Sekcija za glavobol - Združenje nevrologov priSekcija za glavobol - Združenje nevrologov pri Slovenskem zdravniškem društvu inSlovenskem zdravniškem društvu in Društvo za preprecevanje možganskih in žilnih bolezniDruštvo za preprecevanje možganskih in žilnih bolezni Uredila:Uredila: Bojana ŽvanBojana Žvan Marjan ZaletelMarjan Zaletel MIGRENA 2025MIGRENA 2025 Sekcija za glavobol - Združenje nevrologov pri Slovenskem zdravniškem društvu in Društvo za preprecevanje možganskih in žilnih bolezni MIGRENA 2025 zbornik poglavij strokovnega srecanja za zdravnike, zdravstvene delavce in študente Medicinske in Zdravstvene fakultete Uredila: Bojana Žvan in Marjan Zaletel Ljubljana, april 2025 MIGRENA 2025 Izdalo in založilo: Društvo za preprecevanje možganskih in žilnih bolezni Uredila: Bojana Žvan in Marjan Zaletel Oblikovanje in priprava za tisk: Gregor Jurgele Naklada: 250 izvodov Maloprodajna cena: 10 € Ljubljana, april 2025 © Društvo za preprecevanje možganskih in žilnih bolezni Izdajo publikacije sta omogocila: Sekcija za glavobol - Združenje nevrologov pri Slovenskem zdravniškem društvu in Društvo za preprecevanje možganskih in žilnih bolezni v sodelovanju s slovenskimi in tujimi strokovnjaki CIP - Kataložni zapis o publikaciji Narodna in univerzitetna knjižnica, Ljubljana 616.857(075)(0.034.2) 616.831-009.7(075)(0.034.2) MIGRENA (srecanje) (2025 ; Ljubljana) Migrena 2025 [Elektronski vir] : zbornik poglavij strokovnega srecanja za zdravnike, zdravstvene delavce in študente Medicinske in Zdravstvene fakultete / uredila Bojana Žvan in Marjan Zaletel ; [organizatorja] Sekcija za glavobol - Združenje nevrologov pri Slovenskem zdravniškem društvu [in] Društvo za preprecevanje možganskih in žilnih bolezni. - E-zbornik. - Ljubljana : Društvo za preprecevanje možganskih in žilnih bolezni, 2025 ISBN 978-961-7168-05-1 COBISS.SI-ID 231473667 KAZALO Žvan B., Zaletel M. Uvod k zborniku Migrena 2025 13 Žvan B., Zaletel M. Introduction to the Migraine 2025 proceedings 15 Došenovic Bonca P., Perko D., Lotric Dolinar A., Strgar-Hladnik M. Breme migrene za bolnike in družbo / The burden of migraine on patients and society 17 Perko D. Globalno o migreni / Global on migraine 21 Stepanovic A. Kaj lahko zdravnik družinske medicine stori za bolnike z migreno? / What can a family doctor do for migraine patients? 25 Zaletel M. Migrena pri ženskah – pogled nevrologa / Migraine in women – a neurologist perspective 31 Vukovic Cvetkovic V. Migraine - unusual clinical presentations / Migrena – nenavadne klinicne slike 35 Popit M. Migrenska avra in interikticni simptomi / Migraine aura and interictal symptoms 41 Premzl M., Notar L., Licina A. Ali je migrena le nevrološka motnja? Povezave med migreno in srcno/možganskožilnimi boleznimi / Is migraine only a neurological disorder? Associations between migraine and cardiovascular/cerebrovascular diseases 45 Zaletel M., Požlep G. Optimizacija koristi preventivnega zdravljenja migrene z uporabo intravenskega nacina aplikacije / Optimizing the benefits of prophylactic treatment in migraine by utilizing the intravenous route of administration 49 Žvan B. Kdaj izberemo rimegepant pri zdravljenju migrene? / When do we choose rimegepant in migraine treatment? 55 Zupan M. Prednosti atogepanta v preventivi migrene / Benefits of atogepant in migraine prevention 59 Požlep G. Nevromodulacija pri migreni – novi izzivi / Neuromodulation in migraine - new challenges 63 Budincevic H., Marcinko Budincevic A., Caic B. Cluster headache - new treatment approaches / Glavobol v skupkih – novi pristopi k zdravljenju 69 Demarin V., Morovic S., Đerke F. New targets for migraine treatment / Nove tarce zdravljenja migrene 71 Zaletel M. Priporocila za akutno zdravljenje migrene / Recommendations for acute migraine treatment 75 Žvan B. Priporocila za preventivno zdravljenje migrene / Recommendations for preventive treatment of migraine 83 Požlep G. Priporocila za preprecevanje migrene z nefarmakološkimi metodami / Recommendations for migraine prevention with nonpharmacological methods 95 Licina A. Migrena kot dejavnik tveganja za srcno-žilne bolezni / Migraine as a risk factor for cardiovascular disease 99 Naric D. Vloga fizioterapevta in pri obravnavi bolnika z migreno – izkušnje iz tujine / The role of physiotherapists in the treatment of patients with migraine - experiences from abroad 103 Golež A. Akupunktura za lajšanje migrene / Acupuncture as a treatment for migraine 107 SEZNAM AVTORJEV doc. dr. Hrvoje Budincevic, dr. med. Sveti Duh University Hospital, Department of Neurology, Sveti Duh 64, 10000 Zagreb, Croatia in Josip Juraj Strossmayer University of Osijek, Faculty of Medicine, Department of Neurology and Neurosurgery, Ulica Josipa Huttlera 4, 31000 Osijek, Croatia Barbara Caic, dr. med. Sveti Duh University Hospital, Department of Neurology, Sveti Duh 64, 10000 Zagreb, Croatia prof. dr. Vida Demarin, dr. med., FAAN, FAHA, FEAN, FESO, Fellow of Croatian Academy of Sciences and Arts International Institute For Brain Health, Trg Josipa Jurja Strossmayera 14, 10000 Zagreb, Croatia prof. dr. Petra Došenovic Bonca Univerza v Ljubljani, Ekonomska fakulteta, Kardeljeva plošcad 17, 1000 Ljubljana Filip Đerke, dr. med. University Hospital Dubrava, Department of Neurology, Referral Centre for Preoperative Assessment of Patients with Pharmacoresistant epilepsy, Avenija Gojka Šuška 6, 10000 Zagreb, Croatia dr. Ana Golež, dr. med. Splošna bolnišnica Celje, Oblakova ulica 5, 3000 Celje Albina Licina, dipl. m. s. Univerzitetni klinicni center Ljubljana, Nevrološka klinika, Klinicni oddelek za vaskularno nevrologijo in intenzivno nevrološko terapijo, Zaloška cesta 2, 1525 Ljubljana doc. dr. Aleša Lotric Dolinar Univerza v Ljubljani, Ekonomska fakulteta, Kardeljeva plošcad 17, 1000 Ljubljana Anita Marcinko Budincevic, dr. med. Sveti Duh University Hospital, Department of Neurology, Sveti Duh 64, 10000 Zagreb, Croatia asist. prof. Sandra Morovic, dr. med. Arsano Medical Group, Ilica 1 A, 10000 Zagreb, Croatia Dragan Naric, dipl. fiziot. Univerzitetni klinicni center Ljubljana, Nevrološka klinika, Služba za nevrorehabilitacijo, Enota za fizioterapijo, Zaloška cesta 2, 1525 Ljubljana Luka Notar, dr. med. Univerzitetni klinicni center Ljubljana, Nevrološka klinika, Klinicni oddelek za vaskularno nevrologijo in intenzivno nevrološko terapijo, Zaloška cesta 2, 1525 Ljubljana dr. Denis Perko, dr. med. Splošna bolnišnica dr. Franca Derganca Nova Gorica, Ulica padlih borcev 13 A, 5290 Šempeter pri Gorici in Nacionalni inštitut za javno zdravje, Trubarjeva cesta 2, 1000 Ljubljana Matjaž Popit, dr. med. Splošna bolnišnica Murska Sobota, Interni oddelek, Nevrološki odsek, Ulica dr. Vrbnjaka 6, Rakican, 9000 Murska Sobota prim. Gorazd Požlep, dr. med. Univerzitetni klinicni center Ljubljana, Kirurška klinika, Klinicni oddelek za anesteziologijo in intenzivno terapijo operativnih strok, Oddelek za zdravljenje bolecine, Vodnikova cesta 62, 1000 Ljubljana Maša Premzl, dr. med. Univerzitetni klinicni center Ljubljana, Nevrološka klinika, Klinicni oddelek za vaskularno nevrologijo in intenzivno nevrološko terapijo, Zaloška cesta 2, 1525 Ljubljana prim. asist. dr. Aleksander Stepanovic, dr. med. Osnovno zdravstvo Gorenjske, Zdravstveni dom Škofja Loka, Stara cesta 10, 4220 Škofja Loka in Univerza v Ljubljani, Medicinska fakulteta, Katedra za družinsko medicino, Poljanski nasip 58, 1000 Ljubljana Mihaela Strgar Hladnik, dr. med. Zdravstveni dom Ljubljana, Enota Bežigrad, PE Crnuce, Primožiceva ulica 2, 1231 Ljubljana-Crnuce dr. Vlasta Vukovic Cvetkovic, dr. med. Rigshospitalet – Glostrup, Danish Headache Center, Department of Neurology Copenhagen, Denmark dr. Marjan Zaletel, dr. med., višji svetnik Univerzitetni klinicni center Ljubljana, Kirurška klinika, Klinicni oddelek za anesteziologijo in intenzivno terapijo operativnih strok, Oddelek za terapijo bolecine, Vodnikova cesta 62, 1000 Ljubljana in Univerzitetni klinicni center Ljubljana, Nevrološka klinika, Klinicni oddelek za vaskularno nevrologijo in intenzivno nevrološko terapijo, Zaloška cesta 2, 1525 Ljubljana doc. dr. Matija Zupan, dr. med. Univerzitetni klinicni center Ljubljana, Nevrološka klinika, Klinicni oddelek za vaskularno nevrologijo in intenzivno nevrološko terapijo, Zaloška cesta 2, 1525 Ljubljana prim. prof. dr. Bojana Žvan, dr. med., višja svetnica, FESO Sekcija za glavobol, Slovensko zdravniško društvo, Domus Medica, Dunajska cesta 162, 1000 Ljubljana in Društvo za preprecevanje možganskih in žilnih bolezni, Mala ulica 8, 1000 Ljubljana UVOD K ZBORNIKU MIGRENA 2025 »Dobro življenje je smer in ne stanje bivanja. Je smer, ne cilj«. (Neznan avtor) Migrena je ena najstarejših bolezni, ki jih pozna cloveštvo, in že dolgo velja za eno najbolj obremenjujocih ter najpogostejših bolezni po vsem svetu. Predstavlja veliko breme ne le za bolnike, temvec tudi za zdravstvene sisteme. Nekatere najzgodnejše opise resnih glavobolov najdemo že pri starih Egipcanih, pri cemer zapisi segajo v leto 1200 pr. n. št. Veliko kasneje, okoli leta 400 pr. n. št., je Hipokrat opisal motnje vida, ki lahko nastopijo pred migreno, kot so utripajoce luci ali zamegljen vid – pojav, danes znan kot avra. Prav tako je omenil olajšanje, ki ga bolniki obcutijo po bruhanju. Zasluge za prvo natancnejšo opredelitev migrene pripisujemo Areteju iz Kapadokije, ki je v 2. stoletju opisal enostranske glavobole, znacilne za migreno, in z njimi povezano bruhanje. Sam izraz »migrena« izhaja iz latinske besede hemicrania, kar pomeni »polovica lobanje«. Ta termin je prvi uporabil Galen iz Pergamona za opis enostranske bolecine, znacilne za migreno. Menil je, da bolecina izvira iz mening in žilja v glavi ter opozoril na povezavo med želodcem in možgani, saj je migreno pogosto spremljalo bruhanje. Islamski filozof Avicenna je v svojem medicinskem ucbeniku El Qanoon fel teb podrobno opisal migreno ter izpostavil, kako jo lahko poslabšajo dolocena hrana, pijaca, zvoki in svetloba. Omenil je tudi, da bolniki potrebujejo pocitek v temni sobi, dokler napad ne mine. Migrena je bila omenjena tudi v publikaciji Bibliotheca Anatomica, Medic, Chirurgica, izdani v Londonu leta 1712, kjer je bila opisana skupaj z drugimi vrstami glavobolov. Šele v poznih 1930-ih sta Graham in Wolff porocala, da lahko kolac, ki vsebuje ergotamin, olajša migreno, saj povzroca vazokonstrikcijo razširjenih možganskih krvnih žil. Leta 1950 je Harold Wolff predlagal teorijo, da so nenormalnosti krvnih žil povezane z nastankom migrene. Kljub stoletjem raziskav se je šele v zadnjih desetletjih mocno okrepilo razumevanje te kompleksne bolezni, kar je prineslo boljše možnosti zdravljenja in preventive. Tradicionalno je zdravljenje migrene temeljilo na nakljucnih odkritjih zdravil, prvotno razvitih za druge namene. Prvi specificni medikament, metisergid, je bil zaradi varnostnih pomislekov kmalu umaknjen. Kasneje so bili razviti ergotamini in triptani, ki so ciljno namenjeni zdravljenju migrene. Napredek v biokemiji in molekularni biologiji ter razvoj sodobnih metod oblikovanja zdravil so povzrocili pomemben preobrat v zdravljenju migrene. Nova zdravila, kot so gepanti, imajo podobno ucinkovitost kot triptani, vendar brez tveganja za žilne bolezni ali prekomerno uporabo zdravil. Predstavljajo napredno možnost preprecevanja migrene, saj zagotavljajo visoko ucinkovitost in boljšo varnost. Pomemben napredek prinašajo tudi monoklonska protitelesa (mPt), usmerjena proti peptidu CGRP (povezanemu z genom za kalcitonin), ki omogocajo izjemno ucinkovite rezultate pri zdravljenju celotnega spektra migrene. Zaradi minimalnih neželenih ucinkov so presegla ucinkovitost starejših peroralnih zdravil. Poleg triptanov, ki delujejo na receptorje 5HT1B in 5HT1D, so na voljo tudi ditani, ki ciljno delujejo na serotoninske receptorje 5HT1F, ne da bi vplivali na žilni sistem. Zagotavljajo boljšo ucinkovitost, lažjo prenosljivost in vecjo varnost, kar odpira nove možnosti akutnega zdravljenja migrene. Nevromodulacijsko zdravljenje sega v sredino 19. stoletja, a je šele sodobni razvoj nevroznanosti in biomedicinske tehnologije omogocil napredne nevromodulacijske naprave za zdravljenje migrene. Njihova ucinkovitost, sprejetost med bolniki ter stroškovna dostopnost bodo v prihodnje pokazale, ali lahko spremenijo paradigmo zdravljenja in postanejo del standardne oskrbe. Na strokovnem srecanju Migrena 2025 bodo predstavljena slovenska priporocila za akutno in preventivno zdravljenje migrene, ki bodo temeljila na smernicah Mednarodnega združenja za glavobol (IHS – International Headache Society) in Ameriškega združenja za glavobol (AHS – American Headache Society). Priporocila bodo prilagojena slovenski zdravstveni praksi in upoštevala razpoložljive smernice ter strokovna soglasja. Kljub jasnim dokazom o hitrejši in ucinkovitejši obravnavi celotnega spektra migrene ter visoki varnosti novih zdravil številni še vedno vztrajajo pri zahtevi zdravstvenih zavarovalnic, da bolniki najprej preizkusijo starejša peroralna zdravila, preden jim je omogocen dostop do sodobnih terapij. To paradoksno povecuje breme migrene tako za posameznike kot za celotno družbo in povecuje družbene stroške. LITERATURA 1. Mandal A. Migraine History. 2023 [citirano 2025, marec 15]. Dosegljivo na: https://www.news-medical.net/health/Migraine-History.aspx. Bojana Žvan in Marjan Zaletel INTRODUCTION TO THE MIGRAINE 2025 PROCEEDINGS »The good life is a direction, not a state of being. It is a direction not a destination«. (Author Unknown) Migraine is one of the oldest known diseases and has long been considered one of the most burdensome and common illnesses worldwide. It presents a significant burden not only for patients but also for healthcare systems. Some of the earliest descriptions of severe headaches can be found among the ancient Egyptians, with records dating back to 1200 BC. Much later, around 400 BC, Hippocrates described visual disturbances that can precede migraines, such as flashing lights or blurred vision – a phenomenon now known as aura. He also mentioned the relief that patients feel after vomiting. The first precise definition of migraine is attributed to Aretaeus of Cappadocia, who, in the 2nd century, described unilateral headaches characteristic of migraine and the associated vomiting. The term “migraine” originates from the Latin word hemicrania, meaning “half of the skull.” This term was first used by Galen of Pergamon to describe the unilateral pain typical of migraines. He believed that the pain originated from the meninges and blood vessels in the head and noted the connection between the stomach and the brain, as migraines were often accompanied by vomiting. The Islamic philosopher Avicenna provided a detailed description of migraines in his medical textbook El Qanoon fel teb, highlighting how certain foods, drinks, sounds, and light could worsen the condition. He also noted that patients need to rest in a dark room until the attack subsides. Migraine was also mentioned in the publication Bibliotheca Anatomica, Medic, Chirurgica, published in London in 1712, where it was described alongside other types of headaches. It was not until the late 1930s that Graham and Wolff reported that an ergotamine-containing cake could relieve migraines by causing vasoconstriction of dilated cerebral blood vessels. In 1950, Harold Wolff proposed the theory that vascular abnormalities were linked to the development of migraines. Despite centuries of research, it is only in recent decades that the understanding of this complex disease has significantly advanced, leading to better treatment and prevention options. Traditionally, migraine treatment was based on the accidental discovery of medications originally developed for other purposes. The first specific drug, methysergide, was soon withdrawn due to safety concerns. Later, ergotamines and triptans were developed, specifically targeting migraine treatment. Advances in biochemistry and molecular biology, as well as the development of modern drug design methods, have led to a significant breakthrough in migraine treatment. New drugs, such as gepants, have similar efficacy to triptans but without the risk of vascular disease or medication overuse. They represent an advanced option for migraine prevention, offering high effectiveness and better safety. Significant progress has also been made with monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP), which provide exceptional treatment results across the migraine spectrum. Due to minimal side effects, they have surpassed the effectiveness of older oral medications. In addition to triptans, which act on 5HT1B and 5HT1D receptors, ditans are now available, specifically targeting 5HT1F serotonin receptors without affecting the vascular system. They offer improved efficacy, better tolerability, and greater safety, opening new possibilities for acute migraine treatment. Neuromodulation therapy dates back to the mid-19th century, but only modern advances in neuroscience and biomedical technology have enabled the development of advanced neuromodulation devices for migraine treatment. Their effectiveness, patient acceptance, and cost accessibility will determine whether they can change the treatment paradigm and become part of standard care. At the professional meeting Migraine 2025, Slovenian recommendations for acute and preventive migraine treatment will be presented, based on the guidelines of the International Headache Society (IHS) and the American Headache Society (AHS). The recommendations will be adapted to Slovenian healthcare practice, considering available guidelines and expert consensus. Despite clear evidence of faster and more effective management of the entire migraine spectrum, as well as the high safety of new drugs, many still insist on the requirement by health insurance companies that patients first try older oral medications before gaining access to modern therapies. This paradoxically increases the burden of migraines for individuals and society as a whole, leading to higher social costs. LITERATURE 1. Mandal A. Migraine History. 2023 [cited 2025, March 15]. Available at: https://www.news-medical.net/health/Migraine-History.aspx. Bojana Žvan and Marjan Zaletel BREME MIGRENE ZA BOLNIKE IN DRUŽBO THE BURDEN OF MIGRAINE ON PATIENTS AND SOCIETY Petra Došenovic Bonca, Denis Perko, Aleša Lotric Dolinar, Mihaela Strgar-Hladnik POVZETEK Migrena je povezana tako z neposrednimi zdravstvenimi in nezdravstvenimi stroški kot tudi s posrednimi stroški zaradi izgub produktivnosti, negativno pa vpliva na kakovost življenja bolnikov (1). V prispevku prikazujemo preliminarne ocene izbranih elementov neposrednih zdravstvenih stroškov in stroškov bolniškega staleža zaradi migrene v Sloveniji v letu 2023. Ocene neposrednih zdravstvenih stroškov temeljijo na podatkih NIJZ o hospitalizacijah po modelu SPP z glavno diagnozo G43, o kurativnih obravnavah oziroma pregledih (prvih in kontrolnih), pri katerih je ena izmed petih možnih kodiranih diagnoz G43, ter na podatkih o izdatkih za zdravila proti migreni (N02C glede na ATC klasifikacijo). Vrednostni obseg vseh navedenih obravnav je opredeljen s pomocjo šifrantov storitev ZZZS (2) in dogovora o programih zdravstvenih storitev za leto 2023 (3). Ocena stroškov izgub produktivnosti temelji na podatkih o izgubljenih koledarskih dnevih zaradi bolniškega staleža, ovrednotenih po metodi cloveškega kapitala, torej z izgubo dohodka koristnikov staleža. V letu 2023 je bilo zaradi migrene hospitaliziranih 89 pacientov, vrednost 91 hospitalizacij pa je zanašala 62.099 evrov. Na primarni in sekundarni ravni je bilo opravljenih zaradi migrene 11.437 ambulantnih kurativnih pregledov, v ambulantah splošne medicine pa še 10.610 kratkih pregledov in posvetov po telefonu, e-pošti in drugih IKT sredstvih. Ocenjena skupna vrednost teh obravnav znaša 252.199 evrov. Prvi kurativni pregledi so bili opravljeni za 4.724 oseb, kontrolni pregledi za 1.952 oseb, kratki pregledi v splošnih ambulantah za 2.634 oseb, posveti z uporabo IKT pa za 1.355 oseb. Celotna vrednost vseh receptov za zdravila za migreno je znašala 4,96 milijona evrov, kar je skoraj 100 evrov na recept oziroma 366 evrov na prejemnika recepta v povprecju. V obdobju petih let se je vrednost izdatkov za proucevana zdravila povecevala za 59 % letno v povprecju. Zaradi migrene je bilo na bolniškem staležu 4.065 oseb. Izgubljenih je bilo skupaj 18.526 koledarskih dni, torej 4,6 dneva na leto na koristnika staleža v povprecju. Glede na višino povprecnega stroška dela v Sloveniji v letu 2023 na dan (84,8 evra), lahko ocenimo strošek bolniškega staleža na 1,6 milijona evrov. Rezultati kažejo, da imajo med neposrednimi zdravstvenimi stroški kljucno vlogo zdravila proti migreni, breme absentizma pa je tudi obcutno vecje od stroškov hospitalizacij in kurativnih obravnav. Breme migrene je v tem prispevku sicer podcenjeno, saj niso zajeti preventivni pregledi, diagnostika, izobraževalni programi in podobno, prav tako niso zajete vse vrste izgub produktivnosti (npr. prezentizem). Prav tako ocene neposrednih zdravstvenih stroškov temeljijo na diagnozi G43, pri cemer je v praksi za pacienta z migreno pogosto kodirana diagnoza glavobol. Kljub navedenim omejitvam pa rezultati kažejo, da je spremljanje bremena migrene z vidika družbe in ne samo z vidika placnika, torej ZZZS, kljucno, saj lahko s sodobnimi ucinkovitimi nacini obvladovanja migrene zmanjšamo obcutne izgube produktivnosti zaradi migrene. Kljucne besede: ekonomsko breme, migrena, neposredni stroški, stroški absentizma. SUMMARY Migraine is associated with both direct medical and non-medical costs as well as indirect costs due to productivity losses and a significant negative impact on the quality of life of patients. This paper shows preliminary results on key components of direct medical costs and sickness absenteeism costs of migraine in Slovenia in 2023. Estimates of direct medical costs are based on NIJZ data on DRG hospitalizations with G43 as the main diagnosis, data on curative outpatient visits (first and follow-up), in which G43 is one of five possible coded diagnoses, and on data on expenditures for migraine drugs (N02C according to the ATC classification). The costs of studied treatments are estimated based on the services code lists of ZZZS (2) and the agreement on health service programs for 2023 (3). Sickness absenteeism costs reflect lost calendar days due to sick leave, valued according to the human capital method, i.e., by considering income losses of people on sick leave. In 2023, 89 patients were hospitalized due to migraine, costs of 91 hospitalizations amounted to 62,099 euros. At the primary and secondary level, there were 11,437 outpatient curative visits due to migraine, and 10,610 short examinations and consultations by telephone, e-mail and other ICT means were performed by family doctors. The estimated total costs of these treatments amount to 252,199 euros. First curative visits were recorded for 4,724 patients, follow-up visits for 1,952 patients, short examinations in general practice clinics for 2,634 patients, and consultations using ICT for 1,355 patients. The cost of all prescriptions for migraine amounted to 4.96 million euros, which is almost 100 euros per prescription or 366 euros per prescription recipient on average. Over a five-year period, the costs of the studied drugs increased by 59% annually on average. There were 4,065 people on the sick leave due to migraine. A total of 18,526 calendar days were lost, i.e., 4.6 days per year per patient on sick leave on average. Given the average labour cost in Slovenia in 2023 per day (84.8 euros), we can estimate absenteeism costs at 1.6 million euros. The results show that migraine medications play a key role in direct health costs, and the burden of absenteeism is also significantly higher than the costs of hospitalizations and curative outpatient visits. The burden of migraine is underestimated in this paper, as preventive examinations, diagnostics, educational programs, etc. as well as all types of productivity loss (e.g. presenteeism) are not included in the study. Direct medical cost estimates are also based on the G43 diagnosis, while in practice a patient with migraine is often coded as experiencing a headache. Despite the aforementioned limitations, the results show that investigating the burden of migraine from the societal perspective and not only from the perspective of the public payer is crucial, as modern effective methods of migraine management can reduce significant productivity losses due to migraine. Keywords: absenteeism costs, direct costs, economic burden, migraine. LITERATURA / LITERATURE 1. Lotric Dolinar A, Žvan B, Došenovic Bonca P. Productivity Losses Due to Migraine in Slovenia: An Analysis of Absenteeism and Presenteeism Costs Based on Administrative and Self-Reported Data. Zdr Varst. 2020; 59(2):75–82. 