The 5-HT1F receptor as the target of ditans in migraine - from bench to bedside.

Migraine is a leading cause of disability in more than one billion people worldwide, yet it remains universally underappreciated, even by individuals with the condition. Among other shortcomings, current treatments (often repurposed agents) have limited efficacy and potential adverse effects, leading to low treatment adherence. After the introduction of agents that target the calcitonin gene-related peptide pathway, another new drug class, the ditans - a group of selective serotonin 5-HT1F receptor agonists - has just reached the international market. Here, we review preclinical studies from the late 1990s and more recent clinical research that contributed to the development of the ditans and led to their approval for acute migraine treatment by the US Food and Drug Administration and the European Medicines Agency.

Decreased role of neuropeptides in the microvascular function in migraine patients with polycystic ovary syndrome.

BACKGROUND AND AIMS: To understand pathophysiological mechanisms underlying migraine as a cardiovascular risk factor, we studied neuropeptide action and endothelial function as measures of peripheral microvascular function in middle-aged women with or without migraine. METHODS: We included women with the endocrine disorder polycystic ovary syndrome (PCOS), a population with supposed elevated cardiovascular risk, with and without comorbid migraine. In 26 women without and 23 women with migraine in the interictal phase (mean age 50.8 ± 2.9 years) local thermal hyperemia (LTH) of the skin of the volar forearm was measured cross-sectionally under control conditions, after inhibition of neuropeptide release by 5% lidocaine/prilocaine (EMLA) cream application, and after inhibition of nitric oxide formation by iontophoresis of NG-monomethyl-l-arginine (L-NMMA). Hereafter, changes in the natural logarithm of the reactive hyperemia index (lnRHI) and augmentation index (AI) during reperfusion after occlusion-derived ischemia were measured. RESULTS: While mean values under control conditions and L-NMMA conditions were similar, migraine patients had a significantly higher mean area of the curve (AUC) of the total LTH response after EMLA application than those without (86.7 ± 26.5% versus 67.9 ± 24.2%; p = 0.014). This was also reflected by a higher median AUC of the plateau phase under similar conditions in women with migraine compared to those without (83.2% (IQR[73.2-109.5]) versus 73.2% (IQR[54.3-92.0]); p = 0.039). Mean changes in lnRHI and AI scores were similar in both groups. CONCLUSIONS: In PCOS patients with migraine, neuropeptide action was lower compared with those without migraine. While larger studies are warranted, these findings provide a potential mechanism supporting previous findings that migraine may be independent from traditional risk factors, including atherosclerosis.

Prolactin and oxytocin: potential targets for migraine treatment.

Migraine is a severe neurovascular disorder of which the pathophysiology is not yet fully understood. Besides the role of inflammatory mediators that interact with the trigeminovascular system, cyclic fluctuations in sex steroid hormones are involved in the sex dimorphism of migraine attacks. In addition, the pituitary-derived hormone prolactin and the hypothalamic neuropeptide oxytocin have been reported to play a modulating role in migraine and contribute to its sex-dependent differences. The current narrative review explores the relationship between these two hormones and the pathophysiology of migraine. We describe the physiological role of prolactin and oxytocin, its relationship to migraine and pain, and potential therapies targeting these hormones or their receptors.In summary, oxytocin and prolactin are involved in nociception in opposite ways. Both operate at peripheral and central levels, however, prolactin has a pronociceptive effect, while oxytocin appears to have an antinociceptive effect. Therefore, migraine treatment targeting prolactin should aim to block its effects using prolactin receptor antagonists or monoclonal antibodies specifically acting at migraine-pain related structures. This action should be local in order to avoid a decrease in prolactin levels throughout the body and associated adverse effects. In contrast, treatment targeting oxytocin should enhance its signalling and antinociceptive effects, for example using intranasal administration of oxytocin, or possibly other oxytocin receptor agonists. Interestingly, the prolactin receptor and oxytocin receptor are co-localized with estrogen receptors as well as calcitonin gene-related peptide and its receptor, providing a positive perspective on the possibilities for an adequate pharmacological treatment of these nociceptive pathways. Nevertheless, many questions remain to be answered. More particularly, there is insufficient data on the role of sex hormones in men and the correct dosing according to sex differences, hormonal changes and comorbidities. The above remains a major challenge for future development.

