Abortive Treatment Of Migraine Research Articles

Preventive and abortive treatment of migraine with traditional drugs. The state of the art

IntroductionMigraine is a chronic neurological disease, with a prevalence of 15.2% in Brazil. It is 2.2 times more prevalent in women, predominantly in the 18-50 age group. Its pathophysiological mechanism is still not completely understood. Possibly headache attacks and symptoms are associated with cortical spreading depression, the trigeminovascular system, neurogenic inflammation, vasodilation and genetic vulnerability.ObjectiveThis is a narrative review of preventive and abortive treatment of migraine.CommentMigraine treatment is based on three pillars: patient education, treatment of the disease itself or prevention of attacks, and acute treatment of headache attacks. The therapeutic classes of traditional drugs used in migraine prevention are beta-blockers, tricyclic antidepressants, calcium channel antagonists or blockers, and anticonvulsant neuromodulators. Specific drugs used in the treatment of headache attacks are triptans or serotonergic 5-HT1B/1D receptor agonists, ditans or 5-HT1F receptor agonists, and gepants or CGRP receptor antagonists.ConclusionTraditional drugs used in the preventive or abortive treatment of migraine are considered to be effective. Through modulation of the disease mechanisms, there is a reduction in the frequency, intensity and duration of headache attacks, and also in the disability caused by the headache. All this to improve the quality of life of patients. The therapeutic classes of traditional drugs used in migraine prevention are beta-blockers, tricyclic antidepressants, antagonists or blockers of calcium channels and anticonvulsant neuromodulators. Specific drugs used in the treatment of headache attacks are triptans or serotonergic 5-HT1B/1D receptor agonists,ditans or 5-HT1F receptor agonists, and gepants or CGRP receptor antagonists.

Zavegepant: a promising intranasal medication for migraine treatment

Migraine is the third most prevalent and seventh-highest specific cause of disability worldwide1. It is a neurobiological headache disorder that is caused by increased excitability of the central nervous system. This multifactorial ailment has various causes, including lack of sleep, hormonal imbalance, menstrual cycle, and emotional stress. Some individuals may even trigger migraine due to their choice of food, especially chocolate, milk, caffeine, cheese, and alcoholic beverages2. The variability seen in its clinical presentation includes the pattern of associated symptoms and pain intensity along with photophobia, osmophobia, phonophobia, vomiting, nausea, and movement sensitivity3. Considering the acute onset of this excruciating pain, patients demand rapid relief and the cure of all associated symptoms. Several medications have been introduced. However, nowadays, 5HT1B/1D receptor agonists (sumatriptan, zolmitriptan) and ergot alkaloids (dihydroergotamine mesylate) are being used as intranasal or parenteral medications for the immediate treatment of migraines. Many patients prefer intranasal medications over injectable ones because of their rapid action4. Triptans, one of the most effective treatment regimens for migraine, is unfortunately ineffective intranasally. Moreover, its contraindication for cardiovascular patients restricts its use in almost 10% of the migraine population. On the other hand, dihydroergotamine which is still less effective than triptans, the nasal spray is contraindicated in patients with uncontrolled hypertension, ischemic heart disease, and coronary artery vasospasm5. Co-administration with potent cytochrome P450 3A4 inhibitors may also result in potentially fatal peripheral and cerebral ischemia. Recent studies led to the discovery of novel modulators, like calcitonin gene-related peptide (CGRP), that are crucially implicated in the development and chronicity of migraine. This led to new medications known as gepants that can antagonize the CGRP receptor. Successive advances led to the introduction of first-generation and second-generation gepants. However, both were short-lived due to poor oral bioavailability6, associated liver injury, and less effectiveness, respectively. Zavegepant is the third generation but the first intranasally administered gepant. It is a high-affinity antagonist of the CGRP receptor, has adequate oral bioavailability, and, unlike triptans, does not induce active contraction of coronary arteries; therefore, it is safe for patients with cardiovascular comorbidities. Compared with the prior lead, the pharmacophore of zavegepant has a 2-quinolone and a 7-methylindazole, increasing oxidation stability and nasal irritancy potential while maintaining picomolar receptor binding potency7. In addition to that, it is also 10,000 times more selective for the CGRP receptor than for its counterpart, the amylin receptor8. It was FDA-approved in February 2020 for acute treatment, and results demonstrate that it is safe regarding hepatotoxicity9. Recently it cleared the phase 2 trials and now advancing to phase 3 ones. Zavegepant has a tmax of 15–20 minutes as it provides considerable efficacy over 48 hours, with ultra-rapid pain relief starting 15 minutes after a single therapeutic dose (P=0.0015), prolonged and persistent pain freedom for 2–24 hours and 2–48 hours, respectively, along with sustained pain relief for 2–24 hours10. This makes it highly potent and the safest in terms of side effects. Although the provided data gives ample proof that zavegepant is a revolutionary drug to combat migraine attacks but for definite, high-quality evidence about its efficacy and safety, results from the recent clinical trials and future research work are needed. Similarly, soft gel formulations of zavegepant also need more attention as it can be another option for the abortive treatment of migraine. Lastly, extensive trials are needed to see its effect on pregnant women and patients with severe liver and cardiovascular issues. For commercialization, it should be economically friendly so that it can compete with all the available formulas and a maximum number of patients can be benefitted from it. Rest assured. This third-generation gepant can be a promising medication in terms of timely relief from escalating pain, and further research may even help us find the ultimate cure for migraine. Ethical approval Not applicable. Sources of funding None. Author contribution The conceptualization was done by A.S. and B.S.R. The literature and drafting of the manuscript were conducted by A.S., T.N., A.W.K., S.D.E.Z.Z., A.Q. and H.S.R. The editing and supervision were performed by B.S.R. All authors have read and agreed to the final version of the manuscript. Conflicts of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number (UIN) Not applicable. Guarantor All authors take responsibility for the work, access to data and decision to publish.

