeld et al. (36) showed a 3.5–4 day reduction in MHD over 6–12 months of combination treatment after an initial mean reduction from 21.5 MHD to 12.1 MHD with onabotulinumtoxinA alone. A retrospective analysis by Armanious et al. (33) recently demonstrated a 6.8–8.1 reduction in MHD in patients with CM who received 1–3 months of combination treatment with erenumab and onabotulinumtoxinA. The 78 patients included in this analysis had a mean (SD) of 22.5 (8.7) MHD while receiving onabotulinumtoxinA alone and likely represent a more refractory population, possibly explaining the greater reduction in MHD observed with combination treatment in this study. Boudreau (37) recently conducted an observational study comparing the effect of combination treatment with erenumab as an add-on therapy to onabotulinumtoxinA to the individual treatments alone. He found that the addition of erenumab to a preventive therapy was more effective to reduce MHD than erenumab alone. As in our study, patients in a retrospective review of medical records by Cohen et al. (34) experienced a significant (p < 0.001) reduction in MHD with onabotulinumtoxinA treatment and an additional reduction of 5.7 MHD (p < 0.001) with the addition of a CGP mAb.

In this study, lack of treatment insurance coverage was the most common reason for discontinuation of either onabotulinumtoxinA or a CGRP mAb. Insurance coverage for medication is a challenge pervasive throughout headache medicine and an issue that has been cited as a potential cause for increased use of emergency room care, infusion centers, and inpatient admissions (42), resulting in increased financial burden on patients and healthcare systems. Further, suboptimal migraine treatment can lead to increases in headache frequency and severity. Evidence suggests that ineffective migraine treatment is associated with chronification (43), leading to increased challenges longitudinally with treatment effectiveness and headache resolution. Unfortunately, patients with CM are often forced to choose by payers between two clinically-proven, beneficial treatment modalities, which data suggests are safe, additive, and possibly synergistic when combined. The patients described above undoubtedly represent the most severe cases of CM that overutilize direct medical resources and thereby, incur the highest costs. Examination by payers of the cost-benefit ratio of treatment options for these patients is warranted and may justify a more aggressive approach for the treatment of refractory CM. The data presented herein provide additional evidence that the combination use of onabotulinumtoxinA and a CGRP mAb for the preventive treatment of CM was generally well-tolerated, suggesting that the subset of patients with refractory CM could experience clinical benefit with such a combination regimen, without an increase in the side-effect profile.

Several limitations should be considered when interpreting the results of this study. First, data used for this real-world, retrospective study were collected for the purpose of health care, not research. As a result, variables of interest may have been missing as the result of several circumstances, including the data not being applicable for the specific patient, not available in the medical chart, or the data available in the medical chart but not captured by the data extraction processes. Additionally, these findings reflect the study site's clinical practice chart documentation, and some variables of interest, such as acute medication consumption, were not collected. A prospective study design that collects a daily patient diary could capture this information to assess acute treatment reduction and pharmacoeconomic considerations. Not all patients contributed data to all four post-index assessments due to loss to follow-up and discontinuation, which, though common and expected in real-world studies, can introduce bias. As a result, the data from later time points may reflect a responder population that does not capture the outcomes of patients who did not respond to treatment. In addition, study outcome measures were not consistently reported, and reporting methods may have varied across patients. Consistency of treatment with both onabotulinumtoxinA and CGRP mAbs may also have varied between patients. OnabotulinumtoxinA treatment may not always be administered per label, and some variation in dosage and timing of injections is likely. Patient compliance with CGRP mAb injections was not documented as this information is not routinely collected in the clinical setting. Therefore, the exact timing of the initiation of combination treatment is unknown and assessments may not accurately reflect 3, 6, 9, and 12 months of combination use. Lastly, patients in this study were prescribed a CGRP mAb during the 1st year following FDA approval; therefore, the distribution of CGRP mAb brands depended largely on the time of product release and the market availability of each product. For example, erenumab was the first FDA-approved treatment, which most patients (56.8%) received. Consequently, the number of patients treated with fremanezumab and galcanezumab was insufficient to allow for comparisons between different CGRP mAb brands.

These real-world data demonstrate that the combination use of onabotulinumtoxinA and a CGRP mAb for the preventive treatment of CM was generally well-tolerated, with no new safety signals identified in patients who were able to stay on the combination. This combination treatment paradigm was associated with additional, clinically meaningful improvements in headache frequency in patients with chronic migraine compared to treatment with onabotulinumtoxinA alone. Discontinuation of one or both treatments was primarily driven by a lack of insurance coverage. Additional real-world studies and prospective controlled trials are needed to further assess the safety and additive or synergistic benefits of the addition of a CGRP mAb to onabotulinumtoxinA treatment for people with CM.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The New England Independent Review Board reviewed the study protocol prior to study initiation and determined the study as exempt from review. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

LM, NS, JM, and OH participated in data acquisition. All authors participated in the study conception, design, data analysis, interpretation, read, and approved the final manuscript.

This research was supported by Allergan, an AbbVie Company.

LM has received personal compensation for consulting, serving on a scientific advisory board, speaking, research affiliation, or other activities with Alder Pharmaceuticals, Allergan (now AbbVie Inc.), Amgen, Avanir, Biohaven, Boston Biomedical Inc., CellDex, DelMar Pharmaceuticals, electroCore, Novartis, Orbis Pharmaceuticals, Promius, Teva Pharmaceuticals, and Jushi; he has financial interest in Jushi. NS has served as speaker and/or advisory board member for Allergan (now AbbVie Inc.), Amgen, Avanir, Biohaven, Currax, Depomed, Egalet, GammaCore, Eli Lilly, Lundbeck, Pernix, Promius, Supernus, and Teva. JM has served as a speaker and/or received research support from Allergan (now AbbVie Inc.), Amgen/Novartis, Avanir, Biohaven, Eli Lilly, Lundbeck, Theranica, Amneal and Teva. OH is an employee of ICON plc. AT and AA are full-time employees of AbbVie Inc., and may hold AbbVie stock. The authors declare that this study received funding from Allergan, an AbbVie Company. Employees of AbbVie participated in the research, interpretation of data, review of the manuscript, and the decision to submit for publication.

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