Abstract
Dr Torgovnick raises two issues regarding the recently published randomized trials of onabotulinumtoxinA as a preventive treatment for chronic migraine. First, he seems to propose “complete response” as a new endpoint for chronic migraine trials. He defines this endpoint as chronic migraine that fully remits and does not require rescue therapy, akin to a cure for cancer. Although we agree that pharmacological cure of chronic migraine is highly desirable, that is beyond the reach of all currently available therapies, either given alone or in combination.
Without achieving Dr Torgovnick’s currently impossible dream, there is a substantial body of evidence that onabotulinumtoxinA treatment produces clinical meaningful effects. Despite the severity, longevity and refractory nature of chronic migraine, results from both PREEMPT studies demonstrated statistically significant between-group differences for the change from baseline in multiple efficacy measures, including frequency of headache days. These endpoints were chosen a priori, based on international consensus and recognized as clinically informative in patients with chronic migraine. This is the current clinical standard for any randomized controlled trial (1,2). Furthermore, efficacy measures alone do not fully portray the potential benefits of a treatment; Dworkin et al. (2009) recommend consideration of health outcome measures, convenience, patient adherence, uniqueness of the mechanism of action and limitations of existing treatments (3). In this context, there were statistically and clinically significant differences observed across multiple headache symptom measures, headache-related disability and quality-of-life assessments that consistently favored onabotulinumtoxinA over placebo.
Dr Torgovnick also raises the twin issues of cost-effectiveness and the definition of a treatment-responsive subgroup. At present, chronic migraine is the treatment-responsive subgroup. When compared to episodic migraine, chronic migraine is more disabling and more burdensome in terms of migraine-related disability (4), health-related quality of life (5) and health care and treatment utilization (6,7). Thus, direct and indirect individual, health care system, and societal costs of chronic migraine are already substantial. Effective and safe prophylaxis treatment that facilitates chronic migraine remission could be important for containing overall medical costs, as well as relieving the costs associated with the significant burden and disability associated with this disorder.
We would like to remind the community that despite experiencing the most disability of any headache segment, chronic migraine patients have generally been excluded from migraine clinical studies. Consequently, there is little evidence-based medicine available to help physicians care for these patients (8), resulting in a substantial unmet medical need for the prophylactic treatment of chronic migraine.
If we look at the onabotulinumtoxinA trials in their totality, we see a clinically meaningful reduction in headache days, migraine days, moderate/severe headache days and total cumulative hours of headache resulting from treatment. As a result, patients had significantly fewer days on which they took any acute medication and significant reductions in the frequency of intakes and days of triptan use. Patients who received onabotulinumtoxinA had an average of 40 fewer hours of headache per month compared to placebo. Importantly, patients on the active treatment also reported significant improvements in multiple disability measures, including the headache impact test (HIT-6), that exceed established minimally important differences (9). These improvements within this severely disabled and difficult-to-treat population reflect the clinical relevance of headache treatment benefit, including effects on functioning, vitality, psychological distress and overall quality of life.
We believe that this therapy has been studied with the most scientific rigor for chronic migraine. For all clinicians, the needs of our patients are our first and last priority. For patients with chronic migraine, we seek effective and well-tolerated treatments that, within a multidisciplinary approach to management, improve their quality of life and reduce their burden and disability. These studies demonstrate that, for a significant proportion of chronic migraine sufferers, onabotulinumtoxinA is effective in achieving these goals. Our next task as clinician-scientists is to continue to explore and identify factors that may predict treatment response and elucidate the mechanism of action of onabotulinumtoxinA in this disorder. This will undoubtedly shed light on the pathophysiology of the disease and hopefully identify new and more selective targets for new therapies. As with all therapies, there will be individuals who will not respond. In the clinical setting, those who do not respond will not continue, and therefore the expense for nonresponders will be mitigated.