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The triptans class of pharmaceuticals, which was created to treat acute migraine, is made up of indole-containing drugs that bind to a subset (1B/1D) of 5-hydroxytryptamine receptors and are agonists of serotonin receptors. At the moment, naratriptan, eletriptan, zolmitriptan, rizatriptan, almotriptan, and frovatriptan are the seven types of triptans available on the market. Among these are the FDA-approved triptans, Zolmitriptan and Sumatriptan, which are selective serotonin (5-hydroxytryptamine) agonists. Zolmitriptan, a synthetic tryptamine derivative and a well-known member of the triptan family, is available as an orally disintegrating tablet, nasal spray, and tablet. There are melt formulations of rizatriptan and zolmitriptan available on the market that are easier to use and absorb, comparable to regular pills. Recently, the FDA approved zolmitriptan, a medication with tolerability comparable to sumatriptan. Whereas zolmitriptan is only available as an oral melt or tablet, sumatriptan is available as a nasal spray, oral preparation, or self-injectable kit. The only known antimigraine drugs that were widely utilized before the triptan period were ergotamine and dihydroergotamine. However, zolmitriptan binds to plasma proteins only 25% of the time because of significant first-pass degradation. Researchers have looked into fresh ideas for solving this issue and innovations to overcome its pharmacokinetic difficulties. This article emphasizes the role of zolmitriptan in the treatment of migraines, highlighting its pharmacological properties, production, metabolism, and structural features.

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BACKGROUND AND OBJECTIVES: About a quarter of migraine cases among women have menstrual migraine (MM), which is usually more severe, longer lasting, and less responsive to treatment than typical migraine. Randomized controlled trials (RCTs) have evaluated the efficacy of several medication in the acute and preventive treatment of MM; this meta-analysis compared the effectiveness of these treatments. METHODS: We conducted systematic searches in the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase databases. The primary outcomes of acute treatment trials were pain relief at 2 and 24 h after treatment compared with placebo or another treatment. The three endpoints we checked for studying MM prevention were: no recurrence of headaches each month, a 50% reduction in monthly migraine days from baseline, and a decrease in the mean number of headache days per month. RESULTS: Out of 342 studies, 26 RCTs met the criteria. Triptans, combined with or without other analgesics, were superior to placebo in providing pain relief in the acute treatment and prevention of MM. Among the treatments, sumatriptan and lasmiditan demonstrated superior pain relief at 2 h (OR: 4.62) and 24 h (OR: 4.81). Frovatriptan exhibited effectiveness in preventing headache recurrence, whereas galcanezumab and erenumab displayed significant preventive benefits in reducing headache days per month. CONCLUSION: Sumatriptan and lasmiditan are effective first-line treatments for acute MM. For prevention, frovatriptan may be the more effective of triptans. Compared with triptans, CGRP monoclonal antibodies, here including erenumab and galcanezumab, are more effective in reducing headache days, and therefore, in preventing MM.

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BACKGROUND: Migraine presents a significant global health problem that emphasizes the need for efficient acute treatment options. Triptans, introduced in the early 1990s, have substantially advanced migraine management owing to their effectiveness compared to that of traditional medications. However, data on triptan use in migraine management from Asian countries, where migraines tend to have milder symptoms than those in European and North American countries, are limited. This study aimed to identify the trends in triptan usage in Korea. METHODS: This retrospective cohort study used data from the Korean National Health Insurance Service-National Sample Cohort spanning from 2002 to 2019. Patients with migraine were identified using the International Classification of Diseases 10th revision codes, and triptan prescriptions were evaluated annually in terms of quantity, pills per patient, and associated costs. The distribution of triptan prescriptions across different medical specialties was also examined. Factors contributing to the odds of triptan use were analyzed using multivariable logistic regression. RESULTS: From 2002 to 2019, the total number of triptan tablets, prescriptions, and patients using triptans increased by 24.0, 17.1, and 13.6 times, respectively, with sumatriptan being the most frequently prescribed type of triptan. Additionally, the number of prescriptions and related costs have consistently increased despite stable pricing because of government regulation. By 2019, only approximately one-tenth of all patients with migraines had been prescribed triptans, although there was a notable increase in prescriptions over the study period. These prescription patterns varied according to the physician's specialty. After adjusting for patient-specific factors including age and sex, the odds of prescribing triptans were higher for neurologists than for internal medicine physicians (odds ratio 2.875, P < 0.001), while they were lower for general practitioners (odds ratio 0.220, P < 0.001). CONCLUSION: The findings revealed an increasing trend in triptan use among individuals with migraines in Korea, aligning with global usage patterns. Despite these increases, the overall prescription rate of triptans remains low, indicating potential underutilization and highlighting the need for improved migraine management strategies across all medical fields. Further efforts are necessary to optimize the use of triptans in treating migraines effectively.