Neurophysiological and Vascular Mechanisms of Action of the Serotoninergic Drugs for Abortive Migraine Treatment

Neurophysiological and Vascular Mechanisms of Action of the Serotoninergic Drugs for Abortive Migraine Treatment

Acute Treatment of Migraine in Adolescents: Real-World Analysis of Remote Electrical Neuromodulation (REN)

Nearly 10% of children and adolescents in the United States experience migraine. Pharmacologic treatment of migraine in adolescents is limited due to only few US Food and Drug Administration (FDA)-approved medications, limited efficacy, or lack of tolerability. Remote Electrical Neuromodulation (REN) is a nonpharmacologic abortive treatment for migraine, cleared by the FDA for patients aged 12 years and above. This study evaluated real-world efficacy of REN in adolescents aged 12 to 17 years. Real-world data were collected from patients aged 12 to 17 years treated with the REN device (Nerivio) from January 1, 2021, to May 31, 2022. Study's end points included consistent efficacy two hours after treatment, use of REN as a standalone versus as an adjunct therapy, treatment intensity, and safety. Of 1629 adolescents included in the study, consistent response in at least 50% of treatments at two hours posttreatment was achieved by 60.3% of patients for pain relief, 26.3% for pain freedom, 66.3% for functional disability relief, and 41.2% for functional disability freedom. Of 2365 treatments in which medication usage was reported, REN was used as standalone therapy in 64.4% of the treatments, REN was combined with over-the-counter medications in 18.6%, and it was combined with prescription medications in 17%. Mean treatment intensity from 13,716 treatments was 28.5% (±13.6%) of the max stimulator output. Only three device-related adverse events were reported, all minor. This real-world analysis demonstrates the persistent efficacy of REN for abortive treatment of migraine in adolescents, extending findings of prior clinical trials in adolescents and real-world studies in adults.

Rate and Predictors of Intractable Status Migrainosus among Patients Aged 13-18 Years.