2. ZZZS. Navodilo o beleženju in obracunavanju zdravstvenih storitev in izdanih materialov. Verzija 2023-27. https://partner.zzzs.si/sifranti/ 3. Uredba o programih storitev obveznega zdravstvenega zavarovanja, zmogljivostih, potrebnih za njegovo izvajanje, in obsegu sredstev za leto 2023, Uradni list RS, št. 8/23. GLOBALNO O MIGRENI GLOBAL ON MIGRAINE Denis Perko POVZETEK O migreni so porocali že pred tisocimi leti. Za migreno so trpeli številni znani ljudje. Migrena vsako leto prizadene vec kot milijardo ljudi in je ena najpogostejših nevroloških motenj z visoko prevalenco in obolevnostjo, zlasti med mladimi odraslimi in ženskami. Globalna prevalenca migrene se je znatno povecala v zadnjih treh desetletjih (1). Najvecje število primerov je v starostni skupini od 30. do 34. leta s postopnim upadanjem v starejših starostnih skupinah pri obeh spolih. V obsežnih epidemioloških študijah je bilo ugotovljenih vec dejavnikov tveganja za migrenske napade. Intenzivnost in pogostost bolecine sta povezani z biološkimi in psihološkimi motnjami kot tudi z vnetjem (2). Povezana je s številnimi spremljajocimi boleznimi, ki segajo od stresa do samomora. Pogosto je povezana s hormonskimi nihanji, zlasti spolnih (estrogen). Ženske namrec trpijo za migrenami približno dvakrat pogosteje kot moški. Opazne so bile strukturne in funkcionalne razlike na magnetni resonanci. Zdi se, da trenutno razpoložljivi dokazi potrjujejo zapleteno povezavo med migreno in metabolicnim sindromom. Epidemiološke raziskave so pokazale, da imajo genetski dejavniki pomembno vlogo pri razvoju migrene z in brez avre. Med drugim epigenetski dejavniki lahko vplivajo na razvoj, kronifikacijo in celo odziv na zdravljenje migrene. Starost, ženski spol in nizka stopnja izobrazbe so najpomembnejši demografski dejavniki tveganja za kronifikacijo migrene, medtem ko lahko višja izobrazba deluje kot zašcitni dejavnik (3). Obstaja mocna in pomembna povezava med spanjem in migrenami, pri cemer so motnje spanja povezane z vrsto in resnostjo migrene. Ugotovljeno je bilo tudi, da so motnje hranjenja povezane z migreno. Dokazano je, da je migrena dejavnik tveganja za kardiovaskularne bolezni. Ta povezava je mocnejša pri bolnikih z avro kot pri tistih brez avre. Dokazane so tudi povezave med migreno in drugimi nevrološkimi (epilepsija, motnje gibanja, multipla skleroza), gastroenterološkimi in revmatološkimi boleznimi. O povezavi med migreno in nekaterimi psihološkimi dejavniki, kot so nagnjenost k perfekcionizmu, nevroticizem, potlacena agresija in melanholicno razpoloženje porocajo že vec kot stoletje. Narašcajoca raven stresa prispeva k vecji prevalenci migrene. V vec študijah je bilo ugotovljeno, da imajo posamezniki z migreno povecano tveganje za afektivne in anksiozne motnje. Bolniki z migreno imajo tudi petkrat vecjo verjetnost, da bodo zboleli za obsesivno kompulzivno motnjo kot osebe brez migrene. Zelo mocna je tudi povezava med migreno in depresivnimi motnjami. Lahko se zakljuci, da si z jasnejšo opredelitvijo pomembnih bioloških in psiholoških dejavnikov ter razumevanjem patofizioloških mehanizmov lahko ustvarimo nova spoznanja o preprecevanju, preoblikovanju oskrbe, nacrtih upravljanja in personaliziranih strategijah zdravljenja migrene. Kljucne besede: dejavniki tveganja, epidemiologija, komorbidnosti, migrena. SUMMARY Stories about migraines have been reported thousands of years ago. Many notable people have suffered from migraine. Migraine affects more than one billion people each year and is one of the most common neurological disorders with a high prevalence and morbidity, especially among young adults and women. The global prevalence of migraine has increased significantly over the last three decades (1). The highest number of cases is in the age group 30–34 years, with a gradual decline in older age groups in both sexes. Large epidemiological studies have identified several risk factors for migraine attacks. Pain intensity and frequency are associated with biological and psychological disorders as well as inflammation (2). Migraine is associated with a number of comorbidities ranging from stress to suicide. It is also often associated with hormonal fluctuations, particularly sexual (oestrogen). In fact, women suffer from migraines approximately twice as often as men. Structural and functional differences have been observed on MRI. The currently available evidence seems to support a complex link between migraine and metabolic syndrome. Epidemiological studies have shown that genetic factors play an important role in the development of migraine with and without aura. Among other things, epigenetic factors may influence the development, chronicity and even response to treatment of migraine. Age, female sex and low educational attainment are the most important demographic risk factors for migraine chronicity, while higher education may act as a protective factor (3). There is a strong and significant association between sleep and migraine, with sleep disturbances being associated with migraine type and severity. Eating disorders have also been found to be associated with migraine. Migraine has been shown to be a risk factor for cardiovascular disease. This association is stronger in patients with aura than in those without aura. Associations between migraine and other neurological (epilepsy, movement disorders, multiple sclerosis), gastroenterological and rheumatological diseases have also been demonstrated. The association between migraine and certain psychological factors such as perfectionism, neuroticism, repressed aggression and melancholic mood has been reported for more than a century. Increasing stress levels contribute to a higher prevalence of migraine. Several studies have found that individuals with migraine have an increased risk of affective and anxiety disorders. Migraine sufferers are also five times more likely to suffer from obsessive compulsive disorder than non-migraine sufferers. The association between migraine and depressive disorders is also very strong. It can be concluded that by more clearly defining the important biological and psychological factors and understanding the pathophysiological mechanisms, we can generate new insights into prevention, care redesign, management plans, and personalized migraine treatment strategies. Keywords: comorbidities, epidemiology, migraine, risk factors. LITERATURA / LITERATURE 1. Safiri S, Pourfathi H, Eagan A, et al. Global, regional, and national burden of migraine in 204 countries and territories, 1990 to 2019. Pain. 2022; 163: 293–309. 2. Buse DC, Reed ML, Fanning KM, et al. Comorbid and co-occurring conditions in migraine and associated risk of increasing headache pain intensity and headache frequency: results of the migraine in America symptoms and treatment (MAST) study. J Headache Pain. 2020; 21: 23. 3. May A, Schulte LH. Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol. 2016; 12: 455–64. KAJ LAHKO ZDRAVNIK DRUŽINSKE MEDICINE STORI ZA BOLNIKE Z MIGRENO? WHAT CAN A FAMILY DOCTOR DO FOR MIGRAINE PATIENTS? Aleksander Stepanovic POVZETEK Zdravnik družinske medicine prepozna bolnika z migreno in uvede zdravljenje. Ce je potrebno, bolnika napoti na dodatne preiskave ali pregled k nevrologu. Bolnika po uvedbi zdravljenja spremlja in ukrepa ob poslabšanjih ter ob ustrezni indikaciji predpiše preventivna zdravila. Diagnozo postavimo na osnovi težav, ki jih bolnik navaja. Migrena je obicajno huda, kljuvajoca bolecina, ki se najveckrat zacne na eni strani glave in se kasneje lahko tudi razširi. Lahko jo spremlja obcutek slabosti v želodcu, bruhanje ter preobcutljivost na svetlobo in hrup ter bolnika onesposobi za opravljanje vsakdanjih opravil. Telesna aktivnost pogosto simptome še poslabša. Traja lahko od nekaj ur do nekaj dni. Vcasih se opisanim simptomom pridruži avra, ki traja od nekaj minut do ene ure in se kaže z razlicnimi vidnimi, senzoricnimi in motoricnimi simptomi in znaki. Navadno se pojavi najvec eno uro pred nastopom glavobola in obicajno izzveni do zacetka glavobola. S slikovnimi preiskavami ne moremo potrditi diagnoze migrene, kljub temu pa se zlasti v zadnjem casu pogosteje uporabljajo, kar še posebej velja za magnetno resonancno slikanje glave. Razlogov za to je vec: pomanjkanje casa za natancen pogovor in nevrološki pregled, preiskave so postale bolj dostopne in cenejše, bolniki pa vse pogosteje nezaupljivi in jih normalen izvid, ki je pri migreni pricakovan, vsaj nekoliko pomiri. Medicinsko indikacijo za slikovne preiskave predstavljajo: prvi izjemno hud glavobol ali najhujši glavobol v življenju, spremenjen vzorec predhodnih migren, nevrološki izpadi, pricetek migrene po 50 letu starosti, nastanek glavobola pri imunokompromitiranem bolniku (npr. okužba s HIV, rak), pridružena povišana telesna temperatura, epilepsija, novo nastal vsakodneven hud glavobol, stopnjevanje frekvence ali intenzitete glavobola in posteriorni glavobol (1). V primeru atipicnih glavobolov, ko nismo prepricani, ce gre res za migreno ali v primeru neuspešnega zdravljenja, je smiselna obravnava pri nevrologu. Ceprav pri vecini bolnikov ne najdemo sprožilnega dejavnika za nastanek migrene, je potrebno bolnika povprašati o najpogostejših sprožilcih, kot so hormonske spremembe (npr. menstruacija, kontracepcija), prehrana (npr. kava, alkohol, sir, mesni izdelki z nitriti), pomanjkanje spanca, mocna svetloba in hrup. Bolnik naj bo na potencialne sprožilce pozoren in se jih, ce je le možno, izogiba. Poleg naštetih v literaturi vse pogosteje kot sprožilna dejavnika omenjajo stres in spremembe vremena, kjer pa smo vecinoma nemocni (2). Priporocljivo je, da bolniki vodijo dnevnik glavobolov, ki jim pomaga prepoznati sprožilne dejavnike in spremljati celoten vpliv migrene na njihovo vsakdanje življenje. Enostavni analgetiki sami ali v kombinaciji olajšajo blage do zmerno hude glavobole. Akutno zdravljenje je najbolj ucinkovito, ce ga damo v 15 minutah po pojavu bolecine in ko je bolecina blaga. Poleg analgetikov lahko v primeru slabosti in bruhanja predpišemo antiemetike, npr. metoklopramid. Od analgetikov pri blažjih težavah predpišemo paracetamol in nesteroidna protivnetna zdravila. Pri mocnejših bolecinah se uporabljajo agonisti 5-hidroksitriptamina-1 (triptani), v zadnjih letih pa še selektivni agonisti 5-hidroksitriptamina-1F (ditani) in antagonisti CGRP (Calcitonin Gene Related Peptide) oziroma »gepanti«. Ceprav imajo triptani skupen mehanizem delovanja, se razlikujejo po možnih poteh dajanja, zacetku delovanja in trajanju delovanja. Možna je peroralna, intranazalna, subkutana, intramuskularna in transdermalna pot. Vsi triptani so najucinkovitejši, ce jih vzamemo zgodaj med migreno in jih je mogoce po potrebi ponoviti cez 2 uri, najvec 2 odmerka na dan. Medtem ko se lahko v istem 24-urnem obdobju uporabijo razlicne formulacije dolocenega triptana, se lahko v tem casovnem obdobju uporabi samo 1 triptan. Ucinkovitost in prenašanje triptanov se med bolniki razlikujeta. Pomanjkanje odziva ali neželeni ucinki pri enem triptanu ne napovedujejo odziva na drugega. Ceprav so triptani relativno varna zdravila, obstaja možnost nastanka koronarnega vazospazma zaradi uporabe triptana, zato triptanov ne smejo jemati bolniki z boleznijo koronarnih arterij, saj lahko povecajo tveganje za miokardno ishemijo, infarkt ali druge srcno žilne dogodke. Leta 2019 je Ameriška agencija za zdravila (FDA) odobrila lasmiditan, prvi selektivni serotonin 5-HT1F receptor agonist, ki nima vazokonstriktivega ucinka. Med gepanti imajo indikacijo za akutno zdravljenje zavegepant, ubrogepant in rimegepant, na voljo pa so ta so tako v intranazalni kot peroralni obliki. Gepanti delujejo tako, da blokirajo delovanje peptida, povezanega z genom kalcitonina (CGRP), za katerega je znano, da je povezan z migrenskimi napadi. V praksi so se gepanti izkazali kot zelo ucinkoviti in jih lahko v primeru neucinkovitosti ali neprenašanja enostavnih analgetikov in triptanov predpiše tudi zdravnik družinske medicine. Najpogostejši do sedaj znani neželeni ucinki gepantov so utrujenost, slabost, zaprtje in alergijske reakcije (izpušcaj in dispneja). Uporaba zdravil za akutno zdravljenje mora biti omejena na najvec 2-3 dni na teden, da se prepreci razvoj pojava glavobola zaradi cezmerne uporabe zdravil; to pomeni, da akutna zdravila za migreno postanejo dejanski vzrok za nadaljnje glavobole. Zdi se, da slednje ne velja za gepante. Na voljo so tudi nefarmakološki pristopi k preprecevanju migrene, ki se lahko uporabljajo kot dopolnilo k zdravljenju z zdravili. Ti nacini zdravljenja vkljucujejo akupunkturo vitamine in minerale ter pripomocke za nevrostimulacijo. Preventivna zdravila se uporabljajo za preprecevanje napadov migrene. Ta zdravila se morajo jemati redno vsak dan, tudi v odsotnosti migrenskih napadov. O njih velja razmisliti, ce ima bolnik štiri ali vec migrenske dni mesecno, ce ga migrena mocno omejuje pri vsakdanjih aktivnostih oz. mu mocno zmanjšuje kakovost življenja in ce je zdravljenje akutnih glavobolov neuspešno ali bolnik za to uporablja prevec zdravil. Standardna zdravila za preprecevanje migrene, so bila razvita za zdravljenje drugih zdravstvenih težav, ki niso povezane z migreno. To so zdravila za znižanje krvnega tlaka (npr. blokatorji beta), zdravila za zdravljenje depresije (npr. triciklicni antidepresivi), antiepilepticna zdravila (npr. topiramat) in nevrotoksini za injiciranje (botulinum toksin). Ta zdravila se praviloma niso izkazala kot zelo ucinkovita, imajo zahtevno titracijo ali pa jih bolniki slabo prenašajo, zato se zdravniki družinske medicine nismo pogosto odlocali za njihovo samostojno predpisovanje. Zaviranje CGRP je nova metoda za preprecevanje migren. CGRP je mocan vazodilatator in je kljucni nevropeptid, ki je osrednjega pomena za patofiziologijo migrene. Trenutno je v Sloveniji že registriranih vec monoklonskih protiteles (mPt), ki se vežejo na receptor CGRP (erenumab, fremanezumab, galcanezumab, eptinezumab). Zdravila se enostavno odmerjajo in sicer v mesecnih ali cetrtletnih podkožnih (subkutanih) injekcijah. Zanje je znacilen hiter zacetek delovanja, dobra odzivnost pri vecini bolnikov in dober varnostni profil. Proti CGRP usmerjena mPt zacnemo uvajati pri pogosti epizodni (=4 migrenskih dni/mesec) in kronicni migreni po poskusu zdravljenja z vsaj dvema preventivnima zdraviloma, ki sta bila neuspešna. Bolnikom z epizodno in kronicno migreno, ki ne morejo uporabljati drugih preventivnih zdravil zaradi socasnih bolezni, neželenih ucinkov ali slabega sodelovanja, ter bolnikom s kronicno migreno zaradi cezmerne uporabe akutnih zdravil prav tako priporocamo preventivno zdravljenje z mPt. Zdravljenja z mPt ne priporocamo nosecnicam ali dojecim ženskam z migreno, osebam, ki uživajo alkohol ali droge, osebam s srcno žilnimi boleznimi ter osebam s hudimi duševnimi motnjami. Poleg mPT ucinek CGRP na nekoliko drugacen nacin blokirajo tudi gepanti, ki se jih jemlje v obliki tablet. V Sloveniji sta trenutno kot preventivni zdravili registrirana rimegepant in atogepant, ki ju v primeru, da ima bolnik najmanj 4 migrenske dni na mesec in v primeru neucinkovitosti ali neprenašanja vsaj dveh profilakticnih zdravil (oz. v primeru kontraindikacije zanje) v breme ZZZS lahko predpiše tudi zdravnik družinske medicine. Kljucne besede: družinska medicina, migrena, preprecevanje, zdravljenje. SUMMARY The family medicine specialist identifies a patient with a migraine and initiates treatment. If necessary, the doctor refers the patient for additional tests or a neurological consultation. Once treatment has started, the doctor monitors the patient and takes action if symptoms worsen and prescribes preventative medication if indicated. The diagnosis is based on the symptoms described by the patient. Migraine is typically a severe, throbbing headache that often starts on one side of the head and may later spread. It may be accompanied by nausea, vomiting and increased sensitivity to light and sound, which can prevent the patient from carrying out everyday activities. Physical activity often exacerbates the symptoms. They can last from several hours to several days. Sometimes the symptoms described are accompanied by an aura that lasts from a few minutes to an hour and has various visual, sensory and motor symptoms and signs. It usually occurs no more than an hour before the onset of the headache and usually disappears when the headache begins. Imaging tests cannot confirm the diagnosis of migraine, although they are increasingly being used, particularly magnetic resonance imaging (MRI) of the head. The reasons for this include lack of time for a detailed interview and neurological examination, more accessible and cheaper tests, and the increasing scepticism of patients who are somewhat reassured by a normal result, which is typically expected in migraine. Medical indications for imaging tests include: the first extremely severe headache or the worst headache of a lifetime, changes in the pattern of previous migraine attacks, neurological deficits, the onset of migraine after the age of 50, headaches in immunocompromised patients (e.g. HIV, cancer), concomitant fever, epilepsy, new daily severe headaches, worsening frequency or intensity of headaches and posterior headaches. In the case of atypical headaches, if it is unclear whether it is really a migraine or if treatment has been unsuccessful, a referral to a neurologist is recommended. Although in most patients no triggering factor is found, the doctor should enquire about common triggers, such as hormonal changes (e.g. menstruation, contraception), diet (e.g. coffee, alcohol, cheese, processed meat with nitrates), lack of sleep, strong light and noise. The patient should be aware of the potential triggers and avoid them if possible. In addition, stress and weather changes are increasingly cited in the literature as triggers, although we are generally powerless in these cases. It is recommended that patients keep a headache diary to recognise triggers and monitor the impact of migraines on their daily lives. Simple analgesics, alone or in combination, relieve mild to moderate headaches. Acute treatment is most effective when given within 15 minutes of the onset of pain and for mild pain. In addition to analgesics, antiemetics such as metoclopramide can be prescribed for nausea and vomiting. Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed for milder symptoms. Agonists of 5-hydroxytryptamine-1 (triptans) are used for more severe pain. In recent years, selective agonists of 5-hydroxytryptamine-1F (ditanes) and CGRP antagonists (Calcitonin Gene-Related Peptide) antagonists, also known as “gepants,” have been introduced. Although the triptans have a common mechanism of action, they differ in terms of route of administration, onset of action and duration of effect. They can be administered orally, intranasally, subcutaneously, intramuscularly or transdermally. Triptans are most effective when taken at the onset of a migraine and can be repeated after 2 hours, with a maximum of two doses per day. Different formulations of the same triptan can be taken within the same 24-hour period, but only one triptan can be taken within this period. The efficacy and tolerability of triptans varies from patient to patient. The absence of a response or side effects to one triptan does not indicate a response to another triptan. Although triptans are relatively safe medications, there is a risk of coronary vasospasm when taking them. Patients with coronary artery disease should therefore not take triptans as they may increase the risk of myocardial ischaemia, myocardial infarction or other cardiovascular events. In 2019, the US Food and Drug Administration (FDA) approved lasmiditan, the first selective serotonin 5-HT1F receptor agonist that does not cause vasoconstriction. Of the gepants, zavegepant, ubrogepant, and rimegepant are indicated for acute treatment and are available in both intranasal and oral forms. Gepants work by blocking the action of CGRP, a peptide associated with migraine attacks. In practise, gepants have been shown to be highly effective and can be prescribed by a GP when simple analgesics and triptans are ineffective or poorly tolerated. The most common side effects of gepants include fatigue, nausea, constipation and allergic reactions (skin rash and shortness of breath). The use of acute medication should be limited to a maximum of 2-3 days per week in order to prevent the development of headaches from medication overuse, meaning that acute drugs themselves can become a cause of further headaches. This does not seem to apply to gepants. There are also non-pharmacological approaches to migraine prevention that can be used in conjunction with drug treatment. These approaches include acupuncture, vitamins and minerals, and neurostimulation devices. Preventive medications are used to prevent migraine attacks. These medications must be taken regularly every day, even when migraine attacks are not occurring. They should be considered if the patient experiences four or more migraine days per month, if the migraine significantly interferes with daily activities or quality of life, or if acute treatment fails or the patient overuses the medication. The standard medications for migraine prevention were developed for other health conditions not related to migraine. These include antihypertensive medications (e.g. beta blockers), antidepressants (e.g. tricyclic antidepressants), antiepileptic drugs (e.g. topiramate) and neurotoxins for injections (botulinum toxin). These medications are generally not highly effective, require difficult titration or are poorly tolerated by patients, so GPs do not usually prescribe them themselves. CGRP inhibition is a new method for the prevention of migraine. CGRP is a potent vasodilator and an important neuropeptide involved in the pathophysiology of migraine. Several monoclonal antibodies (mAbs) targeting the CGRP receptor (erenumab, fremanezumab, galcanezumab, eptinezumab) are already registered in Slovenia. These medications are easy to administer, usually by monthly or quarterly subcutaneous injections. They are characterised by a rapid onset of action, a good response in most patients and a good safety profile. CGRP-targeted mAbs are introduced for frequent episodic (=4 migraine days/month) and chronic migraine after at least two unsuccessful preventive treatments. They are also recommended for patients who cannot take other preventive medications due to comorbidities, side effects or lack of adherence, as well as for patients with chronic migraine due to overuse of acute medications. However, mAbs are not recommended for pregnant or breastfeeding women, people who consume alcohol or drugs, people with cardiovascular disease or people with severe psychiatric disorders. In addition to mAbs, gepants also block CGRP in a slightly different way and are taken in tablet form. In Slovenia, rimegepant and atogepant are currently registered as preventive medication. They can be prescribed by a GP for patients with at least four migraine days per month and if at least two prophylactic medications are ineffective or intolerable (or if there are contraindications to these), and are covered by health insurance. Keywords: family medicine, migraine, prevention, treatment. LITERATURA / LITERATURE 1. Detsky ME, McDonald DR, Baerlocher MO, et al. Does this patient with headache have a migraine or need neuroimaging? JAMA. 2006 Sep 13; 296(10): 1274-83. 2. Kesserwani H. Migraine Triggers: An Overview of the Pharmacology, Biochemistry, Atmospherics, and Their Effects on Neural Networks. Cureus. 2021 Apr 1; 13(4): e14243. 3. Chawla J. Migraine Headache Treatment & Management. [internet]. 2024 [citirano 2025 Mar 1]; Dosegljivo na: https://emedicine.medscape.com/article/1142556-treatment?_gl=1*s0lisw*_gcl_au*MTk0ODcyNTkzOS4xNzM1NDY3MDU0#showall MIGRENA PRI ŽENSKAH – POGLED NEVROLOGA MIGRAINE IN WOMEN – A NEUROLOGIST PERSPECTIVE Marjan Zaletel POVZETEK Epidemiološke študije razkrivajo, da je aktivnost migrene v dolocenih življenjskih obdobjih povezana s spolom. Prevalenca migrene je med dekleti in fanti v prepubertetnem obdobju primerljiva, med puberteto pa mlade ženske trpijo za migreno približno dvakrat pogosteje kot mladi moški, pri cemer se najvišja stopnja pojavnosti beleži med 30. in 40. letom starosti. Po tem obdobju prevalenca za oba spola upada in se izenacuje. Razlike v prevalenci se pripisujejo spolnim hormonom, zlasti estrogenu, v reproduktivnem obdobju žensk. Vendar pa to ne more biti edini dejavnik, saj ne pojasnjuje povecanja prevalencne stopnje migrene pri moških v primerljivem obdobju, ceprav ne v enaki meri. To nakazuje na kompleksno interakcijo vec dejavnikov, ne le spolnih hormonov. Z biopsihosocialnega vidika je obdobje povecane prevalence povezano s socialnimi dejavniki, kot so sprejemanje družbene vloge, socialna pricakovanja in prepricanja, ter obremenitve na delovnem mestu in doma. Razlicna socialna pricakovanja za ženski in moški spol lahko povzrocijo razlike v odzivanju spolov ter povecanje migrene pri obeh. V sodobnem svetu locimo biološki in psihosocialni spol, kar v angleškem jeziku oznacujemo z izrazoma »sex« in »gender«. To dokazuje, da nekatere kulture zahodne civilizacije povezujejo psihosocialne dejavnike s spolom. Ameriško združenje psihologov (APA) opredeljuje psihosocialni spol kot odnose, obcutke in vedenje, ki jih dolocena kultura povezuje z biološkim spolom osebe. Pojavlja se vprašanje, kako lahko psihosocialni spol vpliva na prevalenco migrene. S fenomenološkega stališca migreno opredeljujemo kot klinicni sindrom, pri katerem je glavobol najpomembnejši simptom, ki ga spremljajo slabost, fotofobija, sonofobija, avra ter prodromalni in postdromalni simptomi. Zaradi tega migreno uvršcamo med primarna bolecinska stanja. Pomembno je dejstvo, da je migrena povezana z oviranostjo, znano kot migrenska oviranost, ki pri ženskah povzroca pomembno obremenjenost. Ženske trpijo zaradi vecjega števila migrenskih epizod kot moški primerljive starosti, pri cemer so glavoboli pogosto bolj intenzivni in spremljani z vecjo stopnjo preobcutljivosti, kot je obrazna alodinija. Vpliv spolnih hormonov na migreno je izrazit, kar potrjuje, da je menstrualna migrena v mednarodni klasifikaciji glavobolov prepoznana kot samostojna entiteta. Sodobna razumevanja migrene vkljucujejo trigeminovaskularni sistem, ki se aktivira ob migrenski epizodi s sprošcanjem peptidov, povezanih z genom za kalcitonin (CGRP) in nastankom nevrogenega vnetja. Ugotovitve, da so estrogenski receptorji prisotni v trigeminusnem gangliju in krvnih žilah, kažejo na pomemben vpliv spolnih hormonov na migreno. Zdravljenje migrene obicajno vkljucuje cimprejšnjo prekinitev migrenske epizode in preventivno zdravljenje. Kljub omejenim podatkom o zdravljenju migrene pri ženskah ni jasnega pristopa. Klinicne študije kažejo, da so triptani ucinkoviti za akutno zdravljenje menstrualne migrene, pri cemer izstopa frovatriptan zaradi manjše ponovitve migrenske epizode. Med menstrualnim obdobjem se sprošcajo prostaglandini, kar povecuje dovzetnost za migreno. Zato je pri menstrualni migreni priporocena kombinacija sumatriptana in naproksena ter kratkotrajna preventiva s triptanom ali nesteroidnim analgetikom za bolnice s predvidljivimi menstrualnimi ciklusi. Preventivno zdravljenje je ucinkovito za menstrualno migreno, kar potrjujejo študije s topiramatom in erenumabom, medtem ko za uporabo gepantov pri menstrualni migreni trenutno nimamo dovolj podatkov. Nihanje estrogena se smatra za pomemben sprožilec migrenske epizode, zato so strategije z uporabo spolnih hormonov alternativna izbira za zdravljenje menstrualne migrene, vkljucno s kratkorocnim nadomešcanjem hormonov v obliki obližev ali gela. Pri bolnicah s perimenopavzalno migreno se priporoca hormonsko nadomestno zdravljenje, vendar je treba upoštevati tudi potencialne neželene ucinke, kot sta pojav trombembolizma in povecano tveganje za raka dojke. Zakljucujemo, da je migrena pri ženskah povezana s psihosocialnimi dejavniki in spolnimi hormoni, pri cemer obstaja interakcija med njima. Ucinek psihološkega stresa