Migraine and the risk of stroke in a middle-aged and elderly population: A prospective cohort study.

BACKGROUND: It has been suggested that patients with migraine have a higher risk of stroke. Despite considerable research on this topic in younger populations, a clear answer is still lacking for older individuals. We studied the association between migraine and the risk of stroke in a middle-aged and elderly population. METHODS: Within the ongoing prospective population-based Rotterdam Study, the presence of migraine was assessed using a validated questionnaire in a structured interview between 2006 and 2011, which formed the baseline. The association between migraine and the risk of stroke was analyzed using Cox proportional-hazards models with adjustments for age, sex, and cardiometabolic risk factors. RESULTS: A total of 6925 (mean age 65.7 ± 11.3 years, 57.8% females) stroke-free participants were included. At baseline, 1030 (14.9%) participants had lifetime history of migraine. During a median follow-up of 6.2 years, 195 participants developed a stroke (163 ischemic stroke). Analyzing the association between migraine and stroke, we found a hazard ratio of 1.44 with a 95% confidence interval of 0.96-2.15. The results were similar for the ischemic stroke (HR 1.50, CI: 0.97-2.32). CONCLUSION: Our data suggested an association between migraine and the risk of stroke in a middle-aged and elderly population, but this was not statistically significant.

European Headache Federation (EHF) consensus on the definition of effective treatment of a migraine attack and of triptan failure.

BACKGROUND: Triptans are migraine-specific acute treatments. A well-accepted definition of triptan failure is needed in clinical practice and for research. The primary aim of the present Consensus was to provide a definition of triptan failure. To develop this definition, we deemed necessary to develop as first a consensus definition of effective treatment of an acute migraine attack and of triptan-responder. MAIN BODY: The Consensus process included a preliminary literature review, a Delphi round and a subsequent open discussion. According to the Consensus Panel, effective treatment of a migraine attack is to be defined on patient well-being featured by a) improvement of headache, b) relief of non-pain symptoms and c) absence of adverse events. An attack is considered effectively treated if patient's well-being, as defined above, is restored within 2 hours and for at least 24 hours. An individual with migraine is considered as triptan-responder when the given triptan leads to effective acute attack treatment in at least three out of four migraine attacks. On the other hand, an individual with migraine is considered triptan non-responder in the presence of failure of a single triptan (not matching the definition of triptan-responder). The Consensus Panel defined an individual with migraine as triptan-resistant in the presence of failure of at least 2 triptans; triptan refractory, in the presence of failure to at least 3 triptans, including subcutaneous formulation; triptan ineligibile in the presence of an acknowledged contraindication to triptan use, as specified in the summary of product characteristics. CONCLUSIONS: The novel definitions can be useful in clinical practice for the assessment of acute attack treatments patients with migraine. They may be helpful in identifying people not responding to triptans and in need for novel acute migraine treatments. The definitions will also be of help in standardizing research on migraine acute care.

Vascular Risk Score and Associations With Past, Current, or Future Migraine in Women: Cohort Study.

BACKGROUND AND OBJECTIVES-: Migraine has consistently been associated with an increased risk of cardiovascular disease (CVD) events. It remains, however, unclear to what extent cardiovascular risk profiles might be linked with migraine activity status, and how these profiles relate to the development of migraine. METHODS-: We used data from a cohort study of female health professionals (Women's Health Study, n=27,539, age ≥45 years at baseline) without a history of CVD or other major diseases and who provided a blood sample at baseline. Framingham risk scores (FRS) estimating the ten-year risk of coronary heart disease calculated at baseline were used to create vascular risk categories. The presence or development of self-reported migraine was assessed by questionnaires. Women were classified as having 'no migraine', 'history of migraine' (experienced migraine in the past but did not experience any migraine attacks in the year before enrollment), 'migraine at baseline' (active), or 'incident migraine' (first report of migraine during follow-up but not at baseline). We used multinomial logistic regression models to calculate odds ratios (ORs) for the association between FRS categories and migraine status. RESULTS-: Of the 27,539 participants, a total of 21,927 women did not report migraine, 1,500 women reported a history of migraine, 3,579 had migraine at baseline, and 533 reported migraine for the first time during follow-up. The odds of the probability of having a history of migraine at baseline (versus never migraine) was 76% higher among those with FRS ≥10% compared with FRS ≤1% after adjustment (OR=1.76, 95%CI: 1.39-2.23). In contrast, having FRS ≥10% was inversely associated with migraine at baseline (OR=0.64, 95%CI: 0.52-0.80), and with newly reported migraine during follow-up (OR=0.42, 95%CI: 0.22-0.81) when compared with women with FRS category ≤1% and those not reporting migraine. A similar inverse association pattern was observed for FRS categories 5-9% and 2-4%. DISCUSSION-: High FRS categories were only observed among women with a history of migraine but not with active migraine at baseline or incident migraine after baseline. Our results suggest that the life course of migraine should be considered when studying associations with the vascular system. Our data further suggest that a relatively healthy vascular system, as assessed by the FRS, is associated with active migraine status or developing migraine in the future.

