This prospective analysis has shown that, in a real-life clinical setting, OnabotulinumtoxinA can effectively reduce headache days and migraine days by at least 50%, and increase headache free days from baseline in chronic migraine sufferers. OnabotulinumtoxinA use also resulted in increased work productivity. The percentage of patients who achieved at least a 50% reduction in headache days and migraine days were 32% and 50% respectively; the percentage of patients who achieved at least a 75% reduction in headache days and migraine days were 14% and 24% respectively. Furthermore, 50% of patients achieved at least a 50% increment in headache free days twice that of the baseline in a 30-day period, and 31% achieved at least a 75% increment in crystal clear days three times the baseline in a 30-day period.

This analysis introduces the Hull criteria for responders as a tool to evaluate response to OnabotulinumtoxinA. It includes headache days, migraine days and headache free days due to the importance of considering severity of headache as well as frequency. The authors noticed that patients with mild headache days often reported as headache free unless they were prompted with the term ‘crystal clear’. We propose to use the term ‘crystal clear’ in establishing true headache free days. Our data showed a reduction in headache days (32%) less than migraine days (50%) or increment in headache free days twice the baseline (50%). NICE guidance[32] used a 30% reduction in headache days as its only criteria to define a meaningful response to OnabotulinumtoxinA. However, from extensive experience, the authors believe that evaluation of headache severity through migraine days is a more valuable measure of efficacy in clinical practice. The authors propose that NICE revisits its definition of a responder. However, applying the NICE criteria of 30% reduction (rather than 50% used in the Hull criteria), the responder rate for headache days in this analysis increased from 32% to 46.5%.

Our study provides the first large prospective data on patients treated with OnabotulinumtoxinA in a real life clinical setting since the publication of PREEMPT. The PREEMPT 56-week clinical trial programme was the largest clinical programme investigating the use of OnabotulinumtoxinA as a prophylactic treatment for chronic migraine using a defined set of diagnostic criteria and defined clinically relevant outcome measures. The pooled analysis of the entire 56-week PREEMPT clinical programme supports the safety and efficacy of OnabotulinumtoxinA for the prophylactic treatment of chronic migraine. Statistically significant reductions were observed for OnabotulinumtoxinA vs. placebo for the primary efficacy variable of headache day frequency at week 56, as well as change from baseline in mean migraine days, moderate/severe headache days, and total cumulative hours of headache on headache days. Furthermore, there were statistically significant reductions in the frequency of acute headache medication use at week 56; also, of triptan intake favouring OnabotulinumtoxinA versus placebo at week 24 and statistically significant improvements from baseline at week 56[18].

Our data supports the results and outcome from PREEMPT, although in some aspects our population was different to PREEMPT patients. In our study, 94.4% of patients had received three or more preventative treatments prior to OnabotulinumtoxinA. In the PREEMPT study, 35% of patients failed three oral therapies and 65% failed one oral therapy, suggesting a more severely affected population in our cohort. Furthermore, the number of headache days before receiving treatment was higher in this analysis[27] compared with the PREEMPT study (19.9 days in OnabotulinumtoxinA group in pooled analysis)[25], also suggesting a more severely affected population. However, only 50% of patients in this cohort fulfilled the criteria for medication overuse compared to 67% in the PREEMPT study. OnabotulinumtoxinA related adverse events were extremely low in this analysis, and no newly emerging safety signals were noted, although pain at the site of injection and neck stiffness was reported in significantly more patients than in the PREEMPT. The relatively low rate of adverse events is consistent with known tolerability profile of OnabotulinumtoxinA, and with results from the PREEMPT study.

Although this analysis is only subjective according to patient diaries, the HIT-6 results suggest an improved quality of life for chronic migraine patients using OnabotulinumtoxinA who often suffer pain, disability and anxiety from their symptoms. In addition, the improved productivity (assessed by reduced days off work) further supports this suggestion.