To assess associations for intractable status migrainosus in the pediatric inpatient setting. A retrospective cohort study of 1,805 patients presenting to the pediatric hospital in Dayton, Ohio with status migrainosus from 2017 to 2022, was performed. Among 1,805 patients, 159 received 3 lines of sequentially more aggressive abortive migraine treatment and were included in this analysis. Responders and non-responders were categorized based on a visual analogue scale (VAS) of pain scores from time of admission to discharge with responders having a reduction of 50% or greater in VAS. Patient demographic information, migraine history, headache type, medication history, self-reported pain, anxiety level and co-morbidities were assessed. Out of 159 patients, 125 (78.6%) achieved the target pain control with decrease in VAS pain score by ≥ 50% from the baseline. The remaining 34/159 (21.4%) patients remained refractory to treatment. Non-responder patients had a longer hospital stay (6.1 days) and greater readmission rate within 7 days (17.6%) compared to responders (4.7 days and .8% respectively). Among the non-responder patients, 14/34 (41.2%) had attention-deficit/hyperactivity disorder (ADHD) compared to the responder group in which 17/125 (13.6%) had ADHD. Among patients who had comorbidity of anxiety, non-responders had greater severe generalized anxiety disorder (GAD-7 ≥15) (6/14, 42.9%) than responders (2/39, 5.1%). ADHD and severe GAD are associated with poorer response to treatment in pediatric patients with refractory migraine admitted for inpatient therapy. This study highlights the prolonged hospital stay and modest clinical outcomes seen with intractable migraine in 13-18-year-old pediatric patients.

A systematic review with expert opinion on the role of gepants for the preventive and abortive treatment of migraine

Introduction Gepants are small molecules targeting the calcitonin gene-related peptide (CGRP) that have been recently introduced and are under additional clinical development as preventive and abortive treatment options for migraine. Areas covered After providing a narrative overview of current preventive and acute treatment options for migraine and summarizing the pathophysiology of migraine attack and the role of CGRP, we performed a systematic review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, on trials on gepants in preventive and acute treatment of migraine. Studies and results were reviewed and discussed, and expert opinion was presented. We also collected data on relevant ongoing trials. Expert opinion Whether direct targeting CGRP pathways within the central nervous system or indirectly modulating them from the peripheral nervous system is more effective and safer in migraine is still unclear. The available data on the efficacy and safety of gepants suggest they may represent an abortive, and to some extent, preventive treatment option for migraine, in patients who do not respond or have adverse effects to first/second line treatments or at high risk for medication overuse headache. Some gepants have been approved as third-line treatments for migraine, thus opening new therapeutic horizons.

PREVALENCE AND PREDICTORS OF FATIGUE IN PATIENTS WITH EPISODIC MIGRAINE.

The aim: We studied prevalence, intensity and predictors of fatigue in patient with episodic migraine (EM). Materials and methods: We enrolled in the study 85 patients with EM and 88 healthy subjects. Fatigue was identified according to Fatigue Severity Scale. We recorded socio-demographic factors: gender, age, marital status, formal education level, employment status, smoking. Anxiety and depression symptoms were assessed by Hospital Anxiety and Depression Scale, daytime sleepiness was measured by Epworth scale. The co-morbidities included history of low back pain during last year, arterial hypertension, diabetes mellitus and abdominal obesity. It was analyzed usage of non-steroidal anti-inflammatory drugs, combined analgesics, triptans for abortive migraine treatment. Results: Fatigue prevalence in patients with EM was 41,2%, which was significantly higher than in healthy controls (11,4%). Fatigue intensity in episodic migraineurs was 5,7 (4,9-6,8) and did not differ significantly from fatigue intensity in healthy individuals - 4,9 (4,5-5,8). In multivariate logistic regression analysis independent predictors of fatigue were only migraine-related factors (number of migraine headache days per month, headache severity and migraine prodrome presence). There was weak direct correlation between the number of headache migraine days per month and fatigue intensity. Conclusions: 1. Fatigue prevalence in patients with EM is significantly higher than in healthy controls. 2. In patients with EM fatigue has migraine-related predictors.