na hipotalamo-hipofizno-gonadno os in sprošcanje spolnih hormonov je znan, kar omogoca razumevanje psiho-gonadnega delovanja kot samostojne celote. Kognicija in z njo povezane dejavnosti igrajo pomembno vlogo pri uravnavanju spolnih hormonov ter prilagajanju na socialne in materialne razmere v okolju. Z vidika biopsihosocialnega modela lahko migreno pri ženskah interpretiramo kot prilagoditveni odziv na zahteve in potrebe njihovega okolja, kar je kljucno za ucinkovito obvladovanje migrene. Kljucne besede: kognicija, menstrualna migrena, spolni hormoni, ženski spol. SUMMARY Epidemiological studies reveal that the incidence of migraines across various life stages is significantly influenced by gender. During the prepubertal phase, the prevalence of migraines is similar between girls and boys; however, this changes during puberty, when young women experience approximately twice the number of migraines compared to young men, with a peak occurrence between the ages of 30 and 40. Following this peak, the prevalence of migraines declines for both sexes and eventually reaches an equilibrium. This gender disparity is primarily attributed to sex hormones, particularly estrogen, during women’s reproductive years. However, this explanation is incomplete, as it does not fully account for the increase in migraines observed among men during a similar period, albeit to a lesser extent. This observation indicates the potential involvement of multiple factors beyond sex hormones. From a biopsychosocial perspective, the increased prevalence of migraines is associated with social factors, including the acceptance of social roles, societal expectations, beliefs, and pressures experienced at work and home. Given that social expectations differ for women and men, these variations can lead to differing responses between the sexes and an increase in migraines for both genders. In contemporary discourse, a distinction is made between biological and psychosocial sex, referred to as “sex” and “gender” in English. This differentiation underscores that certain cultures within Western civilization link psychosocial factors to biological sex. The American Psychological Association (APA) defines psychosocial sex as the relationships, feelings, and behaviors that a specific culture associates with an individual’s biological sex, raising questions about how psychosocial sex may influence migraine prevalence. From a phenomenological standpoint, migraines are characterized as a clinical syndrome with headache as the primary symptom, often accompanied by nausea (with or without vomiting), photophobia, phonophobia, aura, and prodromal and postdromal symptoms. Consequently, migraines are classified as primary pain conditions. It is essential to recognize that migraines are associated with a disability known as migraine-related disability, which imposes a significant burden on women. Research indicates that women experience a higher frequency of migraine episodes than men of similar age, with headaches often being more intense and accompanied by a greater degree of hypersensitivity, such as facial allodynia. The influence of sex hormones on migraines is substantial, as evidenced by the classification of menstrual migraines as a distinct entity in the International Classification of Headache Disorders. Current understanding of migraines encompasses the trigeminovascular system, activated during a migraine episode through the release of peptides associated with calcitonin gene-related peptide (CGRP) and the onset of neurogenic inflammation. The presence of estrogen receptors in the trigeminal ganglion and blood vessels further emphasizes the significant role of sex hormones in migraine pathophysiology. Migraine treatment typically involves the prompt interruption of an episode and preventive measures. However, data on migraine treatment remains limited, resulting in a lack of a clear approach for treating migraines in women. Clinical studies suggest that triptans are effective for the acute treatment of menstrual migraines, with frovatriptan noted for its lower recurrence rate of migraine episodes. During menstruation, elevated levels of prostaglandins increase susceptibility to migraines, leading to the recommendation of a combination of sumatriptan and naproxen for menstrual migraines. Short-term preventive treatment with a triptan or non-steroidal analgesic is advised for those with predictable menstrual cycles, while preventive treatment with topiramate and erenumab has demonstrated effectiveness for menstrual migraines. Currently, there is insufficient data regarding the use of gepants for menstrual migraines. Fluctuations in estrogen are believed to play a significant role in triggering migraine episodes, making strategies involving sex hormones a viable alternative for treating menstrual migraines. Among these strategies, short-term hormone replacement therapy in the form of patches or gels has gained acceptance. For patients experiencing perimenopausal migraines, hormonal replacement therapy is recommended in select cases. It is crucial to acknowledge that hormonal treatments may have side effects, including the risk of thromboembolism and an increased likelihood of breast cancer. In conclusion, migraines in women are influenced by psychosocial factors and sex hormones, with an evident interaction between these elements. The impact of psychological stress on the hypothalamic-pituitary-gonadal axis and the subsequent release of sex hormones is well-documented. Thus, psycho-gonadal functioning can be viewed as a distinct entity, where cognition and related activities significantly influence the regulation of sex hormones and adaptation to social and material conditions in the environment. From this perspective, migraines in women can be interpreted as an adaptive response to the demands and needs of their surroundings. Consequently, employing a biopsychosocial model is essential for effective migraine management in women. Keywords: cognition, hormonal therapy, menstrual migraine, women. LITERATURA / LITERATURE 1. American Psychological Association. Guidelines for psychological practice with lesbian, gay, and bisexual clients. Am Psychol. 2012; 67(1): 10-42. 2. Buse DC, Loder EW, Gorman JA, et al. Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache. 2013; 53(8): 1278-99. 3. Allais G, Sanchez del Rio M, Diener HC, et al. Perimenstrual migraines and their response to preventive therapy with topiramate. Cephalalgia. 2011; 31(2): 152-60. 4. Pavlovic JM, Paemeleire K, Göbel H, et al. Efficacy and safety of erenumab in women with a history of menstrual migraine. J Headache Pain. 2020; 21(1): 95. MIGRAINE - UNUSUAL CLINICAL PRESENTATIONS MIGRENA – NENAVADNE KLINICNE SLIKE Vlasta Vukovic Cvetkovic SUMMARY Headache is a subjective disorder, and many patients fail to fit in the existing rather rigid diagnostic classification of the ICHD 3 criteria. Therefore, any variations in presentation may be easily missed or confusing. Atypical migraine episodes may not include all the pain phases and may present with different symptoms. The 3rd edition of the International Classification of Headache Disorders (ICHD-3) has classified migraine under Group 1 with sub classification for each migraine subtypes. Typical migraine episodes occur in the following order: prodrome, aura, pain, postdrome. The typical migraine headache is throbbing or pulsatile, unilateral, lasts from 4–72 hours and is accompanied by photophobia and/or phonophobia, nausea/vomiting, and worsens with physical activity. However, more than 50% of patients report dull non-throbbing pain, the pain may be bilateral, and not necessarily accompanied by nausea. Although the pain is localized in many patients in the frontotemporal and ocular area, it can be present anywhere in the head or neck, even shoulders. Some patients can have pain only on the lower part of the face (so called “lower face migraine”). The pain in migraine typically builds up over 1–2 hours and can change localization (become bilateral). In approximately Ľ of patients migraine may present with autonomic symptoms and thus sometimes may be confused with cluster headache (the main difference is that migraine patients need to lay down in a dark isolated room, and cluster patients are restless and walk around). Probable migraine can be misdiagnosed with episodic tension type headaches because not all typical migraine symptoms are present. Migraine-like attacks missing one of the features required to fulfil all criteria for a type or sub-type of migraine coded in ICHD 3 criteria, and not fulfilling criteria for another headache disorder are classified as “probable migraine”. The migraine aura consists of a group of transient focal neurological symptoms that develop over 5–20 minutes and lasts up to 60 minutes usually followed by a latent period before the onset of headache. The prevalence of migraine aura is around 33%. The aura can present with visual, sensory, motor or aphasic symptoms. Visual symptoms may be negative or positive and may present in form of homonymous hemianopsy, scinitlating scotomas or various field defects, tunnel vision, photopsias (uniform flashes of light), rarely complete blindness. Other neurologic symptoms include hemiparesis (defines hemiplegic migraine), paresthesias or numbness, aphasia, confusion, vertigo. Visual aura is in some cases followed by sensory aura. Paresthesia, occurring in 40% of cases, in typical migraine should present as “march” with numbness starting in the hand, migrating to the arm, and then jumping to involve the face, lips, and tongue. As with visual auras, positive symptoms typically are followed by negative symptoms; paresthesia may be followed by numbness. It is important to differentiate between sensory aura, transient ischemic attack (TIA) or a sensory seizure by asking the patient about the duration and mode the symptoms happened: visual aura and paresthesia usually spread over 10-20, which is slower than the spread of sensory symptoms of TIA which mostly come abruptly. Motor symptoms may occur in 18% and are often described as a sense of heaviness of the limbs precipitating the headache but no true weakness. Speech and language disturbances occur in up to 20% of patients. Rarely the aura is not followed by a headache (called “typical” or “atypical aura without headache” when aura occurs in isolation) and is reported most commonly in patients older than 45 years who have a history of migraines. In the absence of a prior history of recurrent headache and first occurrence after age 45 years, TIA should be considered and investigated fully. The symptoms of migraine with brainstem aura include: bilateral paresthesia, visual aura, slurred speech, tinnitus, ataxia, double vision, vertigo, deafness, confusion. Hemiplegic migraine can be inherited or sporadic and symptoms include reversible hemiparesis in addition to other aura symptoms such as visual, sensory, or speech. Retinal migraine is characterized by attacks of fully reversible monocular visual loss associated with migraine headache, can be confused with amaurosis fugax. Episodic syndromes that may be associated with migraine such as recurrent gastrointestinal disturbance, cyclical vomiting syndrome, abdominal migraine mostly affect children and reside in teenage years. Some patients however can proceed to have abdominal pain (alone or combined with migraine attacks). Vestibular migraine (in the Appendix, still under field-testing) presents with episodes of spontaneous or positional vertigo accompanied by migraine and/or other migraine symptoms. Epidemiologic data suggest that VM may affect 1 to 3% of the general population and vertigo is present in approx. Ľ of patients with migraine. VM is a clinical diagnosis and requires a history of migraine, temporal association of vestibular symptoms to a migraine attack lasting 5 minutes to 3 days and exclusion of other causes (i.e. absence of objectively demonstrated interictal vestibulopathy). Spontaneous vertigo can be described from mild to extreme sensitivity of a false sensation of self-motion; spinning/flowing of the visual surrounding, as positional vertigo, or triggered by a moving visual stimulus. The duration of episodes is highly variable: in 30% of patients symptoms last minutes, in 30% hours, in 30% several days and in 10% for seconds. Complications of migraine include migraine aura status which can in some cases predispose to migrainous infarct. Furthermore, migrainous infarction is a migraine attack in a patient with aura, where the aura symptoms last for more than an hour and the infarction is visible on MRI. Persistent aura without infarction: refers to the duration of the aura for more than a week after the migraine headache has stopped and there is no evidence of infarction on MRI. Migraine aura-triggered seizure: a seizure may occur as a complication of migraine with aura and may begin during or within 1 hour after an attack. Visual snow (usually permanent visual disturbance characterized by thousands of tiny white-black spots) and can be present as self-standing diagnosis or in combination with migraine attacks. Diagnosing atypical migraine might be challenging in a busy clinical practice and may be often missed due to unusual clinical presentation. To avoid misdiagnosing atypical migraine, it is very important to take a thorough history: the longitudinal headache history (how and when did the headache start; some patients had headache in childhood followed by a longer pause and then again experience headaches), positive family history, menstrual relationship, other signs and symptoms, response to medications, previous head trauma. In some (very atypical) cases, diagnostic work-up is needed. Keywords: migraine, migraine aura, probable migraine, unusual clinical presentation, vestibular migraine POVZETEK Glavobol je subjektivna motnja in mnogi bolniki se ne ujemajo z obstojeco precej togo diagnosticno klasifikacijo kriterijev ICHD 3. Zato lahko morebitne razlike v predstavitvi zlahka spregledamo ali povzrocimo zmedo. Atipicne epizode migrene morda ne vkljucujejo vseh faz bolecine in se lahko kažejo z razlicnimi simptomi. V tretji izdaji Mednarodne klasifikacije glavobolnih motenj (ICHD-3) je migrena razvršcena v skupino 1 s podrazvrstitvijo za vsak podtip migrene. Tipicne migrenske epizode se pojavljajo v naslednjem vrstnem redu: prodrom, avra, bolecina, postdrom. Tipicen migrenski glavobol je utripajoc ali pulsatilen, enostranski, traja od 4 do 72 ur in ga spremljajo fotofobija in/ali fonofobija, slabost/bruhanje in se poslabša s telesno aktivnostjo. Vendar vec kot 50 % bolnikov poroca o topi neutripajoci bolecini, bolecina je lahko obojestranska in ni nujno, da jo spremlja slabost. Ceprav je bolecina pri mnogih bolnikih lokalizirana v frontalno-temporalnem in ocesnem predelu, je lahko prisotna kjerkoli v glavi ali vratu, celo v ramenih. Nekatere bolnike lahko boli le spodnji del obraza (tako imenovana »migrena spodnjega dela obraza«). Bolecina pri migreni se obicajno poslabša v 1-2 urah in lahko spremeni lokalizacijo (postane dvostranska). Pri približno Ľ bolnikov se migrena lahko pojavi z avtonomnimi simptomi in jo je zato vcasih mogoce zamenjati z glavobolom v skupkih (glavna razlika je v tem, da morajo bolniki z migreno ležati v temni izolirani sobi, bolniki z glavobolom v skupkih pa so nemirni in hodijo naokoli). Verjetno migreno lahko napacno diagnosticiramo z epizodnimi tenzijskimi glavoboli, ker niso prisotni vsi znacilni simptomi migrene. Migreni podobni napadi, ki nimajo ene od znacilnosti za izpolnjevanje vseh kriterijev za tip ali podtip migrene, kodirane v kriterijih ICHD 3, in ne izpolnjujejo kriterijev za drugo motnjo glavobola, so razvršceni kot »verjetna migrena«. Migrensko avro sestavlja skupina prehodnih žarišcnih nevroloških simptomov, ki se razvijejo v 5–20 minutah in trajajo do 60 minut, cemur obicajno sledi latentno obdobje pred pojavom glavobola. Prevalenca migrenske avre je okoli 33 %. Avra se lahko kaže z vizualnimi, senzoricnimi, motoricnimi ali afazicnimi simptomi. Vizualni simptomi so lahko negativni ali pozitivni in se lahko kažejo v obliki homonimne hemianopsije, scinitlacijskih skotomov ali razlicnih okvar vidnega polja, tunelskega vida, fotopsij (enotnih bliskov svetlobe), redko popolne slepote. Drugi nevrološki simptomi vkljucujejo hemiparezo (opredeljuje hemiplegicno migreno), parestezije ali otrplost, afazijo, zmedenost, vrtoglavico. Vizualni avri v nekaterih primerih sledi senzoricna avra. Parestezije, ki se pojavijo v 40 % primerov, se morajo pri tipicni migreni pokazati kot »pohod« z otrplostjo, ki se zacne v roki, se seli po roki navzgor in nato preskoci ter zajame obraz, ustnice in jezik. Tako kot pri vizualnih avrah pozitivnim simptomom obicajno sledijo negativni simptomi, ko parestezijam sledi otrplost. Pomembno je razlikovati med senzoricno avro, tranzitorno ishemicno atako (TIA) ali senzoricnim napadom tako, da bolnika povprašamo o trajanju in nacinu pojava simptomov: vidna avra in parestezije se obicajno razširijo v 10-20 minutah, kar je pocasneje od širjenja senzoricnih simptomov TIA, ki se vecinoma pojavijo nenadoma. Motoricni simptomi se lahko pojavijo pri 18 % bolnikov in so pogosto opisani kot obcutek težkih udov, vendar brez jasne šibkosti. Motnje govora se pojavijo pri 20 % bolnikov. Redko avri ne sledi glavobol. To obliko imenujemo »tipicna« ali »atipicna avra brez glavobola«, ko se avra pojavi izolirano. O njej najpogosteje porocajo pri bolnikih, starejših od 45 let, ki so imeli v anamnezi migrene. V odsotnosti predhodne anamneze ponavljajocega se glavobola in prvega pojava po 45. letu starosti je treba razmisliti o TIA in izvesti celotno diagnostiko. Simptomi migrene z avro možganskega debla vkljucujejo: dvostranske parestezije, vidno avro, nejasen govor, tinitus, ataksijo, dvojni vid, vrtoglavico, gluhost in zmedenost. Hemiplegicna migrena je lahko podedovana ali obcasna, simptomi pa vkljucujejo reverzibilno hemiparezo poleg drugih simptomov avre, kot so vidni, senzoricni ali govorni. Za retinalno migreno so znacilni napadi popolnoma reverzibilne monokularne izgube vida, povezane z migrenskim glavobolom, ki jo je mogoce zamenjati z amaurosis fugax. Epizodicni sindromi, ki so lahko povezani z migreno, kot so ponavljajoce se gastrointestinalne motnje, sindrom ciklicnega bruhanja, abdominalna migrena, vecinoma prizadenejo otroke in se pojavljajo v najstniških letih. Pri nekaterih bolnikih pa se lahko bolecine v trebuhu nadaljujejo (same ali skupaj z migrenskimi napadi). Vestibularna migrena (VM) kaže z epizodami spontane ali pozicijske vrtoglavice, ki jo spremljajo migrena in/ali drugi simptomi migrene. Epidemiološki podatki kažejo, da lahko VM prizadene 1 do 3 % splošne populacije, vrtoglavica pa je prisotna pri pribl. Ľ bolnikov z migreno. VM je klinicna diagnoza in zahteva anamnezo migrene, casovno povezavo vestibularnih simptomov z migrenskim napadom, ki traja od 5 minut do 3 dni, in izkljucitev drugih vzrokov, kot so odsotnost objektivno dokazane interiktalne vestibulopatije. Spontano vrtoglavico lahko opišemo od blage do skrajne obcutljivosti lažnega obcutka samogibanja; vrtenje/pretakanje vizualnega okolja, kot pozicijska vrtoglavica ali sprožena zaradi premikajocega se vizualnega dražljaja. Trajanje epizod je zelo razlicno: pri 30 % bolnikov simptomi trajajo minute, pri 30 % ure, pri 30 % vec dni in pri 10 % sekunde. Migrenski zapleti vkljucujejo status migrenske avre, ki lahko v nekaterih primerih povzroci nagnjenost k migrenskemu infarktu. Poleg tega je migrenski infarkt migrenski napad pri bolniku z avro, kjer simptomi avre trajajo vec kot eno uro in je infarkt viden na posnetku MR glave. Vztrajna avra brez infarkta se nanaša na trajanje avre vec kot en teden po prenehanju migrenskega glavobola in na MR ni znakov infarkta. Napad, ki ga sproži migrenska avra se lahko pojavi kot zaplet migrene z avro in se lahko zacne med napadom ali v 1 uri po njem. Vidni sneg je obicajno stalna motnja vida, za katero je znacilno na tisoce drobnih belo-crnih lis in je lahko prisoten kot samostojna diagnoza ali v kombinaciji z migrenskimi napadi. Diagnosticiranje atipicne migrene je lahko v intenzivni klinicni praksi izziv in se lahko zaradi nenavadne klinicne slike pogosto spregleda. Da bi se izognili napacni diagnozi atipicne migrene, je zelo pomembno, da vzamemo temeljito anamnezo: longitudinalno anamnezo glavobola (kako in kdaj se je glavobol zacel; nekateri bolniki so imeli glavobol v otroštvu, ki mu je sledil daljši premor in nato spet glavoboli), pozitivno družinsko anamnezo, menstrualni odnos, druge znake in simptome, odziv na zdravila in prejšnje poškodbe glave. V nekaterih (zelo netipicnih) primerih je potrebna poglobljena diagnosticna obravnava. Kljucne besede: migrena migrenska avra, nenavadna klinicna slika, verjetna migrena, vestibularna migrena. LITERATURE / LITERATURA 1. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018; 38: 1–211. 2. Straube A, Andreou A.J Headache Pain. 2019 Apr 8; 20(1): 35. 3. Kissoon NR, Cutrer FM.Headache. 2017 Jul; 57(7): 1179–19. MIGRENSKA AVRA IN INTERIKTICNI SIMPTOMI MIGRAINE AURA AND INTERICTAL SYMPTOMS Matjaž Popit POVZETEK Migrena ni samo glavobol, temvec zapletena nevrološka motnja, ki vpliva na številne vidike clovekovega življenja. Ceprav je glavobol najprepoznavnejši simptom migrene, ta bolezen vkljucuje številne druge simptome, ki lahko mocno poslabšajo kakovost življenja. Med njimi so migrenska avra in interikticni simptomi, ki se pojavljajo med obdobji brez glavobola. Razumevanje teh pojavov je kljucno za pravilno diagnozo, obravnavo in izboljšanje življenja bolnikov. Migrenska avra je prehoden nevrološki pojav, ki se obicajno pojavi pred fazo glavobola, ceprav lahko nastopi tudi med glavobolom ali celo brez njega. Avra vkljucuje vrsto simptomov, ki najpogosteje prizadenejo vidni sistem, lahko pa se pojavijo tudi senzorni, motoricni in govorni simptomi. Bolniki pogosto opisujejo svetlece crte, utripe svetlobe, slepe pege (skotome) ali celo zacasno izgubo vida. Senzorni simptomi vkljucujejo mravljincenje ali omrtvelost, najpogosteje v rokah in obrazu, medtem ko lahko govorna motnja vkljucuje težave z izražanjem ali razumevanjem besed. Migrensko avro doživi približno 25–30 % bolnikov z migreno. Pojavlja se z razlicnimi frekvencami, pri nekaterih bolnikih le nekajkrat na leto, pri drugih pa ob skoraj vsaki epizodi migrene. Približno 15 % ljudi z avro nikoli ne razvije glavobola, kar je znano kot »migrena z avro brez glavobola. Mehanizem nastanka avre ni popolnoma razumljen, vendar je najbolj sprejeta teorija t. i. kortikalna razširjajoca se depresija. Gre za val depolarizacije nevronov in glialnih celic, ki se širi prek možganske skorje. Ta val povzroci prehodne spremembe v možganskem krvnem pretoku, kar vodi do nevroloških simptomov avre (1). Diagnoza avre temelji na natancni anamnezi in izkljucitvi drugih možnih vzrokov za simptome. Mednarodno združenje za glavobole doloca specificna diagnosticna merila za migrensko avro (2). Nevrološke preiskave, kot so magnetnoresonancno slikanje ali racunalniška tomografija, se izvajajo v primerih, ko obstaja sum na druga stanja, kot so možganski tumorji, epilepsija ali možganska kap. Migrenska avra je obicajno prehodna in ne zahteva specificnega zdravljenja. Vendar se pri bolnikih, ki imajo pogoste epizode avre, lahko uvede preventivna terapija z zdravili, kot so beta-blokatorji, antiepileptiki ali antagonisti kalcijevih kanalov. Nekateri bolniki porocajo o koristih magnezijevih pripravkov in sprememb življenjskega sloga, kot so zmanjšanje stresa, urejena prehrana in izogibanje sprožilcem (1). Poleg avre so pomemben vidik migrene tudi interikticni simptomi – simptomi, ki se pojavijo med napadi migrene in lahko vztrajajo tudi tedne ali mesece. Pogosti interikticni simptomi vkljucujejo kronicno utrujenost, težave s koncentracijo in spominom (možganska megla), motnje razpoloženja, kot so anksioznost in depresija, preobcutljivost za svetlobo in zvok, ki lahko vztraja tudi zunaj migrenskih epizod. Natancen mehanizem teh simptomov ni znan, vendar obstaja vec hipotez. Ena teorija je, da gre za posledico kronicne disregulacije možganskih mrež, vkljucno z omrežji, odgovornimi za procesiranje bolecine in cutnih dražljajev. Povecana obcutljivost teh mrež lahko povzroci trajno zaznavanje dražljajev kot neprijetnih ali bolecih. Druga hipoteza predpostavlja, da je vzrok nevrogeno vnetje ali dolgotrajna disfunkcija možganskega žilja. Zdravljenje teh simptomov je pogosto izziv, saj so lahko razlicni med bolniki. Preventivna zdravila, kot so antidepresivi, antiepileptiki ali zaviralci CGRP, lahko zmanjšajo frekvenco in intenzivnost simptomov. Kognitivno-vedenjska terapija in tehnike sprošcanja lahko pomagajo pri obvladovanju razpoloženjskih motenj in anksioznosti. Urejena spalna rutina, redna telesna dejavnost in zdrava prehrana so kljucni dejavniki, ki lahko zmanjšajo interikticne simptome (3). Migrena je kompleksna nevrološka motnja, ki presega obicajni okvir glavobola. Migrenska avra in interikticni simptomi so pogosti, vendar pogosto prezrti vidiki bolezni. Pravilno razumevanje teh simptomov, njihovo pravocasno prepoznavanje in ustrezno zdravljenje so bistvenega pomena za izboljšanje kakovosti življenja bolnikov. Poleg tega je kljucno, da se pri neobicajnih simptomih izvede dodatna diagnostika, da se izkljucijo resnejša stanja. Z nadaljnjim raziskovanjem patofiziologije migrene pa lahko pricakujemo razvoj bolj ciljanih terapij, ki bodo še dodatno olajšale breme te bolezni. Kljucne besede: avra, interikticni simptomi, migrena. SUMMARY Migraine is not just a headache; it is a complex neurological disorder that affects many aspects of a person’s life. Although headache is the most recognizable symptom of migraine, the condition includes numerous other symptoms that can significantly diminish the quality of life. Among these are migraine aura and interictal symptoms, which occur during headache-free periods. Understanding these phenomena is crucial for proper diagnosis, management, and improving patients’ lives. Migraine aura is a transient neurological phenomenon that typically appears before the headache phase, though it can also occur during the headache or even without it. Aura includes a range of symptoms, most commonly affecting the visual system, but sensory, motor, and speech symptoms may also appear. Patients often describe bright zigzag lines, flashes of light, blind spots (scotomas), or even temporary vision loss. Sensory symptoms include tingling or numbness, most often in the hands and face, while speech disturbances may involve difficulty expressing or understanding words. Around 25–30% of migraine sufferers experience aura. Its frequency varies, with some patients experiencing it only a few times per year, while others have it with almost every migraine episode. Approximately 15% of people with aura never develop a headache, a condition known as “migraine with aura without headache” (1). The mechanism behind aura is not fully understood, but the most widely accepted theory is cortical spreading depression — a wave of neuronal and glial depolarization that spreads across the cerebral cortex. This wave leads to transient changes in cerebral blood flow, resulting in the neurological symptoms of aura (1). Diagnosis of aura is based on a thorough medical history and the exclusion of other possible causes of symptoms. The International Headache Society provides specific diagnostic criteria for migraine aura (2). Neurological examinations, such as magnetic resonance imaging or computed tomography, are performed in cases where conditions like brain tumors, epilepsy, or stroke are suspected. Migraine aura is usually transient and does not require specific treatment. However, in patients with frequent aura episodes, preventive therapy may be introduced, including beta-blockers, antiepileptics, or calcium channel antagonists. Some patients report benefits from magnesium supplements and lifestyle modifications such as stress reduction, a well-balanced diet, and avoiding triggers (1). In addition to aura, interictal symptoms—symptoms that appear between migraine attacks and may persist for weeks or months—are an important aspect of migraine. Common interictal symptoms include chronic fatigue, difficulty concentrating and memory issues (brain fog), mood disorders such as anxiety and depression, and hypersensitivity to light and sound, which can persist even outside migraine episodes (3). The exact mechanism of these symptoms is not well understood, but several hypotheses exist. One theory suggests chronic dysregulation of brain networks, including those responsible for processing pain and sensory stimuli. Increased sensitivity in these networks may cause a persistent perception of stimuli as unpleasant or painful. Another hypothesis proposes neurogenic inflammation or prolonged dysfunction of cerebral blood vessels as the underlying cause (3). Treating these symptoms is often challenging, as they vary between patients. Preventive medications such as antidepressants, antiepileptics, or CGRP inhibitors can help reduce symptom frequency and intensity. Cognitive-behavioral therapy and relaxation techniques can assist in managing mood disorders and anxiety. Additionally, a well-regulated sleep routine, regular physical activity, and a healthy diet are key factors that may alleviate interictal symptoms. (3) Migraine is a complex neurological disorder that extends beyond the typical perception of a headache. Migraine aura and interictal symptoms are common yet often overlooked aspects of the disease. Proper understanding of these symptoms, their timely recognition, and appropriate treatment are essential for improving patients’ quality of life. Furthermore, when atypical symptoms occur, additional diagnostic evaluations should be conducted to rule out more serious conditions. As research into migraine pathophysiology advances, more targeted therapies are expected to further alleviate the burden of this condition. Keywords: aura, interictal symptoms, migraine. LITERATURA / LITERATURE 1. Sanchez Del Rio M, Cutrer FM. Pathophysiology of migraine aura. Handb Clin Neurol. 