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BACKGROUND: Triptans are anti-migraine drugs with a potential central site of action. However, it is not known to what extent triptans cross the blood-brain barrier (BBB). The aim of this study was therefore to determine if triptans pass the brain capillary endothelium and investigate the possible underlying mechanisms with focus on the involvement of the putative proton-coupled organic cation (H+/OC) antiporter. Additionally, we evaluated whether triptans interacted with the efflux transporter, P-glycoprotein (P-gp). METHODS: We investigated the cellular uptake characteristics of the prototypical H+/OC antiporter substrates, pyrilamine and oxycodone, and seven different triptans in the human brain microvascular endothelial cell line, hCMEC/D3. Triptan interactions with P-gp were studied using the IPEC-J2 MDR1 cell line. Lastly, in vivo neuropharmacokinetic assessment of the unbound brain-to-plasma disposition of eletriptan was conducted in wild type and mdr1a/1b knockout mice. RESULTS: We demonstrated that most triptans were able to inhibit uptake of the H+/OC antiporter substrate, pyrilamine, with eletriptan emerging as the strongest inhibitor. Eletriptan, almotriptan, and sumatriptan exhibited a pH-dependent uptake into hCMEC/D3 cells. Eletriptan demonstrated saturable uptake kinetics with an apparent Km of 89 ± 38 µM and a Jmax of 2.2 ± 0.7 nmol·min-1·mg protein-1 (n = 3). Bidirectional transport experiments across IPEC-J2 MDR1 monolayers showed that eletriptan is transported by P-gp, thus indicating that eletriptan is both a substrate of the H+/OC antiporter and P-gp. This was further confirmed in vivo, where the unbound brain-to-unbound plasma concentration ratio (Kp,uu) was 0.04 in wild type mice while the ratio rose to 1.32 in mdr1a/1b knockout mice. CONCLUSIONS: We have demonstrated that the triptan family of compounds possesses affinity for the H+/OC antiporter proposing that the putative H+/OC antiporter plays a role in the BBB transport of triptans, particularly eletriptan. Our in vivo studies indicate that eletriptan is subjected to simultaneous brain uptake and efflux, possibly facilitated by the putative H+/OC antiporter and P-gp, respectively. Our findings offer novel insights into the potential central site of action involved in migraine treatment with triptans and highlight the significance of potential transporter related drug-drug interactions.

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Objective: Migraine attacks are common in women of reproductive age. Although attacks are often less severe and less frequent during pregnancy, they regularly reoccur shortly after delivery. When first-line analgesic treatment is insufficient, triptans may be used for acute treatment of migraine attacks. Milk levels of occasional triptan use have shown to be low, and no adverse effects in breastfed infants have been reported. However, the available knowledge on the safety of triptans during breastfeeding is still limited. Methods: Four (inter)national pharmacovigilance databases were searched for breastfeeding related adverse drug reactions of triptans. These included the Dutch Pregnancy Drug Register and three databases of spontaneous reports (Netherlands Pharmacovigilance Centre Lareb, the European Medicines Agency [EudraVigilance], and the World Health Organization [VigiBase]). Results: A total of 26 reports on 27 breastfeeding related adverse drug reactions were identified (one report involved two separate adverse drug reactions). These involve three main complaints: painful breasts and/or nipples, painful milk ejection reflex, and a decrease in milk production. Discussion and Conclusion: The hypothesized pharmacological mechanism relates to the serotonin-receptor agonistic properties of triptans. These may lead to vasoconstriction in the breasts and nipples, including the vasculature surrounding the milk ducts and alveoli, and may also influence the hormonal function and levels of prolactin. The reported adverse drug reactions do not negatively impact the overall compatibility of triptans with breastfeeding. However, breastfeeding women may experience them as unsettling. Awareness of these potential adverse drug reactions is essential and should be weighed against the potential adverse effects of (untreated) symptoms of migraine attacks.

