Introduction
Chronic migraine (CM) and episodic migraine (EM) are part of the spectrum of migraine disorders. CM (generally defined as ≥15 headache days per month, with ≥8 days fulfilling migraine criteria) [
1,
2] is a complex neurologic disorder with a global prevalence of approximately 1.4% to 2.2% [
3]. It is associated with significant individual disability leading to societal and economic burden [
4‐
7]. Studies have found that CM is associated with increased headache-related disability, psychiatric comorbidities, and greater financial and occupational burden compared with EM (defined as < 15 headache days per month) [
4‐
9]. However, people with CM face barriers in receiving the proper medical management of their disease [
8,
10]. Dodick et al. found that < 5% of people with CM were receiving appropriate care, which included consulting a healthcare professional, being accurately diagnosed, and being prescribed a treatment regimen [
10]. Low consultation rates may be partially attributed to a lack of awareness of the general public to the available treatment options [
11].
Currently, people with CM are generally treated with anticonvulsants (valproate, topiramate), antidepressants (amitriptyline), beta blockers (propranolol, metoprolol, timolol, bisoprolol), and angiotensin II receptor 1A blockers (candesartan), or onabotulinumtoxinA [
12‐
14]. Most preventive treatment options are prescribed based on their effectiveness in EM but have limited or no evidence in CM and no CM-specific guidelines [
12,
13]. Beta blockers and topiramate have been approved as migraine-preventive treatments but not specifically for CM [
15‐
17]. Nonetheless, topiramate has been associated with acceptable efficacy in the prevention of headache in CM [
18]. Despite the severity of the disease, only a minority of people with CM (40%) ever take preventive medication, and < 25% adhere to oral preventive medications 1 year after initiating treatment, primarily because of adverse events [
1,
10].
OnabotulinumtoxinA (BOTOX®, Allergan plc, Dublin, Ireland) is approved in most European countries for reduction of headaches in adults with CM and as a preventive medication when patients are intolerant to or do not respond to other preventive medications [
19]. Recommended treatment with onabotulinumtoxinA consists of intramuscular injections distributed among 7 head/neck muscle groups for a total dosage range of 155 to 195 U every 12 weeks [
19].
The Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program demonstrated the efficacy and safety of onabotulinumtoxinA over 56 weeks as a preventive treatment for adults with CM [
20‐
22]. It was the largest placebo-controlled trial in this patient population and established the injection protocol and dosing specific to this product [
23]. The Chronic Migraine OnabotulinuMtoxinA Prolonged Efficacy open Label (COMPEL) Study, an international, multisite, prospective, open-label study, supported the findings of the PREEMPT Study and provided evidence of the effectiveness and safety of longer-term use of onabotulinumtoxinA, extending to 108 weeks and using the PREEMPT injection paradigm without the “follow-the-pain” strategy [
24]. Additionally, the findings from the COMPEL Study complemented the results of several single-site, longer-term studies conducted in routine clinical settings [
25‐
30]. In one such prospective study in the United Kingdom, there were significant reductions in all outcome measures (headache and migraine days) and significant improvements in quality-of-life measures, such as the Headache Impact Test [
30]. The
REal-life use of botulinum toxin for the symptomatic treatment of adults with chronic migraine, measuring healthcare resource utilisation, and Patient-reported OutcomeS observed in practice (REPOSE) Study is a 24-month observational study that utilised patient- and physician-reported outcomes to assess the effectiveness and safety of real-life, long-term use of onabotulinumtoxinA for CM in multiple sites in Europe and evaluated the utilisation of onabotulinumtoxinA in routine clinical practice across Europe. In this report we present an overview of the real-world clinical utilisation of onabotulinumtoxinA and the associated effectiveness and safety in patients with CM.
Discussion
The REPOSE Study aimed to provide real-world observational data regarding the effectiveness, safety, tolerability, and utilisation of onabotulinumtoxinA for the preventive treatment of CM over a 2-year period. Our results demonstrated that long-term, real-life preventive use of onabotulinumtoxinA is effective and well tolerated, with sustained reductions in headache-day frequency and significant improvement in quality of life. No new safety signals were identified with longer-term use and when used with real-world prescribing patterns. Moreover, onabotulinumtoxinA was largely utilised in routine clinical practice as recommended in the SPC and following the injection paradigm established in the PREEMPT Study. The REPOSE Study real-life observations complement the findings of the double-blind, randomised, placebo-controlled PREEMPT Study. The PREEMPT Study reported a significant reduction in headache-day frequency (
P < 0.001) and significant improvement in all dimensions of the MSQ (
P < 0.001) compared with baseline [
22]. The REPOSE Study was an observational study without strict exclusion criteria; however, patients’ baseline demographics were representative of the CM population seen in routine clinical practice and were comparable to the baseline demographics in the double-blind, randomised, placebo-controlled PREEMPT Study [
20‐
22,
34]. REPOSE Study (vs PREEMPT) patients were primarily women (85.3% vs 87.6%) of similar mean age (45.4 vs 41.1 years old), with a chronic or transformed migraine diagnosis history (91.6%) and baseline headache-day frequency (20.6 vs 19.9) [
22].