Burden and attitude to resistant and refractory migraine: a survey from the European Headache Federation with the endorsement of the European Migraine & Headache Alliance.

BACKGROUND: New treatments are currently offering new opportunities and challenges in clinical management and research in the migraine field. There is the need of homogenous criteria to identify candidates for treatment escalation as well as of reliable criteria to identify refractoriness to treatment. To overcome those issues, the European Headache Federation (EHF) issued a Consensus document to propose criteria to approach difficult-to-treat migraine patients in a standardized way. The Consensus proposed well-defined criteria for resistant migraine (i.e., patients who do not respond to some treatment but who have residual therapeutic opportunities) and refractory migraine (i.e., patients who still have debilitating migraine despite maximal treatment efforts). The aim of this study was to better understand the perceived impact of resistant and refractory migraine and the attitude of physicians involved in migraine care toward those conditions. METHODS: We conducted a web-questionnaire-based cross-sectional international study involving physicians with interest in headache care. RESULTS: There were 277 questionnaires available for analysis. A relevant proportion of participants reported that patients with resistant and refractory migraine were frequently seen in their clinical practice (49.5% for resistant and 28.9% for refractory migraine); percentages were higher when considering only those working in specialized headache centers (75% and 46% respectively). However, many physicians reported low or moderate confidence in managing resistant (8.1% and 43.3%, respectively) and refractory (20.7% and 48.4%, respectively) migraine patients; confidence in treating resistant and refractory migraine patients was different according to the level of care and to the number of patients visited per week. Patients with resistant and refractory migraine were infrequently referred to more specialized centers (12% and 19%, respectively); also in this case, figures were different according to the level of care. CONCLUSIONS: This report highlights the clinical relevance of difficult-to-treat migraine and the presence of unmet needs in this field. There is the need of more evidence regarding the management of those patients and clear guidance referring to the organization of care and available opportunities.

Medication overuse and drug addiction: a narrative review from addiction perspective.

Chronic headache is particularly prevalent in migraineurs and it can progress to a condition known as medication overuse headache (MOH). MOH is a secondary headache caused by overuse of analgesics or other medications such as triptans to abort acute migraine attacks. The worsening of headache symptoms associated with medication overuse (MO) generally ameliorates following interruption of regular medication use, although the primary headache symptoms remain unaffected. MO patients may also develop certain behaviors such as ritualized drug administration, psychological drug attachment, and withdrawal symptoms that have been suggested to correlate with drug addiction. Although several reviews have been performed on this topic, to the authors best knowledge none of them have examined this topic from the addiction point of view. Therefore, we aimed to identify features in MO and drug addiction that may correlate. We initiate the review by introducing the classes of analgesics and medications that can cause MOH and those with high risk to produce MO. We further compare differences between sensitization resulting from MO and from drug addiction, the neuronal pathways that may be involved, and the genetic susceptibility that may overlap between the two conditions. Finally, ICHD recommendations to treat MOH will be provided herein.

Dietary salt modifies the blood pressure response to renin-angiotensin inhibition in experimental chronic kidney disease.