Gepants, calcitonin gene-related peptide antagonists, for abortive treatment of migraine: current status

Migraine is a neurovascular disorder characterized by unilateral, recurrent, pulsating, throbbing, and moderate to severe headache. Triptans use is often limited by their poor efficacy, reports of poor responders, and contraindicated in patients with cardiovascular disorders. Calcitonin gene-related peptide (CGRP), a neuropeptide, regulates vascular tonicity as well as potent pain mediator, and both the mechanisms involved in development of migraine headache. Gepants are non-peptide, small molecules, highly selective, and potent CGRP antagonists. These novel drugs have been approved for abortive treatment of acute migraine with or without aura. These are being evaluated for their effectiveness and showing promising results in the prevention of migraine. Gepants do not have vasoconstrictive properties, are safe to use in patients with cardiovascular risk, and best alternative to triptan therapy. These are available in tablet, orally disintegrating tablet, and nasal forms to improve patient compliance. Ubrogepant and rimegepant are the two oral CGRP antagonists approved whereas atogepant and zavegepant are at late stage of development for approval.

Lasmiditan: Acute Migraine Treatment Without Vasoconstriction. A Review.

Objective: To review the efficacy and safety of the newly Food and Drug Administration approved drug lasmiditan, and its place in therapy in the treatment of acute migraine attacks. Data Sources: A literature search of Web of Science, PubMed, and Google Scholar was preformed (September 1999 to May 2021) using the following search terms: acute migraine treatment, triptans, lasmiditan, Reyvow, Rimegepant, Nurtec, Ubrogepant, Ubrelvy, migraine, vasoconstriction, and cardiovascular risk. Product labeling, https://www.clinicaltriasl.gov, and product monographs were also reviewed. Study Selection and Data Extraction: Relevant English-language studies were considered. Data Synthesis: Lasmiditan is the first in its class approved for acute migraine treatment. Lasmiditan exerts its therapeutic effect through agonism at the 5-HT1F receptor, which has been shown to produce no vasoconstriction in preclinical models. Relevance to Patient Care and Clinical Practice: It is both scientifically and clinically relevant to review lasmiditan and determine the value of an acute migraine drug that does not induce vasoconstriction. Patients with preexisting cardiovascular conditions for which current migraine therapy is contraindicated may benefit from therapeutic use of lasmiditan. However, the potential cardiovascular benefit needs to be weighed against the increased central nervous system risks observed with lasmiditan. Conclusions: Lasmiditan is an oral tablet drug that is used for acute migraine abortive treatment and data suggest that it does not induce vasoconstriction, a common side effect often observed with the current first-line abortive migraine treatment drug class, triptans. This is especially important in acute migraine patients with cardiovascular risk factors in which triptan use is contraindicated.

Ubrogepant: An Oral Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist for Abortive Migraine Treatment.

To review the pharmacology, efficacy, and safety of ubrogepant as an abortive migraine treatment. A literature search of MEDLINE and PubMed was performed (January 2006 through May 2021) using the following search terms: ubrogepant, calcitonin gene related peptide, and abortive migraine therapy. Relevant studies evaluating ubrogepant's pharmacology, efficacy, and safety in humans for the treatment of migraine were considered. Ubrogepant is a calcitonin gene-related peptide receptor antagonist approved by the Food and Drug Administration for the acute treatment of migraine via data from ACHIEVE I and II. From ACHIEVE I, ubrogepant demonstrated superiority to placebo in freedom from migraine pain at 2 hours postdose (50-mg dose: odds ratio [OR] = 1.83, 95% CI = 1.25-2.66; 100-mg dose: OR = 2.04, 95% CI = 1.41-2.95) and freedom from most bothersome symptom (MBS; 50-mg dose: OR = 1.70, 95% CI = 1.27-2.28; 100-mg dose: OR = 1.63, 95% CI = 1.22-2.17). ACHIEVE II trial demonstrated efficacy of ubrogepant 50 mg compared with placebo (2-hour pain freedom: OR = 1.62, 95% CI = 1.14-2.29; 2-hour MBS freedom: OR = 1.65, 95% CI = 1.25-2.20). Ubrogepant is a viable option for patients who are unable to tolerate nonsteroidal anti-inflammatory drug or triptan therapy because of ineffective relief or contraindications that limit use. Ubrogepant is a well-tolerated effective abortive migraine treatment that bridges a gap in therapy for many patients who previously could not tolerate other first-line treatments.

