1 Introduction
Migraine, a disabling neurological disorder characterized by severe headache and associated symptoms (e.g. nausea, vomiting, photophobia and/or phonophobia) [
1], exists along a continuum between episodic and chronic (i.e. more frequent, severe and burdensome) forms of the disease [
2]. According to the current International Headache Society classification of headache disorders (ICHD-3), chronic migraine (CM) is defined as headache on ≥ 15 days per month for > 3 months, of which ≥ 8 days meet the criteria for migraine with or without aura and/or respond to migraine-specific treatment, occurring in a patient with a history of at least five prior migraine attacks not attributed to another causative disorder or medication overuse [
1]. It affects ≈ 1–2% of the general population [
3] and usually evolves from episodic migraine (EM; defined as < 15 headache days per month) [
4], with chronification occurring in ≈ 3% of patients with EM annually [
5]. CM is classified as a distinct clinical entity [
6]; patients with CM experience more headache days, but also increased headache-related disability, reduced health-related quality of life (HR-QOL) and greater co-morbidity than those with EM [
7]. CM is associated with higher healthcare resource utilization and socioeconomic burden compared with EM [
6,
7]. Historically, only a minority of patients with CM have been correctly diagnosed [
8]; however, a simple case-finding tool that accurately identifies most patients with CM has recently been developed and validated [Identify Chronic Migraine (ID-CM)] [
9].
The management of CM centres around three main approaches: lifestyle modification and behavioural therapy; use of acute medications to relieve or ameliorate the symptoms of a migraine attack that has already begun; and the use of preventative pharmacotherapies to reduce the frequency, duration and severity of attacks, thereby limiting the need for acute medications, as these may be causing concurrent medication overuse headache (MOH) [
10,
11]. Various oral agents, including β-adrenoreceptor antagonists and anticonvulsants, have been shown to be effective in the prevention of migraine in general [
12,
13] and are recommended for use as first- or second-line therapies by EU guidelines [
14‐
16]. However, none of these agents are specifically licenced for the prevention of CM in this region. Moreover, they have shortcomings in terms of efficacy, tolerability and adherence; additional pharmacological and non-pharmacological interventions have been investigated in response to the long-identified need for more effective therapies for patients with CM [
11,
17].
OnabotulinumtoxinA (hereafter referred to as onabotA) [Botox
®], a formulation of botulinum toxin type A (BoNT/A) administered by intramuscular injection, is currently the only therapy specifically approved for the prevention of CM (i.e. headaches in adults with CM) in the EU [
18] and North America [
19,
20]. This article briefly summarizes the pharmacological properties of onabotA and, from an EU perspective, provides a narrative review of data from clinical trials and real-world studies pertaining to its efficacy and tolerability in the prevention of CM. The developmental history of onabotA for CM has been described elsewhere [
21].
2 Pharmacological Properties of OnabotulinumtoxinA
The pharmacodynamic properties of onabotA include a well characterized temporary muscle relaxant effect, which results from the toxin entering motor nerve terminals and cleaving nine amino acids from the C-terminus of the Soluble NSF-Attachment Protein Receptor (SNARE) protein SNAP25 (SNAP25
206) to yield SNAP25
197, thereby disrupting exocytosis and blocking neurotransmitter release [
22].
The exact mechanism of action whereby extracranial administration of onabotA prevents headaches in patients with CM is being elucidated [
21,
23].
The most widely promulgated notion is founded on the phenomena of central and peripheral sensitization within the trigeminovascular system, both of which have been implicated in the pathophysiology of migraine/CM [
21,
24‐
27]. According to this theory, injection of onabotA in the trigeminally-innervated cranio-facial-cervical region blocks peripheral sensitization as a result of inhibiting the release of pain-mediating peptides, especially calcitonin gene-related protein (CGRP), from peripheral nociceptive neurones; this reversal of peripheral sensitization leads indirectly to reversal of central sensitization [
21,
24,
28,
29]. In addition to inhibiting the release of pain-mediating peptides, onabotA may reduce peripheral sensitization by interfering with the integration of relevant sensory receptors and ion channels [e.g. transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1) and transient receptor potential cation channel ankyrin subfamily member 1 (TRPA1)] on nociceptive nerve endings [
21,
25,
30]. Both actions are thought to involve inhibition of SNARE-mediated synaptic vesicle trafficking by onabotA [
21].