2023; 198: 71–83. 2. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018 Jan; 38(1): 1–211. 3. Vincent M, Viktrup L, Nicholson RA, et al. The not so hidden impact of interictal burden in migraine: A narrative review. Front Neurol. 2022 Nov 3; 13: 1032103. ALI JE MIGRENA LE NEVROLOŠKA MOTNJA? POVEZAVE MED MIGRENO IN SRCNO/ MOŽGANSKOŽILNIMI BOLEZNIMI IS MIGRAINE ONLY A NEUROLOGICAL DISORDER? ASSOCIATIONS BETWEEN MIGRAINE AND CARDIOVASCULAR/CEREBROVASCULAR DISEASES Maša Premzl, Luka Notar, Albina Licina POVZETEK Migrena, možgansko-žilne in srcno-žilne bolezni sodijo med vodilne vzroke invalidnosti po svetu. Dognanja o patofiziologiji migrene so v zadnjih letih privedla do novih terapevtskih pristopov ter boljšega razumevanja povezave med migreno in žilnimi boleznimi. Migrena ima periferno in centralno patofiziološko komponento. Dezinhibicija trigeminalnega sistema povzroci sprošcanje peptida povezanega z genom za kalcitonin (CGRP) zunaj krvno-možganske bariere. To vodi v vazodilatacijo meningealnih arterij, nevrogeno vnetje in centralno senzitizacijo. Aktivacija možganskega debla vpliva na tonus možganskih žil, kar lahko poveca tveganje za ishemicno kap pri bolnikih z migreno (1). Za žilne zaplete so pomembnejši centralni patofiziološki mehanizmi migrene, ki vkljucujejo aktivacijo hipotalamicnih jeder in širjenje kortikalne depresije (cortical spreading depression – CSD). Slednje je povezano z migrensko avro. Ob CSD pride do kratkotrajne hiperperfuzije možganskega tkiva, ki ji sledi obdobje hipoperfuzije in vnetnega odziva z endotelijsko disfunkcijo. Med migrenskim napadom se poveca sprošcanje vazokonstrikcijskih faktorjev (npr. endotelin-1) in spodbudi protromboticno stanje, kar dodatno poveca tveganje za srcno/možganskožilne dogodke (1). CSD je tudi pomemben mehanizem nevronske okvare pri ishemicni možganski kapi. Številne študije, vkljucno z metaanalizami, potrjujejo dvakrat vecje tveganje za ishemicno kap pri osebah z migreno z avro v primerjavi z osebami brez migrene. Povezava je posebej izrazita pri mlajših ženskah, kadilkah in uporabnicah peroralne kontracepcije. Pri moških je zaradi nižje prevalence migrene povezava manj jasna (2). Metaanaliza šestnajstih opazovalnih študij iz leta 2018, ki je vkljucevala vec kot milijon udeležencev, je pokazala, da migrena z ali brez avre poveca tveganje za ishemicno možgansko kap in miokardni infarkt do dvakrat. Migrena z avro je zaradi CSD vecji dejavnik tveganja za žilne zaplete. V omenjeni metaanalizi spol ni igral kljucne vloge, hormonski vplivi niso bili opredeljeni. Etiološki mehanizmi povecanega tveganja za žilne zaplete ostajajo nejasni, vendar so pri bolnikih z migreno in žilnimi zapleti ugotovili motnje koagulacijske kaskade ter pogostejšo prisotnost odprtega ovalnega okna (3). Povezava med migreno in žilnimi obolenji je pomembna tudi pri zdravljenju. Novejši terapevtski pristopi z antagonisti CGRP zahtevajo previdnost pri bolnikih po prebolelem miokardnem infarktu, po ishemicni možganski kapi, pri bolnikih z angino pektoris ali s hudo obliko Raynaudovega sindroma. Migrena ostaja nevrološka motnja s kompleksno in še ne povsem pojasnjeno patofiziologijo. Glede na dosedanje raziskave predstavlja klinicno pomemben dejavnik tveganja za možgansko-srcno-žilne zaplete, zato je preventiva drugih dejavnikov tveganja kljucnega pomena pri obravnavi bolnikov z migreno. Kljucne besede: migrena, odprto ovalno okno, patofiziologija, peptid povezan z genom za kalcitonin, žilna obolenja. SUMMARY Research on the pathophysiology of migraine has advanced in recent years, enabling new therapeutic approaches and a better understanding of the association between migraine and vascular diseases. Migraine has both peripheral and central pathophysiological components. Disinhibition of the trigeminal system leads to the release of calcitonin gene-related peptide (CGRP) outside the blood-brain barrier. This results in meningeal artery vasodilation, neurogenic inflammation, and central sensitization. Brainstem activation affects cerebrovascular tone, potentially increasing the risk of ischemic stroke in migraine patients (1). The central pathophysiological mechanisms of migraine play a key role in vascular complications. These include activation of hypothalamic nuclei and cortical spreading depression (CSD), the latter being associated with migraine aura. During CSD, a transient hyperperfusion of brain tissue occurs, followed by a period of hypoperfusion and an inflammatory response with endothelial dysfunction. During a migraine attack, the release of vasoconstrictive factors (e.g., endothelin-1) increases, promoting a prothrombotic state, which further elevates the risk of cerebrovascular and cardiovascular events (1). CSD also plays a crucial role in neuronal damage in ischemic stroke. Numerous studies, including meta-analyses, confirm that individuals with migraine with aura have a twofold increased risk of ischemic stroke compared to those without migraine. This association is particularly pronounced in younger women, smokers, and users of oral contraceptives. In men, due to the lower prevalence of migraine, the connection is less clear (2). A 2018 meta-analysis of sixteen observational studies, involving over one million participants, showed that migraine, with or without aura, increases the risk of ischemic stroke and myocardial infarction up to twofold. Migraine with aura poses a higher risk for vascular complications due to cortical spreading depression. In this meta-analysis, gender was not a decisive factor, and hormonal influences were not defined. The etiological mechanisms underlying the increased risk of vascular complications remain unclear. However, patients with migraine and vascular events were found to have coagulation cascade disorders and a higher prevalence of patent foramen ovale (3). The link between migraine and vascular diseases is also significant in treatment. New therapeutic approaches with CGRP antagonists require caution in patients with a history of myocardial infarction, ischemic stroke, angina pectoris, or severe Raynaud’s syndrome. Migraine remains a neurological disorder with a complex and not yet fully understood pathophysiology. Based on current research, it represents a clinically significant risk factor for cerebrovascular and cardiovascular complications, emphasizing the importance of preventive management of other risk factors in migraine patients. Keywords: calcitonin gene-related peptide (CGRP), cerebrovascular and cardiovascular diseases, migraine, patent foramen ovale, pathophysiology. LITERATURA / LITERATURE 1. Ravi V, Osouli Meinagh S, Bavarsad Shahripour R. Reviewing Migraine-Associated Pathophysiology and Its Impact on Elevated Stroke Risk. Front Neurol. 2024; 15: 1435208. 2. Řie LR, Kurth T, Gulati S, Dodick DW. Migraine and risk of stroke. J Neurol Neurosurg Psychiatry. 2020 Jun;91(6): 593–604. 3. Mahmoud AN, Mentias A, Elgendy AY, et al. Migraine and the risk of cardiovascular and cerebrovascular events: a meta-analysis of 16 cohort studies including 1,152,407 subjects. BMJ Open. 2018 Mar; 8(3): e020498. OPTIMIZACIJA KORISTI PREVENTIVNEGA ZDRAVLJENJA MIGRENE Z UPORABO INTRAVENSKEGA NACINA APLIKACIJE OPTIMIZING THE BENEFITS OF PROPHYLACTIC TREATMENT IN MIGRAINE BY UTILIZING THE INTRAVENOUS ROUTE OF ADMINISTRATION Marjan Zaletel, Gorazd Požlep POVZETEK Migrena, ena vodilnih bolezni, ki prispevajo k oviranosti, je nevrološka motnja, ki jo je kljub številnim terapevtskim možnostim težko nadzorovati. Ucinkovitost eptinezumaba potrjujejo dolgorocni podatki iz raziskave DELIVER, ki kažejo trajne pozitivne ucinke ne glede na predhodne neuspešne poskuse preventivnega zdravljenja migrene (1). Sporocilo te študije je, da pri osebah z migreno, ki so imeli dve do štiri neuspešne predhodne nespecificne preventivne terapije, je eptinezumab v primerjavi s placebom pokazal pomembne preventivne ucinke. Ob tem je ohranil ugoden varnostni profil in dobro prenosljivost. To nakazuje, da eptinezumab predstavlja ucinkovito možnost zdravljenja za to skupino bolnikov. Skoraj 40 % udeležencev v študiji je imelo vsaj tri neuspešne predhodne poskuse zdravljenja. Podobno kot pri drugih klinicnih preskušanjih migrene je bil placebo odziv razmeroma visok. Kljub temu je bilo aktivno zdravljenje z eptinezumabom pri katerem koli odmerku vec kot dvakrat ucinkovitejše pri primarnem opazovanem dogodku v primerjavi s placebom. V podaljšani študiji so bolniki, ki so prej prejemali placebo, prešli na zdravljenje z 100 mg ali 300 mg eptinezumaba. Tri tedne po prehodu je bilo povprecno zmanjšanje števila dni z migreno na mesec (MMD) pri 100-mg odmerku eptinezumaba 5,8 dni pri 300mg odmerku pa 7,2 dni. Ohranjena zmanjšanja v obdobju podaljšane študije potrjujejo hiter zacetek delovanja zdravljenja. Spekter neželenih ucinkov je bil podoben v skupinah, ki so prejemale aktivno zdravljenje, in v skupini s placebom. O anafilaksiji so porocali pri dveh bolnikih (<1 %). Prednost eptinezumaba v primerjavi z izhodišcem pri primarnem izidu je bila podprta z vec kazalniki, vkljucno z zmanjšanjem simptomov, ocenjenih s testom vpliva na glavobol (HIT-6), zmanjšanjem intenzivnosti migrene na podlagi porocil bolnikov ter pomembnim zmanjšanjem uporabe zdravil za akutni glavobol. V post hoc analizi študije DELIVER je avtorica (2) porocala, da je bilo zmanjšanje uporabe zdravil za glavobol od izhodišca statisticno znacilno. Pri bolnikih, ki so bili sprva randomizirani v skupino s placebom in so nato prešli na zdravljenje z eptinezumabom, so enak ucinek opazili tudi v naslednjih 48 tednih zdravljenja. V celotnem naboru podatkov pri bolnikih, ki so sprva prejemali placebo, je bilo povprecno zmanjšanje števila dni z uporabo zdravil za akutni glavobol v prvih štirih tednih 4,6 dneva pri 100-mg odmerku in 4,8 dneva pri 300-mg odmerku eptinezumaba. Pri podskupini bolnikov, ki so na zacetku študije prekomerno uporabljali zdravila, je bilo zmanjšanje še izrazitejše – 6,5 dneva pri 100-mg odmerku in 6,6 dneva pri 300-mg odmerku. V vseh skupinah zdravljenja so bolniki v 18 mesecih zdravljenja ohranili ali dodatno zmanjšali uporabo akutna zdravila. Glede na drugo post-hoc analizo študije DELIVER, je bil ucinek eptinezumaba za zmanjšanje števila dni z migreno na mesec (MMD) v primerjavi s placebom neodvisna od razreda predhodnega neuspešnega zdravljenja migrene (3). Ne glede na to, ali so bolniki predhodno doživeli neuspeh zdravljenja s topiramatom, zaviralci adrenergicnih receptorjev beta, amitriptilinom ali flunarizinom, je bilo povprecno zmanjšanje števila dni z migreno na mesec (MMD) pri bolnikih, ki so prejemali placebo, 2,6 dni ali manj v obeh izhodih. Pri zdravljenju z eptinezumabom je bilo zmanjšanje po 12 tednih v skupini s 100-mg odmerkom med 4,8 in 5,0 dni, v skupini s 300-mg odmerkom pa med 5,5 in 6,0 dni za vse te razrede zdravil. V analizi podskupine študije DELIVER so ugotovili, da se ucinkovitost eptinezumaba neposredno odraža v vecjih klinicnih koristih, kot jih ocenjujejo bolniki. Pri merilih pacientove zaznave spremembe (PGIC), vprašalniku kakovosti življenja, specificnem za migreno (MSQ), ter vprašalniku splošne kakovosti življenja (EQ-5D-5L VAS) so bile povprecne spremembe po 24 tednih glede na izhodišcno vrednost in placebo statisticno zelo znacilne za oba odmerka eptinezumaba (4). Na podlagi vprašalnika o poslabšanju delovne produktivnosti zaradi migrene, ki so ga bolniki v študiji DELIVER izpolnjevali vsakih šest tednov, so tisti, ki so bili randomizirani na katerikoli odmerek eptinezumaba, v primerjavi s placebom dosegli znatno vecje zmanjšanje absentizma, izgube delovne produktivnosti in poslabšanja aktivnosti ter opazno izboljšanje prezentizma (5). Torej je študija DELIVER je zaznala, da eptinezumab pomembno zmanjšuje oviranost pri bolnikih, ki so predhodno neuspešno poskusili zdravljenje z vec nespecificnimi profilakti, zato je lahko zdravilo prvega izbora med monoklonskimi protitelesi proti CGRP. Podatki o ucinkovitosti eptinezumaba izhajajo predvsem iz klinicnih preskušanj, medtem ko so podatki iz resnicnega sveta še vedno omejeni. Politika povracila stroškov v Nemciji vodi do tega, da se eptinezumab vecinoma uporablja pri bolnikih, pri katerih predhodno zdravljenje z drugimi monoklonskimi protitelesi proti CGRP ni bilo uspešno (6). Do danes še ni povsem jasno, ali je eptinezumab pri teh bolnikih ucinkovit, kako dobro se prenaša in kako se njihov odziv na zdravljenje razlikuje od bolnikov, ki prej niso prejemali monoklonskih protiteles proti CGRP. Analiza je pokazala, da je eptinezumab lahko ucinkovit tudi pri posameznih bolnikih po treh neuspešnih poskusih zdravljenja s predhodnimi terapijami, usmerjenimi proti CGRP. Vendar placebo ucinka infuzije v kontekstu podatkov iz resnicnega življenja ni mogoce oceniti. Poleg vidika ucinkovitosti, je bila tudi prenašanje eptinezumaba dobro, kljub temu da se daje v obliki infuzije. V kohorti so bili neželeni ucinki blagi, stopnja zadovoljstva s terapijo pa visoka. Rezultati študije podpirajo ucinkovitost eptinezumaba pri preventivnem zdravljenju migrene v razmerah resnicnega sveta ter zagotavljajo dobre dokaze o njegovi prenosljivosti pri bolnikih, ki so odporni na obicajna profilakticna zdravila za migreno. Kljub temu je zdravljenje izrazito manj ucinkovito pri bolnikih, ki so bili v preteklosti odporni na druge monoklonske protitelesa proti CGRP. Glede na omejene možnosti zdravljenja se zamenjevanje razlicnimi monoklonskih protiteles proti CGRP šteje za ustrezno možnost za te bolnike z refraktarno migreno. Študije iz resnicnega sveta kažejo na zelo spremenljivo stopnjo odziva na tovrstna prehajanja (7). Ugotovitve analize iz resnicnega sveta kažejo, da se lahko nekateri bolniki z migreno, odporni na zdravljenje, ki niso dosegli zadovoljivega odziva na vec subkutanih monoklonskih protiteles proti CGRP, vseeno odzovejo na intravensko terapijo z eptinezumabom. Približno ena tretjina bolnikov je po prehodu na eptinezumab dosegla klinicno pomembno zmanjšanje števila dni z migreno na mesec (MMD) za vec kot 30 %. Glede na razpoložljive podatke lahko zakljucimo, da je eptinezumab lahko ucinkoviti tako pri bolnikih, ki so predhodno prejemali nespecificna preventivna zdravila, ki so bila neucinkovita kot tudi monoklonska protitelesa proti CGRP pri refraktorih bolnikih z migreno. Glede na trenutne smernice, da je potrebno cimprej priceti s specificni zdravljenjem migrene in, da so lahko monoklonska protitelesa proti CGRP prva izbira, je možno zakljuciti, da je eptinezumab lahko prvo zdravilo izbora med monoklonskimi protitelesi za preventivo migrene pri izbranih bolnikih z migreno. Kljucne besede: eptinezumab, migrena, monoklonska protitelesa proti CGRP. SUMMARY Migraine, one of the leading causes of disease-related disability, is a neurological disorder that remains difficult to control despite numerous therapeutic options. The efficacy of eptinezumab is supported by long-term data from the DELIVER study, which demonstrates sustained positive effects regardless of previous unsuccessful attempts at preventive migraine treatment (1). The key message of this study is that in migraine patients with two to four unsuccessful prior non-specific preventive therapies, eptinezumab showed significant preventive effects compared to placebo while maintaining a favorable safety profile and good tolerability. This suggests that eptinezumab represents an effective treatment option for this patient group. Nearly 40% of study participants had at least three previous unsuccessful treatment attempts. As seen in other clinical migraine trials, the placebo response was relatively high. However, active treatment with eptinezumab, at any dose, was more than twice as effective in the primary observed outcome compared to placebo. In the extension study, patients who had initially received a placebo switched to treatment with either 100 mg or 300 mg of eptinezumab. Three weeks after switching, the average reduction in monthly migraine days (MMD) was 5.8 days with the 100-mg dose and 7.2 days with the 300-mg dose. Sustained reductions observed during the extension study confirm the rapid onset of treatment action. The spectrum of adverse effects was similar between actively treated groups and the placebo group. Anaphylaxis was reported in two patients (<1%) (2). The advantage of eptinezumab over baseline in the primary outcome was supported by multiple indicators, including a reduction in symptoms assessed by the Headache Impact Test (HIT-6), a reduction in migraine intensity based on patient reports, and a significant decrease in the use of acute headache medications. In a post hoc analysis of the DELIVER study, the author (3) reported that the reduction in the use of acute headache medications from baseline was statistically significant. In patients initially randomized to the placebo group who later switched to eptinezumab treatment, the same effect was observed over the next 48 weeks of treatment. Across the entire dataset, for patients who initially received placebo, the average reduction in days using acute headache medications in the first four weeks was 4.6 days with the 100-mg dose and 4.8 days with the 300-mg dose of eptinezumab. In the subgroup of patients who initially overused acute medications, the reduction was even more pronounced—6.5 days with the 100-mg dose and 6.6 days with the 300-mg dose. Across all treatment groups, patients maintained or further reduced their use of acute medications over 18 months of treatment. According to another post-hoc analysis of the DELIVER study, the effect of eptinezumab in reducing monthly migraine days (MMD) compared to placebo was independent of the class of previous unsuccessful migraine treatment (4). Regardless of whether patients had previously failed treatment with topiramate, beta-adrenergic receptor blockers, amitriptyline, or flunarizine, the average reduction in MMD for placebo-treated patients was 2.6 days or less at both time points. For those receiving eptinezumab, the reduction after 12 weeks was between 4.8 and 5.0 days in the 100-mg group and between 5.5 and 6.0 days in the 300-mg group across all drug classes. A subgroup analysis of the DELIVER study found that the efficacy of eptinezumab was directly reflected in greater clinical benefits as assessed by patients. In measures such as the Patient Global Impression of Change (PGIC), the Migraine-Specific Quality of Life Questionnaire (MSQ), and the general quality of life questionnaire (EQ-5D-5L VAS), average changes after 24 weeks compared to baseline and placebo were statistically significant for both doses of eptinezumab (5). Based on the Work Productivity and Activity Impairment Questionnaire for Migraine (WPAI:M), which patients in the DELIVER study completed every six weeks, those randomized to either dose of eptinezumab showed significantly greater reductions in absenteeism, loss of work productivity, and activity impairment, as well as noticeable improvements in presenteeism compared to placebo (6). Thus, the DELIVER study found that eptinezumab significantly reduces disability in patients who previously failed multiple non-specific prophylactic treatments, suggesting that it could be the first-choice monoclonal antibody therapy targeting CGRP. The efficacy data for eptinezumab primarily come from clinical trials, while real-world data remain limited. In Germany, reimbursement policies lead to eptinezumab being predominantly used in patients for whom prior treatment with other monoclonal antibodies against CGRP failed (7). To date, it remains unclear whether eptinezumab is effective in these patients, how well it is tolerated, and how their response to treatment differs from those who have not previously received monoclonal antibodies against CGRP. The analysis indicated that eptinezumab can still be effective in some patients even after three unsuccessful attempts with prior CGRP-targeted therapies. However, the placebo effect of infusion cannot be assessed in the real-world data context. Beyond efficacy, eptinezumab demonstrated good tolerability despite being administered via infusion. In the cohort, adverse effects were mild, and patient satisfaction with therapy was high. The study results support the effectiveness of eptinezumab in preventive migraine treatment under real-world conditions and provide strong evidence of its tolerability in patients resistant to conventional prophylactic migraine medications. Nevertheless, treatment is significantly less effective in patients previously resistant to other monoclonal antibodies targeting CGRP. Given the limited treatment options, switching between different monoclonal antibodies against CGRP is considered a viable option for these patients with refractory migraine. Real-world studies indicate highly variable response rates of approximately 30% for such switches (8). Findings from the real-world analysis suggest that some treatment-resistant migraine patients who did not achieve satisfactory responses to multiple subcutaneous monoclonal antibodies against CGRP may still benefit from intravenous therapy with eptinezumab. Approximately one-third of patients demonstrated a clinically significant reduction in MMD by more than 30% after transitioning to eptinezumab. Based on the available data, it can be concluded that eptinezumab may be effective both in patients who previously received ineffective non-specific prophylactics and in refractory migraine patients who had an inadequate response to CGRP-targeting monoclonal antibodies. Considering current guidelines that emphasize the importance of initiating specific migraine treatment as early as possible and that monoclonal antibodies against CGRP can be a first-choice therapy, it is reasonable to conclude that eptinezumab could be the preferred monoclonal antibody for migraine prophylaxis in selected migraine patients. Keywords: eptinezumab, migraine, monoclonal antibodies against CGRP. LITERATURA / LITERATURE 1. Ashina M, Lanteri-Minet M, Pozo-Rosich P, et al. Safety and efficacy of eptinezumab for migraine prevention in patients with two-to-four previous preventive treatment failures (DELIVER): a multi-arm, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 2022; 21(7): 597–607. 2. Gryglas-Dworak A, Schim J, Ettrup A, et.al. Long-term reductions in acute headache medication use after eptinezumab treatment in patients with migraine and prior preventive treatment failures: Post hoc analysis of the DELIVER randomized trial. Headache. 2025; 65(1): 101–12. 3. Pozo-Rosich P, Ashina M, Tepper SJ, et al. Demonstrated Efficacy Regardless of Prior Preventive Migraine Treatment Failure Type: Post Hoc Analyses of the DELIVER Study. Neurol Ther. 2024; 13(2): 339–53. 