Abstract
Since the advent of Onabotulinumtoxin-A, and in the last few years with the introduction into the migraine armamentarium of monoclonal antibodies targeting the CGRP pathway (CGRP-mAbs) as well as, even more recently, small molecules such as gepants, we have been witnessing a revolution in the management of migraine patients (1).
Indeed, thanks to their high efficacy in reducing attack frequency and severity, along with excellent tolerability and safety profiles, the novel treatments allow us to set such high and challenging aims that were previously considered unachievable, thereby improving patients’ adherence to treatment.
However, although clinical trials and real-world studies have revealed meaningful reductions in monthly migraine day (MMD) rates of ≥50%, ≥75%, and even – in a smaller percentage of subjects – 100% from baseline using, for instance, CGRP-mAbs or gepants, we continue to care for a non-negligible subset of patients who still experience a significant disease burden in terms of residual migraine days, attack severity, non headache symptoms of attacks or poor response to acute treatment – despite achieving a substantial reduction in monthly migraine days. It is intuitive that this implies the disruption of emotional health, social connections, work productivity, and overall quality of life of our patients.
All this calls for a broader reflection on the current approach to evaluating clinical results, which basically consists of a simplistic assessment of outcomes as a “delta” between the baseline and what we have achieved following preventive migraine treatment.
As recently highlighted in a position statement by the International Headache Society (IHS) (2), we should call for a “paradigm shift”, ideally underpinned by a “mindset shift”, pushing ourselves beyond merely evaluating a percentage reduction in migraine symptoms — such as the commonly accepted benchmark of a > 50% reduction in MMD (or its proxy, moderate-to-severe headache days) — toward a more comprehensive assessment that closely reflects the patients’ well-being, such as evaluating the residual migraine burden over the course of treatment.
Indeed, it is noteworthy that the same reduction rate can result in varying degrees of functional effects based on the baseline migraine frequency, with a high risk of concealing important aspects of the residual migraine burden in many individuals.
In this cultural and clinical scenario, we should be as ambitious as possible and “strive for migraine freedom.” However, since the complete elimination of migraine attacks or migraine-related disability is considered a “tough-to-achieve” goal to date, we need to adopt a more proactive and comprehensive treatment approach that could bring us, if not to symptom freedom (as already occurs in other areas of neurology such as epilepsy or multiple sclerosis), then at least to “optimal disease control” (i.e., fewer than four days with migraine).
Nonetheless, the optimal strategy for managing this segment of the migraine population and achieving “migraine freedom” or “optimal disease control” remains unclear, highlighting an urgent need for research into complementary or alternative approaches to further improve the (ictal and interictal) well-being of our patients. Indeed, advancing the field of migraine management requires a commitment to rigorous scientific standards to determine the most effective strategies, and progress should be driven by properly designed registrative clinical trials (RCTs) that ensure treatment recommendations are based on the highest level of evidence rather than on observational, real-life studies.
In this context, pragmatic trials — providing valuable insights into the advantages of new treatments in improving migraine care — seem to emerge as a critical tool, offering on one hand a real-world approach to evaluating open clinical questions and, on the other hand, mitigating the biases inherent in real-world observations (3).
Among these, TACTIC — a multicenter, randomized, double-blind, sham-controlled, parallel-group pilot RCT including subjects with ≥8 monthly migraine days in the last 30 days despite treatment with CGRP-mAbs — provides promising preliminary evidence that a non-invasive neuromodulation technique (targeting central migraine mechanisms), such as transcranial direct current stimulation (tDCS), may complement the peripherally acting CGRP-mAbs by enhancing clinical outcomes
Moreover, and this deserves to be deeply considered, as demonstrated in the TACTIC study where no association between treatment and adverse events was found, we must be as aware as possible that the “add-on” treatments should not only improve the effectiveness of the therapy, but also must not affect the tolerability and safety of the overall therapeutic strategy (CGRP-mAbs in this case)—characteristics that represent one of the strengths of the novel anti-migraine preventive therapies.
Therefore, the TACTIC study, beyond demonstrating the additive effects of tDCS in patients treated with CGRP-mAbs, underlines two important concepts in headache medicine: the need to be ambitious regarding the therapeutic goals we want to (or aim to) achieve in our patients (without restricting ourselves to merely evaluating the percentage improvement compared to baseline) and the necessity of producing scientific results by employing methodological approaches — such as pragmatic trials — that offer a real-world perspective while avoiding the biases inherent in real-world evidence.
Footnotes
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
