Migraine is a common, yet disabling, neurological disorder that is characterised by recurrent attacks of headache. Typical migraine attacks last from 4–72 hours and involve headaches with varying characteristics: pulsating, unilateral location, moderate or severe intensity and aggravation by routine physical activity. Headaches may also present with associated symptoms, such as nausea, vomiting, photophobia and/or phonophobia (Headache Classification Committee of the International Headache Society, 2018).
The International Headache Society (IHS) classifies migraine into two major subtypes: migraine with aura and migraine without aura. Patients can suffer from migraine both with or without aura. Aura symptoms are focal, neurological symptoms, usually occurring prior to, or sometimes during, a migraine attack.
There is a distinction between episodic migraine (EM) and chronic migraine (CM). The IHS defined CM as headache on 15 days or more per month for over 3 months, of which, over 8 days meet the criteria for migraine with or without aura and/or respond to migraine-specific treatment, occurring in a patient with history of at least five prior migraine attacks not attributed to another causative disorder or medication overuse (Headache Classification Committee of the International Headache Society, 2018). Approximately 1–2% of the general population are affected by CM, and this usually develops from EM. EM is defined as less than 15 headache days per month (May and Schulte, 2016). Classed as a distinct clinical entity, patients with CM suffer from more headache days, increased headache disability, reduced health-related quality of life and greater co-morbidity than those with EM (Blumenfeld et al, 2011). CM is also considered a greater socioeconomic burden and is associated with higher healthcare resource utilisation compared to EM (Blumenfeld et al, 2011).
Management and pharmacological treatment
Management of CM involves multiple factors (Weatherall, 2015), including:
- Lifestyle modifications, such as losing weight, modifying response to stressors and getting sufficient sleep (Schwedt, 2014)
- Trigger management: avoidance of caffeine, alcohol and stress (Schwedt, 2014)
- Effective use of acute and preventative medications (i.e. the 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 responsible for concurrent medication overuse headache.
The main goal in CM treatment is to reduce the impact of migraine on the patient's life. Therefore, the aim is to keep the migraine attacks as rare, short and less impairing as possible.
Pharmacological management of CM is based on two aims: immediate treatment of acute migraine attacks and prophylactic treatment. The two most commonly used medications for the immediate treatment of migraine are non-steroidal anti-inflammatory drugs (NSAIDS) and triptans. Both of these medications have good clinical evidence for their use. However, both NSAIDS and triptanes have been linked to medication overuse headaches. For this reason, the use of these drugs must be limited to the least amount necessary.
Prophylactic medication can be initiated as soon as diagnosis has been established. The substances that have been studied in patients with CM specifically are valproate (Yurekli et al, 2008), amitriptyline (Couch and Amitriptyline versus Placebo Study Group, 2011), gabapentin (Spira et al, 2003), topiramate (Diener et al, 2007) and onabotulinumtoxin A (onabotA). These medications are recommended for use as first-or second-line therapies by European Union (EU) guidelines (National Institute for Health and Care Excellence (NICE), 2015). However, with the exception of onabotA, none of these treatments are licensed for use in treating CM. Each medication is seen to have shortcomings in regard to efficacy, tolerability and adherence. OnabotA is a formulation of botulinum toxin A administered by intramuscular injection and is currently the only therapy specifically approved for the prevention of CM in the EU (Health Products Regulatory Authority, 2017) and in North America (Allergan Inc, 2014; 2016).
In the UK, NICE recommends onabotA as a prophylactic treatment for CM in patients who did not respond to at least three prior pharmacologic prophylaxis therapies and whose condition is appropriately managed for medication overuse. NICE criteria recommends that treatment with onabotA should be stopped when patients do not respond to treatment adequately (defined as a reduction of monthly headache days of over 30%) or when the patient's condition changes to EM (defined as a headache on less than 15 days per month in three consecutive months) (NICE, 2012).
Mechanism of action of botulinum toxin
Botulinum toxin is a protein complex derived from the gram-positive, anaerobic bacterium Clostridium botulinum. Of the seven known botulinum serotypes, two are currently in use clinically: serotypes A and B.
Chronic migraine is defined as headache occuring on 15 days or more per month, while episodic migraine happen less than 15 days per month
Following injection of serotype A, the toxin is internalised into peripheral motor neurons via SV2 binding protein. Once translocated into the cytosol, the toxin cleaves the SNAP-25 protein. SNAP-25 acts to mediate the fusion of neurotransmitter containing vesicles within the cell membrane. This disruption of exocytosis blocks neurotransmitters, such as acetylcholine, from being released at the neuromuscular junction (Simpson, 2004).