Drug interactions and risks associated with the use of triptans, ditans and monoclonal antibodies in migraine.

The aim of this study was to review current evidence concerning potential risks and interactions associated with concomitant use of drugs indicated for the abortive treatment of migraine, namely triptans and ditans, and more recently developed drugs used for the preventive treatment. The latter drug class encompasses monoclonal antibodies (mAbs), which target either calcitonin gene-related peptide (CGRP) or its receptor. To date, no pharmacokinetic interactions between these drug classes have been reported. However, patients who suffer from triptan- (or ditan-) induced medication overuse headache or those who are nonresponders to triptans might respond less effectively to mAbs. Caution is warranted when coadministrating these drugs in migraine patients with comorbid cardiovascular disease or with an increased cardiovascular risk profile. In this review, the main mechanisms of action of triptans, ditans and mAbs targeting CGRP or its receptor are summarized as well as the current evidence on their individual risks. Studies on risks and interactions in case of concomitant use of triptans, ditans and mAbs in migraine patients are relatively scarce. Therefore, these aspects have been considered from a theoretical and hypothetical point of view by taking both their overlapping target, CGRP, and contraindications into account.

Migraine treatment and the risk of postoperative, pain-related hospital readmissions in migraine patients.

Migraine treatment may mitigate migraine and associated pain in the perioperative period. The aim of the study was to estimate the effect of perioperative acute and prophylactic migraine treatment on the risk of postoperative 30-day hospital readmission with an admitting diagnosis specifying any pain complaints among migraine patients. Electronic health records were analysed for 21,932 adult migraine patients undergoing surgery between 2005 and 2017 at Beth Israel Deaconess Medical Center and Massachusetts General Hospital in Boston, Massachusetts, USA. Perioperative abortive migraine treatment was defined as guideline-recommended medication (triptan, ergotamine, acetaminophen, nonsteroidal anti-inflammatory drug) prescription after surgery, within 30 days after discharge and prior readmission. Perioperatively continued prophylactic migraine treatment was defined as prescription both prior to surgery and perioperatively for recommended medications (beta-blockers, antidepressants, antiepileptics, onabotulinumtoxin A). Overall, 10,921 (49.8%) patients received a prescription for abortive migraine drugs. Of these, 1.2% and 1.5% of patients with and without such prescription were readmitted for pain, respectively. Patients with abortive treatment had lower odds of pain-related readmission (adjusted odds ratio 0.63 [95% confidence interval 0.49-0.81]). Prophylactic migraine treatment showed no effect on pain-related readmission independently of acute treatment (adjusted odds ratio 0.97 [95% confidence interval 0.72-1.32]). Migraine patients undergoing surgery with a perioperative prescription for abortive migraine drugs were at decreased risk of pain-related hospital readmission.

Gepants for abortive treatment of migraine: A network meta-analysis.