An alternative hypothesis, namely that onabotA exerts a direct effect on central pain processing as a result of retrograde transport in peripheral nociceptive neurones and transcytosis to second-order neurones [
31], has received support from an in vitro study that examined the trafficking of clostridial neurotoxins (including onabotA) in central neurones grown in microfluidic devices [
32]. However, an in vivo study that used a highly selective antibody for SNAP25
197 combined with 3-dimensional imaging and quantitative analysis found no evidence in favour of transcytosis [
33]. Under the prevailing experimental conditions, onabotA was confined to primary motorneurones following peripheral administration in rats; any suggestion of distal activity was due to limited systemic spread of the toxin at higher doses [
33].
Interestingly, distinct structural and functional brain changes have been observed in patients with CM who respond to prophylactic therapy with onabotA (i.e. revert to EM) compared with those who do not respond to therapy [
34].
The pharmacokinetics of onabotA have not been studied due to the neurotoxic nature of the product. However, little systemic absorption of onabotA is believed to occur following intramuscular injection of therapeutic doses; it is probably metabolised by proteases and the molecular components recycled through normal metabolic pathways [
35]. Like other BoNT/A products, onabotA exhibits a low immunogenic potential [
36], as exemplified by the fact that none of 496 analysable patients with EM or CM had a confirmed positive test for neutralizing antibodies after up to three 12-week treatment cycles in phase II studies [
37].
4 Tolerability of OnabotulinumtoxinA
Repeated injection of onabotA (155–195 U) every 12 weeks for up to five cycles was generally well tolerated in the PREEMPT clinical trial programme discussed in Sect.
3.1 [
38‐
41,
51]. OnabotA recipients mostly reported adverse events (AEs) that were mild or moderate in severity and resolved without sequelae; they infrequently discontinued therapy due to AEs [3.8 (vs. 1.2% of placebo recipients) during the double-blind phase of the pooled PREEMPT studies; 2.6% during the open-label extension phase of the pooled PREEMPT studies] [
40,
41].
Moreover, treatment-related AEs (TRAEs) were consistent with the known tolerability profile of onabotA when injected into head and neck muscles; no new safety events were observed [
40,
41,
51]. The overall rates of TRAEs were 29.4% for patients receiving two cycles of onabotA during the double-blind phase (
n = 687) [vs. 12.7% for placebo (
n = 692)] [
40] and 34.8% for patients receiving all five cycles of onabotA during the double-blind and open-label extension phases (
n = 515) [
51]. Of note, the rate of TRAEs decreased progressively with each subsequent treatment session, being 48.3, 37.2, 37.8, 26.3 and 19.1% after the first, second, third, fourth and fifth cycles of onabotA, respectively [
51]. The most commonly observed TRAEs in patients receiving onabotA included neck pain [6.7 (vs. 2.2% with placebo) during the double-blind phase; 4.6% during the open-label extension phase of the pooled PREEMPT studies], muscle weakness [5.5 (vs. 0.3%); 3.9%], eyelid ptosis [3.3 (vs. 0.3%); 2.5%], injection-site pain [3.2 (vs. 2.0%); 2.0%] and musculoskeletal pain [2.2 (vs. 0.7%); 1.1%] [
41]. Facial paresis accounted for two-fifths of the reports of muscle weakness during the double-blind phase (incidence of 2.2%) and for nearly one-third of the reports of muscle weakness during the open-label extension phase (incidence of 1.2%) [
41]. Only one onabotA recipient in the pooled PREEMPT studies experienced a serious TRAE (migraine requiring hospitalization) [
39].
Design differences notwithstanding, tolerability findings from the PREEMPT trials are supported and extended by those of the long-term, open-label COMPEL study [
53] (Sect.
3.2) and, where reported, several real-world studies [
63‐
65,
70,
71] (Sect.
3.3). In COMPEL, for example, the overall rate of TRAEs was 15.0% at week 24 [
55] and 18.3% at week 108 [
53]. The most frequently reported TRAE was neck pain, both at week 24 (occurring in 2.9% of patients) [
55] and week 108 (4.1%) [
53]. As in the PREEMPT programme, only one patient in COMPEL reported a serious TRAE (rash); no novel safety signals were seen [
56].