The exact mechanism by which onabotA works to relieve migraine is still being studied. The most widely thought of notion is based on central and peripheral sensitisation within the trigeminovascular system, both of which have been implicated in the pathophysiology of CM (Whitcup et al, 2014). This theory states that injection of onabotA in the trigeminally-innervated cranio-facial-cervical region blocks peripheral sensitisation, as a result of inhibiting the release of pain-mediating peptides, in particular, calcitonin gene-related protein (CGRP), from peripheral nociceptive neurones. This reversal of peripheral sensitisation leads indirectly to reversal of central sensitisation (Whitcup et al, 2014; Cernuda-Morollón et al, 2015). In addition to inhibiting the release of pain-mediating peptides, onabotA may reduce peripheral sensitisation by interfering with the integration of relevant sensory receptors and ion channels (for example, 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 (Whitcup et al, 2014; Zhang et al, 2016). Both actions are thought to involve inhibition of soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE)-mediated synaptic vesicle trafficking by onabotA (Whitcup et al, 2014).
Therapeutic efficacy of Onabotulinumtoxin A
The efficacy of injectable onabotA for headache prevention in adults with CM has been studied universally. The most pivotal studies evaluated efficacy over 1 year in the phase 3 clinical trials of PREEMPT 1 and PREEMPT 2. A longer term study over a period of 2 years also took place, and this phase 4 study was known as COMPEL.
PREEMPT 1 and PREEMPT 2
PREEMPT 1 and PREEMPT 2 were both double-blind, randomised placebo-controlled multi-centre trials. They were phase 3 research evaluating migraine prophylaxis therapy clinical trials. Trials consisted of a 24-week placebo-controlled phase followed by a 32-week open-label extension phase. Eligible patients were men and women aged 18–65 years with CM (as defined by International classification of headache disorders, 2nd edition (ICHD-2) criteria). To enter the placebo-controlled phase, they were required to have had:
- More than 15 headache days (with each day consisting of over 4 hours of continuous headache and with over 50% of days being migraine or probable migraine days)
- At least four distinct headache episodes (with each episode lasting over 4 hours) during a 28-day baseline period prior to randomisation.
Patients were stratified according to whether they met the protocol definition for overuse of acute headache pain medications during this period.
OnobotA was injected into 31 sites across seven very specific head and neck muscle areas: the frontalis, corrugator, procerus, occipitalis, temporalis, trapezius and cervical paraspinal at 12 weekly intervals. Each injection was 5 U, and there was the possibility for eight additional injections in up to three specific muscles: the occipitalis, temporalis and trapezius, according to a ‘follow-the-pain’ strategy. The total dose of onabotA used was 155–195 U, injected into 31–39 sites. This is referred to as the PREEMPT injection protocol. Patients underwent up to five treatment cycles: two with onabotA or a placebo during the double-blind phase and three with onabotA during the open label phase.
During the trial, 1384 patients received with onabotA or a placebo. Approximately two-thirds of these CM patients were overusing headache medications at baseline.
Results were analysed and presented (Bendtsen et al, 2018) as follows:
There was no significant effect on the primary endpoint—headache episodes—in the PREEMPT 1 trial, while there was a significant effect on headache and migraine days. The PREEMPT 2 trial met its primary endpoint (headache days). The results of the PREEMPT 1 and 2 trials have been evaluated in a pooled analysis (Dodick et al, 2010). The pooled analysis reported a large decrease from baseline in headache days, but due to a large placebo effect, the efficacy of onabotA over placebo was modest (-8.4 versus -6.6 days per 4 weeks) (Dodick et al, 2010). Responder rate, defined as the percentage of patients with a decrease in frequency of headache days from baseline of at least 50%, was 47.1% versus 35.1%). Post-hoc analysis demonstrated that 71.4%, 9.4% and 5.4% of patients responded to treatment cycles 1, 2 and 3, respectively, using 30% reduction of headache days compared with baseline as responder rate (Silberstein et al, 2015). OnabotA was also significantly more effective in reducing a number of secondary efficacy variables, including disability. The Headache Impact Test (HIT)-6 score was reduced by 4.8 by onabotA compared with 2.4 by placebo. Post-hoc analyses demonstrated that headache intensity was reduced in non-responders (patients with less than 50% reduction in headache frequency) (Matharu et al, 2017), and that quality of life was still improved after 1 year of treatment (Lipton et al, 2016). OnabotA was well tolerated, the most common adverse events compared with placebo were neck pain (6.7% versus 2.2%), muscular weakness (5.5% versus 0.3%), eyelid ptosis (3.3% versus 0.3%) and injection site pain (3.2% versus 2.0%). Discontinuation rates due to adverse events were low (3.8% versus 1.2%). A secondary analysis of the PREEMPT study investigating the subgroup of patients (1005 out of 1384) who received all five treatment cycles demonstrated continued efficacy and tolerability of onabotA (Aurora et al, 2014).
COMPEL
In the multinational, open-label COMPEL study, adults with CM (as defined by ICHD-2 criteria) received up to nine onabotA treatment cycles (155 U/12-week cycle; administered as per the PREEMPT injection protocol). As with the PREEMPT studies, the majority of the 715 evaluable participants were female (85%) and Caucasian (81%). They reported an average of 22 headache days per month at baseline and just over one-half (52.1%) completed all nine treatment cycles (108 weeks) (Blumenfeld et al, 2018).