ObjectivesTo evaluate and compare the efficacy and safety of gepants for abortive treatment of migraine by network meta‐analysis.Materials & MethodsPublications, which were randomized controlled trials (RCTs) about gepants for abortive treatment of migraine, were acquired from Pubmed and Cochrane Library. The literatures screening and quality assessment followed the Cochrane handbook. Review manager 5.3 and Addis v1.16.8 were utilized for data analyzing.ResultsTotally, 15 RCTs were included in the network meta‐analysis. The trials enrolled were with high quality. There are 7 treatments were analyzed: BI 44370 TA, MK‐3207, olcegepant, rimegepant, telcagepant, ubrogepant, and placebo. Of these trials, 11,118 patients and 10,917 patients were assigned to one of 7 treatments randomly for efficacy assessment and safety assessment, respectively. In meta‐analysis of direct comparisons, all gepants were superior to placebo in achieving pain freedom 2 hr postdose and only rimegepant and telcagepant were higher than placebo in incidence of any adverse events. In network meta‐analysis, the rank best 3 drugs were olcegepant, BI 44370 TA, and MK‐3207 for efficacy outcomes. And the rank best 3 drugs were BI 44370 TA, placebo, and ubrogepant for safety outcomes.ConclusionGepants were effective for abortive treatment of migraine. The most effective treatment of gepants for migraine might be olcegepant which were administrated transvenously. And all of gepants were safe for migraine treatment with single dose.

Ubrogepant for the treatment of migraine

ABSTRACT Introduction Migraine is a neurovascular disorder involving neurogenic inflammation and transmission of trigeminovascular nociceptive pathways mediated by Calcitonin Gene-Related Peptide (CGRP). Several small molecules antagonizing the CGRP receptor have been developed as migraine-specific acute medications. The CGRP receptor antagonist ubrogepant, also known as MK-1602, has been recently evaluated in phase III clinical trials for clinical efficacy and long-term safety as an abortive migraine treatment. Areas covered This paper discusses the pharmacodynamics, pharmacokinetics, clinical efficacy, safety, and tolerability profile of ubrogepant for the acute treatment of migraine with or without aura. Expert opinion Ubrogepant, a selective CGRP antagonist belonging to the gepants family, has been evaluated in large short- and long-term Phases 2 and 3 clinical trials aimed to assess clinical efficacy and safety as acute migraine medication. It did not significantly affect liver function and was not associated with other serious adverse events. Long-term non-serious adverse events were similar between placebo and ubrogepant. The efficacy was evaluated in large placebo-controlled studies and ubrogepant 50 mg and 100 mg was superior, even if the therapeutic gain seems to be low. Nevertheless, the favorable safety profile compared to other abortive drugs makes ubrogepant a promising option for the acute treatment of migraine.

Targeting CGRP via receptor antagonism and antibody neutralisation in two distinct rodent models of migraine-like pain

Rodent disease models can play an indispensable role in drug development. Confirming that translationally-relevant disease mechanisms are engaged in such models is a crucial facet of this process. Accordingly, we have validated the role of calcitonin gene-related peptide signaling in a mouse model of glyceryl trinitrate-provoked migraine-like pain and a spontaneous rat model of migraine-like pain by assessing their pharmacological responsiveness to the small molecule calcitonin gene-related peptide receptor antagonist olcegepant, and the humanised monoclonal calcitonin gene-related peptide antibody ALD405. Cutaneous sensitivity to hind paw, and periorbital mechanical stimulation were used as surrogate markers of activation of relevant pain pathways in each respective model. Separate experiments were performed to identify the time-course of treatment response to olcegepant (1 mg/kg i.p.) and ALD405 (10 mg/kg i.p.). Olcegepant and ALD405 significantly alleviated cutaneous mechanical hypersensitivity in both models compared with corresponding control treatments (saline and IgG control antibody respectively). As expected, the duration of anti-nociceptive action obtained with ALD405 was considerably longer than that associated with olcegepant. Surprisingly, in the spontaneous rat model the onset of action of ALD405 occurred within just 4 hours after administration. The current data clearly show that calcitonin gene-related peptide-mediated signaling is critically involved in the manifestation of cutaneous hypersensitivity in distinct rodent models of migraine-like pain and emphasise their translational relevance. Moreover, the unexpected rapidity of onset observed for ALD405 supports i) a probable site of action outside the blood-brain barrier, and ii) a potential clinical utility of specific monoclonal calcitonin gene-related peptide antibodies in the abortive treatment of migraine.

Timolol Eyedrops in the Treatment of Acute Migraine Attacks

This randomized, crossover pilot study explores timolol eyedrops as an abortive migraine treatment in adults.