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PURPOSE OF REVIEW: To summarize recent findings regarding triptan use in the acute treatment of pediatric migraine. RECENT FINDINGS: Prevalence of pediatric migraine is rising. The American Headache Society and American Academy of Neurology updated guidelines to provide evidence-based recommendations for the treatment of acute migraine in youth. In the setting of a dearth of new randomized controlled trials (RCTs), we review current guidelines, triptan use in the emergency department, and an era of secondary analyses. Measuring the efficacy of triptans in pediatric migraine has been challenged by high placebo response rates. Secondary analyses, combining data from multiple RCTs, support that triptans are safe and effective in the treatment of migraine. Triptans are a vital tool and the only FDA-approved migraine-specific treatment available in pediatrics. There is a need for further studies and funding support in pediatric headache medicine.

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OBJECTIVE: The objective of this systematic review and meta-analysis was to determine whether patients with episodic (EM) or chronic migraine (CM), who were treated with anti-CGRP antibodies, showed a reversal from medication overuse (MO) or medication overuse headache (MOH) status at their baseline to non-overuse status. Furthermore, this study aimed to establish which acute headache medication (AHM) categories responded more effectively to anti-CGRP antibodies. METHODS: A systematic search was conducted in the PubMed database for relevant studies from January 2013 to September 2023. We included phase three randomized controlled trials to examine the role of anti-CGRP antibodies in patients with EM or CM and their MO status. A meta-analysis was conducted to find the association between anti-CGRP antibodies and the number of EM and CM patients with MO or MOH at baseline that reverted to non-MO status or below the MOH threshold. RESULTS: The initial search yielded a total of 345 studies. After removing duplicates and screening with inclusion criteria, 5 studies fulfilled our conditions. Each study reviewed the response to changes in the MO status of patients after receiving anti-CGRP antibodies, including eptinezumab, fremanezumab, galcanezumab, and erenumab, compared to placebo. Our study analyzed three AHM categories: triptans, simple analgesics, and multiple drugs. The overall relative risk (RR) was 1.44 (95% CI, 1.31 to 1.59; p < 0.001). The RRs for triptans, simple analgesics, and multi-drug groups were 1.71 (95% CI, 1.53 to 1.91; p < 0.001), 1.10 (95% CI, 0.83 to 1.47; p = 0.5), and 1.29 (95%CI 1.14 to 1.46; p < 0.001) respectively. CONCLUSION: The meta-analysis has shown that anti-CGRP antibodies were statistically significant in transitioning from MO or MOH status to non-MO status or below the MOH threshold (RR = 1.44) for all included studies and all AHM categories except for simple analgesics. Patients from the triptan group had the highest RR of 1.71 with a p-value < 0.001, while the simple analgesics group had an RR of 1.10, however, with a p-value > 0.05. Interestingly, this analysis can be interpreted as that anti-CGRP antibodies might not be effective in reducing simple analgesics use in EM or CM patients. Further studies are needed to investigate these matters.

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BACKGROUND: Migraine is common in women of reproductive age. Migraine's episodic manifestation and acute and preventive pharmacological treatment options challenge studying drug safety for this condition during pregnancy. To improve such studies, we aimed to develop algorithms to identify and characterize migraines in electronic healthcare registries and to assess the level of care. METHODS: We linked four registries to detect pregnancies from 2009-2018 and used three algorithms for migraine identification: i) diagnostic codes, ii) triptans dispensed, and iii) a combination of both. We assessed migraine severity using dispensed drugs as proxies. ICD-10 diagnostic subcodes of migraine (G43) allowed the allocation of four subtypes: complicated and/or status migrainosus; with aura; without aura; other/unspecified. RESULTS: We included 535,089 pregnancies in 367,908 women with available one-year lookback. The prevalence of migraines identified was 2.9%-4.3% before, and 0.8%-1.5% during pregnancy, depending on algorithm used. Pregnant women with migraine were mostly managed in primary care. CONCLUSIONS: Primary care data in combination with drug dispensation records were instrumental for identification of migraine in electronic healthcare registries. Data from secondary care and drug dispensations allow better characterization of migraines. Jointly, these algorithms may contribute to improved perinatal pharmacoepidemiological studies in this population by addressing confounding by maternal migraine indication.

