Acute Migraine Attacks Research Articles

Acute headache management in emergency department. A narrative review.

Headache is a significant reason for access to Emergency Departments (ED) worldwide. Though primary forms represent the vast majority, the life-threatening potential of secondary forms, such as subarachnoid hemorrage or meningitis, makes it imperative for the ED physician to rule out secondary headaches as first step, based on clinical history, careful physical (especially neurological) examination and, if appropriate, hematochemical analyses, neuroimaging or lumbar puncture. Once secondary forms are excluded, distinction among primary forms should be performed, based on the international headache classification criteria. Most frequent primary forms motivating ED observation are acute migraine attacks, particularly status migrainous, and cluster headache. Though universally accepted guidelines do not exist for headache management in an emergency setting, pharmacological parenteral treatment remains the principal approach worldwide, with NSAIDs, neuroleptic antinauseants, triptans and corticosteroids, tailored to the specific headache type. Opioids should be avoided, for their scarce effectiveness in the acute phase, while IV hydration should be limited in cases of ascertained dehydration. Referral of the patient to a Headache Center should subsequently be an integral part of the ED approach to the headache patients, being ascertained that lack of this referral involves a high rate of relapse and new accesses to the ED. More controlled studies are needed to establish specific protocols of management for the headache patient in the ED.

Ubrogepant to treat migraine.

Migraine is the primary headache disorder affecting a significant population worldwide. Ubrogepant is an orally bioavailable calcitonin gene-related peptide (CGRP) receptor antagonist (gepant) approved by the U.S. Food and Drug Administration (FDA) for the acute treatment of migraine headaches with or without aura in adults. Ubrogepant is the first oral CGRP receptor antagonist approved for the acute treatment of migraine. CGRP is an important key mediator of migraine pain; CGRP levels have been shown to be significantly higher during a migraine attack. Two pivotal phase III clinical trials (ACHIEVE I and ACHIEVE II) demonstrated effectiveness and safety of ubrogepant in acute migraine attacks. Ubrogepant can be administered as 50- and 100-mg tablets, with a maximum dose of 200 mg within 48 h. Besides minimizing pain, the drug is equally effective in alleviating migraine-associated symptoms such as nausea, photophobia and sound sensitivity. Unlike other gepants, ubrogepant is free from hepatotoxicity at the therapeutic doses. In certain cases (1 in 5), a full relief of pain was achieved with a single dose of the drug. The molecule is not effective as a preventive migraine therapy. The present review discusses the background, preclinical and clinical pharmacology, indication and safety of ubrogepant for the treatment of migraine attacks.

Formulation and Evaluation of Sustained Release Sumatriptan Mucoadhesive Intranasal in-Situ Gel


 Sumatriptan(ST) is a selective agonist at serotonin 5-HTI receptors, as well as 5-HT1B/1D subtypes. It is effective for acute migraine attacks, but has a short half life (about 2 hours) and low oral bioavailability (15%). The purpose of this study was to develop and optimize nasal mucoadhesive in-situ gel(IG) of ST to enhance nasal residence time for migraine management. Cold method was used to prepare different formulas of ST nasal IG, using thermosensitive polymers (poloxamer 407 alone or with poloxamer 188) with a mucoadhesive polymer hyaluronic acid (HA) which were examined for gelation temperature and gelation time, pH, drug content, gel strength, spreadability, mucoadhesive force determination, viscosity, in-vitro drug release, and the selected formula was subjected to fourier transform infrared (FTIR) compatibility studies, and to ex-vivo permeation study, histological evaluation of the sheep mucosal tissue after ST nasal gel application for 6 hours.The results showed that the formula IG7 prepared from poloxamer 407(19%), poloxamer188 (4%) and HA (0.5%) had an optimum gelation temperature (32.66±1.52°C), gel strength (43.66± 1.52 sec), mucoadhesive force (8067.93± 746.45dyne\cm2), in-vitro drug release (95.98%) over 6h, ex-vivo permeation study (89.6%) during the 6 h. study with no histological or pathological change in the nasal sheep tissue and no interaction between drug and other additives in IG7. Formulation of ST as a nasal insitu gel to avoid first pass metabolism and ease of administration coupled with less frequent and sustained drug release, will enhance patient compliance.