4. Goadsby PJ, Barbanti P, Lambru G, et al. Eptinezumab improved patient-reported outcomes and quality of life in patients with migraine and prior preventive treatment failures. Eur J Neurol. 2023; 30(4): 1089–98. 5. Barbanti P, Awad SF, Rae-Espinoza H, et al. Impact of eptinezumab on workproductivity beyond reductions in monthly migraine days: post hoc analysis of the DELIVER trial. J Patient Rep Outcomes. 2024; 8(1): 146. 6. Scheffler A, Wenzel P, Bendig M, et al. Effectiveness and tolerability of eptinezumab in treating patients with migraine resistant to conventional preventive medications and CGRP (receptor) antibodies: a multicentre retrospective real-world analysis from Germany. J Headache Pain. 2024; 25(1): 79. 7. Triller P, Blessing VN, Overeem LH, et al. Efficacy of eptinezumab in non-responders to subcutaneous monoclonal antibodies against CGRP and the CGRP receptor: A retrospective cohort study. Cephalalgia. 2024; 44(10): 3331024241288875. KDAJ IZBEREMO RIMEGEPANT PRI ZDRAVLJENJU MIGRENE? WHEN DO WE CHOOSE RIMEGEPANT IN MIGRAINE TREATMENT? Bojana Žvan POVZETEK Antagonisti majhnih molekul receptorja CGRP (t. i. gepanti) so odobreni za akutno zdravljenje migrene (rimegepant, ubrogepant, zavegepant) kot tudi za preventivno zdravljenje (atogepant, rimegepant), medtem ko so monoklonska protitelesa (mPt) proti CGRP (eptinezumab, fremanezumab in galcanezumab) ali njegovemu receptorju. (erenumab) odobreni samo za preventivno zdravljenje (1). Rimegepant je peroralni gepant, ki je bil v letu 2024 odobren v vec kot 65 državah za zdravljenje migrene (1). Vec klinicnih študij je pokazalo, da je rimegepant varno in ucinkovito zdravilo za akutno in preventivno zdravljenje migrene pri odraslih. Rimegepant za akutno zdravljenje migrene so ovrednotili v štirih kratkorocnih randomiziranih s placebom nadzorovanih študijah in eni nenadzorovani dolgotrajni odprti študiji (2, 3, 4, 5). Za preventivno zdravljenje migrene je bil rimegepant ovrednoten v študiji z 12-tedenskim dvojno slepim, s placebom nadzorovanim obdobjem zdravljenja, ki mu je sledilo 52-tedensko odprto obdobje nenadzorovanega zdravljenja (6) ter tudi v 3-mesecni neposredni študiji z galkanezumabom (7). Študije so pokazale, da rimegepant pri akutnem zdravljenju dosledno zmanjša bolecino in druge simptome migrene 2 uri po zaužitju odmerka zdravila, pri cemer ucinki trajajo do 48 ur (2, 3, 4, 5). Kot preventivno zdravljenje je rimegepant povezan z dolgorocnim zmanjšanjem števila mesecnih migrenskih dni in izboljšanjem z migreno povezanih rezultatov kakovosti življenja (6). Rimegepant pacienti z migreno dobro prenašajo tako v akutnem ali preventivnem zdravljenju, s profilom neželenih ucinkov, ki je primerljiv s placebom. Zaradi ugodnega varnostnega profila rimegepanta je zdravilo primerno za številne bolnike, zlasti tiste s kontraindikacijami, intoleranco ali neustreznim odzivom na druge vrste standardnega zdravljenja migrene (1). Kljucne besede: akutno zdravljenje, CGRP, preventivno zdravljenje, rimegepant. SUMMARY Small-molecule antagonists of the CGRP receptor (i.e. gepants) are approved for acute (rimegepant, ubrogepant, zavegepant) or preventive (atogepant, rimegepant) treatment of migraine, whereas monoclonal antibodies (mAbs) against CGRP (eptinezumab, fremanezumab, and galcanezumab) or its receptor (erenumab) are approved for preventive treatment (1). Rimegepant is an oral gepante that was approved in more than 65 countries in 2024 for the treatment of migraine (1). Rimegepant as an acute treatment of migraine has been evaluated in four short-term randomized placebo-controlled trials and one uncontrolled long-term open-label trial (2, 3, 4, 5). Rimegepant for the preventive treatment of migraine has been evaluated in one trial with a 12-week double-blind placebo-controlled treatment period (followed by a 52-week open-label uncontrolled treatment period) (6), and in one 3-month head-to-head trial with galcanezumab (7). As an acute treatment, rimegepant consistently improves pain, other symptoms of migraine, and function at 2 hours post dose, with effects sustained up to 48 hours (2, 3, 4, 5). As a preventive treatment, rimegepant is associated with long-term decreases in monthly migraine days and improved migraine-related quality of life scores (6). Rimegepant is well tolerated as an acute or preventive treatment, with an adverse event profile comparable to placebo. There are few direct head-to-head studies comparing rimegepant with other migraine therapies (7). Several clinical trials established rimegepant as a safe and effective treatment (acute andpreventive) of migraine in adults. However, the favorable safety profile of rimegepant makes it appropriate for many patients, particularly those with contraindication, intolerance, or inadequate response to other classes of standard-of-care migraine treatments (1). Keywords: acute treatment, CGRP, preventive treatment, rimegepant. LITERATURA / LITERATURE 1. Edvinsson L. Rimegepant for the acute and preventive treatment of migraine: a narrative review of the evidence. Expert Review of Neurotherapeutics. 2024; 24(12): 1141–55. 2. Lipton RB, Croop R, Stock EG, et al. Rimegepant, an oral calcitoningene–related peptide receptor antagonist, for migraine. N EnglJ Med. 2019; 381(2):142–9. 3. Croop R, Goadsby PJ, Stock DA, et al. Efficacy, safety, and toler-ability of rimegepant orally disintegrating tablet for the acutetreatment of migraine: a randomised, phase 3, double-blind,placebo-controlled trial. Lancet. 2019; 394(10200): 737–45. 4. Yu S, Kim BK, Guo A, et al. Safety and efficacy of rimegepant orallydisintegrating tablet for the acute treatment of migraine in Chinaand South Korea: a phase 3, double-blind, randomised,placebo-controlled trial. Lancet Neurol. 2023; 22(6): 476–84. 5. Lipton RB, Thiry A, Morris BA, et al. Efficacy and safety of rimegepant75 mg oral tablet, a CGRP receptor antagonist, for the acute treatmentof migraine: a randomized, double-blind, placebo-controlled trial.J Pain Res. 2024;17:2431–441. 6. Croop R, Lipton RB, Kudrow D, et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet. 2021; 397(10268): 51–60. 7. Schwedt TJ, Myers Oakes TM, Martinez JM, et al. Comparing the efficacy and safety of galcanezumab versus rimegepant for prevention of episodic migraine: results from a randomized, controlled clinical trial. Neurol Ther. 2024; 13(1): 85–105. PREDNOSTI ATOGEPANTA V PREVENTIVI MIGRENE BENEFITS OF ATOGEPANT IN MIGRAINE PREVENTION Matija Zupan POVZETEK Atogepant je drugi gepant, ki je v Sloveniji na voljo za preventivno zdravljenje epizodicne in kronicne migrene pri odraslih, ki imajo vsaj štiri migrenske dni na mesec. Po pravilih ZZZS ga lahko predpišemo le v primeru neucinkovitosti ali neprenašanja vsaj dveh preventivnih zdravil ali ce je uporaba drugih preventivnih zdravil kontraindicirana zaradi komorbidnosti. Priporoceni odmerek je 60 mg atogepanta enkrat na dan v obliki peroralne tablete, ki jo je treba zaužiti. Znižani odmerek atogepanta 10 mg na dan je priporocen pri socasni uporabi mocnih zaviralcev CYP3A4 (npr. ketokonazol, itrakonazol, klaritromicin, ritonavir) oziroma mocnih zaviralcev polipeptidnih prenašalcev organskih anionov (OATP - organic anion transporting polypeptide), kot sta rifampicin in ciklosporin, ki lahko pomembno zvecajo sistemsko izpostavljenost atogepantu. Znižani odmerek atogepanta 10 mg priporocajo tudi pri bolnikih s hudo okvaro ledvic (ocistek kreatinina 1529 ml/min) in pri bolnikih s koncno odpovedjo ledvic (ocistek kreatinina < 15 ml/min). Pri bolnikih z blago ali zmerno okvaro jeter ne priporocajo prilagoditve odmerka. Atogepant ni priporocljiv pri bolnikih s hudo okvaro jeter. Varnost in ucinkovitost atogepanta pri mlajših od 18 let še nista bili dokazani. Socasna uporaba atogepanta s peroralnima kontraceptivnima ucinkovinama etinilestradiolom in levonorgestrelom, paracetamolom, naproksenom ali sumatriptanom ni povzrocila pomembnih farmakokineticnih interakcij bodisi atogepanta bodisi socasno uporabljanih zdravil. Socasna uporaba s famotidinom ali esomeprazolom ni povzrocila klinicno pomembnih sprememb izpostavljenosti atogepantu. Atogepanta med nosecnostjo in pri ženskah v rodni dobi, ki ne uporabljajo kontracepcije, ne priporocajo. Ni znano, ali se atogepant izloca v materino mleko, razpoložljivi toksikološki podatki pri živalih pa kažejo na izlocanje atogepanta v mleko. Tveganja za dojenega novorojencka/otroka ni moc izkljuciti. Odlociti se je treba med prenehanjem dojenja in prenehanjem/prekinitvijo zdravljenja z atogepantom, pri cemer je treba pretehtati prednosti dojenja za otroka in prednosti zdravljenja za mater. Ceprav atogepant nima vpliva ali ima zanemarljiv vpliv na sposobnost vožnje in upravljanja strojev, pa lahko pri nekaterih bolnikih povzroca zaspanost. Med poglavitnimi stranskimi ucinki navajajo navzeo, zaprtje, utrujenost, zaspanost, zmanjšanje telesne mase, med obcasnimi pa zvišanje ALT/AST. Pogostnost preobcutljivostnih reakcij ni znana. Ucinkovitost in varnost atogepanta so proucevali v randomiziranih s placebom nadzorovanih dvojno slepih raziskavah. V raziskavo ADVANCE (1) so zajeli 873 odraslih z epizodicno migreno, ki so prejemali bodisi atogepant 10 mg, 30 mg ali 60 mg dnevno ali placebo 12 tednov. Dokazali so statisticno znacilno znižanje števila mesecnih migrenskih dni v primerjavi s placebom (atogepant 60 mg: -4,2 dni; atogepant 10 mg: -3,7 dni; placebo: -2,5 dneva). Atogepant je bil ucinkovit v zmanjšanju pogostnosti migrene in so ga bolniki dobro prenašali. V raziskavo PROGRESS (2) so zajeli 778 odraslih s kronicno migreno, ki so prejemali atogepant 30 mg ali 60 mg dnevno ali placebo 12 tednov. Dokazali so statisticno znacilno znižanje števila mesecnih migrenskih dni v primerjavi s placebom (atogepant 30 mg: -6,9 dni; atogepant 60 mg: -7,5 dni; placebo: -5,1 dni). Atogepant je bil ucinkovit v preventivi kronicne migrene. V raziskavo ELEVATE (3) so zajeli 313 odraslih z epizodicno migreno, ki se niso odzvali na 2 do 4 predhodne razrede oralnih migrenskih preventivnih zdravil. Bolniki so prejemali atogepant 60 mg dnevno ali placebo 12 tednov. V skupini, ki je prejemala atogepant, se je število mesecnih migrenskih dni v primerjavi s placebom statisticno znacilno znižalo (atogepant: -4,2 dni, placebo: -1,9 dni). Ob tem je višji delež bolnikov v skupini z atogepantom dosegel vsaj 50-% znižanje števila mesecnih migrenskih dni v primerjavi s placebom, hkrati pa je atogepant privedel do pomembnega znižanja števila dni, ko so bolniki potrebovali abortivno zdravljenje migrene. Dolgorocno varnost, prenosljivost in ucinkovitost atogepanta v odmerku 60 mg dnevno so raziskovali v randomizirani odprti raziskavi, ki je trajala 52 tednov in v katero so zajeli 744 odraslih z epizodicno migreno. Znižanje števila mesecnih migrenskih dni v prvih štirih tednih zdravljenja z atogepantom je bilo -3,8 dni, v zadnjih štirih tednih pa -5,2 dni. Delež bolnikov, ki je dosegel vsaj 50-% znižanje števila mesecnih migrenskih dni, je s 60,4 % v prvih štirih tednih zdravljenja narastel na 84,2 % v zadnjih štirih tednih zdravljenja. Atogepant so proucevali v raziskavi resnicnega življenja pri 55 bolnikih s kronicno migreno, ki so v preventivi že prejemali onabotulinum toksin A. Atogepant je dodatno znižal število mesecnih dni z glavobolom za 4,53 po 3 mesecih in 8,75 po 6 mesecih kombiniranega zdravljenja, pri 45 % bolnikov pa je prišlo do vsaj 50-% znižanja mesecnih dni z glavobolom po 3 mesecih kombiniranega zdravljenja. Bolniki so kombinirano zdravljenje v splošnem prenašali dobro in v raziskavi niso zaznali morebitnih nepricakovanih oz. novih neželenih ucinkov zdravljenja. Trenutno potekajo raziskave atogepanta glede njegove dolgorocne varnosti in ucinkovitosti pri bolnikih s kronicno in epizodicno migreno (opazovanje predvideno 156 tednov), njegove ucinkovitosti in varnosti v abortivnem zdravljenju migrene in raziskave na pediatricni populaciji. Atogepant predstavlja novo možnost ucinkovitega preventivnega zdravljenja z ugodnim varnostnim profilom za široko populacijo bolnikov tako z epizodicno kot kronicno migreno. Njegova bistvena prednost izhaja iz vsakodnevnega jemanja, ki lahko pripomore k izboljšani adherenci bolnikov in ucinkovitosti zdravljenja v klinicni praksi. Kljucne besede: atogepant, migrena, preventivno zdravljenje. SUMMARY Atogepant is the second gepant available in Slovenia for the preventive treatment of episodic and chronic migraine in adults who have at least four migraine days per month. According to the rules of the Slovenian Health Insurance Institute, it can only be prescribed in case of ineffectiveness or intolerance of at least two preventive medications or if the use of other preventive medications is contraindicated due to comorbidity. The recommended dose is 60 mg of atogepant once daily in the form of an oral tablet. A reduced dose of atogepant 10 mg per day is recommended in concomitant use of strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, ritonavir) or strong inhibitors of organic anion transporting polypeptide (OATP) such as rifampicin and cyclosporine, which can significantly increase systemic exposure to atogepant. A reduced dose of atogepant 10 mg is also recommended in patients with severe renal impairment (creatinine clearance 15-29 ml/min) and in patients with end-stage renal disease (creatinine clearance < 15 ml/min). No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Atogepant is not recommended in patients with severe hepatic impairment. The safety and efficacy of atogepant in children under 18 years of age have not yet been established. Co-administration of atogepant with the oral contraceptives ethinylestradiol and levonorgestrel, paracetamol, naproxen, or sumatriptan did not result in significant pharmacokinetic interactions of either atogepant or the concomitant medicinal products. Co-administration with famotidine or esomeprazole did not result in clinically significant changes in atogepant exposure. Atogepant is not recommended during pregnancy and in women of childbearing potential not using contraception. It is not known whether atogepant is excreted in human milk, but available toxicological data in animals indicate excretion of atogepant in milk. A risk to the breast-fed new-born/infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from atogepant therapy considering the benefit of breast-feeding for the child and the benefit of therapy for the woman. Although atogepant has no or negligible influence on the ability to drive and use machines, it may cause drowsiness in some patients. The most common side effects are nausea, constipation, fatigue, somnolence, weight loss, and uncommonly, increased ALT/AST. The frequency of hypersensitivity reactions is unknown. The efficacy and safety of atogepant have been studied in randomised, placebo-controlled, double-blind trials. The ADVANCE trial (1) enrolled 873 adults with episodic migraine who received either atogepant 10 mg, 30 mg or 60 mg daily or placebo for 12 weeks. A statistically significant reduction in the number of monthly migraine days compared with placebo was demonstrated (atogepant 60 mg: -4.2 days; atogepant 10 mg: -3.7 days; placebo: -2.5 days). Atogepant was effective in reducing migraine frequency and was well tolerated. The PROGRESS trial (2) enrolled 778 adults with chronic migraine who received atogepant 30 mg or 60 mg daily or placebo for 12 weeks. They demonstrated a statistically significant reduction in the number of monthly migraine days compared to placebo (atogepant 30 mg: -6.9 days; atogepant 60 mg: -7.5 days; placebo: -5.1 days). Atogepant was effective in the prevention of chronic migraine. The ELEVATE study (3) enrolled 313 adults with episodic migraine who had failed to respond to 2 to 4 previous classes of oral migraine preventive medications. Patients received atogepant 60 mg daily or placebo for 12 weeks. In the atogepant group, the number of monthly migraine days was statistically significantly reduced compared to placebo (atogepant: -4.2 days, placebo: -1.9 days). In addition, a higher proportion of patients in the atogepant group achieved at least a 50% reduction in the number of monthly migraine days compared to placebo, and atogepant led to a significant reduction in the number of days on which patients required migraine abortive treatment. The long-term safety, tolerability and efficacy of atogepant 60 mg daily were investigated in a randomised, open-label study of 52 weeks` duration in 744 adults with episodic migraine. The reduction in monthly migraine days during the first 4 weeks of atogepant treatment was -3.8 days and during the last 4 weeks it was -5.2 days. The proportion of patients achieving at least a 50% reduction in monthly migraine days increased from 60.4% during the first 4 weeks of treatment to 84.2% during the last 4 weeks of treatment. Atogepant was studied in a real-life study in 55 patients with chronic migraine who were already receiving onabotulinum toxin A for prophylaxis. Atogepant additionally reduced the number of monthly headache days by 4.53 after 3 months and 8.75 after 6 months of combination treatment, and 45% of patients had at least a 50% reduction in monthly headache days after 3 months of combination treatment. Patients generally tolerated the combination treatment well and no unexpected or new adverse effects of treatment were observed in the study. Atogepant is currently being studied for its long-term safety and efficacy in patients with chronic and episodic migraine (156 weeks of follow-up), its efficacy and safety in abortive treatment of migraine, and studies in the paediatric population. Atogepant represents a new option for effective preventive treatment with a favourable safety profile for a broad population of patients with both episodic and chronic migraine. Its essential advantage stems from daily administration, which can contribute to improved patient adherence and treatment effectiveness in clinical practice. Keywords: atogepant, migraine, preventive treatment. LITERATURA / LITERATURE 1. Ailani J, Lipton RB, Goadsby PJ, et al; ADVANCE Study Group. Atogepant for the Preventive Treatment of Migraine. N Engl J Med. 2021; 385(8): 695–706. 2. Pozo-Rosich P, Ailani J, Ashina M, et al. Atogepant for the preventive treatment of chronic migraine (PROGRESS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023; 402(10404): 775–85. 3. Tassorelli C, Nagy K, Pozo-Rosich P, et al. Safety and efficacy of atogepant for the preventive treatment of episodic migraine in adults for whom conventional oral preventive treatments have failed (ELEVATE): a randomised, placebo-controlled, phase 3b trial. Lancet Neurol. 2024; 23(4): 382–92. NEVROMODULACIJA PRI MIGRENI – NOVI IZZIVI NEUROMODULATION IN MIGRAINE - NEW CHALLENGES Gorazd Požlep POVZETEK Nevromodulacija predstavlja obetavno terapevtsko možnost za preprecevanje migrene, zlasti pri bolnikih, ki se ne odzivajo na farmakološke pristope. Razlicne metode, vkljucno z nevrostimulacijo zatilnega živca (ONS), transkranialno magnetno stimulacijo (TMS), transkranialno stimulacijo z enosmernim tokom (tDCS), stimulacijo vagusa (VNS), transkutano elektricno stimulacijo (TENS), blokado živcev ter akupunkturo, so pokazale pozitivne rezultate pri zmanjšanju pogostosti in intenzivnosti migrenskih napadov. Kljucne besede: migrena, nefarmakološke metode preprecevanja, nevromodulacija. UVOD Migrena je nevrološka motnja, ki pomembno vpliva na kakovost življenja. Farmakološko zdravljenje pogosto ni zadostno, zato nevromodulacijske metode predstavljajo alternativno možnost za preprecevanje migrenskih napadov (1). Mehanizmi delovanja nevromodulacije Nevromodulacija deluje preko: • Modulacije bolecinskih poti: elektricni impulzi vplivajo na centralne in periferne bolecinske mehanizme (2). • Zmanjšanja centralne senzitizacije: zmanjšana hiperekscitabilnost trigeminovaskularnega sistema (3). • Spodbujanja inhibitornih mehanizmov: aktivira endogene analgeticne poti, ki zmanjšujejo zaznavanje bolecine (4). Nevromodulacijske metode 1. Nevrostimulacija zatilnega živca (ONS) Metoda zmanjšuje pogostost migrenskih napadov pri bolnikih, ki se ne odzivajo na farmakološko zdravljenje (5). Uporablja se pri kronicni migreni in tenzijskih glavobolih, kjer zmanjša intenzivnost bolecine (6). 2. Transkranialna magnetna stimulacija (TMS) TMS s ponavljajocimi se magnetnimi impulzi modulira kortikalno ekscitabilnost, kar zmanjša migrenske simptome (7). Klinicne študije kažejo, da je TMS ucinkovit pri preprecevanju epizodicnih in kronicnih migren (5). 3. Transkranialna stimulacija z enosmernim tokom (tDCS) tDCS spreminja ekscitabilnost možganske skorje in zmanjša število migrenskih dni na mesec (8). Kombinacija tDCS in kognitivno-vedenjske terapije povecuje ucinkovitost zdravljenja (9). 4. Stimulacija vagusa (VNS) Neinvazivna stimulacija vagusa zmanjšuje intenzivnost glavobolov in izboljša kakovost spanja (10). Klinicne raziskave potrjujejo ucinkovitost pri kronicni migreni in glavobolu v skupkih (11). 5. Transkutana elektricna stimulacija živcev (TENS) TENS zmanjšuje frekvenco tenzijskih glavobolov in izboljšuje prekrvavitev vratnih mišic (12). Uporablja se kot dopolnilna metoda pri obvladovanju kronicnih glavobolov (13). 6. Blokade živcev, vkljucno z izstopišci trigeminusa Blokade zatilnega živca in sfenopalatinega ganglija lahko zagotavljajo dolgotrajno olajšanje pri kronicnih glavobolih (14). Uporaba anestetikov in kortikosteroidov zmanjša centralno senzitizacijo. Blokade izstopišc trigeminusa se uporabljajo pri bolnikih z nevralgijo trigeminusa in kronicno migreno, kjer dokazano zmanjšujejo bolecino (15). 7. Akupunktura Klinicne študije kažejo, da akupunktura zmanjša pogostost in intenzivnost migren (16). Ucinki akupunkture so primerljivi s farmakološko terapijo, vendar z manj stranskimi ucinki (17). Akupunktura vpliva na sprošcanje endorfinov in regulacijo živcnega sistema, kar prispeva k lajšanju glavobolov (18). ZAKLJUCEK Nevromodulacija predstavlja pomembno dopolnilo farmakološkim pristopom za preprecevanje migrene. Klinicne raziskave potrjujejo njeno ucinkovitost pri zmanjševanju pogostosti in intenzivnosti glavobolov, zlasti pri bolnikih z težko obvladljivimi oblikami migrene. SUMMARY Neuromodulation represents a promising therapeutic option for migraine prevention, especially in patients who do not respond to pharmacological approaches. Various methods, including occipital nerve stimulation (ONS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), transcutaneous electrical nerve stimulation (TENS), nerve blocks, and acupuncture, have shown positive results in reducing migraine attack frequency and intensity. Keywords: migraine, neuromodulation, non-pharmacological therapy. INTRODUCTION Migraine is a neurological disorder that significantly impacts quality of life. Pharmacological treatment is often insufficient, making neuromodulation methods a promising alternative for the prevention of migraine attacks (1). Mechanisms of Neuromodulation Neuromodulation works through: • Modulation of pain pathways: Electrical impulses affect both central and peripheral pain mechanisms (2). • Reduction of central sensitization: It decreases the hyperexcitability of the trigeminovascular system (3). • Activation of inhibitory mechanisms: It stimulates endogenous analgesic pathways, reducing pain perception (4). Neuromodulation Techniques 1. Occipital Nerve Stimulation (ONS) This method reduces the frequency of migraine attacks in patients who do not respond to pharmacological treatments (5). It is used for chronic migraine and tension-type headaches, where it helps decrease pain intensity (6). 2. Transcranial Magnetic Stimulation (TMS) TMS uses repetitive magnetic impulses to modulate cortical excitability, alleviating migraine symptoms (7). Clinical studies have shown that TMS is effective in preventing both episodic and chronic migraines (5). 3. Transcranial Direct Current Stimulation (tDCS) tDCS alters cortical excitability and reduces the number of migraine days per month (8). Combining tDCS with cognitive-behavioral therapy further enhances treatment efficacy (9). 4. Vagus Nerve Stimulation (VNS) Non-invasive vagus nerve stimulation decreases headache intensity and improves sleep quality (10). Clinical research supports its effectiveness in treating chronic migraine and cluster headaches (11). 5. Transcutaneous Electrical Nerve Stimulation (TENS) TENS reduces the frequency of tension-type headaches and improves blood circulation in the neck muscles (12). It is used as an adjunctive method in managing chronic headaches (13). 6. Nerve Blocks, Including Trigeminal Nerve Exits Blocks of the occipital nerve and sphenopalatine ganglion can provide long-term relief for chronic headaches (14). The use of anesthetics and corticosteroids helps to reduce central sensitization. Blocking trigeminal nerve exits is employed in patients with trigeminal neuralgia and chronic migraine, where it has been proven to alleviate pain (15). 7. Acupuncture Clinical studies have shown that acupuncture reduces the frequency and intensity of migraines (16). Its effects are comparable to pharmacological therapy but with fewer side effects (17). Acupuncture promotes the release of endorphins and regulates the nervous system, contributing to headache relief (18). CONCLUSION Neuromodulation offers an important complement to pharmacological approaches for migraine prevention. Clinical research confirms its effectiveness in reducing the frequency and intensity of headaches, particularly in patients with difficult-to-treat forms of migraine. LITERATURA / LITERATURE 1. Diener HC, Holle D, Naegel S, et al. Treatment of migraine attacks and prevention of migraine: Guidelines by the German migraine and headache society and the German society of neurology: Clinical & Translational Neuroscience, Jan–Jun 2019: 1–40. 2. Weiner RL, Reed KL. Peripheral neurostimulation for control of intractable occipital neuralgia. Neuromodulation. 1999 Jul;2(3): 217–21. 3. Saper JR, Dodick DW, Silberstein SD, et al. Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study. Cephalalgia. 2011 Feb; 31(3): 271–85. 4. Chowdhury, D, Datta, D, Mundra, A. Role of greater occipital nerve block in headache disorders: A Narrative Review. Neurology India. 2021; 69(Suppl 1): p S228–S56. 5. Chen YF, Bramley G, Unwin G, et al. Occipital nerve stimulation for chronic migraine--a systematic review and meta-analysis. PLoS One. 2015 Mar 20; 10(3): e0116786. 