Patients with chronic migraine represent a treatment challenge[1, 17, 23], and are an important clinical, social and financial burden[4, 12, 13, 36–38]. One analysis showed that, although the direct costs of migraine are high, 70-90% of the total cost of migraine is generally as a result of indirect costs[39]. Oral therapies traditionally used in chronic migraine are associated with limitations, e.g. lack of evidence base to support their use, adverse events and contraindications. Apart from OnabotulinumtoxinA, only topiramate (licensed for both episodic and chronic migraine) is supported by randomised, double-blind, placebo-controlled trial data[15, 16]. From the authors’ clinical experience seeing hundreds of patients with chronic migraine in the specialist clinic, the authors feel that OnabotulinumtoxinA should be given after first-line treatments (e.g. tricyclic antidepressants, beta-blockers and topiramate) have been tried and failed, and before some other preventive treatments, such as sodium valproate, methysergide, and greater occipital nerve block/nerve stimulation. The authors feel that the responder rate observed in PREEMPT and this analysis justifies this position for OnabotulinumtoxinA in the care pathway. OnabotulinumtoxinA may well be preferred as a first choice prophylaxis in chronic migraine although authors feel its cost may well hinder its use as a first line.

In terms of how representative the patient cohort in this analysis is to clinical practice, from the authors’ experience, it is felt that this cohort is representative of patients seen in an average tertiary headache centre. For this reason, it can be projected that clinicians in other centres could observe similar benefits from using OnabotulinumtoxinA in their chronic migraine patients who fail oral prophylactic therapies.

Concerning study limitations, a well-known effect in migraine studies is the high placebo response rate. Furthermore, parenteral procedures are additionally associated with increased placebo response rates[40]. Clearly, this cannot be assessed in this analysis. Furthermore, the absence of an active comparator precludes comparison of the efficacy of OnabotulinumtoxinA with other therapies. However, patients included in this analysis had failed other traditional treatment options (at least one), were suffering from a considerable number of headache and migraine days and were heavily overusing acute pain medications. All of these measures improved with OnabotulinumtoxinA.

The authors do not have a comparison between those who tried one versus two versus three or more preventive treatments prior to OnabotulinumtoxinA but such an analysis will be performed as these data will become available. The authors also do not have data as to whether there is correlation between the number of headache days prior to treatment and response to OnabotulinumtoxinA. There is no doubt that patient expectations play an important role in determining whether a given treatment is effective. However, in the authors’ experience, no difference was observed between those who were treated in Allergan sponsored workshops versus those who were given treatment on the NHS.

The long-term outcome of patients treated with OnabotulinumtoxinA remains unclear. The only data available is from Rothrock et al., where 68% of patients continued to receive treatment after two years, although these patients were receiving treatment through insurance reimbursement and criteria for the continuation of treatment remains unclear[31]. The authors intend to see the outcome in this patient cohort where treatment is largely funded through the NHS based on NICE guidance where treatment must stop once the migraine becomes episodic.

Implications in the United Kingdom (UK)

The healthcare system (NHS) in the UK offers free treatment at the point of entry. However, expensive treatments such as OnabotulinumtoxinA are subject to approval by the NICE who evaluates the cost effectiveness and the gain in Quality Adjusted Life Year (QALY) of a treatment before recommending it. Patients with chronic migraine often suffer for many years and either stays in the healthcare system or return periodically. In the current health care environment, costs of treatment as well as costs of a particular condition (direct and indirect) must, of course, be an important consideration. The UK’s NICE - now a globally considered monitor of cost-effectiveness - approved the use of OnabotulinumtoxinA in chronic migraine in 2012, indicating that it is considered to be a cost-effective option in eligible chronic migraine sufferers[33]. It can be calculated that, overall, relatively few patients with chronic migraine would be eligible for OnabotulinumtoxinA. Such a calculation needs to take into account the total adult population, the estimated prevalence of chronic migraine (1.8%)[3], and the fact that only around 20% of patients with chronic migraine receive a formal diagnosis[6]. Of sufferers, those who have failed three preventive treatments would be around one third of this number[26–28] and around 50% of chronic migraine patients respond to OnabotulinumtoxinA treatment[26, 41]. Consequently, the budget impact will be small, particularly compared with the cost of wasted medications, repeat consultations, hospitalisations and the use of greater occipital nerve block or occipital nerve stimulation in these patients.

The significant improvement in work productivity with OnabotulinumtoxinA must also be considered an additional important finding for commissioners of health. Costs lost to reduced work productivity from chronic migraine are considerable, with 50% of chronic migraine sufferers losing ≥2 hours/week in the previous two weeks of their total productive time in one study[42]. Furthermore, over a three month period, chronic migraine has been shown to significantly reduce activities of daily living, for example, ability to perform household work and participate in family activities[6]. In both the PREEMPT study and in this analysis, OnabotulinumtoxinA was shown to improve productivity.

The authors acknowledge that the data reported here are a snapshot of a group of patients, and that there is a need for a more robust study which is now far more possible due to the recent NICE approval.