Medical Undergraduate Survey on Headache Education in Singapore: Knowledge, Perceptions, and Assessment of Unmet Needs.

There have been no prior studies assessing the status of undergraduate headache training and education in Singapore. Unmet needs of undergraduate medical students in terms of knowledge-practice gaps pertaining to diagnosis and management of headache disorders are unknown. The possible underemphasis of this aspect of the curriculum as compared to other chronic conditions such as diabetes mellitus has also not been ascertained. The aim of this article is to assess the knowledge base and perceptions, thereby identifying the unmet needs of headache disorder education in undergraduate medical students. Students reported their perceived time that was devoted to the subject matter and this was recorded and reported. In order to provide a comparative indication on the level of prioritization, the total duration within the syllabus dedicated to headache education vs other chronic diseases (using diabetes mellitus as a surrogate) was sought. A comprehensive survey consisting of questions assessing the headache curriculum, knowledge, and perceptions was developed. The questionnaire was distributed to final year medical students attending a full-day Neurology review course in their last semester. Attendees were given the duration of the course to complete the questionnaire, and forms were collected at the end of the day. About 127 final year medical students completed our survey. More than half (55.1%) did not receive formal teaching on how to take a complete headache history. The majority (90.6%) have not attended a headache sub-specialty clinic. The mean total number of hours exposed to headache disorders was 5.69h (SD ± 5.19). The vast majority (96.1%) were unfamiliar with locally published clinical practice guidelines, and a significant proportion (74.0%) were unfamiliar with the third edition (beta) of the International Classification of Headache Disorders. Nearly half (47.2%) were unfamiliar with 'medication overuse headache' as a disease entity. Only one (0.8%) respondent was able to correctly classify all listed primary and secondary headache disorders correctly. Only 37.0% were able to identify all 4 indications (headaches that were new, worsening, and unresponsive to treatment or associated with neurological symptoms) that warranted neuroimaging in a patient with a pre-existing diagnosis of migraine. The antidepressants were the most frequently reported incorrect option for the abortive treatment of migraine (16.5%). Nearly one-fifth (18.9%) were unable to name a single abortive treatment correctly, while a significant proportion (39.4%) could not identify a single correct prophylactic migraine treatment. A large proportion (62.2%) opined that their exposure to 'headache diagnosis and management' was inadequate, with a minority (3.1%) being 'very comfortable' in the diagnosing migraine. A significant proportion felt uncomfortable in treating special population groups diagnosed with migraine - pregnant (79.5%), elderly (48.0%), those with cardiac conditions (51.2%). The current medical undergraduate curriculum on headache disorders in Singapore may harbor significant unmet needs. A review of the syllabus to increase headache education may be one method to address this gap. Further studies in this area are required.

Vagus nerve stimulation suppresses acute noxious activation of trigeminocervical neurons in animal models of primary headache

Vagus nerve stimulation (VNS) has been reported to be effective in the abortive treatment of both migraine and cluster headache. Using validated animal models of acute dural-intracranial (migraine-like) and trigeminal-autonomic (cluster-like) head pain we tested whether VNS suppresses ongoing and nociceptive-evoked firing of trigeminocervical neurons to explain its abortive effects in migraine and cluster headache. Unilateral VNS was applied invasively via hook electrodes placed on the vagus nerve. A single dose of ipsilateral or contralateral VNS, to trigeminal recording and dural-stimulating side, suppressed ongoing spontaneous and noxious dural-evoked trigeminocervical neuronal firing. This effect was dose-dependent, with two doses of ipsilateral VNS prolonging suppression of ongoing spontaneous firing (maximally by ~60%) for up to three hours, and dural-evoked (Aδ-fiber; by ~22%, C-fiber: by ~55%) responses for at least two hours. Statistically, there was no difference between ipsilateral and contralateral groups. Two doses of VNS also suppressed superior salivatory nucleus-evoked trigeminocervical neuronal responses (maximally by ~22%) for 2.5h, to model nociceptive activation of the trigeminal-autonomic pathway. VNS had no effect on normal somatosensory cutaneous facial responses throughout. These studies provide a mechanistic rationale for the observed benefits of VNS in the abortive treatment of migraine and cluster headache. In addition, they further validate these preclinical models as suitable approaches to optimize therapeutic efficacy, and provide an opportunity to hypothesize and dissect the neurobiological mechanisms of VNS in the treatment of primary headaches.

