Importance of botulinum toxin for prevention of migraine

Since its first introduction into scientific study, botulinum toxin type A (BoNTA) has been looked upon with somewhat of a jaundiced eye, if you would. Originally purified by Edward Schantz as part of a military program on chemical warfare, it went on to be refined and eventually provided to a San Francisco ophthalmologist who used it as part of a treatment for blepharospasm. From here, the rights to a version of the original toxin called 79-11 were acquired by Allergan. The subsequent studies led to the approval of 79-11, now called Botox^®, by the US FDA in 1989 for this condition. It then found its way into a variety of clinical applications for treating conditions such as pediatric cerebral palsy, hemifacial spasm and cervical dystonia, and eventually as a tool for the treatment of wrinkles in lieu of surgery. It was during its use in cosmetic surgery that the first reports of its benefits in migraine surfaced. Subsequently a study by Binder et al. reported its success in an open-label study [1].

Over the next 8 years a variety of clinical trials were carried out in a variety of headache disorders. These trials reported results that ranged from showing BoNTA was completely ineffective as a treatment to remarkably superlative results and everything in between. During this same time a plan of study was launched to investigate its use in migraine. The first of these compared two different doses of BoNTA with placebo, with the curious outcome of a low dose of the toxin proving more effective than a higher dose. Further studies attempted to understand in which patients with migraine and in which specific clinical scenarios the toxin would prove to be most effective. From the various independent studies as well as the multicenter clinical trials much has been gleaned that, at the least, provides guidance to the patient and clinician considering BoNTA as a treatment in headache.

It would seem that use of the toxin is most likely to be effective in those who have had their headaches evolve to a chronic state, which includes maintaining at least some headaches meeting the criteria for migraine. This end-stage process of migraine is, as would be expected, one that proves most challenging across the range of caregivers. However, the curiosities of Botox continue, as it seems from the largest of the Phase II trials that those who are taking other preventative medications for chronic migraine are less likely to benefit than those who are not [2]; a clinical situation that certainly produces a bit of a conundrum for practitioners as these are the patients who are most likely to be taking preventative medicines. It will only raise additional questions, such as how long does one need to be off (on?) prevention to influence the outcome and what about those who are overusing acute medications? The general clinical impression is that for most of these patients, unless they are detoxed from the offending agents, the chances for success are diminished. However, this is not so if BoNTA is used, as the overuse of acute medications does not interfere with efficacy and may possibly be associated with a better outcome. That being said, there are smaller investigator-initiated trials that tend to refute at least some of these findings and there exist still other clinical features that have not been studied as intensely, which may offer other concerns that could influence the outcome for patients.

Allodynia and scalp tenderness with their chronic daily headache may be a positive indicator for response to BoNTA [3], as may the nature of the pain [4]. Those who have headaches that feel as if there is pressure building from the inside, as if their head was going to explode, are most unlikely to respond to BoNTA, whereas those whose headache pain is more crushing or vice-like or where there is an eye popping sensation have a significantly greater chance for response, whether the headaches be chronic or still episodic in occurrence. A positive-predictive response in episodic migraine may have implications for altering the natural history of migraine, which is in the process of transforming to the chronic stage, and this would lead to significant improvements in long-term quality of health for migraine patients.

So why are these issues of importance? First, this is one of the few scenarios in headache medicine where we begin to have some potential to define who is most likely to respond to a given treatment. Even if the response may be less than sterling and the cost of treatment seen by some as exorbitant, we have not previously had a means of predicting who should receive which therapy. This is something I examined years ago, but when confronted with having proven the null hypothesis, that amongst standard migraine treatments there exists no clinical characteristic or combination of characteristics that would be predictive of successful preventative treatment of episodic migraine, whether with a β-blocker, calcium channel antagonist, nonsteroidal anti-inflammatory drug or antiepileptic agent, I gave up on this avenue of research [Freitag FG, Unpublished Data]. Second, the population that appears to be most likely to benefit in general, those with chronic migraine, have a low likelihood of successful therapy or have greater than expected issues of adverse events to the treatments, limiting their usefulness. However, in BoNTA we have a treatment that it seems from the studies yields improving results with each round of treatment and with an adverse event profile that yields a low likelihood of discontinuation of treatment. Third, even if Botox is approved by the FDA, the costs involved will surely generate steps by insurers to limit access to this agent. Therefore, just as now, for those who elect to pay cash for their treatment with this agent, being able to predict success may make it a surer ‘bet’ for insurers as well as self-pay patients. Hopefully the cost savings generated by diminished use of expensive healthcare resources [Freitag FG, Unpublished Data], such as the emergency departments and almost invariable CT scan, hospitalizations for refractive acute headache episodes, as well as improved workplace productivity and presenteeism, let alone the improved quality of life that patients will experience, will make it a more reasonable approach for businesses and insurers to bear. Last, if it can be demonstrated in future trials that there exists a body of patients who have episodic migraine that is responsive to BoNTA and that they demonstrate the same stepwise decline in headache frequency seen amongst those with the chronic stage of the disorder then perhaps we will have a medicinal tool as part of the headache medicine armamentarium that may help to change the natural history of migraine and just leave our headache patients with more furrows in their brows from distressing over other worries and concerns of the day and not their headaches.

Financial & competing interests disclosure

Frederick G Freitag is a member of the Board of Directors of the National Headache Foundation. He has served on Allergan’s International Botox in Headache Advisory Board. He has been a primary investigator for the Clinic for Allergan sponsored multicenter clinical trials and an investigator-initiated clinical trial. He received no income directly related to his role in these studies. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.