To date, the largest completed study to evaluate the safety of onabotA for the preventative treatment of CM in routine clinical practice has been a prospective, observational, multinational, post-authorization study (hereafter referred to as ‘CM-PASS’) [
74,
75]. Briefly, the study population consisted of 1160 patients (84% women; 98% Caucasian) enrolled at 58 centres across Germany, Spain, Sweden and the UK. The majority (86%) had a diagnosis of CM or transformed (i.e. chronified) migraine at baseline; approximately one-quarter (24.7%) were medication overusers. Almost one-half (43.9%) were receiving ≥ 1 acute and ≥ 1 preventative therapy at baseline; approximately one-half (51%) had previously received onabotA for CM [
74]. Participating physicians were provided with the summary of product characteristics, but were not mandated to follow the PREEMPT injection protocol set out therein. Most (90.1%) patients underwent ≥ 1 treatment session that deviated from the recommended label treatment paradigm, although the median dose (155 U) and median number of injection sites (
n = 31) were consistent across all observed onabotA treatment sessions (
n = 4017) and in line with the PREEMPT protocol. The median interval between sessions was 13.7 weeks [
74].
Over a period of 64 weeks, one-quarter (25.1%) of CM-PASS participants reported ≥ 1 TRAE, most frequently neck pain (4.4%) and eyelid ptosis (4.1%). TRAEs of special interest included worsening of migraine (4.0%), intractable migraine (0.4%) and dysphagia (0.3%) [
74]; the incidence rates of intractable migraine and dysphagia (secondary and primary outcome measures, respectively) were 1.6 and 0.4 per 1000 person-months [
75]. As in the PREEMPT and COMPEL studies, only one patient reported a serious TRAE (worsening of migraine) [
74]. Of note, approximately three-quarters (74.4%) of 1090 evaluable patients indicated they were satisfied/extremely satisfied with onabotA therapy; this included, respectively, 83 and 65% of patients who had and had not previously received onabotA [
74].
5 Dosage and Administration of OnabotulinumtoxinA
In the EU, onabotA has been approved for the prevention of headaches in adults with CM through the mutual recognition procedure, with Ireland as the reference state [
18]. However, the exact wording of the indication may vary between member states, and local prescribing information should be consulted for specific details.
As per the PREEMPT clinical protocol, the recommended dose of onabotA is 155–195 U administered intramuscularly as 0.1 mL (5 U) injections to 31 and up to 39 sites across seven specific head/neck muscle areas as follows: corrugator [10 U (2 sites)]; procerus [5 U (1 site)]; frontalis [20 U (4 sites)]; temporalis [40 U (8 sites) up to 50 U (up to 10 sites)]; occipitalis [30 U (6 sites) up to 40 U (up to 8 sites)]; cervical paraspinal muscle group [20 U (4 sites)]; and trapezius [30 U (6 sites) up to 50 U (up to 10 sites)] [
35]. All muscles should be injected bilaterally, with the exception of the procerus, which should be injected at one site only (midline). The recommended retreatment schedule is every 12 weeks [
35].
Local prescribing information should be consulted for full details of dosage and administration guidelines, contraindications and warnings and precautions relating to the use of onabotA for the prevention of CM.
6 Place of OnabotulinumtoxinA in the Prevention of Chronic Migraine
The pivotal PREEMPT programme showed that treatment with up to five cycles of onabotA (155–195 U/cycle) at 12-week intervals was generally well tolerated (Sect.
4) and effective in reducing headache symptoms, headache impact and acute headache pain medication usage, as well as improving HR-QOL, in patients with CM, approximately two-thirds of whom were medication overusers and approximately one-third of whom had failed to respond to ≥ 3 prior preventative therapies (Sect.
3.1). Improvements in headache symptoms, headache impact and HR-QOL favouring onabotA over placebo were seen regardless of whether or not patients were medication overusers and, in general, irrespective of whether or not they had received prior first-line prophylactics (Sect.
3.1). Moreover, onabotA not only reduced headache-day frequency, but also headache-day severity; a reduction in headache-day severity was seen even in patients who did not experience a clinically meaningful (i.e. ≥ 50%) reduction in headache-day frequency (Sect.
3.1).
During the open-label phase, in which all patients received three cycles of onabotA, all assessments of headache symptoms, acute medication usage, headache impact and HR-QOL continued to improve relative to baseline (Sect.
3.1). Further evidence of the benefit over time of repeated administration of onabotA exists in the form of the observation that around one-quarter of those patients who did not achieve a clinically meaningful (i.e. ≥ 50%) reduction in headache symptoms after the first treatment cycle did respond after the second cycle, while approximately one-third of those patients who did not achieve a clinically meaningful reduction in headache impact after the first treatment cycle did respond after the second cycle (Sect.
3.1). Moreover, around one-quarter of those patients who did not respond in terms of these endpoints after the first and second cycles did respond after the third cycle (Sect.