Profiling lasmiditan as a treatment option for migraine

ABSTRACTIntroduction: In recent years, research into acute migraine treatment has aimed to develop molecules capable of inhibiting trigeminal pathways, mediated by agonism to 5-HT1F receptors in order to avoid the vasoconstrictive action due to the stimulation of 5-HT 1B/1D receptors. A novel migraine drug class, called ‘neurally acting anti-migraine agents’, has been developed for the management of acute migraine attacks. Lasmiditan is the only compound of this drug class that has been evaluated in Phase III clinical trials.Areas covered: This review discusses lasmiditan including its pharmacokinetics, pharmacodynamics, efficacy and safety profile. Original research and review articles, relative to the period 2010–2019, were included in the reviewed literature.Expert opinion: The most recent phase III trials have demonstrated the efficacy of lasmiditan for acute migraine treatment, even if compared only with placebo. Nevertheless, the low rate of cardiovascular side effects with lasmiditan might offer a potential therapeutic option for migraine patients with cardiovascular disorders. With the lack of data on lasmiditan’s pharmacokinetic features, several phase I clinical trials are still ongoing in order to evaluate half-life, metabolism, excretion and the potential production of active metabolites. Possible pharmacodynamic interaction with drugs acting on central nervous system should be evaluated in future studies.

Headache and Methemoglobinemia

This basic review is intended to summarize the current knowledge of methemoglobinemia as an important cause of secondary headache with the hope of generating a growing interest in studying this phenomenon. We describe the pathological underpinnings of headaches generated by hypoxia. Possible mechanisms include cerebral vasodilation-associated stretching of the vessel nociceptors, sensitization of perivascular nociceptors mediated by nitric oxide, cerebral calcitonin gene-related peptide, activation of the cyclic adenosine monophosphate pathway, cortical spreading depression, disruption of the blood-brain barrier, and neurogenic inflammation. We review the clinical features, pathophysiology, and management of methemoglobinemia. We conducted a literature review of reports of symptomatic methemoglobinemia with headache. In addition, we describe a case report of a patient who presented with an acute onset of severe holocranial headache associated with rapidly progressive perioral paresthesia, cyanosis in lips and hands, nausea, and mild dyspnea on exertion. These features can be misinterpreted as an acute attack of migraine with pain-related hyperventilation syndrome and anxiety leading to clinically detrimental delay in the management of the progressive hypoxia. Her symptoms resolved following treatment with methylene blue. The complex relationship of migraine and hypoxia-related headaches is also reviewed. We propose that methemoglobinemia-associated headaches are possibly generated by stretching of the nociceptor nerve endings during cerebral vasodilation and hypoxia-mediated oxidative stress. The case highlights the need to broaden the formulated differential diagnosis of an acute onset severe holocranial headache and pay careful attention to other signs and symptoms that may provide hints on potential mechanism(s) for secondary headaches. We provide justification for the need to incorporate "Headache attributed to Methemoglobinemia" as a subtype under the section "Headache attributed to hypoxia and/or hypercapnia" of the International Classification of Headache Disorders to support clinical decision making.

Abnormal neurovascular coupling as a cause of excess cerebral vasodilation in familial migraine.