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OBJECTIVE: This study is describing subjects with migraine interrupting or not receiving triptans for acute treatment and providing a national-level estimate of people who might benefit from different therapeutic approaches. METHODS: This is a retrospective analysis using IQVIA Longitudinal Patient Database. Starting from 18 + years old individuals with migraine, we selected two cohorts: subjects with triptans prescriptions before and no triptans prescriptions after Index Date (triptan withdraw) and subjects without triptans prescriptions both before and after Index Date (no triptan prescriptions). Index Date was the first record of a health encounter for migraine in 2019. Individuals with cardiovascular disease (CVD) within no triptan prescriptions group were also quantified. RESULTS: Triptan withdraw and no triptan prescriptions cohorts numbered 605 and 3270, respectively, 5% and 29% of subjects with migraine. Mean age was 47 and 51 years respectively; women were more represented (~ 80%). Hypertension and thyroid disease were most frequent comorbidities; non-steroidal anti-inflammatory drugs were among most frequently recorded treatments. Subjects with CVD within no triptan prescriptions cohort were 621 and with triptan withdraw cohort subjects represented the basis to estimate those who might benefit from alternative options for the acute treatment of migraine, who were around 60,000 and accounted for 11% of subjects seeking primary care due to migraine. CONCLUSIONS: This analysis provides a real-word estimate of Italian people that might benefit from different therapeutic approaches as an alternative to triptans, which sometimes might be not effective and/or poorly tolerated. Such estimate should be intended as the lower limit of a wider range due to strict criteria adopted.

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Nitric oxide (NO) is one of the reactive nitrogen species (RNS) that has been proposed to be a key signaling molecule in migraine. Migraine is a neurological disorder that is linked to irregular NO levels, which necessitates precise NO quantification for effective diagnosis and treatment. This work introduces a novel fluorescent probe, 2,3-diaminonaphthelene-1,4-dione (DAND), which was designed and synthesized to selectively detect NO in-vitro and in-vivo as a migraine biomarker. DAND boasts high aqueous solubility, biocompatibility, and facile synthesis, which enable highly selective and sensitive detection of NO under physiological conditions. NO reacts with diamine moieties (recognition sites) of DAND, results in the formation of a highly fluorescent product (DAND-NO) known as 1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione at λem 450 nm. The fluorescence turn-on sensing mechanism operates through an intramolecular charge transfer (ICT) mechanism. To maximize fluorescence signal intensity, parameters including DAND concentration, reaction temperature, reaction time and pH were systematically optimized for sensitive and precise NO determination. The enhanced detection capability (LOD = 0.08 µmol L-1) and high selectivity of the probe make it a promising tool for NO detection in brain tissue homogenates. This demonstrates the potential diagnostic value of the probe for individuals suffering from migraine. Furthermore, this study sheds light on the potential role of zolmitriptan (ZOLM), an antimigraine medication, in modulating NO levels in the brain of rats with nitroglycerin-induced migraine, emphasizing its significant impact on reducing NO levels. The obtained results could have significant implications for understanding how ZOLM affects NO levels and may aid in the development of more targeted and effective migraine treatment strategies.

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Symptomatic treatment of migraine includes patient education, mainly to avoid medication overuse and known trigger factors, as well as pharmaceutical and nonpharmaceutical interventions. Disease-specific and mechanism-based agents include ergotamine and dihydroergotamine targeting the adrenergic, dopaminergic, and serotoninergic systems followed by triptans, specific agonists for 5-HT1B/1D/1F receptors, the latest being more favorable in terms of safety and documentation of efficacy. Recently, antagonists of calcitonin gene-related peptide (gepants) and selective agonists of the 5-HT1F receptor (ditans) have been added, with promising efficacy and safety. Triptans stay as the first option treatment when attacks are moderate to severe, followed by nonspecific agents, including aspirin and paracetamol/acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs, ibuprofen and naproxen share the best documentation) for mild-to-moderate migraine attacks. Combinations with caffeine are effective as well, but barbiturates and opioids alone or in combinations should be avoided. Simple analgesics and NSAIDs attenuate cephalic pain via prostaglandin mediated mechanisms and may induce peptic, renal and hepatic adverse effects. Neuromodulation techniques include single-pulse transcranial magnetic stimulation (s-TMS), external trigeminal nerve stimulation (e-TNS), remote electrical neuromodulation (REN) and noninvasive vagus nerve stimulation (nVNS). All share good documentation and safety profile and are worthy of alternative treatment options along with physical therapy when medicines are contradicted or not well tolerated or unwanted by the patients.