Chronic kidney disease contributes to hypertension, but the mechanisms are incompletely understood. To address this, we applied the 5/6th nephrectomy rat model to characterize hypertension and the response to dietary salt and renin-angiotensin inhibition. 5/6th nephrectomy caused low-renin, salt-sensitive hypertension with hyperkalemia and unsuppressed aldosterone. Compared with sham rats, 5/6th nephrectomized rats had lower Na+/H+ exchanger isoform 3, Na+-K+-2Cl- cotransporter, Na+-Cl- cotransporter, α-epithelial Na+ channel (ENaC), and Kir4.1 levels but higher serum and glucocorticoid-regulated kinase 1, prostasin, γ-ENaC, and Kir5.1 levels. These differences correlated with plasma renin, aldosterone, and/or K+. On a normal-salt diet, adrenalectomy (0 ± 9 mmHg) and spironolactone (-11 ± 10 mmHg) prevented a progressive rise in blood pressure (10 ± 8 mmHg), and this was enhanced in combination with losartan (-41 ± 12 and -43 ± 9 mmHg). A high-salt diet caused skin Na+ and water accumulation and aggravated hypertension that could only be attenuated by spironolactone (-16 ± 7 mmHg) and in which the additive effect of losartan was lost. Spironolactone also increased natriuresis, reduced skin water accumulation, and restored vasorelaxation. In summary, in the 5/6th nephrectomy rat chronic kidney disease model, salt-sensitive hypertension develops with a selective increase in γ-ENaC and despite appropriate transporter adaptations to low renin and hyperkalemia. With a normal-salt diet, hypertension in 5/6th nephrectomy depends on angiotensin II and aldosterone, whereas a high-salt diet causes more severe hypertension mediated through the mineralocorticoid receptor.NEW & NOTEWORTHY Chronic kidney disease (CKD) causes salt-sensitive hypertension, but the interactions between dietary salt and the renin-angiotensin system are incompletely understood. In rats with CKD on a normal-salt diet targeting aldosterone, the mineralocorticoid receptor (MR) and especially angiotensin II reduced blood pressure. On a high-salt diet, however, only MR blockade attenuated hypertension. These results reiterate the importance of dietary salt restriction to maintain renin-angiotensin system inhibitor efficacy and specify the MR as a target in CKD.

Giving Researchers a Headache - Sex and Gender Differences in Migraine.

Migraine is a common neurovascular disorder affecting ~15% of the general population. Ranking second in the list of years lived with disability (YLD), people living with migraine are greatly impacted by this especially burdensome primary headache disorder. In ~30% of individuals with migraine, transient neurological symptoms occur (migraine aura) that further increase migraine burden. However, migraine burden is differential with respect to sex. Though one-year prevalences in childhood are similar, starting with puberty, migraine incidence increases at a much higher rate in females than males. Thus, migraine over the life course occurs in women three to four times more often than in men. Attacks are also more severe in women, leading to greater disability and a longer recovery period. The sex disparity in migraine is believed to be partly mediated through fluctuations in ovarian steroid hormones, especially estrogen and progesterone, although the exact mechanisms are not yet completely understood. The release of the neuropeptide calcitonin gene-related peptide (CGRP), followed by activation of the trigeminovascular system, is thought to play a key role in the migraine pathophysiology. Given the burden of migraine and its disproportionate distribution, the underlying cause(s) for the observed differences between sexes in the incidence, frequency, and intensity of migraine attacks must be better understood. Relevant biological as well as behavioral differences must be taken into account. To evaluate the scope of the existing knowledge on the issue of biological sex as well as gender differences in migraine, we conducted a systematized review of the currently available research. The review seeks to harmonize existing knowledge on the topic across the domains of biological/preclinical, clinical, and population-level research, which are traditionally synthesized and interpreted in isolation. Ultimately, we identify knowledge gaps and set priorities for further interdisciplinary and informed research on sex and gender differences as well as gender-specific therapies in migraine.

Extracranial Trigger Site Surgery for Migraine: A Systematic Review With Meta-Analysis on Elimination of Headache Symptoms.