Acute migraine attack in familial hemiplegic migraine type 2 (FHM2) patients is characterized by sequential hypo- and hyperperfusion. FHM2 is associated with mutations in the Na, K-ATPase α2 isoform. Heterozygous mice bearing one of these mutations (α2+/G301R mice) were shown to have elevated cerebrovascular tone and, thus, hypoperfusion that might lead to elevated concentrations of local metabolites. We hypothesize that these α2+/G301R mice also have increased cerebrovascular hyperaemic responses to these local metabolites leading to hyperperfusion in the affected part of the brain. Neurovascular coupling was compared in α2+/G301R and matching wild-type (WT) mice using Laser Speckle Contrast Imaging. In brain slices, parenchymal arteriole diameter and intracellular calcium changes in neuronal tissue, astrocytic endfeet, and smooth muscle cells in response to neuronal excitation were assessed. Wall tension and smooth muscle membrane potential were measured in isolated middle cerebral arteries. Quantitative polymerase chain reaction, western blot, and immunohistochemistry were used to assess the molecular background underlying the functional changes. Whisker stimulation induced larger increase in blood perfusion, i.e. hyperaemic response, of the somatosensory cortex of α2+/G301R than WT mice. Neuronal excitation was associated with larger parenchymal arteriole dilation in brain slices from α2+/G301R than WT mice. These hyperaemic responses in vivo and ex vivo were inhibited by BaCl2, suggesting involvement of inward-rectifying K+ channels (Kir). Relaxation to elevated bath K+ was larger in arteries from α2+/G301R compared to WT mice. This difference was endothelium-dependent. Endothelial Kir2.1 channel expression was higher in arteries from α2+/G301R mice. No sex difference in functional responses and Kir2.1 expression was found. This study suggests that an abnormally high cerebrovascular hyperaemic response in α2+/G301R mice is a result of increased endothelial Kir2.1 channel expression. This may be initiated by vasospasm-induced accumulation of local metabolites and underlie the hyperperfusion seen in FHM2 patients during migraine attack.

Evaluate Efficacy & Safety of Eptinezumab Administered Intravenously in Subjects Experiencing Acute Attack of Migraine

Evaluate Efficacy & Safety of Eptinezumab Administered Intravenously in Subjects Experiencing Acute Attack of Migraine

Acupuncture methods for acute migraine attack: a Bayesian network meta-analysis protocol

IntroductionMigraine is a primary cause of disability worldwide, particularly affecting young adults and middle-aged women. Although multiple clinical trials and systematic reviews have suggested that acupuncture could be effective in...

Hypothalamic regulation of headache and migraine.

The clinical picture, but also neuroimaging findings, suggested the brainstem and midbrain structures as possible driving or generating structures in migraine. This has been intensely discussed in the last decades and the advent of modern imaging studies refined the involvement of rostral parts of the pons in acute migraine attacks, but more importantly suggested a predominant role of the hypothalamus and alterations in hypothalamic functional connectivity shortly before the beginning of migraine headaches. This was shown in the NO-triggered and also in the preictal stage of native human migraine attacks. Another headache type that is clinically even more suggestive of hypothalamic involvement is cluster headache, and indeed a structure in close proximity to the hypothalamus has been identified to play a crucial role in attack generation. It is very likely that spontaneous oscillations of complex networks involving the hypothalamus, brainstem, and dopaminergic networks lead to changes in susceptibility thresholds that ultimately start but also terminate headache attacks. We will review clinical and neuroscience evidence that puts the hypothalamus in the center of scientific attention when attack generation is discussed.

Sumatriptan Increases Skin Flap Survival through Activation of 5-Hydroxytryptamine 1b/1d Receptors in Rats: The Mediating Role of the Nitric Oxide Pathway.

