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      Serotonin receptor agonists in the acute treatment of migraine: a review on their therapeutic potential

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          Abstract

          Migraine is an important socioeconomic burden and is ranked the sixth cause of years of life lost because of disability in the general population and the third cause of years of life lost in people younger than 50 years. The cornerstone of pharmacological treatment is represented by the acute therapy. The serotonin (5-hydroxytryptamine [5-HT]) receptor subtype 1 B/1 D agonists, called triptans, are nowadays the first-line acute therapy for patients who experience moderate-to-severe migraine attacks. Unfortunately, a high percentage of patients are not satisfied with this acute treatment, either for lack of response or side effects. Moreover, their mechanism of action based on vasoconstriction makes them unsuitable for patients with previous cardio- and cerebrovascular diseases and for those with uncontrolled hypertension. Since the introduction of triptans, no other acute drug class has passed all developmental stages. The research for a new drug lacking vasoconstrictive effects led to the development of lasmiditan, a highly selective 5-HT1 F receptor agonist with minimized interactions with other 5-HT receptor subtypes. Lasmiditan is considered to be the first member of a new drug category, the neurally acting anti-migraine agent (NAAMA). Phase II and III trials had shown superiority compared to placebo and absence of typical triptan-associated adverse events (AEs). Most of the AEs were related to the central nervous system, depending on the high permeability through the blood–brain barrier and mild to moderate severity. The results of ongoing long-term Phase III trials will determine whether lasmiditan will become available in the market, and then active triptan comparator studies will assess patients’ preference. Future studies could then explore the safety during pregnancy and breastfeeding or the risk that overuse of lasmiditan leads to medication overuse headache.

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          Pathophysiology of migraine.

          Migraine is a collection of perplexing neurological conditions in which the brain and its associated tissues have been implicated as major players during an attack. Once considered exclusively a disorder of blood vessels, compelling evidence has led to the realization that migraine represents a highly choreographed interaction between major inputs from both the peripheral and central nervous systems, with the trigeminovascular system and the cerebral cortex among the main players. Advances in in vivo and in vitro technologies have informed us about the significance to migraine of events such as cortical spreading depression and activation of the trigeminovascular system and its constituent neuropeptides, as well as about the importance of neuronal and glial ion channels and transporters that contribute to the putative cortical excitatory/inhibitory imbalance that renders migraineurs susceptible to an attack. This review focuses on emerging concepts that drive the science of migraine in both a mechanistic direction and a therapeutic direction.
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            Cost of healthcare for patients with migraine in five European countries: results from the International Burden of Migraine Study (IBMS)

            Migraine is a disabling neurological disease that affects 14.7 % of Europeans. Studies evaluating the economic impact of migraine are complex to conduct adequately and with time become outdated as healthcare systems evolve. This study sought to quantify and compare direct medical costs of chronic migraine (CM) and episodic migraine (EM) in five European countries. Cross-sectional data collected via a web-based survey were screened for migraine and classified as CM (≥15 headache days/month) or EM (<15 headache days/month), and included sociodemographics, resource use data and medication use. Unit cost data, gathered using publicly available sources, were analyzed for each type of service, stratified by migraine status. Univariate and multivariate log-normal regression models were used to examine the relationship between various factors and their impact on total healthcare costs. This economic analysis included data from respondents with migraine in the UK, France, Germany, Italy, and Spain. CM participants had higher level of disability and more prevalent psychiatric disorders compared to EM. CM participants had more provider visits, emergency department/hospital visits, and diagnostic tests; the medical costs were three times higher for CM than EM. Per patient annual costs were highest in the UK and Spain and lower in France and Germany. CM was associated with higher medical resource use and total costs compared to EM in all study countries, suggesting that treatments that reduce headache frequency could decrease the clinical and economic burden of migraine in Europe. Comparing patterns of care and outcomes among countries may facilitate the development of more cost-effective care, and bring greater recognition to patients affected by migraine.
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              Headache disorders are third cause of disability worldwide