Akin to this REPOSE Study, other clinical studies have collected data on onabotulinumtoxinA use in a routine clinical setting. A retrospective study in Italy aimed to determine whether onabotulinumtoxinA remained effective after 6 quarterly cycles of treatment in adult CM patients with or without medication overuse, utilising the PREEMPT injection protocol [
25]. A total of 47 patients completed all treatment cycles; after the sixth cycle, they reported significant reductions in mean (SD) monthly headache days compared with baseline [25.9 (5.3) vs 6.3 (5.7)] [
25]. Similar results were reported by several European prospective studies that observed significant reductions in monthly headache days, migraine days, and improvements in health-related quality-of-life measures [
30,
34‐
36]. In Germany, 96.3% of patients reported benefit after 4 treatment cycles, including reductions in monthly headache days (− 53.7%), reductions in monthly migraine days (− 55.1%), and 1.4 to 2.0 standard deviations improvement in MSQ domain scores [
35]. Patients in these single-site, real-life setting studies were similar in baseline demographics to the REPOSE Study and to previous epidemiologic and interventional studies [
34,
35]. However, the REPOSE Study is the largest and most diverse observational study reported to date.
An additional aim of the REPOSE Study was to observe routine clinical utilisation of onabotulinumtoxinA. Although treating physicians were trained on the PREEMPT injection paradigm and the onabotulinumtoxinA SPC, the participating physicians in the REPOSE Study were not required to comply. At every treatment session, physicians recorded injection details such as total dose per session and muscle area, total number and location of injection sites, and total muscle areas treated, as well as deviations from the licensed recommendations. Overall, the mean (SD) total dose per treatment session [155.1 (21.4)] and mean (SD) total number of injection sites per session [31.4 (4.1)] were similar to licensed recommendations and consistent with most other real-life onabotulinumtoxinA observational studies [
19,
25,
35,
36].
The most frequent deviation reported was in the treatment interval, with a majority of patients (79.1%,
n = 501) receiving treatment at a dosing interval > 13 weeks and almost half of all patients (46.0%,
n = 291) receiving treatment at a dosing interval > 16 weeks at least once. We did not capture reasons for deviations in treatment interval because asking this question may have inadvertently influenced the approach to treatment and resulted in more physicians following the recommended treatment protocol. However, we hypothesise that this may be partly attributed to difficulties in scheduling repeat appointments. Despite the increase in dosing interval, outcome measures remained significant, suggesting that increased treatment intervals may also be partly due to a longer duration of effect of onabotulinumtoxinA observed in some patients. Similar results were reported in a European multicentre observational study that aimed to record real-life onabotulinumtoxinA utilisation patterns over a 52-week period [
37]. A majority of physicians followed the licensed recommendations regarding muscle areas injected, number of sites (
n = 31), and total dose per treatment (155 U); 72.8% of patients received treatment at > 13 weeks [
37]. Patients reported a high level of satisfaction at the final follow-up interview [
37].
Less commonly, patients received onabotulinumtoxinA at dosing intervals < 11 weeks (14.8%; n = 94). For a small number of patients (1.1%, n = 7), onabotulinumtoxinA was administered 13 times within the 24-month observation period, indicating an average dosing interval of < 8 weeks. The rationale for the < 8-week dosing interval is unknown, but all 7 cases were from study centres in Germany.
During the 24-month observation period in this study, there were no new safety concerns reported, and the incidence and nature of ADRs were comparable to the PREEMPT study [
22]. Most ADRs were mild (7.3%) to moderate (7.4%), with the most common being eyelid ptosis (5.4%), neck pain (2.8%), and musculoskeletal stiffness (2.7%). Only 22.7% of patients chose to discontinue onabotulinumtoxinA treatment. The most frequent reason for discontinuation was lack of efficacy in the physician’s and/or patient’s opinion (14.2%).