Random pattern skin flaps are applicable for reconstructing any defect in plastic surgery. However, they are difficult to apply because of necrosis. Sumatriptan, a selective 5-hydroxytryptamine 1b/1d agonist, is routinely used to offset acute migraine attacks. Recent studies have suggested that sumatriptan may induce vasodilation at lower concentrations. The authors' aim is to investigate the effect of sumatriptan on skin flap survival and the role of nitric oxide in this phenomenon. Seventy-two male Sprague-Dawley rats were divided into eight groups. Increasing doses of sumatriptan (0.1, 0.3, and 1 mg/kg) were given intraperitoneally to three different groups after dorsal random pattern skin flaps were performed. To assess the exact role of 5-hydroxytryptamine 1b/1d receptors, GR-127935 was administered solely and with sumatriptan. N-ω-nitro-L-arginine methyl ester (L-NAME, a nonselective nitric oxide synthase inhibitor) was used to evaluate any possible involvement of nitric oxide in this study. All rats were examined 7 days later. The authors' results demonstrated that flap survival was increased by lower doses of sumatriptan compared to a control group for both 0.3 mg/kg (p = 0.03, mean difference = 32, SE = 8) and 0.1 mg/kg (p = 0.02, mean difference = 26, SE = 8). This protective effect was eliminated by coadministration of GR-127935 or N-ω-nitro-L-arginine methyl ester with sumatriptan. Histopathologic studies revealed a significant increase in capillary count and collagen deposition and a decreased amount of edema, inflammation, and degeneration. Sumatriptan in lower concentration increases skin flap survival by means of activation of 5-hydroxytryptamine 1b/1d receptors. This effect is mediated through the nitric oxide synthase pathway.

Pentraxin 3 level in acute migraine attack with aura: Patient management in the emergency department

ObjectivesWe investigated the state of inflammation, PTX3 level and other routine inflammatory markers (high sensitivity C-reactive protein [hsCRP], and white blood cells [WBC]), in patients who presented to the emergency department (ED) with migraine. We also investigated the relationship between the clinical presentation, PTX3 level, and other routine inflammatory markers in the emergency management of these patients. MethodsThe study included 44 patients (group 1) who presented to the ED due to a migraine attack with aura and 44 controls (group 2) with similar demographic characteristics. ResultsThe WBC count was 8.82 ± 2.10 × 109/L in group 1 and 7.85 ± 2.04 × 109/L in group 2. The mean PTX3 level was 11.57 ± 3.99 ng/mL in patients who presented at the ED with a migraine attack, and 4.59 ± 1.28 ng/mL in controls. The differences values of WBC and PTX3 between the two groups were significant (respectively; P = 0.031, P < 0.001). ROC analyses indicated significant results for PTX3 as a marker for acute migraine attack. It had a sensitivity of 93% and specificity of 84% at a cut-off value of 5.80 ng/mL. ConclusionThis is the first study to investigate plasma levels of PTX3 in patients with acute migraine. PTX3 as a biomarker may be used as an additional examination to the current subjective criteria to support the diagnosis of patients presenting to the ED with an acute migraine attack.

When Clinical History Addresses the Diagnosis in a Case of Uncommon Meningitis

Migraine pain is usually cyclic and may be evocated by inflammatory mediators released around the nerves and blood vessels. Acute migraine pain is more common in women than in men, and correlates with age. In this study, we report the development of an acute migraine attack in a young man (32 years old), which led to his admission to the emergency department. The positive functional brain changes recorded by electroencephalogram (EEG) during the migraine attack, and the non-contrast brain computed tomography scan showed the presence of an arachnoid cyst, which explained the acute migraine attack inducing a misdiagnosis. Using the case described herein, we aim to draw the attention of clinic/scientific communities toward the existence of brain infections in absence of the typical symptoms (e.g., fever and/or rigor nucalis). Considering this case, we propose that when a diagnosis is uncertain the invasive liquor test should be performed.

Comparing the Therapeutic Effects of Dexamethasone-Metoclopramide with Ketorolac in Relieving Headache in Patients with Acute Migraine Attacks Presenting to the Emergency Department.

