Unmet needs for migraine

Introduction

Migraine is a neurological disease that affects approximately one billion of individuals worldwide, and has been considered by the Global Burden of Diseases 2019 as the second leading cause of disability in the world, first when considering young women under the age of 50¹.

Facing this transversal disease with a large social, occupational and economic impact deriving from it, global health systems have generally proven to be unprepared in recent decades. The discovery of Calcitonin Gene Related Peptide (CGRP) as a molecule implicated in the pathophysiology of migraine and the appearance of new drugs targeting it or its receptor, the monoclonal antibodies and CGRP antagonists, or agonists of the 5-HT1F receptor^2–7, has raised in recent years the need for a systematic approach to this vast multitude of patients following criteria shared by the scientific community. This approach, coagulated around the unmet needs of these patients, is trying to identify a stratification of the different clinical expressions and a definition of the cut-offs useful for defining the levels of application of these new molecules. It is also important to reiterate the necessity for a more widespread education in the multidisciplinary subspecialty of headache medicine, to reduce the gap between the need for seeking care and obtaining a fair, effective and safe treatment for migraine.

Burden of migraine worldwide

For many years now, migraine has been positioned among the first places in the unenviable ranking of disability^8,9, not only in adults but also in adolescents¹⁰, and the awareness of its importance as a social disease has now been established. Numerous studies on very large patient populations have shown in different geographical areas how the burden of migraine affects these patients widely at all latitudes when evaluated in terms of Health-Related Quality of Life, work productivity, healthcare resource utilization, cost of illness^11–15.

The tidal phenomenon in publication research

We have always witnessed the exponential and tumultuous growth of scientific publications in the imminence and during the stages of RCTs registration of new drugs for a specific disease. All this upstream of the identification of new pathophysiological mechanisms that have led to the development of new molecules contrasting the evolution of the disease. All of this is happening in the multidisciplinary clinical area of ​​migraine. After the realization that Calcitonin Gene Related Peptide (CGRP) played a pivotal role in the development of migraine attacks, in the activation of the trigeminovascular system and therefore the generation of migraine pain, and after new pharmacological classes (monoclonal antibodies for CGRP or its receptor (CGRPr) or small molecules such as gepants, antagonists of the same receptor for CGRP or ditans, agonists of the 1 F serotonin receptor (5-HT1F) have progressively appeared on the market, the following question has arisen: are we ready for the transition to novel treatments?

Now, more than two years later the start of this new era for migraine, we must say that we weren’t. Various barriers have stood in the way of this transition. We were aware of the burden of migraine, induced disability, but little was known about the social and personal costs of the disease, the extent and safety of using standard of care (SOC) migraine in both prevention and acute phase. All information that would have justified or even encouraged the large-scale use of the new pharmacological classes^14,16.

But now we must consider that this CGRP new pharmacological class rightly defined as Disease-Modifying-Migraine-Drugs (DMMDs) can rapidly slow down or freeze or revert the natural course of migraine by reducing also absenteeism or presenteeism at work^17,18. Consequently, new consultations, further diagnostic and therapeutic pathways and the repeated use of old SOC drugs, even in combination, which are the harbingers of a well-known poor adherence to treatment, appear unnecessary. All this has to change in order to be beneficial not only clinically for the patient but also economically sustainable for the National Health Systems or the Insurance Companies. However, this economic benefit of the use of DMMDs while valid in high-income countries is to be reconsidered in medium-low-income countries by purely social parameters.

Many studies have been undertaken to define the critical issues relating to incorrect migraine management, from the completely avoidable costs of migraine derived from access and its management in the Emergency Departments^19,20, from Healthcare Resource Use (HRU) and indirect costs²¹, from the impact of migraine disease on workplace productivity and related monetary loss^14,22, from the underestimation of the binomial spontaneous progression towards chronicity/resistance/refractoriness with secondary appearance of psychiatric comorbidity^23,24.

Recently, numerous studies have defined the cut-offs necessary to make the patient with migraine eligible for an innovative treatment, such as monoclonal therapy²⁵. They are very often non-independent studies, which demonstrate evidence and barriers on the inadequate treatment of migraines and indicate them to us as unmet needs.

Eligibility criteria for new therapies have been established and currently accepted in the clinical practice, either for inadequate response to the SOC or low adherence or safety concerns. These criteria put new acute drugs such as gepants and ditans as third line treatment options, and preventative CGRP(r) MoAbs as fourth line²⁶.

Facing all this, a large tidal phenomenon has arisen, witnessed by the incessant increase in scientific publications in the area. It should be noted that due to competition between publishers, we often see replications obviously unaffected by plagiarism, but all rooted on the same mainstream, which testifies to the high scientific interest in headache medicine.

Inadequate education in headache disorders

The crucial step after learning about migraine and all its related problems is the search for solutions that are applicable on a large scale.

The key issue passes through the analysis of the level of experts on the disease available in the area, experts who populate the Headache Centers and their efficiency in negotiating with the NHS on the appropriate large-scale use of new drugs.

Without the first requirement, a widespread education of doctors on headache medicine, the final goal, that is the control of the disease, cannot be achieved. While individual educational events on migraine are carried out extensively with the unconditioned support of drug companies, society training on headaches promoted by independent, academic or scientific society is not very rich in initiatives and cannot fill the existing educational gap in the short term. Only two Academies established international master programs on headaches, Sapienza University of Rome²⁷ and Copenhagen University²⁸. However, education on headaches should reach many more subjects, and many more neurologists, encouraging their inclusion in this subspecialty, but also many other subjects, emergency room doctors, anesthetists, internists, etc., as well as General Practitioners, a real crux of this much-desired educational campaign.

There already are various Syllabuses to optimize this campaign, both Reference Programs produced by individual national Headache Societies²⁹ and Aids for Management by supranational companies³⁰, and these management schemes must be widely applied in daily real-life.

What’s the solution?

Steiner recently closed a long cycle of valorizing headaches as epidemiologically relevant non-communicable diseases, impacting long-life, qualitatively burdensome, sub-optimally treated, with a reflection that can only be shared.

In the end the close link between the scientific evidence of headache-related disability, loss of productivity and availability of novel effective drugs now needs to be combined with health reform policies that value headache services that, by applying the cost-effectiveness model and giving an economic value to their work while providing services to patients³¹.

If we add to this the fact that long-term data on safety and tolerability and quality of life of CGRP MOAb are positive up to 5 years of use and that for gepants, studies lasting 3–12 months also reported excellent safety profiles, we can say that we have the right weapons to fight this war against migraine^3,32.

We believe that these steps are acceptable, that it is necessary, after applying the outcomes of translational research, to make headache services more efficient and better, always keeping in mind that the cornerstone of this reformist project can only be a broader, more widespread, continuous medical education activities on headache disorders.

Only in this way the unmet needs will be fully satisfied and a positive, stable and virtuous impact of science on migraine patients can be obtained.

Paolo Martelletti
Department of Clinical and Molecular Medicine, Sapienza University, Via di Grottarossa 1035, Rome 00189, Italy
Regional Referral Headache Centre, Sant’Andrea University Hospital, Rome, Italy
[email protected]
Martina Curto
Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy
International Consortium for Mood Psychotic and Mood Disorders Research, McLean Hospital, Belmont, MA, USA
Department of Mental Health, Rome, Italy

Transparency

Declaration of funding

The paper was not sponsored.

Declaration of financial/other relationships

P.M. and M.C. disclosed that they have no actual or potential financial, personal, political, academic, ideological, or religious conflicts of interest to declare. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.