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Menstrually related migraine is a disabling condition affecting 35% to 54% females with migraine during their fertile years. The International Headache Classification distinguishes menstrually related migraine from pure menstrual migraine based on the occurrence of the attacks even outside the perimenstrual periods. Hormonal fluctuations are the main driver for the disease in subjects with genetic susceptibility and alterations of brain structures and connectivity. Menstrually related attacks are often particularly severe and disabling requiring proper management. Acute treatment mainly consists of nonsteroidal anti-inflammatory drugs (NSAIDs), recommended in patients also suffering from dysmenorrhea, and triptans. Prevention is specifically indicated in women with high monthly headache frequency or burdensome attacks during perimenstrual periods. Trials proved the efficacy of short-term prevention with triptans and NSAIDs but did not evaluate possible long-term effectiveness and tolerability. Evidence of prevention using hormonal treatments is poor, but extended-cycle treatments might be suitable for women requiring hormonal replacement for concomitant conditions. Few data are available on treatments targeting CGRP, among whom gepants are the most promising because of their utility both in migraine acute and preventive treatment. A greater recognition of disease and a deep knowledge of patients' comorbidities are essential to its proper management.

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OBJECTIVE: This study aimed to explore decision-making impulsivity and its neural mechanisms in patients with episodic migraine without aura (EMoA). BACKGROUND: Previous evidence indicates increased impulsivity and altered reward processing in patients with chronic migraine and medication overuse; however, whether the same holds true for those with EMoA is unclear. METHODS: Patients newly diagnosed with EMoA (n = 51) and healthy controls (HC, n = 45) were recruited. All participants completed delay discounting task, cognitive assessments, a questionnaire for headache profile, and resting-state function magnetic resonance imaging scans. Resting-state functional connectivity (RSFC) between the regions of interest and the entire brain was explored. RESULTS: Patients with EMoA showed a steeper subjective discount rate than HCs (F = 4.74, p = .032), which was positively related to a history of migraines (r = .742, p < .001). RSFC among the ventral striatum (vSTR), ventromedial prefrontal cortex, and occipital cortex was lower in patients with EMoA than in control groups, which was correlated with history (r' = .294, p = .036) and subjective discount rate (r' = .380, p = .006). Additionally, discounting rates and RSFC between the vSTR and occipital regions were significantly abnormal in the triptan group than the non-triptan group. Mediating effect analysis indicated a significant mediating effect in the change in RSFC between the vSTR and occipital status, history of triptan use, and subjective discount rate. CONCLUSION: This study further elucidated that an increase in delayed discounting rate exists in patients with EMoA and is related to the abnormality of the value processing network.

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OBJECTIVE: To investigate the prescription patterns for patients aged 6-17 years with headaches in the REZULT database. METHODS: We cross-sectionally investigated (Study 1) the pattern of prescription and the proportion of triptan overprescription (≥30 tablets/90 d of triptans) among patients diagnosed with headaches in 2020. Next, we longitudinally studied patients (Study 2) for more than two years from the initial headache diagnosis (July 2010 to April 2022). The number of prescribed tablets was counted every 90 days. RESULTS: In Study 1, headache diagnoses were assigned to 62,568 of 543,628 (11.51%) patients, and 1524 of 62,568 (2.44%) patients received acute medication. Single nonsteroidal anti-inflammatory drugs and triptans were prescribed to 620/624 (99.36%) and 5/624 (0.80%) of patients aged 6-11 years, respectively, and 827/900 (91.89%) and 91/900 (10.11%) of patients aged 12-17 years, respectively. Triptan overprescription was observed in 11/96 (11.46%) patients, and 5/11 (45.45%) of those patients received prophylactic medication. In Study 2, 80,756/845,470 (9.55%) patients aged 6-17 years were diagnosed with headaches that persisted for at least two years. Over two years, 44/80,756 (0.05%) patients were overprescribed triptans, and 3408/80,756 (4.22%) patients were prescribed prophylaxis on at least one occasion. CONCLUSIONS: Based on real-world data, the appropriate use of prophylactic treatment is still problematic. Overprescription of triptans was observed, although the number of patients was small.