Introduction:Migraine is a frequent chief complaint of patients in the emergency department. A wide range of treatments are used for acute migraine. Objective:This study aimed to compare the therapeutic effects of a combination of metoclopramide + dexamethasone with those of ketorolac for treatment of acute migraine in the emergency department. Method:This quasi-experimental study enrolled patients identified as migraine headache cases admitted to the emergency departments of Shohadaye Tajrish and Sina hospitals, Tehran, Iran. The patients were divided into two groups and treated with either 8 mg Dexamethasone + 10 mg Metoclopramide or 60 mg ketorolac, and then compared regarding the rate of pain control based on visual analogue scale (VAS) on arrival and 1 and 2 hours afterward.Results:Overall, 86 patients were recruited, of whom 50 were male (58.1%). Their mean age was 37.6 ± 10.3 years. Thirty-five (40.7%) were in the ketorolac group and 51 (59.3%) were in the dexamethasone + metoclopramide group. Treatment success was defined as a reduction of at least 3 points in pain severity in comparison to the admission time. One hour after administration of medications, the reported pain intensity was 4.7 ± 2.0 and 6.2 ± 2.3 in ketorolac group and dexamethasone + metoclopramide group, respectively. By the second hour, pain intensity was 3.4 ± 1.2 and 2.9 ± 1.3 in ketorolac group and dexamethasone + metoclopramide group, respectively. The two groups did not show a significant difference in terms of the reported pain at this time (p= 0.04).Conclusion:Based on our findings, the pain reduction time was relatively shorter for ketorolac in acute migraine, but the final response was identical in the two groups.

Novel Approaches to the Development of Antimigraine Drugs: A Focus on 5-HT2A Receptor Antagonists

The review is devoted to promising directions of the search for chemical compounds which can be used as the basis for the development of new drugs for migraine treatment. It considers promising biological targets, whose effects are capable of eliminating the manifestations of acute migraine attacks, and also indicates the main existing developments in the form of chemical compounds and drug prototypes interacting with these targets, including those that will soon enter or are at the stage of clinical trials. In particular, preclinical and clinical data on compounds whose effects are determined by the influence on the calcitonin gene-related peptide (CGRP) receptors, serotonin 5-HT2A and 5-HT1F receptors, NO-synthase, orexin and glutamate receptors, are discussed. The review focuses on the description of 5-HT2A receptors as a promising target for the development of novel antimigraine drugs. Information about the structural features of this serotonin receptor subtype, the localization and functions is given; also it involves the pharmacological capabilities of new substances affecting 5-HT2A receptors. The final part of the review is devoted to new trends in the search for 5-HT2A antagonists among compounds synthesized based on a serotonin bioisostere, benzimidazole.

The treatment of migraine patients with triptans – is there a need for further Rx-to-OTC switches?

Abstract Objective The disease migraine affects a large share of the German population and is linked to a high economic potential in terms of direct and indirect sickness costs. Triptans are the recommended treatment in the case of an acute migraine attack. Both, the disease and its appropriate treatment are of interest in the context of self-medication and Rx-to-OTC switch efforts. Therefore, a survey was carried out with the intention to collect data among migraine patients regarding the use of analgesics in general and of triptans specifically. This data can be the basis for further health economic considerations. Methods By an online survey among 206 migraine patients, different data regarding patients suffering from migraine, the frequency and sort of symptoms and the use of analgesics in general as well as triptans specifically was collected and analysed. A special focus was on symptoms affecting patients’ productivity, their use of triptans and their satisfaction with the current supply situation with triptans. Results The survey revealed among other findings that most patients suffer from symptoms which limit their productivity or their ability to work and make an immediate treatment necessary. Most patients know well about their disease and feel able to treat themselves in the context of self-medication once they are diagnosed by a physician. In this context a demand for further triptans available without a prescription could be identified. This is specifically, because patients respond differently to various triptans. Therefore, a larger variety of prescription free triptans would increase the number of patients with access to OTC triptans significantly. Conclusion Most survey respondents know well about their disease and the appropriate treatment and feel able to treat themselves within the scope of self-medication. Nevertheless, they mostly respond to one triptan only. In the case of an acute migraine attack an immediate treatment is required, ideal is an intake of triptans as soon as first symptoms occur. In this context pharmacies play an important role as fast and low-threshold access point to medications. Because only a limited number of patients responds to the already prescription free available triptans, there is a demand for further Rx-to-OTC switches of triptans among migraine patients which should be considered in further switch efforts in Germany.