              From time to time, there is news that is of particular consequence to all people affected by headache. In December 2012, Lancet published the Global Burden of Disease Study 2010 (GBD2010). We wrote then [1]: “Few reports are likely to have more profound meaning for people with headache, or carry greater promise for a better future, than the seven papers (and one in particular [2]) that were presented.” So it was: the essential finding – that migraine was the seventh highest specific cause of disability worldwide – has been widely cited in both scientific and informal literature, pointedly noted by health commentators, trumpeted loudly by lay organisations and quietly harnessed by those seeking grants for headache research. It has given legitimacy to arguments that headache disorders contribute in a big way to public ill-health and disability [3], and strong backing to pleas for political recognition of this fact [4]. Now there is more, from the Global Burden of Disease Study 2013 (GBD2013), and it is of similarly arresting significance. Published in Lancet earlier this month [5], its key findings for those whose interests focus on headache are threefold: migraine is the sixth highest cause of disability worldwide; medication-overuse headache (MOH) is included in these surveys for the first time and enters the top twenty causes of disability at 18th; and adding together just these two puts headache disorders third among the worldwide causes of disability, measured in years of life lost to disability (YLDs). Thus in the 23 years of the Global Burden of Disease project (GBD), from 1990 to 2013, headache has come from nowhere – wholly ignored, not thought even worth measuring – into the leading three of the several hundred contributors to the global burden of disease that GBD counts. The background and a little of the history of this extraordinary transition should be told. What we are reporting here are the outcomes of huge, sustained, coordinated effort. GBD itself is a massive, ongoing, iterative enterprise [6]. It was undertaken initially, in 1990 and 2000, by the World Health Organization (WHO) but now is led by the Institute of Health Metrics and Evaluation (IHME) of the University of Washington, Seattle, WA, USA. Its stated purpose now is to set out “a comprehensive picture of what disables and kills people across countries, time, age, and sex”; towards this, it provides “a tool to quantify health loss from hundreds of diseases, injuries, and risk factors, so that health systems can be improved and disparities can be eliminated” [6]. The data in GBD2013 came through a consortium of more than 1,000 researchers in over 100 countries, capturing premature death and disability in 188 countries from more than 300 diseases [6]. Our objective has been to secure among these diseases the rightful inclusion of migraine, tension-type headache (TTH) and MOH: headache disorders that we know cause substantial disability [3]. The Global Campaign against Headache was launched in 2003 with a clear ultimate purpose: to reduce the burden of headache worldwide [7]. At that time, 12 years ago, it was not at all clear what this burden was, either in scope or scale. As a result of some lobbying during discussions with WHO in the years prior to the Campaign’s launch, GBD2000 included migraine [8]. No other headache disorders made it, but this was nevertheless a major advance for those concerned about headache, not just because GBD1990 had ignored headache totally but far, far more because migraine was found – on the evidence submitted – to be in the leading 20 causes (19th) of disability worldwide [8]. This “discovery” propelled headache disorders into WHO’s priorities [3, 4]. For the Campaign this was merely a call to arms, because also clear at that time was that the evidence submitted to GBD2000 was seriously deficient. Of course it related only to migraine, which was neither the most prevalent nor the most disabling of headache disorders, but this was not the issue. Migraine was certainly the best studied of the headache disorders, from all aspects including epidemiologically, and the epidemiological evidence then available from all studies of acceptable quality had been thoroughly collated (it was later published as a review [9]). The problem was that it focused strongly on North and South America and Western Europe, with a small Far-East cluster of studies in Japan, Taiwan and the Korean peninsula; left unrepresented were most of the Western Pacific Region (including mainland China), all of South East Asia (including India), all of the Eastern Mediterranean Region, most of Africa and all of Eastern Europe (including Russia). The people unrepresented in these territories were more than half the world’s population. Not long after the Global Campaign launched, data collection began for GBD2010 (which was initially to be GBD2005). Filling the largest of the data gaps was therefore the first priority of Lifting The Burden (LTB), the UK-registered charity conducting the Campaign [10, 11]. LTB had two objectives for GBD2010: to secure inclusion of the other headache disorders of public-health importance – TTH and MOH – and to show, as we then believed, that headache disorders collectively were among the top ten causes of disability worldwide. It became something of a race against time, firstly to develop the methodology for population-based door-to-door studies with a validated diagnostic questionnaire based on ICHD-II [12] and then to implement it in the big countries: China, India and Russia, home to 2.5 billion people. These things were done, and, with much better information, GBD2010 reported migraine more realistically as the seventh highest specific cause of disability measured in YLDs [1, 2]. This of course achieved LTB’s first objective. As for the second, TTH was included in the survey, but with a very low disability weight (DW) allocated to it. GBD2010 reported TTH as the second most prevalent disorder in the world (after dental caries), and migraine third [2], but despite this TTH added rather little compared with migraine to the global disability burden. What about MOH? This was initially included but not in the end reported because, it was argued – correctly, we believe, that prevalence data were not good enough to support regional estimates of burden attributable to this disorder. The particular difficulties of estimating MOH prevalence were recently discussed [13, 14]. Nonetheless, a DW was allocated to MOH, which was of crucial importance when it came to GBD2013. In the interim, between GBD2010 and GBD2013, LTB had supported further Global Campaign studies in Nepal in South East Asia, in Saudi Arabia and Pakistan in Eastern Mediterranean and in Zambia and Ethiopia in Africa – huge knowledge gaps – while collaborating with GBD in collating data published by other workers. The particular importance of the LTB studies lay in their use of similar methodology [15], the inclusion of MOH in their enquiries and the purposive selection of countries for survey. GBD2013 was therefore considerably better informed than GBD2010, not only with more comprehensive regional data but also, and in particular, with greatly enhanced data on MOH (and a DW available from GBD2010 for YLD estimates). LTB has prioritised this work on data gathering and our collaboration with GBD above all else. It has involved multiple complex studies in all world regions, and taken most of our resources, but as a policy we believe it has been strategically correct. If the ultimate purpose of the Campaign is to reduce the burden of headache worldwide, it must first be known what this burden is – the Campaign’s first objective [7]. At the same time, working with GBD does much to achieve the Campaign’s second objective, which is creation of awareness of this burden. Indeed this work of data gathering continues, with studies ongoing or planned in countries in Central and South America, North and West Africa and South East Asia. We have not forgotten children and adolescents, for which studies can be school-based [16]. All of these will not only benefit future iterations of GBD but also, just as importantly, serve as needs-assessment studies informing health policy locally, in the countries and regions where the data are gathered. To end, it would be easy to claim the findings of GBD2013 as a triumphal conclusion of prolonged hard effort, since on a technical level they are, but that would overlook their tragic meaning. As we reported earlier [1], GBD measures disease burden as it is – alleviated by whatever treatments are made available. Headache disorders, we said at the time of GBD2010, were among the top ten causes of disability because they were common and disabling, but we asked: “For what conceivable reason do headache disorders remain among these ignominious top ten when they are largely treatable?” [1]. Now we must ask the chastening question: “Why are they among the top three?”
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2018
                08 March 2018
                : 11
                : 515-526
                Affiliations
                [1 ]Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy
                [2 ]Department of Internal and Emergency Medicine, Regional Referral Headache Centre, Sant’Andrea Hospital, Rome, Italy
                [3 ]Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University, Rome, Italy
                Author notes
                Correspondence: Andrea Negro, Department of Internal and Emergency Medicine, Regional Referral Headache Centre, Sant’Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy, Email andrea.negro@ 123456uniroma1.it
                Article
                jpr-11-515
                10.2147/JPR.S132833
                5848843
                © 2018 Negro et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Review

                Anesthesiology & Pain management

                5-ht1f agonists, lasmiditan, acute treatment, migraine

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