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INTRODUCTION: Migraine as headache attacks with autonomic symptoms is a serious condition and it is important to treat a single attack effectively in order to improve not only the patient's quality of life at a given moment but also to prevent the migraine from becoming a chronic one. AREA COVERED: The article briefly presents the guidance in selecting the most appropriate pharmacological treatment of migraine attack, indicating a personalized approach to migraine patient. EXPERT OPINION: In this short paper, we show the implementation of new drugs into everyday clinical practice. Good cooperation between the physician and the patient and having the patient's trust is one of the elements of a personalized therapeutic approach and the key to achieving satisfaction of both the patient and the doctor.

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BACKGROUND: The present study aimed to investigate prescription patterns for patients aged over 17 years with headaches in the REZULT database. METHODS: We conducted a cross-sectional study (Study 1) of the proportion of over-prescription of acute medications (≥30 tablets/90 days for triptans, combination non-steroidal anti-inflammatory drugs (NSAIDs) and multiple types; ≥45 tablets/90 days for single NSAIDs) among patients with headache diagnosed in 2020. We longitudinally studied (Study 2) patients for >2 years from initial headache diagnosis (July 2010 to April 2022). The number of prescribed tablets was counted every 90 days. RESULTS: In Study 1, headache was diagnosed in 200,055 of 3,638,125 (5.5%) patients: 13,651/200,055 (6.8%) received acute medication. Single NSAIDs were prescribed to 12,297/13,651 (90.1%) patients and triptans to 1710/13,651 (12.5%). Over-prescription was found in 2262/13,651 (16.6%) patients and 1200/13,651 (8.8%) patients received prophylactic medication. In Study 2, 408,183/6,840,618 (6.0%) patients were first diagnosed with headaches, which persisted for ≥2 years. Over time, the proportion of patients over-prescribed acute medications increased. Over 2 years, 37,617/408,183 (9.2%) patients were over-prescribed acute medications and 29,313/408,183 (7.2%) patients were prescribed prophylaxis at least once. CONCLUSIONS: According to real-world data, prophylaxis remains poorly prescribed, and both acute and prophylactic treatment rates for headaches have increased over time.

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Objective: To investigate whether the incidence of triggers, prodromal symptoms, hypersensitivity symptoms accompanying headache and responses to triptans were modified during a continuous 9-month fremanezumab therapy for migraine prophylaxis. Patients and methods: We studied 63 patients with high-frequency episodic migraine (HFEM). Enrolled patients received fremanezumab for nine consecutive months before defining the response rates and being stratified into treatment responders (≥50-74% reduction in monthly headache days (MHDs)), super responders (≥75%), partial non-responders (<50%) and super non-responders (<30%). Through headache diaries, patients provided data in order to document the impact of fremanezumab on the incidence of triggers, associated symptoms followed by headache and response to triptans (the use of the migraine treatment optimization questionnaire-4 (mTOQ-4)) during the 9-month treatment period. Results: Fremanezumab had early (after 3 monthly cycles) beneficial effects on the response to triptans in the majority of responders with relevant increases in mTOQ-4 scoring, but also in half of partial non-responders. A significant reduction in median days with migraine-associated symptoms was seen in responders after 6 months of therapy with fremanezumab, mostly for osmophobia, photophobia, phonophobia and nausea/vomiting, but partial non-responders also benefited. Likewise, the incidence of self-reported prodromal symptoms was significantly reduced in responders and was modestly diminished in partial non-responders. Triggers remained unaffected in both responders and non-responders. Conclusions: Fremanezumab given for at least 6-9 months may exert neuromodulatory effects in the migraine brain. These effects could result both in the inhibition of migraine chronification, but also in the diminishing of the magnitude of migraine-associated symptoms, mostly in responders and in partial non-responders.