Pharmacologic Characterization of ALD1910, a Potent Humanized Monoclonal Antibody against the Pituitary Adenylate Cyclase-Activating Peptide.

Migraine is a debilitating disease that affects almost 15% of the population worldwide and is the first cause of disability in people under 50 years of age, yet its etiology and pathophysiology remain incompletely understood. Recently, small molecules and therapeutic antibodies that block the calcitonin gene-related peptide (CGRP) signaling pathway have reduced migraine occurrence and aborted acute attacks of migraine in clinical trials and provided prevention in patients with episodic and chronic migraine. Heterogeneity is present within each diagnosis and patient's response to treatment, suggesting migraine as a final common pathway potentially activated by multiple mechanisms, e.g., not all migraine attacks respond to or are prevented by anti-CGRP pharmacological interventions. Consequently, other unique mechanisms central to migraine pathogenesis may present new targets for drug development. Pituitary adenylate cyclase-activating peptide (PACAP) is an attractive novel target for treatment of migraines. We generated a specific, high-affinity, neutralizing monoclonal antibody (ALD1910) with reactivity to both PACAP38 and PACAP27. In vitro, ALD1910 effectively antagonizes PACAP38 signaling through the pituitary adenylate cyclase-activating peptide type I receptor, vasoactive intestinal peptide receptor 1, and vasoactive intestinal peptide receptor 2. ALD1910 recognizes a nonlinear epitope within PACAP and blocks its binding to the cell surface. To test ALD1910 antagonistic properties directed against endogenous PACAP, we developed an umbellulone-induced rat model of neurogenic vasodilation and parasympathetic lacrimation. In vivo, this model demonstrates that the antagonistic activity of ALD1910 is dose-dependent, retaining efficacy at doses as low as 0.3 mg/kg. These results indicate that ALD1910 represents a potential therapeutic antibody to address PACAP-mediated migraine.

Acute migraine therapy with external trigeminal neurostimulation (ACME): A randomized controlled trial.

ObjectiveTo assess the safety and efficacy of external trigeminal nerve stimulation for acute pain relief during migraine attacks with or without aura via a sham-controlled trial.MethodsThis was a double-blind, randomized, sham-controlled study conducted across three headache centers in the United States. Adult patients who were experiencing an acute migraine attack with or without aura were recruited on site and randomly assigned 1:1 to receive either verum or sham external trigeminal nerve stimulation treatment (CEFALY Technology) for 1 hour. Pain intensity was scored using a visual analogue scale (0 = no pain to 10 = maximum pain). The primary outcome measure was the mean change in pain intensity at 1 hour compared to baseline.ResultsA total of 109 participants were screened between February 1, 2016 and March 31, 2017. Of these, 106 patients were randomized and included in the intention-to-treat analysis (verum: n = 52; sham: n = 54). The primary outcome measure was significantly more reduced in the verum group than in the sham group: −3.46 ± 2.32 versus −1.78 ± 1.89 (p < 0.0001), or −59% versus −30% (p < 0.0001). With regards to migraine subgroups, there was a significant difference in pain reduction between verum and sham for ‘migraine without aura’ attacks: mean visual analogue scale reduction at 1 hour was −3.3 ± 2.4 for the verum group versus −1.7 ± 1.9 for the sham group (p = 0.0006). For ‘migraine with aura’ attacks, pain reduction was numerically greater for verum versus sham, but did not reach significance: mean visual analogue scale reduction at 1 hour was −4.3 ± 1.8 for the verum group versus −2.6 ± 1.9 for the sham group (p = 0.060). No serious adverse events were reported and five minor adverse events occurred in the verum group.ConclusionOne-hour treatment with external trigeminal nerve stimulation resulted in significant headache pain relief compared to sham stimulation and was well tolerated, suggesting it may be a safe and effective acute treatment for migraine attacks.Study protocolClinicalTrials.gov Identifier: NCT02590939.