Introduction: The headache phase of migraine could in selected cases potentially be treated by surgical decompression of one or more "trigger sites," located at frontal, temporal, nasal, and occipital sites. This systematic review with subsequent meta-analysis aims at critically evaluating the currently available evidence for the surgical treatment of migraine headache and to determine the effect size of this treatment in a specific patient population. Methods: This study was conducted following the PRISMA guidelines. An online database search was performed. Inclusion was based on studies published between 2000 and March 2018, containing a diagnosis of migraine in compliance with the classification of the International Headache Society. The treatment must consist of one or more surgical procedures involving the extracranial nerves and/or arteries with outcome data available at minimum 6 months. Results: Eight hundred and forty-seven records were identified after duplicates were removed, 44 full text articles were assessed and 14 records were selected for inclusion. A total number of 627 patients were included in the analysis. A proportion of 0.38 of patients (random effects model, 95% CI [0.30-0.46]) experienced elimination of migraine headaches at 6-12 months follow-up. Using data from three randomized controlled trials, the calculated odds ratio for 90-100% elimination of migraine headaches is 21.46 (random effects model, 95% CI [5.64-81.58]) for patients receiving migraine surgery compared to sham or no surgery. Conclusions: Migraine surgery leads to elimination of migraine headaches in 38% of the migraine patients included in this review. However, more elaborate randomized trials are needed with transparent reporting of patient selection, medication use, and surgical procedures and implementing detailed and longer follow-up times.

Blocking CGRP in migraine patients - a review of pros and cons.

Migraine is the most prevalent neurological disorder worldwide and it has immense socioeconomic impact. Currently, preventative treatment options for migraine include drugs developed for diseases other than migraine such as hypertension, depression and epilepsy. During the last decade, however, blocking calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for prevention of migraine attacks. CGRP has been shown to be released during migraine attacks and it may play a causative role in induction of migraine attacks. Here, we review the pros and cons of blocking CGRP in migraine patients. To date, two different classes of drugs blocking CGRP have been developed: small molecule CGRP receptor antagonists (gepants), and monoclonal antibodies, targeting either CGRP or the CGRP receptor. Several trials have been conducted to test the efficacy and safety of these drugs. In general, a superior efficacy compared to placebo has been shown, especially with regards to the antibodies. In addition, the efficacy is in line with other currently used prophylactic treatments. The drugs have also been well tolerated, except for some of the gepants, which induced a transient increase in transaminases. Thus, blocking CGRP in migraine patients is seemingly both efficient and well tolerated. However, CGRP and its receptor are abundantly present in both the vasculature, and in the peripheral and central nervous system, and are involved in several physiological processes. Therefore, blocking CGRP may pose a risk in subjects with comorbidities such as cardiovascular diseases. In addition, long-term effects are still unknown. Evidence from animal studies suggests that blocking CGRP may induce constipation, affect the homeostatic functions of the pituitary hormones or attenuate wound healing. However, these effects have so far not been reported in human studies. In conclusion, this review suggests that, based on current knowledge, the pros of blocking CGRP in migraine patients exceeds the cons.

Dihydroergotamine, ergotamine, methysergide and sumatriptan - basic science in relation to migraine treatment.

The 5-hydroxytryptamine (5-HT) receptor family mediates the effects of several drugs highly effective in migraine primarily by activating 5-HT(1B) , 5-HT(1D) , and 5-HT(1F) receptors. Ergotamine, dihydroergotamine, and methysergide, as well as the "triptan" sumatriptan, are all agonists for these receptors. The receptor profile and degree of selectivity of these four drugs differ, which is reflected by their side effects that limit their use in the acute and prophylactic treatment of migraine. The acute antimigraine efficacy of these remedies is very much dependent on the formulation used where, in general, parenteral formulations are more effective in reliving the symptoms of a migraine attack.

Coronary vasoconstrictor potential of triptans: a review of in vitro pharmacologic data.

This article reviews the in vitro pharmacology of the triptans in human isolated coronary arteries. As expected, based on their similar pharmacologic profiles, the triptans cannot be easily differentiated with respect to effects at human isolated coronary arteries. Furthermore, the data show that at therapeutically relevant concentrations, triptans have little potential to cause clinically significant constriction of nondiseased coronary arteries. These data, considered in the context of clinical findings reviewed elsewhere in this supplement, support the conclusion that, while all triptans have the potential to produce small contractions of human isolated coronary arteries, their craniovascular selectivity, when used at therapeutic doses, renders them unlikely to cause serious adverse coronary events in patients with healthy coronary arteries.