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Migraine represents the most common neurologic disorder, ranking second among the world's causes of disability [expressed as years lived with disability (YLDs)]. Patients often do not receive the best therapy because of safety issues, tolerance, and prescription accessibility. General practitioners are not always educated about the disease, and specialists are few and often difficult to reach. Therapies are limited and have many side effects that can impede the prescription. Prophylactic therapy is recommended in case of four or more headaches a month, eight or more headache days a month, debilitating headaches, and medication-overuse headaches. The available therapeutic options are in constant development. The classic one consists of non-specific drugs: ß-blockers, tricyclics, antiepileptics, and botulinum toxin. Monoclonal antibodies targeting the calcitonin gene receptor (CGRP) peptide or its receptor are the only ones specifically designed to treat migraine. Their efficiency and convenient safety profile have been demonstrated in a number of trials versus both placebo and classic therapies. The treatment of acute migraine attack consists of medications designed to affect the painful symptoms. For over 30 years, the cornerstones of treatment in clinical practice have continued to be represented by triptans and non-steroidal anti-inflammatory drugs (NSAIDs), with the well-know related adverse effects. Opioids are used inappropriately and overprescribed. Polytherapy is strongly not recommended but is still a common practice because treatment is not optimized and thus not efficient. Great promise comes from gepants, also targeting CGRP, and ditans, 5-HT1F receptor agonists. They seem to outweigh the risk of medication overuse headache because of their efficacy and rapid onset and have no cardiovascular contraindications. Nonetheless, these points remain to be confirmed. Although therapies have been implemented in the last years, significant unmet treatment needs remain a reality in patients' lives. This commentary aims to identify the most important unmet needs in the acute treatment of migraine, analyzing the current status of available therapies and their limits. We also analyzed some of the prophylactic therapies available, especially focusing on anti-CGRP monoclonal antibodies, to better understand the importance of setting a therapeutic strategy that includes the two modes, both acute and prophylactic, to reach the best result. We hope that having an overview of the shortcomings will help to provide constructive ideas for improvement.

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Migraine symptoms were described in ancient Babylonia, and supernatural forces were felt to play a role in etiology and treatment. This changed in the Greco-Roman period, when the (dis)balance of humors was considered in (patho)physiology and treatment based on this. Aretaeus distinguished between cephalalgia, cephalea, and heterocrania. The latter term was changed to hemicrania by Galen. Physicians in the 17th century attributed headache to the meninges, extracranial periost, and cranial blood vessels. As for the pathophysiology, Willis suggested intracranial vasoconstriction with subsequent dilatation. Tissot and Fothergill gave comprehensive descriptions of migraine, including visual symptoms. Symptomatic and idiopathic hemicrania were distinguished in the early 19th century. Vasomotor pathophysiology was scientifically studied in the 1860s, leading to sympathicotonic and angioparalytic theories. Latham combined them, stating the latter follows the first. Ergot was introduced in 1868; ergotamine was isolated in 1918. This led to the vasodilatation theory of migraine (Wolff), the discovery of 5-HT, and later the specific agonists. Aura and cortical spreading depression were studied in the early 1940s and related to spreading oligemia in the 1980s. Subsequently, hyperemia followed by oligemia after CSD was found. After the discovery of CGRP, a new a class of drugs became the subject of clinical studies.

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BACKGROUND: Underdiagnosis of migraine causes a significant health burden, including lower quality of life, excessive medication use, and a delay in effective treatment. The purpose of this study was to evaluate migraine diagnosis accuracy and to review the treatment approaches used by neurologists in the Baltic states. METHODS: The research was conducted as an anonymous e-survey with four cases in March and April 2021. RESULTS: 119 practicing adult neurologists have participated. The migraine diagnostic accuracy was 63.2%. The most commonly used diagnostic criteria were moderate/severe pain, unilateral pain, and disruption of daily activities. Diagnostic accuracy did not differ significantly between neurologists who always use ICHD-3 criteria and those who don't (68.4% vs. 58.5%, p = 0.167). It was higher in neurologists who were working in headache centers (91.7% vs. 60.9%, p = 0.012), and was related to a higher percentage of migraine diagnoses in all consulted headache patients (R2 = 0.202, adjusted R2 = 0.195, p < 0.001), prophylaxis with onabotulinumtoxin A [OR = 4.332, 95% Cl (1.588-11.814)], and anti-CGRP monoclonal antibodies [OR = 2.862, 95% Cl (1.186-6.907)]. CONCLUSIONS: Migraine diagnostic accuracy is improved through practical patient counseling and modern treatment prescription. Although the neurologists in the Baltic states follow current European guidelines, there is room for improvement in diagnostic accuracy to reduce migraine burden.

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