Pain Management Using Acupuncture Method in Migraine Headache Patients; A Single Blinded Randomized Clinical Trial.

BackgroundThere were numerous studies using acupuncture for pain relief and in most, the effect of this technique on preventing migraine attacks has been investigated. In those several studies that surveyed the effect of acupuncture on treatment of migraine headaches, the conclusion was not completely persuaded and they suggested further researches on this topic.ObjectivesThe purpose of this study is to examine the effect of acupuncture on controlling acute migraine attacks.MethodsThis study was a single blinded randomized clinical trial that was conducted on patients with a diagnosis of acute migraine attacks. At the time of reference, the patient’s pain intensity was measured and recorded in a written checklist. Acupuncture was done in the intervention group with thin metallic needles, which enter certain points in the ear’s skin; including shen men, autonomic, thalamus, frontal, and temple. In the placebo group, similar needles were used, however, they were inserted into unusual points. Thereafter, in 30 minutes, one, two, and four hours after the treatment, the pain intensity was also asked and compared with the reference time’s score.ResultsA total of 60 patients with the mean age of 31.4 ± 7.6 years were enrolled and 83.3% of them were women. There was no significant difference between two groups in terms of the baseline characteristics of participants including age, sex and pain duration before admission (P > 0.05). According to the results, there was a significant difference between the two groups on the checkpoints of 15, 30, 45, and 60 minutes after acupuncture (P < 0.05); however, the pain scores were not statistically different between the two groups on two, three, and four hours after intervention (P > 0.05).ConclusionsBased on the findings of our study, although the pain score was lower in the intervention group than the control group during first hour after the acupuncture, there was no significant change in pain score thereafter. Comparison of the two groups showed no differences between acupuncture and placebo acupuncture on decreasing the mean pain score.

Identifying and managing acute migraine attacks in adults.

Paul Bates, Senior Lecturer/Advanced Nurse Practitioner, University of Lincoln, pbates@lincoln.ac.uk , explains the most common symptoms, triggers and treatments of migraine, and the role of the nurse in patient care.

Modulation of tetrodotoxin-resistant Na+ channels by amitriptyline in dural afferent neurons

Migraine is characterized by recurrent and disabling headaches; therefore, several drugs have been widely prescribed to prevent acute migraine attacks. Amitriptyline, a tricyclic antidepressant, is among the most commonly administered. It is poorly known, however, whether amitriptyline modulates the excitability of dural afferent neurons that transmit pain signals from the dura mater. In this study, the effects of amitriptyline on tetrodotoxin-resistant (TTX-R) Na+ channels were examined in acutely isolated rat dural afferent neurons, which were identified by the fluorescent dye DiI. The TTX-R Na+ currents (INa) were recorded from medium-sized DiI-positive neurons using a whole-cell patch clamp technique. Amitriptyline (3 μM) slightly reduced the peak component of transient INa and induced a marked decrease in the steady-state component of transient TTX-R INa, as well as in the slow ramp-induced TTX-R INa. Our findings suggest that amitriptyline specifically inhibits persistent Na+ currents mediated by TTX-R Na+ channels. While amitriptyline had minor effects on voltage-activation/inactivation, it increased the extent of the use-dependent inhibition of TTX-R Na+ channels. Amitriptyline also affected the inactivation kinetics of TTX-R Na+ channels by significantly accelerating the inactivation of TTX-R Na+ channels and slowing the subsequent recovery. Amitriptyline decreased the number of action potentials by increasing the threshold for their generation. In conclusion, the amitriptyline-mediated diverse modulation of TTX-R Na+ channels would be, at least in part, responsible for its prophylactic efficacy for migraine attacks.