Clinical benefits persisted during long-term (2 years) onabotA therapy. Regarding the monthly frequency of headache days, there was a significant reduction relative to baseline at week 108.
Assessments of headache impact (total HIT-6 score)—including migraine-related disability, quality of life, sleep disturbance, fatigue, depression and anxiety—were also significantly improved from baseline at week 108; similar improvements were seen at all earlier assessments.
Despite differences in study design, the patient population in COMPEL was, as noted above, similar to that in the PREEMPT trials, and outcomes at week 24 were generally consistent, based on a descriptive comparison of COMPEL and pooled PREEMPT data (Aurora et al, 2015).
Implications for aesthetics
At present, onabotA (brand name, Botox) is the only botulinum toxin preparation that has been approved for the treatment of CM. There are no prospective trials using other botuliunum toxin preparations in patients with CM that have been published. There has been one retrospective case series, in which, 21 patients with CM were treated with incobotulinumtoxinA (brand name, Xeomin, Merz) (Kazerooni et al, 2015). In this case series, treatment with incobotulinumtoxinA showed significant improvements in headache frequency and severity.
AbobotulinumtoxinA (brand name, Dysport, Beaufour Ipsen) has been investigated in patients with EM, but no significant effects were found on the frequency and severity of headache (Petri et al, 2009).
There are numerous studies on the duration of the effect of onabotA in muscles in an aesthetic treatment; however, little is known about the duration of its analgesic effects. For the majority of trials, it is assumed that it is similar to its relaxant effects, and so, include a fixed interval duration of 12 weeks between injections. Clinical experience in the use of botulinum toxins for other neurological indications would suggest that it would be useful to adapt the treatment intervals individually based upon the patient's needs (Dressler et al, 2015). However, it should be noted that, as with its use in cosmetic treatments, intervals between treatments that are shorter than 12 weeks have been linked with an increased risk of antibody formation against botulinum toxin (Lange et al, 2009). Despite evidence for this risk being minimal, intervals between treatments are still kept to a 12-week minimum.
Due to the neurotoxic nature of onabotA, the pharmacokinetics have not been tested; however, it is believed that little systemic absorption of onabotA occurs following intramuscular injection of therapeutic doses. It is thought to be metabolised by proteases and that the molecular components are recycled through normal metabolic pathways. OnabotA, as with other botulinum toxins, exhibits a low immunogenic potential. This was demonstrated when none of the 496 analysable patients with EM or CM had a confirmed positive test for neutralising antibodies after up to three 12-week treatment cycles in phase 2 studies.
Safety and tolerability
Systemic adverse effects or reactions to botulinum toxin are very rare (Silberstein, 2016), and any effects suffered are usually related to the injection. Injection-related adverse effects are usually mild and transient, and they rarely lead to the discontinuation of treatment. Adverse effects that were most commonly reported in the PREEMT studies included neck pain (4.3%), injection site pain (2.1%), eyelid ptosis (1.9%) and muscular weakness (1.6%) (Aurora, 2014). Overall, studies of onabotA document the treatment as tolerable (Silberstein et al, 2005).
Conclusion
OnabotA is the substance that has been best studied in the prophylactic treatment of CM. Preferably, patients have tried 2–3 other migraine prophylactics before the start of onabotA. This may sometimes be difficult, as patients with CM often have a number of other co-morbidities, meaning that it may be difficult to choose an oral prophylactic due to their contraindication with many conditions, such as cardiovascular disease, depression and obesity. Treatment with oral prophylactics are also often complicated by poor tolerability, resulting in poor compliance. The success of treatment not only relies on correct administration of onabotA, but also thorough consultation with the patient, including education about their condition and treatment and realistic expectation on treatment results (i.e. being told that the treatment may be able to reduce frequency and intensity of their migraine, but that it does not cure migraine). They should be told that effect is usually seen within 3–7 days, that the effect may wear off before the next treatment cycle and that response should be evaluated by continued use of headache calendars.
In conclusion, good clinical evidence has been found that treatment with onabotA leads to a reduction of monthly headache days, as well as improvement in quality of life. OnabotA is both safe and well tolerated. Further studies need to be carried out to pinpoint the exact mechanism of action that onabotA has in pain relief.
Key points
- Management of chronic migraine (CM) involves multiple factors, including lifestyle modifications, trigger management and effective use of acute and preventative medication
- The main goal in CM treatment is to reduce the impact of migraine on the patient's life
- Onabotulinumtoxin A is both safe and well tolerated and has good clinical evidence that it leads to a reduction of monthly headache days, as well as improvement in quality of life.
CPD reflective questions
- What are the treatment options for migraine?
- What are the common symptoms of migraine and in what ways can they be triggered?
- How is it thought that onabotulinumtoxin works in migraine?