A real-life observational study provides outcomes that promote an increased understanding of use of the treatment in clinical practice. For example, in the REPOSE Study, treating physicians were trained in the PREEMPT injection paradigm but were not required to comply. Nonetheless, results indicate that overall injection patterns in routine clinical care were similar to licensed recommendations. Similarly, there were variations in dosing intervals that may have been attributable to difficulty in scheduling treatment appointments within the recommended 12-week interval or to a duration of effect of onabotulinumtoxinA longer than 12 weeks in some patients. However, outcome measures remained consistent despite deviations in dosing interval. In addition, other than recent treatment with or contraindications to onabotulinumtoxinA, the REPOSE Study had no strict exclusion criteria, which should have led to a patient population that was representative of the CM general population; indeed, demographics collected at baseline were similar to epidemiologic findings.
Nonetheless, there are also limitations inherent to an observational study in a real-life clinical setting. Observational studies typically have less monitoring and are more reliant on the healthcare professional accurately entering study-related data. This could potentially result in more data discrepancies than in a clinical trial. However, outcome measures and safety and tolerability were similar to those seen in the PREEMPT clinical trials, suggesting that the data recording was robust in the REPOSE Study. Discontinuation of onabotulinumtoxinA treatment during the study due to lack of efficacy may have resulted in an enriched patient population that could potentially skew the outcome measures. In addition, these results represent real-world treatment conditions where many patients were likely taking concomitant preventive medications, which should be taken into account when interpreting these data. Furthermore, study outcomes such as headache-day frequency, MSQ, and EQ-5D were self-reported and therefore dependent on the memory and perception of the patient. Poor recollection could introduce improper data or lead to missing data. Nevertheless, outcome data were similar to previous clinical and real-life studies [
25,
34,
35,
38]. Lastly, whereas the EQ-5D is not a migraine-specific health state measure, it has been used to evaluate a number of chronic disease states associated with disabling pain, including rheumatoid arthritis, osteoarthritis of the knee, back pain, and CM [
33,
38]. We could have used the unidimensional visual analog scale to measure pain intensity [
39]; however, the use of this tool is not common in migraine studies [
40]. We used the EQ-5D because it provided a broader assessment of health status [
33].
Acknowledgments
Editorial support for development of this manuscript was provided by Lauriaselle Afanador, PhD, and Dana Franznick, PharmD, at Complete Healthcare Communications, LLC (North Wales, PA), a CHC Group company, and funded by Allergan plc (Dublin, Ireland). The authors thank the patients and study investigators who participated in this study. REPOSE Principal Investigators: Germany: Peter Asmus, Veit Becker, Andrea Böger, Dirk Buschmann, Andrea Dulcius, Markus Ebke, Christoph Engelmann, Anna-Katharina Eser, Heike Förster, Frank Freitag, Charly Gaul, Astrid Gendolla, Klaus Gerlach, Martin Gessler, Hartmut Göbel, Olaf Günther, Frank Halbgewachs, Jürgen Hamacher, Dorothea Händel, Matthias Haslbeck, Volker Heinicke, Bernhard Hellwig, Heinz Peter Herbst, Sabine Hesselbarth, Hanno Jaeger, Jan-Peter Jansen, Wolfgang Jost, Holger Kaube, Ulrike Kirchhöfer, Michael Kiszka, Lothar Klimpel, Ulrike Köhler, Katja Kollewe, Anselm Kornhuber, Michaela Krause, Kathrin Krome, Borries Kukowski, Andreas Kupsch, Roland Leger, Eberhard Albert Lux, Gabriele Müller, Gerhard Müller-Schwefe, Stephan Nautscher-Timmermann, Dietmar Walter Noack, Manfred Oberling, Ingo Palutke, Elmar Pinkhardt, Sonja Resch, Matthias Röder, Juliane Scheunemann, Andreas Schwittay, Erik Strauß, Andreas Straube, Nicole Strickling, Jochen Ulzheimer, Klaus Wrenger, Hans-Dieter Zug; Italy: Francesco De Cesaris, Licia Grazzi, Paolo Martelletti; Norway: Julie Sønnervik; Russia: Ada Artemenko, Julia Azimova, Olga Doronina, Ilya Falkovskiy, Olga Orlova; Spain: Juan Carlos García-Moncó, Julio Pascual Gómez, José Antonio Heras, Fernando Iglesias, Carmen Jurado, Rogelia Leira; Sweden: Rune Johansson, Håkan Löfving, Joakim Tedroff; United Kingdom: Fayyaz Ahmed, Amir Al Din, Brendan Davies.