3.1). This suggests, therefore, that in practice at least two to three cycles of onabotA should be attempted before categorizing those patients who do not respond initially as nonresponders [
52].
Debate surrounding the PREEMPT studies has centred on the small treatment effect of onabotA relative to placebo, the possibility that blinding was inadequate and the relevance of the evaluated population [
17,
27]. The totality of data from the PREEMPT programme has, nonetheless, led to onabotA becoming the first (and so far only) headache prophylactic therapy to be specifically approved for CM in the UK (Sect.
1). Importantly, results from the PREEMPT programme are specific to onabotA and cannot be extrapolated to other commercially available formulations of botulinum toxin A, namely abobotulinumtoxinA (Dysport™) and incobotulinumtoxinA (Xeomin
®).
The current European Federation of Neurological Societies guideline on the pharmacological treatment of migraine predates the approval of onabotA and does not mention the drug [
16]. As regards national guidelines, onabotA has a level 1 (highest) recommendation for the preventive treatment of CM in Italy [
76]. In the UK, both NICE [
47] and the Scottish Medicines Consortium [
77] recommend that onabotA be reserved for patients with CM (i.e. headaches on ≥ 15 days per month of which ≥ 8 days meet the criteria for migraine) who have failed to respond to ≥ 3 prior preventative therapies and whose condition is appropriately managed for medication overuse.
Key findings for onabotA over a period of 1 year in the PREEMPT programme have been substantiated and extended by the results of a 2-year clinical study (COMPEL; Sect.
3.2) and several large real-world studies from Europe, including REPOSE (Sect.
3.3) and CM-PASS (Sect.
4). These studies have generally enrolled patients similar to those who participated in PREEMPT and have variously confirmed the efficacy and safety of short and longer-term prevention with onabotA administered as per the PREEMPT protocol or, in the case of the multinational REPOSE [
74] and CM-PASS [
78,
79] studies, largely administered in line with this injection paradigm. In COMPEL, sustained benefits were seen in patients who received up to nine treatment cycles (Sect.
3.2), while in real-world studies, benefits have been seen in patients who have failed to respond to or are intolerant of prior oral preventative therapies, including those with concomitant medication overuse or comorbid MOH (Sect.
3.3). In addition, a small real-world from Europe [
80] has reported a delayed and progressively beneficial effect among patients who continue to receive treatment after failing to respond to the first cycle; this supports the notion that at least another one to two cycles should be attempted before deeming those individuals who do not respond initially to be nonresponders [
81].
Data are also emerging from real-world studies that address current areas of uncertainty surrounding the use of onabotA for the prevention of CM, including how to identify patients who are more (or less) likely to respond, the appropriate duration of therapy in responders, the rate of sustained benefit in patients who successfully stop therapy (positive stopping rule), and the rate of relapse in patients who stop therapy. Duration of disease [
73], unilaterality of pain [
73], intensity of headache [
73], interictal CGRP levels [
82] and (in women) polymorphisms in genes encoding CGRP [
83,
84] and TRPV1 [
84] are among the potential predictors of efficacy that have been identified, based on data collected from clinical practice in Spain [
73,
82‐
84] and the UK [
85]. Among actual responders, the pattern of response appeared to be predictive of longer-term outcome [
66]. Based on 2 years’ follow-up at one UK centre [
67], nearly two-thirds of patients who successfully stopped therapy showed sustained benefit, while approximately one-fifth relapsed. Overall, approximately one-half of initial responders were still receiving therapy at 2 years (Sect.
3.3). Issues relevant to optimizing the long-term management of CM with onabotA in real-world clinical practice, such as when to initiate therapy and how to define (and appropriately treat) responders and nonresponders, are discussed in more detail elsewhere [
81].
On the basis of pharmacoeconomic analyses that incorporate data from the PREEMPT trials, the use of onabotA for the prevention of CM can be considered cost-effective from the perspective of the National Health Service in Italy [
86] and the UK [
87]. The real-world cost-effectiveness of onabotA in clinical practice in Europe remains to be determined, although relevant data regarding healthcare resource utilization (HRU) are being collected as part of the multinational REPOSE study [
88]. In this regard, interim (1-year) data from participating centres in Germany indicated that use of onabotA not only reduced HRU (e.g. physician visits and technical investigations), but also improved work performance and disability [
88].
In conclusion, the totality of evidence from clinical trials and real-world studies indicates that onabotA is an effective and generally well tolerated option for the prevention of CM that may be particularly useful for patients who have previously failed to respond to or are intolerant of commonly prescribed oral prophylactics.