6. Schwedt TJ, Dodick DW, Hentz J, et al. Occipital nerve stimulation for chronic headache--long-term safety and efficacy. Cephalalgia. 2007 Feb; 27(2): 153–7. 7. Hong P, Liu Y, Wan Y, et al. Transcranial direct current stimulation for migraine: a systematic review and meta-analysis of randomized controlled trials. CNS Neurosci Ther. 2022 Jul; 28(7): 992–8. 8. Dasilva AF, Mendonca ME, Zaghi S, et al.. tDCS-induced analgesia and electrical fields in pain-related neural networks in chronic migraine. Headache. 2012 Sep; 52(8): 1283–95 9. Peiwei Hong, Yao Liu, Yang Wan, et al. Transcranial direct current stimulation for migraine: a systematic review and meta-analysis of randomized controlled trials. CNS. 2022; 28(7): 992–8. 10. Goadsby PJ, de Coo IF, Silver N, et al. Vagus nerve stimulation for migraine and cluster headache: a review of clinical data. Cephalalgia. 2018; 38(6): 967–77. 11. Trimboli M, Al-Kaisy A, Andreou AP, et al. Non-invasive vagus nerve stimulation for the management of refractory primary chronic headaches: A real-world experience. Cephalalgia. 2017; 38(7): 1276–85. 12. Johnson M. Transcutaneous electrical nerve stimulation: Mechanisms, clinical application and evidence. Rev Pain. 2007 Aug; 1(1): 7–11. 13. Gibson W, Wand BM, Meads C, et al. The role of TENS in the management of chronic headache disorders: a meta-analysis. J Pain Research. 2021; 14: 589–602. 14. Inan N, Inan LE, Coskun Ö, et al. Effectiveness of greater occipital nerve blocks in migraine prophylaxis. Noro Psikiyatr Ars. 2016 Mar; 53(1): 45–48. 15. Caputi CA, Firetto V. Therapeutic blockade of the greater occipital and supraorbital nerves in migraine patients. Headache. 1998 Jan; 38(1): 56. 16. Linde K, Allais G, Brinkhaus B, et al. Acupuncture for tension-type headache update in: Cochrane Database Syst Rev. 2016 Apr 19; 4: CD007587. 17. Xia R, Linde K, Freilinger T, et al. Acupuncture for the prevention of episodic migraine. Cochrane Database Syst Rev. 2025 Feb 11; 2(2): CD015528. 18. Chunay Y, Min Wu,Qin L, et al. Acupuncture for migraine prophylaxis: A systematic review and meta-regression of randomized controlled trials. Complementary Th in Medicine. 2024 Nov; Vol 86: 103083–91. CLUSTER HEADACHE - NEW TREATMENT APPROACHES GLAVOBOL V SKUPKIH – NOVI PRISTOPI K ZDRAVLJENJU Hrvoje Budincevic, Anita Marcinko Budincevic, Barbara Caic SUMMARY Cluster headache (CH) is a primary headache, classified as trigeminal autonomic cephalgia, severely impacting patients’ quality of life. It is characterized by recurrent, severe, unilateral headaches associated with autonomic symptoms. Epidemiological data indicate that CH affects approximately 0.1% of the general population, with a male-to-female ratio of about 3:1, most commonly occurring in middle age. The pathophysiological mechanisms are still not fully understood. Recent studies show that targeting the trigeminal autonomic reflex by neurostimulation or the neuropeptide calcitonin gene-related peptide (CGRP) might lessen the attack burden. Cluster headache treatments are divided into 1) acute, 2) transitional, and 3) preventive interventions. Acute interventions are based on using oxygen and triptans, transitional interventions are focused on corticosteroids (oral or as suboccipital blocks), and preventive interventions include mostly verapamil. Alternative preventive treatments include lithium and topiramate, and only for episodic cluster headaches, galcanezumab, and noninvasive vagus nerve stimulation. Keywords: cluster headache, headache, treatment. POVZETEK Glavobol v skupkih (GS) je primarni glavobol, ki je razvršcen kot trigeminalna avtonomna cefalgija. GS mocno vpliva na kakovost življenja bolnikov. Zanj so znacilni ponavljajoci, hudi, enostranski glavoboli, povezani z avtonomnimi simptomi. Epidemiološki podatki kažejo, da GS prizadene približno 0,1 % splošne populacije, pri cemer je razmerje med moškimi in ženskami približno 3:1, najpogosteje pa se pojavi v srednjih letih. Patofiziološki mehanizmi še vedno niso popolnoma znani. Nedavne študije kažejo, da lahko ciljanje na trigeminalni avtonomni refleks z nevrostimulacijo ali ciljanje na peptid, povezan z genom nevropeptida za kalcitonin (CGRP), zmanjša breme napada. Zdravljenje tega glavobola delimo na 1) akutne, 2) prehodne in 3) preventivne nacine. Akutno zdravljenje temelji na uporabi kisika in triptanov, prehodno lahko uporabljamo kortikosteroide (peroralno ali v obliki subokcipitalnih blokad), za preventivno zdravljenje pa vecinoma uporabljamo verapamil. Alternativna preventivna zdravljenja vkljucujejo litij in topiramat ter samo za epizodne glavobole galkanezumab in neinvazivno stimulacijo vagusovega živca. Kljucne besede: glavobol, glavobol v skupkih, zdravljenje. LITERATURE / LITERATURA 1. Petersen AS, Lund N, Goadsby PJ, et al. Recent advances in diagnosing, managing, and understanding the pathophysiology of cluster headache. Lancet Neurol. 2024 Jul; 23(7): 712–24. 2. Peng KP, Burish MJ. Management of cluster headache: Treatments and their mechanisms. Cephalalgia. 2023 Aug; 43(8): 3331024231196808. 3. May A, Evers S, Goadsby PJ, et al; European Academy of Neurology Task Force. European Academy of Neurology guidelines on the treatment of cluster headache. Eur J Neurol. 2023 Oct; 30(10): 2955–79. NEW TARGETS FOR MIGRAINE TREATMENT NOVE TARCE ZDRAVLJENJA MIGRENE Vida Demarin, Sandra Morovic, Filip Đerke SUMMARY Migraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation and release of calcitonin gene-related peptide (CGRP) play a pivotal role in the pathogenesis of migraine. This knowledge has led to the development of CGRP(-receptor) therapies. Yet, a substantial proportion of patients do not respond to these treatments. Therefore, alternative targets for future therapies are warranted (1). Ongoing advances in migraine research have identified a number of other promising, non-CGRP therapeutic targets. Multiple mechanisms have been identified in the induction and maintenance of migraine symptoms; and this divergent set of targets have highly distinct biological effects. Analyzing some of targets of the metabotropic receptors (pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), amylin, and adrenomedullin), intracellular targets (nitric oxide (NO), phosphoiesterase-3 (PDE3) and -5 (PDE5)) it was found out that these targets were able to induce migraine-like attacks. On the other hand for ion channels like potassium, calcium channels, transient receptor potential (TRP), and acid-sensing ion channels (ASIC) it was not yet possible to elucidate their precise involvement in inducing migraine attacks thus far. (2) It is an exciting time in migraine research and patient care. There are a number of promising targets that have been identified as migraine regulators and future work will hopefully lead to the next breakthrough drug. (3) Keywords: future targets beyond CGRP, metabotropic receptors, new treatment targets in migraine, nitric oxide, transient receptor potential (TRP). POVZETEK Migrena je onesposabljajoca in kronicna nevrovaskularna glavobolna motnja. Trigeminalna vaskularna aktivacija in sprošcanje peptida, povezanega z genom za kalcitonin (CGRP), imata kljucno vlogo pri patogenezi migrene. Te ugotovitve so pripeljale do razvoja zdravljenja z zdravili usmerjena proti CGRP, na ligand kot na receptor. Precejšen delež bolnikov se ne odzove na ta zdravljenja. Zato so upraviceni alternativni cilji za zdravljenje migrene v prihodnosti (1). Stalni napredek v raziskavah migrene je odkril številne druge obetavne terapevtske tarce, ki niso usmerjene proti CGRP. Pri nastanku in vzdrževanju simptomov migrene je bilo ugotovljenih vec mehanizmov. Razlicne tarce imajo zelo razlicne biološke ucinke. Analiza nekaterih tarc metabotropnih receptorjev, kot so polipeptid, ki aktivira hipofizno adenilat ciklazo (PACAP), vazoaktivni intestinalni peptid (VIP), amilin in adrenomedulin ter intracelularne tarce: dušikov oksid (NO), fosfoesteraza-3 (PDE3) in -5 (PDE5) je ugotovila, da lahko te tarce povzrocijo napade, podobne migreni. Po drugi strani pa za ionske kanale, kot so kalijevi, kalcijevi kanali, prehodni receptorski potencial (TRP) in ionski kanali, ki zaznavajo kislino (ASIC), doslej še ni bilo mogoce razjasniti njihove natancne vpletenosti v povzrocanje napadov migrene (2). Danes se spet soocamo z vznemirljivim casom v raziskovanju migrene, ki prinaša nova zdravljenja bolnikom z migreno. Obstajajo številne obetavne tarce, ki so bile opredeljene kot regulatorji migrene in upajmo, da bo prihodnje delo vodilo do naslednjega uspešnega zdravila (3). Kljucne besede: cilji prihodnosti, ki presegajo CGRP, dušikov oksid, metabotropni receptorji, novi cilji zdravljenja migrene, prehodni receptorski potencial (TRP). LITERATURE / LITERATURA 1. Bertels Z, Pradhan AAA. Emerging Treatment Targets for Migraine and Other Headaches. Headache. 2019; 59: 50–65. 2. Al-Hassany L, Boucherie DM, Creeney H, et al. Future targets for migraine treatment beyond CGRP. J Headache Pain. 2023; 24: 76. 3. Chiang, Chia-Chun, Porreca F, Robertson CE, et al. Potential treatments targets for migraine: emerging options and future prospects. The Lancet Neurology. 2024; (23)3: 313–24. SEKCIJA ZA GLAVOBOL - ZDRUŽENJE NEVROLOGOV PRI SLOVENSKEM ZDRAVNIŠKEM DRUŠTVU TRIPTAN ALI/IN GEPANT KOT ZDRAVILO PRVEGA IZBORA ZA AKUTNO ZDRAVLJENJE MIGRENE / TRIPTAN AND/OR GEPANT AS FIRST-LINE TREATMENT FOR ACUTE MIGRAINE GEPANT/MONOKLONSKO PROTITELO KOT ZDRAVILO PRVEGA IZBORA ZA PREVENTIVNO ZDRAVLJENJE MIGRENE / GEPANT/MONOCLONAL ANTIBODY AS FIRST-LINE DRUG FOR PREVENTIVE MIGRAINE TREATMENT avtorji: B. Žvan, Marjan Zaletel, G. Požlep soavtorji: G. Klanjšcek, J. Magdic, D. Perko, M. Popit, A. Stepanovic, B. Rojc, Majda Zaletel, M. Strgar Hladnik PRIPOROCILA ZA AKUTNO ZDRAVLJENJE MIGRENE RECOMMENDATIONS FOR ACUTE MIGRAINE TREATMENT Marjan Zaletel POVZETEK Migrena predstavlja pomembno družbeno breme in povzroca migrensko oviranost. Najpomembnejši razlog za migrensko oviranost so migrenske epizode, ki potekajo z migrenskim glavobolom in bolnika onesposobijo. Zato je pomembno ucinkovito prekiniti migrensko epizodo z optimalnim zdravljenjem. Osrednji del zdravljenja predstavljajo zdravila, ki jih dopolnjuje nefarmakološko zdravljenje. Najpomembnejši cilj farmakološkega zdravljenja je prekinitev, zato jih je potrebno uporabiti ob zacetku migrenskega glavobola. Zdravila, ki jih uporabljamo v ta namen, razdelimo na enostavne analgetike, nesteroidne analgetike, specificne analgetike in analgetike z antidopaminergicno aktivnostjo. Izbor analgetika je odvisen od jakosti migrenske epizode, odzivnosti na že uporabljene analgetike, profila stranskih ucinkov, spremljajocih bolezenskih stanj, preferenc bolnika, spremljajocega preventivnega zdravljenja in drugih dejavnikov. Zato akutno zdravljenje migrenske epizode predstavlja zahtevno odlocitev, ki je povezana z izkušnjami zdravnika na podrocju zdravljenja glavobola. Za oporo pri odlocitvi je mednarodno združenje za glavobol (IHS) v letu 2024 izdal prakticna priporocila (1), ki upoštevajo sodobna spoznanja akutnega zdravljenja. Namenjena so kot prakticna in hitra referenca, uporabna v vseh državah in razlicnih okoljih oskrbe, vkljucno s primarno oskrbo. Te smernice so zasnovane tako, da nadomestijo lokalne odobritve in predstavljajo instrument za motiviranje ter olajšanje sprememb razlicnih politik na podrocju migrene. Predvidevajo standarde, ki bodo služili kot referenca za spodbujanje optimalne oskrbe migrenske epizode. Izbrana soglasna priporocila omogocajo prepoznavanje vprašanj, razvoj priporocil in oblikovanje strateških nacrtov. Podrobnosti vsakega klinicnega vprašanja v priporocilih so povezane s priporocili za optimalno in bistveno raven. Priporocila vsebujejo 17 priporocil za vzpostavitev nacionalnih priporocil akutnega zdravljenja migrene. Pomembna priporocila so zajeta v naslednjih tockah, ki jih podajamo: 1) Pri osebah z migreno, ki se ne odzivajo na enostavne ali nesteroidne analgetike, ce so ti jemani v ustreznih odmerkih in zgodaj med epizodo, se priporoca prehod na kateri koli razpoložljivi triptan. Pri osebah z migreno in hudimi napadi so lahko triptani ucinkovitejši od nesteroidnih protivnetnih zdravil, zato se lahko uporabljajo kot prva linija zdravljenja. 2) Ce so na voljo le peroralne tablete, se priporoca odmerjanje na dve tableti (sumatriptan 100 mg) pri naslednjem napadu. Dva razlicna triptana se ne smeta jemati v istem 24-urnem obdobju. Prav tako se triptan ne sme uporabljati v razmaku manj kot 24 ur. Ce je odziv še vedno nezadosten, priporocajo prehod na drug nacin dajanja zdravila ali na drug triptan za naslednji napad. Ce so bili trije razlicni triptani preizkušeni v ustreznih odmerkih brez zadovoljivega odziva, priporocajo prehod na drugo vrsto akutnega zdravila. 3) Ce se osebe z migreno ne odzivajo na prvi triptan, ki je bil uporabljen v ustreznih odmerkih, pravilnem nacinu dajanja in ob pravem casu, v dveh od treh napadov, priporocajo prehod na drug triptan. Ta strategija se lahko ponovi najvec trikrat z razlicnimi triptani, nato pa priporocajo prehod na drugo skupino zdravil. 4) Pri osebah z migreno, ki imajo slabost in/ali bruhanje, ki ga ni mogoce obvladati s pravocasnim vnosom zdravila za akutne napade, priporocajo dodajanje antiemetika k enostavnim, nesteroidnim analgetikom. V nekaterih primerih bo pri veckratni uporabi nesteroidnih protivnetnih zdravil (NSAID) morda potrebna gastroprotekcija. 5) Pri bolnikih z migreno, ki se le delno odzovejo na triptane kot samostojne ucinkovine, tudi po optimiziranem zdravljenju s triptani, priporocajo kombinacijo peroralnega sumatriptana (50–100 mg) in peroralnega natrijevega naproksena (550 mg) kot prvo izbiro. Alternativno lahko triptan kombiniramo s katerokoli peroralno formulacijo nesteroidnega protivnetnega zdravila s hitrim sprošcanjem. 6) Gepanti in lasmiditan so možnosti zdravljenja akutnega napada migrene pri osebah, pri katerih monoterapija s triptanom ali kombinirana terapija ni ucinkovita, je le delno ucinkovita ali ni dobro prenosljiva. Prav tako so priporoceni pri osebah s kontraindikacijami za uporabo triptanov. 7) Bolniki z migreno brez avre naj vzamejo svoje zdravilo, dokler je intenzivnost bolecine še blaga, po možnosti cim prej v fazi glavobola. Bolniki z migreno z avro naj zacnejo zdravljenje takoj, ko se zacne faza glavobola. 8) Ceprav zanesljivi dokazi manjkajo, pri osebah z epizodami, ki trajajo vec kot 72 ur (status migrainosus), priporocajo uporabo intramuskularnih ali drugih oblik dajanja nesteroidnih protivnetnih zdravil ali uporabo subkutanega sumatriptana. Dokazi podpirajo dajanje subkutanega dajanja sumatriptana ter parenteralnega dajanja proklorperazina ali metoklopramida za zdravljenje akutnih migrenskih napadov v urgentni ambulanti. Intravenski deksametazon (ki je na seznamu razpoložljivih zdravil WHO) je lahko prav tako možnost zdravljenja. 9) Priporocajo omejitev jemanja analgetikov in nesteroidnih protivnetnih zdravil na 2–3 dni na teden in najvec 10 dni na mesec. Za kombinacijo analgetikov in triptanov priporocajo omejitev uporabe na najvec 2 dni na teden in manj kot 8 dni na mesec. Gepanti niso bili povezani z glavobolom zaradi prekomerne uporabe zdravil, zato lahko postanejo prednostna izbira pri osebah z migreno, ki potrebujejo pogostejšo uporabo akutnih zdravil. 10) Pri nosecnicah, pri katerih napadov ni mogoce ustrezno obvladati z nefarmakološkimi pristopi, se lahko paracetamol in triptani uporabljajo previdno v vseh treh trimesecjih nosecnosti. Po potrebi se lahko doda metoklopramid za obvladovanje slabosti ali bruhanja oziroma pri ženskah, pri katerih lajšanje bolecin ni zadostno. Med dojenjem je paracetamol prednostna izbira. Diklofenak, naproksen, triptani in gepanti se lahko uporabljajo previdno, pri cemer se priporoca prekinitev dojenja za 8–12 ur. 11) Pri osebah z migreno, starejših od 65 let, z normalnim delovanjem jeter priporocajo paracetamol kot prvo linijo zdravljenja. Kombinacije paracetamola s kofeinom se lahko uporabljajo, vendar je priporocljivo omejiti vnos zaradi tveganja prekomerne uporabe kofeina, kar lahko povzroci glavobol zaradi prekomerne uporabe zdravil ali odtegnitveni glavobol. Kot drugo linijo zdravljenja priporocajo acetilsalicilno kislino ali nesteroidna protivnetna zdravila, pri cemer je potrebno spremljati morebitne neželene ucinke, povezane s krvavitvami v prebavilih, ledvicno okvaro in jetrno insuficienco. Pri osebah brez nenadzorovane hipertenzije ali resnih kardiovaskularnih oziroma cerebrovaskularnih bolezni priporocajo uporabo triptanov kot tretjo linijo zdravljenja. Ce triptani sami niso ucinkoviti, se lahko uporabi kombinacija triptana z nesteroidnim protivnetnim zdravilom. Dodatno zdravljenje z antiemetiki je lahko koristno, vendar je potrebna previdnost zaradi povecanega tveganja za sedacijo in ekstrapiramidne neželene ucinke. Pri sicer zdravih osebah z migreno, starejših od 65 let, ki nimajo znanih socasnih bolezni, ki bi lahko pomembno vplivale na farmakokinetiko zdravil, lahko priporocila sledijo tistim za mlajše starostne skupine, vendar je potrebno natancnejše spremljanje morebitnih neželenih ucinkov. 12) Pri osebah z akutnim migrenskim napadom, ki imajo v anamnezi možgansko kap, bolezni srca in ožilja ali nenadzorovano hipertenzijo, priporocajo paracetamol kot zdravljenje prve izbire ter nesteroidna protivnetna zdravila kot možnost druge izbire. Uporabo nesteroidnih protivnetnih zdravil je treba omejiti, zlasti ob socasnem jemanju antitromboticnih zdravil. Dodatno zdravljenje z antiemetiki je lahko koristno. Razpoložljive triptane je mogoce uporabljati previdno pri osebah, pri katerih so zgoraj navedena stanja pod nadzorom in pri katerih paracetamol ni bil ucinkovit. 13) Pri ženskah z menstrualno migreno priporocajo NSAID ali triptane kot zdravila prve izbire. V primeru nezadostne ucinkovitosti posameznega zdravila se lahko uporabijo kombinacije: triptani z NSAID, triptani z antiemetiki, NSAID z antiemetiki. Ce zgoraj navedena zdravila niso ucinkovita, pri ženskah z rednimi ciklusi priporocajo kratkotrajno preventivno zdravljenje z naproksenom ali frovatriptanom, ce so na voljo. Ce vse navedene možnosti niso ucinkovite, se lahko razmisli o hormonskem zdravljenju z neprekinjenim kombiniranim režimom hormonske kontracepcije ali s kontracepcijskimi sredstvi, ki vsebujejo samo progesteron (ce so na voljo). Pri ženskah z migreno brez avre in nizkim pragom za zacetek rednega preventivnega zdravljenja je ta pristop še posebej priporocljiv. Zakljucimo, da so dosedanja priporocila Sekcije za glavobol, SZD (2) za akutno zdravljenje migrene usklajena s priporocili Mednarodnega združenja za glavobol, ker upoštevajo posamezna priporocila in lahko predstavljajo standard za zdravljenje migrenske epizode v Sloveniji. Kljucne besede: akutno zdravljenje, migrena, priporocila IHS. Slika 1. Algoritem za akutno zdravljenje migrene NSAID – nesteroidni antirevmatiki SUMMARY Migraine represents a significant social burden and is a leading cause of migraine-related impairment. The primary contributor to this impairment is the frequency of migraine episodes, which can cause severe disability. Therefore, it is crucial to effectively interrupt a migraine episode through optimal treatment strategies. The foundation of treatment includes pharmacological interventions, complemented by non-pharmacological approaches. The main goal of pharmacological treatment is to achieve interruption at the onset of a migraine headache. Medications for this purpose are categorized into simple analgesics, non-steroidal analgesics, specific analgesics, and analgesics with antidopaminergic properties. The choice of analgesics depends on various factors, including the severity of the migraine episode, previous responses to analgesics, side effect profiles, coexisting medical conditions, patient preferences, concurrent preventive treatments and others. Consequently, the acute management of migraine episodes requires a complex decision-making process, significantly influenced by the physician’s expertise in headache management. To aid this decision-making, practical recommendations from the International Headache Society were published in 2024, reflecting contemporary insights into acute treatment (1). These guidelines serve as a practical and rapid reference applicable across diverse healthcare settings, including primary care, and are designed to supersede local protocols while enhancing migraine management policies. They establish standards to guide optimal care for migraine episodes, enabling the identification of challenges, the development of actionable recommendations, and the formulation of strategic plans. Each clinical question within the recommendations is linked to optimal and essential care levels, encompassing 17 specific recommendations for establishing national guidelines for acute migraine treatment. Key recommendations include following: 1) For individuals with migraine who do not respond to simple or non-steroidal analgesics taken in appropriate doses early in the episode, transitioning to any available triptan is advised. In cases of severe migraine attacks, triptans may demonstrate greater efficacy than non-steroidal anti-inflammatory drugs (NSAID) and can be utilized as first-line treatment. 2) If only oral tablets are accessible, a dosage of two tablets (sumatriptan 100 mg) is recommended for subsequent attacks. It is advised against taking two different triptans within the same 24-hour period, as well as using a triptan within less than 24 hours. If the response remains inadequate, switching to an alternative route of administration or another triptan is recommended for the next attack. Should three different triptans be tested without satisfactory response, transitioning to another class of acute medication is warranted. 3) If individuals with migraine do not respond to the first triptan used in appropriate doses, correct administration, and at the right time, in two out of three attacks, switching to another triptan is recommended. This strategy may be repeated up to three times with different triptans, after which switching to another medication class is advised. 4) For individuals experiencing nausea and/or vomiting that cannot be managed with timely administration of acute medication, adding an antiemetic to simple or non-steroidal analgesics is recommended. Gastroprotection may be necessary with repeated NSAID use. 5) For patients who only partially respond to triptans, a combination of oral sumatriptan (50–100 mg) and oral sodium naproxen (550 mg) is recommended as the first choice. Alternatively, a triptan can be combined with any rapidly released oral formulation of an NSAID. 6) Gepants and lasmiditan are viable treatment options for acute migraine attacks in individuals for whom monotherapy with triptans or combination therapy is ineffective, only partially effective, or poorly tolerated. They are also recommended for individuals with contraindications to triptan use. 7) Patients with migraine without aura should initiate medication while pain intensity is still mild, preferably as soon as possible in the headache phase. Conversely, patients with migraine with aura should commence treatment at the onset of the headache phase. 8) Although reliable evidence is limited, for individuals with attacks lasting over 72 hours (status migrainous), the use of intramuscular or alternative forms of NSAID administration or subcutaneous sumatriptan is recommended. Evidence supports the use of subcutaneous sumatriptan and parenteral prochlorperazine or metoclopramide for treating acute migraine attacks in emergency settings. Intravenous dexamethasone may also be considered as a treatment option. 9) It is advisable to limit the use of analgesics and NSAIDs to 2–3 days per week and a maximum of 10 days per month. For combinations of analgesics and triptans, usage should be restricted to a maximum of 2 days per week and fewer than 8 days per month. Gepants have not been associated with medication overuse headaches, making them a preferred choice for individuals requiring more frequent acute medication use. 10) In pregnant women, when attacks cannot be adequately managed with non-pharmacological approaches, paracetamol and triptans may be used cautiously throughout all trimesters. If necessary, metoclopramide can be added to manage nausea or vomiting, or in cases where pain relief is insufficient. During breastfeeding, paracetamol is the preferred option, while diclofenac, naproxen, triptans, and gepants can be used cautiously, with a recommendation to interrupt breastfeeding for 8–12 hours. 11) For individuals over 65 with normal liver function, paracetamol is recommended as the first-line treatment. Combinations of paracetamol with caffeine may be utilized, but intake should be limited due to the risk of caffeine overuse leading to medication overuse headaches or withdrawal headaches. As a second-line treatment, acetylsalicylic acid or NSAIDs are recommended, with monitoring for potential side effects related to gastrointestinal bleeding, kidney impairment, and liver failure. For individuals without uncontrolled hypertension or serious cardiovascular or cerebrovascular diseases, triptans are recommended as a third-line treatment. If triptans alone are ineffective, a combination of triptan with an NSAID may be employed. Additional treatment with antiemetics may be beneficial, but caution is warranted due to the increased risk of sedation and extrapyramidal side effects. For otherwise healthy individuals over 65 without significant comorbidities affecting medication pharmacokinetics, recommendations may align with those for younger populations, albeit with closer monitoring for potential side effects. 12) For individuals experiencing acute migraine attacks with a history of stroke, cardiovascular disease, or uncontrolled hypertension, paracetamol is recommended as the first-choice treatment, with NSAID as a second-choice option. The use of NSAID should be limited, particularly when taken concurrently with antithrombotic medications. Additional treatment with antiemetics may be beneficial. Available triptans can be used cautiously in individuals whose conditions are well-controlled and for whom paracetamol has proven ineffective. 