Protective Roles of N-acetyl Cysteine and/or Taurine against Sumatriptan-Induced Hepatotoxicity.

Purpose: Triptans are the drug category mostly prescribed for abortive treatment of migraine. Most recent cases of liver toxicity induced by triptans have been described, but the mechanisms of liver toxicity of these medications have not been clear. Methods: In the present study, we obtained LC50 using dose-response curve and investigated cell viability, free radical generation, lipid peroxide production, mitochondrial injury, lysosomal membrane damage and the cellular glutathione level as toxicity markers as well as the beneficial effects of taurine and/or N-acetyl cysteine in the sumatriptan-treated rat parenchymal hepatocytes using accelerated method of cytotoxicity mechanism screening. Results: It was revealed that liver toxicity induced by sumatriptan in in freshly isolated parenchymal hepatocytes is dose-dependent. Sumatriptan caused significant free radical generation followed by lipid peroxide formation, mitochondrial injury as well as lysosomal damage. Moreover, sumatriptan reduced cellular glutathione content. Taurine and N-acetyl cysteine were able to protect hepatocytes against sumatriptan-induced harmful effects. Conclusion: It is concluded that sumatriptan causes oxidative stress in hepatocytes and the decreased hepatocytes glutathione has a key role in the sumatriptan-induced harmful effects. Also, N-acetyl cysteine and/or taurine could be used as treatments in sumatriptan-induced side effects.

Comparative efficacy of triptans for the abortive treatment of migraine: A multiple treatment comparison meta-analysis

Migraine is the most common neurological condition in developed countries. The abortive treatment of migraine attacks is important both for quality of life and costs associated with illness. Triptans, serotonin 5-HT1B/1D receptor agonists, effectively relieve the pain, disability, and associated symptoms of migraine while improving health-related quality of life. Although a number of direct head-to-head triptan comparisons have been made, data for all possible permutations are not available, and unlikely to ever be so, although in clinical practice such information would be useful. We aimed to determine the relative efficacy of all available triptans to abort migraine headache among patients with previous adequate response to migraine treatments. We included only double-blinded randomized clinical trials comparing triptans to either placebo or another triptan. Our primary outcomes were pain-free response at two hours and 24-hour sustained pain-free response, and our secondary outcomes were headache response at two hours and 24-hour sustained headache response. We used Bayesian multiple treatment comparison meta-analyses of seven triptans used in adult patients to abort migraine attacks. We applied a random-effects analysis with meta-regression adjusting for dose. Results are reported as odds ratios with 95% credible intervals. We included data from 74 randomized clinical trials. All triptans were significantly superior to placebo for all outcomes, with the exception of naratriptan for 24-hour sustained pain-free response. Eletriptan consistently yielded the highest treatment effect estimates. For the two-hour endpoints, eletriptan was statistically significantly superior to sumatriptan, almotriptan, naratriptan, and frovatriptan for at least one of the two outcomes. Rizatriptan yielded the second highest treatment effects followed by zolmitriptan. For the 24-hour endpoints, eletriptan was statistically significantly superior to sumatriptan, rizatriptan, almotriptan, and naratriptan for at least one of the two outcomes. Frovatriptan data were not available at that endpoint. Further, the probability that eletriptan is the most likely of all triptans to produce a favorable outcome was 68% for pain-free response at two hours, and 54% for 24-hour sustained pain-free response. Triptans appear to offer differing treatment effects. In the populations studied eletriptan was most likely to produce pain-free responses that were sustained.