When should the effectiveness of a botulinum toxin A for chronic migraine be assessed in the face of newest International Headache Society recommendations?

Onabotulinumtoxin A (onaBoNT-A) is a class A medication for chronic migraine (CM) prevention, approved by the US and Food and Drug Admistration in 2010. The only valid injection protocol for the treatment is the PREEMPT paradigm, which involves the administration of the drug at a dose of 155–195 units into 31–39 injection sites every three months (1).

The minimum number of treatment cycles of onaBoNT-A effectiveness evaluation has been debated. The most commonly applied method is to conduct at least two or three cycles of injections, 12 weeks apart, with a minimum dose of 155 units, in 31 sites and then to assess for efficacy with a reduction in the number of mean headache days (MHD) as an indicator of patient's response. Some guidelines require a 50% reduction from baseline in MHD and other require a seven-day reduction in MHD from baseline.

The latest International Headache Society (IHS) recommendations for the preventive treatment of migraine, recommend the evaluation of response after minimum of three months for injectable drugs taken on a monthly basis, and a minimum of six months for injectable drugs administered quarterly (2). This means that the effectiveness of onaBoNT-A in CM would be assessed after the second treatment cycle.

IHS recommendation is to appraise the preventive therapy as effective and continue if any one of the following is achieved: (a) ≥50% decrease in monthly migraine days or moderate-to-severe headache days, optimally based on the use of a headache diary; (b) a clinically meaningful subjective improvement as reported by the person with migraine or evaluated by Patient Global Impression scales; and (c) a clinically meaningful improvement in MIDAS or HIT-6 questionnaire scores (2).

This is consistent with the currently prevailing expert opinion that the primary goal of onaBoNT-A treatment is to improve the patient's health-related quality of life (HRQoL), not just the number of headache days recorded.

In the PREEMPT studies, onaBoNT-A responders were defined as patients with at least a 50% reduction in MHD, achieved by: 49.3%, 11.3% and 10.3% of patients after the first, second and third treatment cycle respectively, giving a total of over 70% of patients with at least a 50% reduction in MHD after the first three treatment cycles (1).

Patients with CM not meeting the criteria for at least 50% reduction in MHD still might have a good clinical outcome; thus, most experts consider a 30% reduction in MHD as a response to onaBoNT-A, especially if accompanied by improvement in other variables such as reduction in headache intensity or improvement in HRQoL (3). According to the European Headache Federation guideline on the use of onaBoNT-A in CM, patients should be defined as non-responders if they have less than a 30% reduction in MHD within the first month after BoNT-A treatment compared to the month before the first treatment. However, other factors such as headache intensity, disability and patient preference should also be considered. Treatment should be discontinued if the patient does not respond to the drug within the first two or three treatment cycles (4).

Analysis of the response of almost 2900 patients with CM showed that those responding at least 30% to onaBoNT-A during the first two cycles have a good chance of benefiting from the third cycle of treatment, whereas the probability that patient with <30% reduction in MHD to the first two cycles will start responding during the third cycle is low. This percentage of response (whether it is < or at least 30% and more) can help in making an individual decision to discontinue or continue treatment after the second cycle (5).

Therefore, in our opinion, if it is necessary to assess the percentage effect of onaBoNT-A in CM after two cycles of therapy, 30% reduction in MHD would be a “success indicator” and predictor of further good response as well as the need of treatment continuation. Consistent and even long-term treatment with onaBoNT-A is crucial for initial responders as many real world open studies have shown a cumulative effect of repeated BoNT-A injections.