13) For women with menstrual migraine, NSAID or triptans are recommended as first-choice medications. In cases of insufficient efficacy from a single medication, combinations may be employed: triptans with NSAID, triptans with antiemetics, or NSAID with antiemetics. If these medications are ineffective, short-term preventive treatment with naproxen or frovatriptan is recommended for women with regular cycles. If all mentioned options fail, hormonal treatment with a continuous combined regimen of hormonal contraception or contraceptives containing only progesterone may be considered, particularly for women with migraine without aura and a low threshold for initiating regular preventive treatment. In conclusion, the existing recommendations from the Headache Society at the Slovenian Medical Association for the acute treatment of migraine (2) align with the guidelines of the International Headache Society, as they incorporate individual recommendations and can serve as a standard for migraine episode management in Slovenia. Keywords: acute treatment, HIS recommendations, migraine. Picture 1. Algorithm for acute migraine treatment NSAID - non-steroidal anti-inflammatory drugs LITERATURA / LITERATURE 1. Puledda F, Sacco S, Diener HC, et al. International Headache Society global practice recommendations for the acute pharmacological treatment of migraine. Cephalalgia. 2024 Aug; 44(8): 3331024241252666. 2. Zaletel M, Zvan B, Zupan M et al. Predlog algoritma za zdravljenje migrenskih epizod = Proposal for an algorithm for the treatment of migraine episodes. In: Zvan B, Zaletel M, Zupan M, editors. Migrena 2023: zbornik poglavij strokovnega srecanja in ucbenik za zdravnike, zdravstvene delavce in študente Medicinske in Zdravstvene fakultete. Ljubljana: Društvo za preprecevanje možganskih in žilnih bolezni; 2023. p. 143–55. PRIPOROCILA ZA PREVENTIVNO ZDRAVLJENJE MIGRENE RECOMMENDATIONS FOR PREVENTIVE TREATMENT OF MIGRAINE Bojana Žvan POVZETEK Slovenska priporocila za preventivno zdravljenje migrene temeljijo pretežno na priporocilih Mednarodnega združenja za glavobol (IHS – International Headache Society) (1), kjer so upoštevane razpoložljive smernice za zdravljenje migrene in soglasja strokovnjakov. V tabeli 1 so navedena vsa zdravila, ki jih uporabljamo za preventivno zdravljenje migrene (2, 3). V smernicah bomo podali priporocila na osnovi klinicnih vprašanj od 1–16: 1) Katere osebe z migreno so kandidati za preventivno farmakološko zdravljenje? 9 Štiri ali vec mesecnih dni glavobola; 9 Migrena vpliva na osebno, družbeno in poklicno življenje; 9 Optimizirano akutno zdravljenje migrene je neucinkovito; 9 Pogosta uporaba akutnih zdravil. 2) Kdaj naj se ucinkovitost preventivnega zdravljenja migrene ocenjuje? 9 Najmanj tri mesece za zdravila za injiciranje, ki se aplicirajo mesecno in najmanj šest mesecev za zdravila, ki se injicirajo cetrtletno. 3) Ali bi morali upoštevati alternativne možnosti zdravljenja, ce je zacetno zdravilo za preprecevanje migrene neucinkovito oziroma, ce ga bolniki ne prenašajo? 9 Priporocamo prehod na drug razred zdravil. 9 Pri posameznikih z vec neuspešnimi zdravljenji z zdravili, je možen prehod na razlicno preventivno zdravljenje v istem terapevtskem razredu ali prehod na zdravila, kot je npr. onabotulinumtoksin A, monoklonska protitelesa (mPt) proti CGRP in gepanti. 4) Ali je za preprecevanje migrene primerno uporabiti kombinirano zdravljenje z dvema zdraviloma, ce je zdravilo za preprecevanje migrene neucinkovito? 9 Kombinirano zdravljenje z dvema preventivnima zdraviloma pri osebah, ki nimajo dovolj koristi od nobene monoterapije ali, ce kombinacija dveh zdravil predstavlja prednost pri obvladovanju socasne bolezni. 9 Zdravila, ki ciljajo na CGRP in onabotulinumtoxinA imajo zelo malo ali so brez interakcij med zdravili, zato ga je enostavno kombinirati z oralnimi preventivnimi zdravili. 5) Kako dolgo naj bi nadaljevali s preventivnim zdravljenjem migrene, kadar je le to ucinkovito? 9 Vsaj šest mesecev za zdravila za peroralno uporabo; 9 Vsaj 12 mesecev za neoralno zdravljenje, preden razmislimo o prekinitvi; 9 Za osebe s kronicno migreno je treba upoštevati daljše obdobje zdravljenja. 9 Za prekinitev zdravljenja mora pacient imeti manj kot štirih mesecne migrenske dneve v obdobju treh zaporednih mesecev ali glede na bolnikovo zadovoljstvo z zmanjšanjem bremena bolezni. 6) Kakšna so merila za oceno preventivnega zdravljenja, ali je zdravljenje ucinkovito? 9 =50 % zmanjšanje števila mesecnih dni migrene ali dni z zmernim do hudim glavoboloma, ki temelji na uporabi dnevnika glavobola; 9 Klinicno pomembno subjektivno izboljšanje, glede na porocanje osebe z migreno; 9 Klinicno pomembno izboljšanje na osnovi rezultatov vprašalnikov MIDAS ali HIT-6; 9 Za osebe s kronicno migreno, ki niso dosegle =50-odstotnega zmanjšanja mesecnega števila dni migrene ali dni z zmernimi do hudimi glavoboli z vec preventivnimi zdravili (vkljucno s peroralnimi zdravili, onabotulinumtoksinom A in zdravili, ki ciljajo na CGRP), vendar z =30-odstotnim zmanjšanjem mesecnega števila dni migrene ali dni z zmernimi do hudimi glavoboli je sprejemljivo nadaljevanje zdravljenje po treh mesecih 7) Kakšna so merila za ponovni pricetek preventivnega zdravljenja pri osebah, ki so prekinile preventivno zdravljenje migrene po uspešnem obdobju? 9 Osebe naj pocakajo z zdravljenjem vsaj en mesec, preden razmislimo o ponovnem pricetku zdravljenja, ce še vedno izpolnjujejo merila za preprecevanje migrene; 9 Spremljanje frekvence glavobolov z dnevnikom glavobola ali mesecnim koledarjem tudi po prekinitvi zdravljenja. 8) Ali bi pri izbiri zdravila za preventivno zdravljenje migrene morali upoštevati prisotnost socasnih bolezni? 9 Prva možnost zdravljenja mora biti vedno specificno zdravilo za migreno. 9 Pri posameznikih z migreno in komorbidnimi stanji, je možna uporaba zdravil, ki koristijo tako za zdravljenje migrene kot socasnim komorbidnostim. To še posebej velja za oralno preventivo zdravljenje. 9) Katero preventivno zdravilo je priporocljivo za ljudi s kronicno migreno? 9 Atogepant, erenumab, eptinezumab, fremanezumab, galcanezumab, onabotulinumtoksin A in topiramat; 9 Opozoriti je treba, da se je topiramatu treba izogibati med nosecnostjo in pri ženskah v rodni dobi, ki ne uporabljajo ucinkovite kontracepcije. 10) Ce zdravljenje z monoklonskim protitelesom (mPt) prot CGRP ni ucinkovito, je koristna menjava z drugim mPt proti-CGRP? 9 Prehod na drugo proti-CGRP mPt pri osebah, ki nimajo druge terapevtske možnosti med drugimi preventivnimi zdravili proti migreni zaradi kontraindikacij oz težav s prenašanjem zdravila. 11) Katere so preventivne možnosti za osebe z migreno, ki se pozitivno odzivajo na mPt proti CGRP, vendar imajo še vedno klinicno pomembno rezidualno breme migrene? 9 Dodamo tradicionalno oralno preventivno zdravilo; 9 Ce ima oseba kronicno migreno, dodamo onabotulinumtoksinA. 12) Ali ima blokada velikega okcipitalnega živca mesto pri preprecevanju migrene? 9 Blokada z lokalnimi anestetiki in z ali brez kortikosteroidov, ima omejeno ucinkovitost glede na dokaze, lahko pa predstavlja možnost za preprecevanje migrene. 13) Katera zdravila za preprecevanje migrene predlagamo pri otrocih in mladostniki? 9 Zaviralci adrenergicnih receptorjev beta ali flunarizin v odmerkih prilagojenih telesni teži, ceprav so dokazi o ucinkovitosti omejeni; 9 V primeru neucinkovitosti so možne alternative nizki odmerki topiramata ali amitriptilin. 14) Katera zdravila za preprecevanje migrene se lahko uporablja med nosecnostjo in dojenjem? Nosecnost: 9 Nefarmakološko zdravljenje ali blokada perifernih živcev; 9 Ce je nefarmakološko zdravljenje neucinkovito, predlagamo propranolol ali amitriptilin, po uravnoteženju tveganj in koristi ter porocanje osebe o morebitnih sekundarnih ucinkih in povezanimi tveganji; 9 Propranolol je treba opustiti v zadnjem delu tretjega tromesecja v izogib tveganja za neželene dogodke za plod in novorojencka; 9 Za ženske s kronicno migreno priporocamo onabotulinumtoksinA, glede na omejene sistemske ucinke; 9 Priporocamo izogibanje valproatu in topiramatu zaradi teratogenih ucinkov; 9 Kandesartanu in lizinoprilu se je treba izogibati zaradi tveganja za poškodbe in malformacije ploda; Dojenje: 9 Prvi izbor preventivnega zdravljenja je nefarmakološko zdravljenje ali periferne živcne blokade; 9 Ce nefarmakološko zdravljenje ni ucinkovito, predlagamo propranolol ali amitriptilin ob obvestilu bolnice o možnih sekundarnih ucinkih in tveganjih, oz. onabotulinumtoksinA za osebe s kronicna migrena; 9 Kandesartan se lahko uporablja s previdnostjo. Lizinoprilu se je treba izogibati; 9 mPt proti CGRP, lahko uporabljamo previdno vsaj dva tedna po porodu. 15) Katera zdravila za preprecevanje migrene se lahko uporablja pri osebah z migreno starejših od 65 let? 9 Izberemo zdravilo glede na oceno komorbidnosti in prilagodimo odmerke za vsa zdravljenja. 9 Priporocamo skrbno klinicno spremljanje, ki omogoca zgodnje odkrivanje neželenih ucinkov, kot tudi morebitne potrebe po spremembi poteka zdravljenja. 9 Nekatera zdravila, ki zavirajo CGRP, pri populaciji starosti do 80 let niso pokazala varnostnih težav, zato lahko predstavljajo možnost preventivnega zdravljenja migrene. 9 Za ljudi s kronicno migreno lahko onabotulinumtoksinA predstavlja opcijo, ker nima sistemskega ucinka. 16) Kaj priporocamo osebam z migreno in cezmerno uporabo zdravil? 9 Zmanjšanje vnosa cezmerne uporabe zdravil socasno z zacetkom preventivnega zdravljenja; 9 Zmanjšanje vnosa cezmerne uporabe zdravil po zacetku preventivnega zdravljenja; 9 Prekinitev cezmerne uporabe zdravil, cemur sledi zacetek preventivnega zdravljenja. 9 Izbira preventivnega zdravljenja mora temeljiti na dokazih o terapevtski ucinkovitosti, glede na bolnikovo anamnezo in socasne bolezni. 9 Monoklonska protitelesa, usmerjena proti CGRP, topiramat in onabotulinumtoksinA so se izkazali za ucinkovite ne glede na prisotnost cezmerne uporabe zdravil. Zato pri osebah, ki uvajajo takšno zdravljenje, takojšnji umik ali zmanjšanje cezmerne uporabe zdravil morda ni potrebna. 9 Pri posameznikih, ki cezmerno uporabljajo opioide ali barbiturate, bo za varno in uspešno opustitev zdravil morda potrebna hospitalizacija. SKLEPI Cilj preventivnega zdravljenja migrene je dvigniti merila pri preprecevanju in obvladovanju migrene ter spodbudil klinike, ponudnike zdravstvenega varstva in bolnike, da si prizadevajo za najboljše možne rezultate s preventivnimi zdravljenji migrene. Ceprav se zmanjšanje števila dni z migreno ali glavobolov pogosto šteje za uspeh, je cilj nenehno izboljševanje, ki si prizadeva za idealne in ne le sprejemljive rezultate. Spodbuja premik k postavljanju ambicioznih ciljev v resnicni klinicni praksi doseci popolno prekinitev migrene. Ta pristop spodbuja nenehno ponovno ocenjevanje in inovacije v strategijah zdravljenja, s ciljem doseci najboljšo oskrbo in podporo. Kliniki se moramo zavezati, da moramo preseci sedanje konvencionalne cilje in preoblikovati obvladovanje migrene tako, da bodo bolniki pridobili ne le olajšanje, ampak tudi priložnost za bolj izpolnjujoce življenje brez migrene z možnostjo vpliva na družbo kot celoto (3). Kljucne besede: Mednarodno združenje za glavobole, migrena, priporocila, preventivno zdravljenje. Tabela 1. Zdravila, ki jih mednarodne smernice priporocajo za preventivno zdravljenje migrene (2023) (2) Vrsta zdravila Razpoložljiva formulacija in odmerek Priporocljiv odmerek Antiepileptiki Valprojska kislina* Oralna tekocina: 300 mg/ml; Tableta: 300 mg in 500 mg; Oralno 400–2000 mg /dan Topiramat* Oralno 25–200 mg /dan Lamotrigin Tableta: 25 mg, 50 mg, 100 mg, 200 mg; Tableta (žvecljiva, disperzibilna): 2 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg Oralno 25–200 mg /dan Beta-blokatorji Metoprolol Oralno 25–200 mg /dan Propranolol Tableta: 20 mg, 40 mg (hidroklorid) Oralno 120–240 mg /dan Atenolol Oralno 50–200 mg /dan Bisoprolol Tableta: 1.25 mg; 5 mg Oralno 5 mg /dan Nadolol Oralno 40–160 mg /dan Zaviralci angiotenzinskih receptorjev/zaviralci ACE Kandesartan Oralno 8–16 mg /dan, lahko do 32 mg Lisinopril Oralno 10–20 mg /dan Blokatorji kalcijevih kanalov Flunarizin V Sloveniji ni na voljo Oralno 5–10 mg /dan Antagonisti serotonina Pizotifen V Sloveniji ni na voljo Oralno 0,5–4,5 mg /dan Antidepresivi Amitriptilin Tableta: 10 mg, 25 mg – na voljo v Sloveniji Oralno 25–150 mg /dan Venlafaksin Oralno 37,5–300 mg /dan Monoklonska protitelesa proti CGRP Erenumab S.c. injekcija 70–140 mg mesecno Frenanezumab S.c. injekcija 225 mg mesecno S.c. injekcija 675 mg cetrtletno Galkanezumab S.c. injekcija 240 udarni odmerek, sledi 120 mg mesecno Eptinezumab I.v. infuzija 100–300 mg cetrtletno OnabotulinumtoxinA tramuskularna injekcija 155–195U cetrtletno Lokalni anestetiki Lidokain Injekcija 1 %; 2 % (hidroklorid) viala Lokalna i.m. injekcija 1–2 % Bupivakain Injekcija 0,25 %; 0,5 % (hidroklorid) viala Lokalna i.m. injekcija 0,5 % Steroidi Metilprednizolon Lokalna i.m. injekcija 40–80 mg Deksametazon I.v. ali i.m. injekcija 4–8 mg Gepanti Rimegepant Oralno (disperzibilna tableta) 75 mg vsak drugi dan Atogepant Oralno 10 mg, 30 mg 2x /dan; 60 mg /dan s.c. – subkutano; i.v. – intravensko, i.m. – intramuskularno *Po mnenju Evropske agencije za zdravila se je treba tem zdravilom izogibati med nosecnostjo in pri ženskah v rodni dobi, ki ne uporabljajo zelo ucinkovite kontracepcije. Slika 1. Algoritem za preventivno zdravljenje migrene GCZ – Glavobol zaradi cezmerne rabe zdravil; mPt – monoklonsko protitelo; CGRP – peptid povezan z genom za kalcitonin; tMS – transkranialna magnetna stimulacija; TENS – transkutana elektrostimulacija SUMMARY Slovenian recommendations for the preventive treatment of migraine are based mainly on the recommendations of the International Headache Society (IHS) (1), which take into account available migraine treatment guidelines and expert consensus. The guidelines will provide recommendations based on clinical questions from 1–16: 1) Which individuals with migraine are candidates for preventive pharmacologic treatment? 9 Four or more headache days per month; 9 Migraine has an impact on personal, social, and professional life; 9 Optimized acute migraine treatment is ineffective; 9 Frequent use of acute medications. 2) When should the effectiveness of a migraine preventive treatment be assessed? 9 Evaluation the effectiveness after three months at the target dose (minimum of three months for injectable drugs taken on a monthly basis, and a minimum of six months for injectable drugs administered quarterly). 3) If an initial migraine preventive drug is ineffective or not well tolerated, should alternative drug options be considered? 9 We suggest switching to a different class of medication. In individuals with multiple drug failures, further option may be switching to different preventive treatment in the same therapeutic class or to drugs such as onabotulinumtoxinA, monoclonal antibodies (mAbs) targeting CGRP and gepants, 4) If a migraine preventive drug is ineffective, is it appropriate to use a combination therapy with two migraine preventive drugs? 9 Combination therapy with two migraine preventive agents in individuals who do not have enough benefit from any single migraine preventive treatment, or if the combination of two agents represents an advantage on the management of comorbidities; 9 Drugs targeting the CGRP pathway and onabotulinumtoxinA have very low or absent drug-to-drug interactions and they can therefore be easily combined with oral preventive treatment. 5) How long should effective migraine prevention be continued? 9 For at least six months for oral drugs and 12 months for non-oral treatments before considering discontinuation. 9 For people with chronic migraine, longer treatment periods should be considered. 9 The decision to stop a migraine preventive drug should be based on having less than four monthly migraine days over a period of three consecutive months or based on the patient’s satisfaction with the reduction of disease burden achieved. 6) What are the success criteria to rate preventive therapy as effective? 9 A =50% decrease in monthly migraine days or moderate-to-severe headache days, optimally based on the use of a headache diary; 9 A clinically meaningful subjective improvement as reported by the subject; 9 A clinically meaningful improvement in MIDAS or HIT-6 questionnaire scores. 9 For subjects with chronic migraine who have not achieved a =50% decrease in monthly migraine days or moderate-to-severe headache days with multiple preventive options (including oral drugs, onabotulinumtoxina and drugs targeting the CGRP pathway) a =30% decrease in monthly migraine days or moderate-to-severe headache days is acceptable for treatment continuation beyond three months. 7) In individuals who have discontinued a migraine preventive after a successful period, what are the criteria for restarting preventive treatment? 9 We suggest waiting at least one month before considering restarting treatment, provided they still satisfy the criteria for prevention. 9 Monitoring of headache frequency with a headache diary or a monthly calendar is recommended after stopping a migraine preventive treatment. 8) Should the choice of migraine preventive drugs be determined by the presence of comorbidities? 9 The first treatment option should always be a migraine-specific drug; 9 In individuals with migraine and an ongoing comorbid condition, it is possible to use agents that can provide benefit on both the migraine and the existing comorbidity. This applies specifically to oral preventive treatments. 9) Which preventive medication is suggested for people with chronic migraine? 9 We suggest atogepant, erenumab, eptinezumab, fremanezumab, galcanezumab, onabotulinumtoxinA and topiramate for people with chronic migraine. 9 Topiramate should be avoided during pregnancy and in women of childbearing age who are not using highly effective contraception methods. 10) If a mAbs targeting the CGRP pathway is not effective, is it beneficial to switch to another anti-CGRP monoclonal antibody? 9 We suggest switching to another anti-CGRP mAb in individuals who have no other viable therapeutic options among other migraine preventive drug classes due to ineffectiveness, contraindications or tolerability issues. 11) What are the possible preventive options for people with migraine who have a positive response to a mAbs targeting the CGRP pathway, but still have a clinically meaningful residual migraine burden? 9 We suggest adding a traditional oral preventive drug or, if the person has chronic migraine, onabotulinumtoxinA. 12) Do greater occipital nerve blocks have a place in migraine prevention? 9 Greater occipital nerve blocks with local anesthetics, with or without corticosteroids, have limited evidence of efficacy, but may represent an option for migraine prevention; 9 They can be used in pregnant women. 13) What are the suggested drugs for migraine prevention in children and adolescents? 9 Beta-blockers or flunarizine, at doses adapted to body weight, can be used, although evidence of efficacy is very limited; 9 In case of ineffectiveness, low dose topiramate or amitriptyline represent possible alternatives. 14) Which migraine preventive drugs can be used during pregnancy and lactation? Pregnancy: 9 We suggest non-pharmacologic treatments or peripheral nerve blocks as first line options in pregnant or breastfeeding women; 9 If non-pharmacological treatment is not possible or effective, we suggest propranolol or amitriptyline, after balancing risks and benefits and informing the person on potential secondary effects and associated risks. Propranolol should be discontinued in the last part of the third trimester to avoid the risk of adverse events to the fetus and neonate; 9 For women with chronic migraine, onabotulinumtoxinA, may represent an option after balancing risks and benefits given the limited systemic effects; 9 We strongly recommend avoiding valproate and topiramate during pregnancy due to their teratogenic effects; 9 Similarly, candesartan and lisinopril should be avoided during pregnancy because of the risk of harm and malformation to the fetus. Breastfeeding: 9 Non pharmacologic treatment or peripheral nerve blocks should be considered first line; 9 If non-pharmacologic treatment is not possible or effective, we suggest propranolol or amitriptyline, after informing the individuals of the potential secondary effects and associated risks, or onabotulinumtoxinA for people with chronic migraine; 9 Candesartan can be used with caution. Lisinopril should be avoided; 9 mAbs targeting CGRP can be used with caution after at least two weeks postpartum. 15) Which migraine preventive drugs can be used in people with migraine over 65 years of age? 9 We suggest selecting the drug after considering possible comorbidities and the needs of dose adjustments, for all treatments; 9 We suggest careful clinical monitoring to allow for early detection of adverse effects, as well as the potential need to modify the course of treatment; 9 Some drugs targeting the CGRP pathway have been tested in populations up to 80 years old without safety issues and can therefore represent an option; 9 For people with chronic migraine, onabotulinumtoxinA may represent an option given the limited, if any, systemic effect. 16) What is the recommended approach to people with migraine and medication overuse? 9 Reduced intake of overused drug(s) simultaneous with the initiation of preventive treatment; 9 Reduced intake of overused drug(s) followed by initiation of preventive treatment; 9 Interruption of overused drug(s) followed by initiation of preventive treatment. 9 The selection of the preventive treatment must be based on evidence of therapeutic efficacy, patient history and comorbidities. 9 mAbs targeting the CGRP pathway, topiramate and onabotulinumtoxinA have proven effective regardless of the presence of medication overuse, therefore the immediate withdrawal or reduction of the overused drug might not be necessary in subjects who are initiating such a treatment. 9 Individuals overusing opioids or barbiturate containing drugs may require hospitalization to manage drug discontinuation safely and successfully. CONCLUSIONS The goal of preventive migraine treatment is to raise the bar in migraine prevention and management and to encourage clinicians, healthcare providers, and patients to strive for the best possible outcomes with preventive migraine treatments. Although a reduction in the number of migraine days or headaches is often considered success, the goal is continuous improvement, striving for ideal rather than just acceptable outcomes. It encourages a shift towards setting ambitious goals in real-world clinical practice to achieve complete cessation of migraine. This approach encourages ongoing reassessment and innovation in treatment strategies, with the goal of achieving the best possible care and support. As clinicians, we must commit to going beyond current conventional goals and transforming migraine management so that patients gain not only relief but also the opportunity for a more fulfilling migraine-free life with the potential to impact society as a whole (3). Keywords: International Headache Society, migraine, preventative treatments, recommendations. Table 1. Drugs recommended for the preventive treatment of migraine by international guidelines, (2023) (2) Drug type Available formulation and dose Recommended formulation and dose Antiepileptics Valproic acid* Oral liquid: 300 mg/ml; Tablet: 300 mg and 500 mg Oral 400–2000 mg /day Topiramate* Oral 25–200 mg /day Lamotrigine Tablet: 25 mg, 50 mg, 100 mg, 200 mg; Tablet (chewable, dispersible): 2 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg Oral 25–200 mg /day Beta-blockers Metoprolol Oral 25–200 mg /day Propranolol Tablet: 20 mg, 40 mg (hydrochloride) Oral 120–240 mg /day Atenolol Oral 50–200 mg /day Bisoprolol Tablet: 1.25 mg; 5 mg Oral 5 mg /day Nadolol Oral 40–160 mg /day Angiotensin Receptor Blockers/ACE inhibitors Candesartan Oral 8–16 mg /day Lisinopril Oral 10–20 mg /day Calcium Channel Blockers Flunarizine Not available in Slovenia Oral 5–10 mg /day Serotonin antagonists Pizotifen Not available in Slovenia Oral 0,5–4,5 mg /day Antidepressants Amitriptyline Tablet: 10 mg, 25 mg Oral 25–150 mg /day Venlafaxine Oral 37.5–300 mg /day Monoclonal antibodies anti-CGRP pathway Erenumab S.c. injection 70–140 mg /month Frenanezumab S.c. injection 225 mg /month S.c. injection 675 mg quarterly Galkanezumab S.c. injection 240 loading dose, followed by 120 mg /month Eptinezumab I.v. infusion 100–300 mg quarterly OnabotulinumtoxinA tramuskularna injection 155–195U quarterly Local anesthetics Lidocaine Injection 1%; 2% (hydrochloride) in vial Local i.m. injection 1–2% Bupivakain Injection 0.25%; 0.5% (hydrohloride) in vial Local i.m. injection 0.5% Steroids Methylprednisolone Local i.m. injection 40–80 mg Dexamethasone I.v. ali i.m. injection 4–8 mg Gepants Rimegepant Oral (dispersible tablet) 75 mg every other day Atogepant Oral 10mg, 30 mg 2x /day; 60 mg /day s.c. – subcutaneously; i.v. – intravenously, i.m. – intramuscularly *According to the European Medicines Agency these drugs must be avoided during pregnancy and in women of childbearing age who are not using highly effective contraception. Picture 1. Algorithm for preventive treatment of migraine MOH – Medication overuse headache; mAb – monoclonal antibody; CGRP – calcitonin gene-related peptide; tMS – transcranial magnetic stimulation; TENS – transcutaneous electrostimulation LITERATURA / LITERATURE 1. Puledda F, Sacco S, Diener H-C, et al. International Headache Society Global Practice Recommendations for Preventive Pharmacological Treatment of Migraine. Cephalalgia. 2024 Sept; 44(9): 3331024241269735. 2. World Health Organization. World Health Organization Model List of Essential Medicines 2023 [cited 2025, Februar 21]. Available at: https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2023.02. 3. Sacco S, Ashina M, Diener H-C, et al. Setting higher standards for migraine prevention: A position statement of the International Headache Society. Cephalalgia. 2025; 45(2): 1–11. PRIPOROCILA ZA PREPRECEVANJE MIGRENE Z NEFARMAKOLOŠKIMI METODAMI RECOMMENDATIONS FOR MIGRAINE PREVENTION WITH NONPHARMACOLOGICAL METHODS Gorazd Požlep POVZETEK Migrenski glavoboli so ena najpogostejših zdravstvenih težav, ki vplivajo na kakovost življenja posameznikov. Farmakološki pristopi k preprecevanju migren so kljucni za zmanjševanje pogostosti in intenzivnosti težav. Enako pomembne pa so tudi nefarmakološke metode, vkljucno s prehranskimi prilagoditvami, telesno dejavnostjo, obvladovanjem stresa, tehnikami sprošcanja ter nevromodulacijskimi metodami, kot so blokade zatilnih živcev, blokade izstopišc trigeminusa, transkranialna stimulacija z enosmernim tokom (tDCS), transkranialna magnetna stimulacija (TMS) in transkutana elektricna stimulacija živcev (TENS). Kljucne besede: migrena, nefarmakološke metode preprecevanja. UVOD Glavoboli, vkljucno z migrenami in tenzijskimi glavoboli, prizadenejo milijone ljudi po vsem svetu (2). Medtem ko je farmakološka terapija pogosto prva izbira pri zdravljenju, vse vec raziskav potrjuje pomen nefarmakoloških metod za preprecevanje in obvladovanje glavobolov. NEFARMAKOLOŠKE METODE 1) Prehranske prilagoditve: identifikacija in izogibanje sprožilcem, kot so kofein, alkohol in predelani sladkorji (3). Redno in uravnoteženo prehranjevanje za ohranjanje stabilne ravni krvnega sladkorja. Dodatki, kot so magnezij, riboflavin (vitamin B2) in koencim Q10, so dokazano koristni pri zmanjševanju pogostosti glavobolov (3). 2) Telesna dejavnost: redna vadba, kot so joga, pilates in aerobna vadba, pomaga zmanjšati napetost in izboljšati prekrvavitev (2). Vadba povecuje raven endorfinov, naravnih analgetikov v telesu. 3) Obvladovanje stresa: tehnike, kot so meditacija, kognitivno-vedenjska terapija in biofeedback, dokazano zmanjšujejo stres, ki je pogosto povezan s pojavom glavobolov – Ohranjanje zdravega spanca in ucinkovito upravljanje casa sta kljucna dejavnika pri preprecevanju stresno povzrocenih glavobolov. 4) Tehnike sprošcanja: progresivna mišicna sprostitev in dihalne vaje pomagajo zmanjšati mišicno napetost. Akupunktura in masažna terapija lahko prispevata k zmanjšanju pogostosti in intenzivnosti glavobolov (1). 5) Nevromodulacijske metode: blokade zatilnih živcev in izstopišc trigeminusa: te invazivne, a ucinkovite metode vkljucujejo uporabo lokalnih anestetikov ali steroidov za zacasno prekinitev prenosa bolecinskih signalov, kar lahko zmanjša intenzivnost in pogostost glavobolov. Transkranialna stimulacija z enosmernim tokom (tDCS): metoda, ki vkljucuje uporabo blagega elektricnega toka na dolocenih podrocjih možganov, kar lahko modulira nevronalno aktivnost in zmanjša pojavnost glavobolov (4). Transkranialna magnetna stimulacija (TMS): Uporaba magnetnih pulzov za stimulacijo možganskih predelov, povezanih z bolecino, je pokazala obetavne rezultate pri zmanjševanju migren in drugih vrst glavobolov (4). Transkutana elektricna stimulacija živcev (TENS): tehnika, ki vkljucuje aplikacijo nizkofrekvencnih elektricnih impulzov preko kože za lajšanje bolecine in zmanjšanje napetosti mišic, je ucinkovita pri obvladovanju kronicnih glavobolov (5). Botulinum toksin za preprecevanje migrenskih glavobolov deluje tako, da sprošca mišice in zavira sprošcanje dolocenih nevrotransmiterjev, ki sodelujejo pri zaznavanju bolecine. Uporablja se pri kronicni migreni, kar pomeni, da oseba doživlja glavobole vsaj 15 dni na mesec, od tega je vsaj 8 migren (6). Akupunktura: je enako ucinkovita metoda za preprecevanje migren, kot nespecificna zdravila za njeno preprecevanje (7). ZAKLJUCEK Nefarmakološke metode so pomembne pri celostnem, biopsihosocialnem pristopu k preprecevanju glavobolov. Kombinacija zdrave prehrane, redne telesne dejavnosti, obvladovanja stresa, tehnik sprošcanja in nevromodulacijskih metod lahko bistveno prispeva k zmanjšanju pojava glavobolov in izboljšanju kakovosti življenja. SUMMARY Headaches are one of the most common health issues affecting quality of life. Non-pharmacological approaches, such as dietary adjustments, physical activity, stress management, and relaxation techniques, are essential for reducing the frequency and intensity of headaches. Neuromodulation methods, including occipital nerve blocks, trigeminal nerve exit point blocks, transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), and transcutaneous electrical nerve stimulation (TENS), are also important. Keywords: migraine, non-pharmacological therapy. INTRODUCTION Headaches, including migraines and tension-type headaches, affect millions of people worldwide (2). While pharmacological therapy is often the first choice of treatment, an increasing number of studies confirm the importance of non-pharmacological methods for the prevention and management of headaches. NON-PHARMACOLOGICAL METHODS 1) Dietary Adjustments: Identifying and avoiding triggers such as caffeine, alcohol, and processed sugars (3). Maintaining regular and balanced meals to stabilize blood sugar levels. Supplements such as magnesium, riboflavin (vitamin B2), and coenzyme Q10 have been proven beneficial in reducing headache frequency (3). 2) Physical Activity: Regular exercise, such as yoga, Pilates, and aerobic workouts, helps reduce tension and improve circulation (2). Exercise increases endorphin levels, the body’s natural painkillers. 3) Stress Management: Techniques such as meditation, cognitive-behavioral therapy, and biofeedback have been proven to reduce stress, which is often associated with headache occurrence. Maintaining healthy sleep habits and effective time management are key factors in preventing stress-induced headaches. 4) Relaxation Techniques: Progressive muscle relaxation and breathing exercises help reduce muscle tension. Acupuncture and massage therapy can contribute to reducing the frequency and intensity of headaches (1). 5) Neuromodulation Methods: Occipital and trigeminal nerve blocks: These invasive but effective methods involve the use of local anesthetics or steroids to temporarily interrupt the transmission of pain signals, which can reduce the intensity and frequency of headaches. Transcranial Direct Current Stimulation (tDCS): A method that involves applying a mild electrical current to specific areas of the brain, which can modulate neuronal activity and reduce headache occurrence (4). Transcranial Magnetic Stimulation (TMS): The use of magnetic pulses to stimulate brain areas associated with pain has shown promising results in reducing migraines and other types of headaches (4). Transcutaneous Electrical Nerve Stimulation (TENS): A technique that involves applying low-frequency electrical impulses through the skin to relieve pain and reduce muscle tension, proving effective in managing chronic headaches (5). Botulinum Toxin: Used for the prevention of migraine headaches by relaxing muscles and inhibiting the release of certain neurotransmitters involved in pain perception. It is used in cases of chronic migraine, meaning the individual experiences headaches at least 15 days per month, with at least 8 being migraines (6). Acupuncture: Shown to be as effective as nonspecific pharmacological treatments for migraine prevention (7). CONCLUSION Non-pharmacological methods play an important role in a comprehensive biopsychosocial approach to headache prevention. A combination of healthy nutrition, regular physical activity, stress management, relaxation techniques, and neuromodulation methods can significantly contribute to reducing headache occurrence and improving quality of life. LITERATURA / LITERATURE 1. Diener HC, Holle D. Non-pharmacological treatment options for headache: An overview. Journal of Headache and Pain. 2019; 20(1): 1–10. 2. Bendtsen L, Evers S, Linde M, et al; EFNS. EFNS guideline on the treatment of tension-type headache - report of an EFNS task force. Eur J Neurol. 2010 Nov; 17(11): 1318–25. 3. Sun-Edelstein C, Mauskop A. Role of magnesium in the pathogenesis and treatment of migraine. Expert Rev Neurother. 2009 Mar; 9(3): 369–79. 4. Lefaucheur, J. P. Aleman A, Baeken C, et al. Transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) in neurology. Clinical Neurophysiology. 2020; 131(1): 219–39. 5. Johnson M. Transcutaneous electrical nerve stimulation: mechanisms, clinical application and evidence. Rev Pain. 2007 Aug; 1(1): 7–11. 6. Escher CM, Paracka L, Dressler D, et al. Botulinum toxin in the management of chronic migraine: clinical evidence and experience. Ther Adv Neurol Disord. 2017 Feb; 10(2): 127–35. 7. Yang CP, Wu M, Luoet Q, et al. Acupuncture for migraine prophylaxis: A systematic review and meta-analysis. J Pain Research. 2021; 14: 453–67. MIGRENA KOT DEJAVNIK TVEGANJA ZA SRCNO-ŽILNE BOLEZNI MIGRAINE AS A RISK FACTOR FOR CARDIOVASCULAR DISEASE Albina Licina POVZETEK Migrena je pogosto obravnavana kot primarna nevrološka motnja, za katero so znacilni ponavljajoci se napadi glavobola, pogosto spremljani s slabostjo, bruhanjem in preobcutljivostjo na svetlobo ali zvok. Vedno vec raziskav kaže, da migrena ni zgolj nevrološko stanje, temvec kompleksna motnja z vplivi na srcno-žilni in možganski sistem (1, 2). Migrena je pomemben dejavnik tveganja za vecino srcno-žilnih bolezni. Študija, objavljena v The BMJ leta 2018, je raziskovala to povezavo z analizo zdravstvenih podatkov bolnikov z migreno in posameznikov iz splošne populacije, ki so bili ujemajoci po starosti, spolu in koledarskem letu. V obdobju 19-letnega spremljanja so raziskovalci ugotovili, da imajo bolniki z migreno povecano tveganje za vec srcno-žilnih dogodkov v primerjavi s splošno populacijo. Relativna tveganja so bila povecana za miokardni infarkt (1,5-krat vecje tveganje), ishemicno možgansko kap (2,3-krat vecje tveganje), hemoragicno možgansko kap (1,9-krat vecje tveganje), vensko trombembolijo (1,6-krat vecje tveganje) in atrijsko fibrilacijo ali atrijski flutter (1,3-krat vecje tveganje) (1). Migrena z avro je še posebej mocan dejavnik tveganja za ishemicno možgansko kap, pri cemer so izpostavljene predvsem mlajše ženske, ki uporabljajo hormonsko kontracepcijo. Mehanizmi, ki pojasnjujejo to povezavo, vkljucujejo zacasne motnje možganske perfuzije, povecano agregacijo trombocitov in prisotnost mikroembolizmov. Pri bolnikih z migreno pogosto opažene bele lezije v možganih, kar kaže na kronicno poškodbo možganskega tkiva. Vec študij je pokazalo, da imajo bolniki z migreno z avro približno dvakrat vecje tveganje za ishemicno možgansko kap v primerjavi s tistimi brez migrene ali z migreno brez avre (2). Vloga medicinske sestre pri obvladovanju srcno-žilnih tveganj pri bolnikih z migreno Medicinske sestre igrajo kljucno vlogo pri celostni obravnavi bolnikov z migreno, saj sodelujejo pri izobraževanju, spremljanju simptomov ter spodbujanju zdravega življenjskega sloga za zmanjšanje tveganja za srcno-žilne in možganske zaplete. Poleg zdravljenja migrene je pomembno, da se osredotocimo tudi na preventivne ukrepe za zmanjšanje tveganja za srcno-žilne bolezni pri bolnikih z migreno. Medicinske sestre lahko pri bolnikih z migreno zgodaj odkrijejo simptome, ki bi nakazovali na tveganje za srcno-žilne bolezni (povišan krvni tlak, debelost, kajenje, povišan holesterol). Aktivno spremljajo napredek bolnikov in jih spodbujajo k rednemu obvladovanju tveganj za srcno-žilne bolezni, kot so uravnotežena prehrana, redna telesna aktivnost in obvladovanje stresa (2, 3). Kljucne besede: migrena, migrena z avro, možganska kap, srcno-žilne bolezni, vloga medicinske sestre. SUMMARY Migraine is often regarded as a primary neurological disorder characterized by recurrent headache attacks, often accompanied by nausea, vomiting, and hypersensitivity to light or sound. Increasing research suggests that migraine is not merely a neurological condition, but a complex disorder with impacts on the cardiovascular and brain systems (1, 2). Migraine is an important risk factor for various cardiovascular diseases. A study published in The BMJ in 2018 explored this connection by analyzing health data from patients with migraine and individuals from the general population, matched for age, sex, and calendar year. Over a 19-year follow-up period, researchers found that patients with migraine had an increased risk of several cardiovascular events compared to the general population. The relative risks were increased for myocardial infarction (1.5 times higher risk), ischemic stroke (2.3 times higher risk), hemorrhagic stroke (1.9 times higher risk), venous thromboembolism (1.6 times higher risk), and atrial fibrillation or flutter (1.3 times higher risk) (1). Migraine with aura is particularly a strong risk factor for ischemic stroke, especially in younger women using hormonal contraception. Mechanisms explaining this connection include temporary disturbances in cerebral perfusion, increased platelet aggregation, and the presence of microembolisms. In patients with migraine, white matter lesions in the brain are often observed, indicating chronic damage to brain tissue. Several studies have shown that patients with migraine with aura have approximately twice the risk of ischemic stroke compared to those without migraine or those with migraine without aura (2). The Role of Nurses in Managing Cardiovascular Risks in Patients with Migraine Nurses play a key role in the holistic management of patients with migraine, as they are involved in education, symptom monitoring, and promoting a healthy lifestyle to reduce the risk of cardiovascular and cerebrovascular complications. In addition to treating migraines, it is important to focus on preventive measures to reduce the risk of cardiovascular diseases in patients with migraines. Nurses can early identify symptoms in migraine patients that may indicate a risk for cardiovascular diseases (elevated blood pressure, obesity, smoking, high cholesterol). They actively monitor patients’ progress and encourage regular management of cardiovascular risk factors, such as a balanced diet, regular physical activity, and stress management (2, 3). Keywords: cardiovascular diseases, migraine, migraine with aura, role of nurses, stroke. LITERATURA / LITERATURE 1. Adelborg K, Szépligeti S, Holland-Bill L, et al. Migraine and risk of cardiovascular diseases: Danish population based matched cohort study. BMJ. 2018; 360: k96. 2. Sacco S, Kurth T. Migraine and the risk for stroke and cardiovascular disease. Curr Cardiol Rep. 2014; 16(9): 524. 3. Veenstra P, Kollen BJ, de Jong G, et al. Nurses improve migraine management in primary care. Cephalalgia. 2016; 36(8): 772–8. VLOGA FIZIOTERAPEVTA IN PRI OBRAVNAVI BOLNIKA Z MIGRENO – IZKUŠNJE IZ TUJINE THE ROLE OF PHYSIOTHERAPISTS IN THE TREATMENT OF PATIENTS WITH MIGRAINE - EXPERIENCES FROM ABROAD Dragan Naric POVZETEK Uvod Migrena je pogosto razširjena med delovno in najbolj produktivno populacijo, kar posledicno manifestira slabšo ucinkovitost na delovnem mestu ali odsotnost z njega in zmanjšano participacijo pri aktivnostih v družbenem in domacem okolju. Pomembnost multidisciplinarnega pristopa k bolniku z migreno prinaša boljše rezultate in bolj zadovoljne bolnike, kar govorijo prakse iz tujine. Bolnik je na ta nacin aktivno udeležen pri reševanju svoje bolezni, ter istocasno podprt s tudi s strani medikamentozne terapije. Izvajanje fizioterapije v obliki aerobne vadbe znatno zmanjšuje število dni migrene s povprecnim zmanjšanjem 0,6 ± 0,3 migrene/mesec. Razen na sposobnost za delo, migrena pomembno vpliva tako na družbeno, kot tudi na telesno aktivnost bolnikov. Ti se lahko odzivajo na dva nacina, bodisi z izogibanjem aktivnosti bodisi z vztrajanjem pri njej kljub bolecini, ki je prisotna. Pomembna vidika migrene, sta tudi njen morebiten vpliv na zmanjšano zmožnost bolnika pri dnevnem funkcioniranju in pojav anksioznosti ter depresije. Predstavljam dve najbolj ucinkoviti aerobni vadbi. Hitra hoja in Amitriptylin 24 oseb je 12 tednov izvajalo hitro hojo 3x/teden po 40 min ob jemanju Amitryptilina 25 mg/dnevno. Intenzivnost vadbe so ocenjevali s srcno frekvenco in Borgovo lestvico. Kontrolna skupina je bila 26 oseb, ki je jemala samo Amitryptilin 25 mg/dan. Število migrenskih dni se je zmanjšalo za 78 %, kar nakazuje na dobro ucinkovitost hitre hoje ob uporabi antidepresiva Amitryptilina. Obstajajo pa tudi dokazi nizke kakovosti, da hitra hoja z uporabo Amitryptilina zmanjša trajanje napada in intenzivnost bolecine. Visoko-intenzivni intervalni trening in zmerna kontinuirana aerobna vadba 30 oseb je bilo razdeljeno v dve skupini po 15. Obe interventni skupini sta izvajale aerobni trening 12 tednov po 2x/teden. Prva interventna skupina je izvajala visoko intenzivni intervalni trening (angl. HIT) 4 minute do srcne frekvence 90% in 3 minute pocitka oziroma do srcne frekvence 70%, to so ponovili 4x. Druga interventna skupina je izvajala zmerno kontinuirano aerobno vadbo (angl. MCT) 45 min s submaksimalno srcno frekvenco 70%. Kontrolna skupina je bila 15 oseb, ki so ohranjali dnevno aktivnost po splošnih priporocilih. Za dolocanje napora so pri HIT upoštevali srcno frekvenco med 90-95 %, pri MCT pa 70 %. Pri visoko intenzivnem intervalnem treningu je prišlo do zmanjšanja migrenskih dni za 63 %, pri zmerni kontinuirani aerobni vadbi pa za 29 %, kar nakazuje na zmerno do dobro izboljšanje števila migrenskih dni. Pri teh dveh interventnih skupinah ni bilo zabeleženih nobenih stranskih ucinkov. Razprava Na podlagi rezultatov obstaja zmerno število dokazov, da aerobna vadba zmanjšuje število migrenskih dni. Poleg tega pa obstajajo dokazi nizke kakovosti, da aerobna vadba zmanjša trajanje napada in intenzivnost bolecine. Zdi se, da je vecji obseg vadbe, kot je visoko intenziven trening ali daljše trajanje vadbe, povezan z vecjim zmanjšanjem števila migrenskih dni v intervencijski skupini. Na tem podrocju ne obstaja veliko klinicnih raziskav in se priporoca nadaljnje raziskovanje. Vprašanje, ki se pojavlja je kako bi samo hitra hoja, brez uporabe Amitryptilina, vplivala na število migrenskih dni in ali obstaja možnost za dokazovanje ali aerobna vadba vpliva na zmanjševanje intenzivnosti in trajanja napada. Kljucne besede: Amitryptilin, fizioterpija, migrena. SUMMARY Introduction Migraine is widespread among the working and most productive population, which consequently leads to reduced efficiency at work, absence from work, and decreased participation in social and home activities. The importance of a multidisciplinary approach to migraine patients results in better outcomes and more satisfied patients, as evidenced by practices abroad. This approach allows patients to be actively involved in addressing their condition while also being supported by pharmacological therapy. Physiotherapy, in the form of aerobic exercise, significantly reduces the number of migraine days, with an average reduction of 0.6 ± 0.3 migraines/month. In addition to work capacity, migraines have a significant impact on both social and physical activity of patients. They may respond in two ways: either by avoiding activity or by persisting with it despite the pain. Two important aspects of migraines are their potential impact on daily functioning and the occurrence of anxiety and depression. The two most effective aerobic exercises are presented. Brisk Walking and Amitriptyline 24 individuals engaged in brisk walking three times a week for 40 minutes over a 12-week period while taking Amitriptyline 25 mg/day. Exercise intensity was assessed using heart rate and the Borg scale. The control group consisted of 26 individuals taking only Amitriptyline 25 mg/day. The number of migraine days decreased by 78%, indicating the good effectiveness of brisk walking combined with the antidepressant Amitriptyline. There is also low-quality evidence suggesting that brisk walking, in conjunction with Amitriptyline, reduces the duration of attacks and pain intensity. High-Intensity Interval Training and Moderate Continuous Aerobic Exercise 30 individuals were divided into two groups of 15. Both intervention groups engaged in aerobic training for 12 weeks, twice a week. The first intervention group performed high-intensity interval training (HIIT) for 4 minutes at 90% heart rate, followed by 3 minutes of rest or 70% heart rate, repeated four times. The second group performed moderate continuous aerobic exercise (MCT) for 45 minutes at a submaximal heart rate of 70%. The control group consisted of 15 individuals who maintained daily activity according to general recommendations. For effort measurement, the HIIT group aimed for a heart rate of 90-95%, and the MCT group aimed for 70%. The high-intensity interval training group showed a 63% reduction in migraine days, while the moderate continuous aerobic exercise group showed a 29% reduction, indicating a moderate to good improvement in the number of migraine days. No side effects were reported in either intervention group. Discussion Based on the results, there is moderate evidence that aerobic exercise reduces the number of migraine days. Additionally, low-quality evidence suggests that aerobic exercise reduces the duration of attacks and pain intensity. It appears that a larger volume of exercise, such as high-intensity training or longer exercise duration, is associated with a greater reduction in the number of migraine days in the intervention group. There is a lack of clinical research in this field, and further investigation is recommended. A question that arises is how brisk walking alone, without Amitriptyline, would impact the number of migraine days and whether there is potential to demonstrate if aerobic exercise affects the reduction of attack intensity and duration. Keywords: Amitriptyline, migraine, physiotherapy. LITERATURA / LITERATURE 1. Hanssen H, Minghetti A, Magon S, et al. Effects of different endurance exercise modalities on migraine days and cerebrovascular health in episodic migraineurs: A randomized controlled trial. Scand J Med Sci Sports. 2018 Mar; 28(3): 1103–12. 2. Lemmens J, Joke DP, Timia VS, et al. The effect of aerobic exercise on the number of migraine days, duration and pain intensity in migraine: a systematic literature review and meta-analysis. J Headache Pain. 2019; 20(1): 16. 3. Ruscheweyh R, Pereira D, Hasenbring MI, Straube A. Pain-related avoidance and endurance behaviour in migraine: an observational study. J Headache Pain. 2019 Jan 18;20(1): 9. 4. Santiago MD, Carvalho Dde S, Gabbai AA, et al. Amitriptyline and aerobic exercise or amitriptyline alone in the treatment of chronic migraine: a randomized comparative study. Arq Neuropsiquiatr. 2014 Nov; 72(11): 851–5. AKUPUNKTURA ZA LAJŠANJE MIGRENE ACUPUNCTURE AS A TREATMENT FOR MIGRAINE Ana Golež POVZETEK Migrena je zelo razširjena bolezen, pomemben vir invalidnosti in slabše produktivnosti po vsem svetu (1, 2). Najpogosteje na nastanek migrene vplivajo custveni stres, menstruacija, izpušcanje obrokov, vremenske spremembe, motnje spanja, pitje alkohola, kajenje, mocna svetloba, utripajoci zasloni, povišana telesna temperatura, dolocena hrana, prehranski dodatki in pretirana telesna aktivnost (1, 2). Ker se akupunktura pogosto uporablja kot možnost lajšanja migrene, so avtorji vec clankov, tudi sistematicnih pregledov, raziskovali njeno ucinkovitost in varnost (1, 2). S pomocjo podatkovnih baz MEDLINE, Cochrane Library in UpToDate ter casovnice od prvih objavljenih virov do februarja 2025 je bilo možno najti skupno 473 clankov in v nadaljevanju so predstavljeni rezultati nekaterih. Li YX in soavtorji so na podlagi dobljenih rezultatov zakljucili, da je akupunktura lahko ucinkovita ter varna terapija migrene; vendar bi bilo potrebnih še vec kakovostnih sistematicnih pregledov (1). Xu S in soavtorji so porocali, da je bilo dvajset akupunkturnih obravnav boljših od navidezne akupunkture ali zdravil za epizodno migreno brez avre, zato ti rezultati podpirajo uporabo akupunkture pri osebah, ki neradi prejemajo zdravila ali so ta neucinkovita, kar bi bilo potrebno upoštevati v prihodnjih smernicah (2). Zhao L in soavtorji so zapisali, da je akupunktura pri osebah z migreno brez avre lahko vodi do dolgorocnega zmanjšanja ponovitev v primerjavi z navidezno akupunkturo ali le cakanja na akupunkturo (3). Celovit pristop, ki vkljucuje tudi akupunkturo, verjetno daje najboljše rezultate. Opraviti bi bilo potrebno vec kakovostnih raziskav, da bi lahko zanesljiveje ocenili ucinkovitost akupunkture pri migreni. Kljucne besede: akupunktura, migrena, nefarmakološki pristopi, zdravila. SUMMARY Migraine is a highly prevalent disease, a significant source of disability and lost of productivity all over the world (1, 2). Most often, beginning of migraine is affected by emotional stress, menstruation, skipping meals, weather changes, sleep disturbances, alcohol intake, smoking, bright light, flickering screens, fever, certain food, nutritional supplements and excessive physical activity (1, 2). As acupuncture is widely used as a treatment option for migraine, authors of several articles and systematic reviews have investigated its effectiveness and safety (1, 2). MEDLINE, Cochrane Library and UpToDate database and articles from inception to February 2025 were chosen. A total amount of 473 articles were found and here are results of some. Li YX and coauthors concluded, that based on reported results it seems that acupuncture may be an effective and safe therapy for migraine; however the quality of systematic reviews in acupuncture for migraine still needs more improvement (1). Xu S and coauthors reported, that twenty sessions of manual acupuncture were superior to sham acupuncture and usual care for the prophylaxis of episodic migraine without aura, so these results support the use of manual acupuncture in patients who are reluctant to use prophylactic drugs or when prophylactic drugs are ineffective, and it should be considered in future guidelines (2). Zhao L with coauthors wrote, that among patients with migraine without aura, true acupuncture may be associated with long-term reduction in migraine recurrence compared with sham acupuncture or assigned to a waiting list (3). A comprehensive approach, also including acupuncture, probably povides the best results. More qualitive research must be done to evaluate the efficacy of acupuncture for migraine. Keywords: acupuncture, medications, migraine, non-pharmacological approaches. LITERATURA / LITERATURE 1. Li YX, et al. Effectiveness and Safety of Acupuncture for Migraine: An Overview of Systematic Reviews. Pain Res Manag. 2020 Mar 23;2020:3825617. doi: 10.1155/2020/3825617. PMID: 32269669; PMCID: PMC7125485. 2. Xu S, et al. Manual acupuncture versus sham acupuncture and usual care for prophylaxis of episodic migraine without aura: multicentre, randomised clinical trial. BMJ. 2020 Mar 25;368:m697. doi: 10.1136/bmj.m697. PMID: 32213509; PMCID: PMC7249245. 3. Zhao L, et al. The Long-term Effect of Acupuncture for Migraine Prophylaxis. A Randomized Clinical Trial. JAMA Intern Med. 2017;177(4):508-15. doi:10.1001/jamainternmed.2016.9378 SEZNAM SODELUJOCIH DRUŽB AbbVie Biofarmacevtska družba d. o. o. Pfizer Luxembourg SARL, podružnica Ljubljana PLIVA / TEVA d. o. o. Lundbeck - Pharma d. o. o.