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Sepsis is a severe systemic inflammatory response with high mortality rate resulting from different microorganisms. Cytokines activation is essential for the immune response, but in painful conditions like sepsis, cytokines act as a double-edged sword and dysregulate immune response which is life-threatening owing to multiple organ dysfunction. The abnormality in 5-HT function is involved in pathological conditions like irritable bowel syndrome, inflammation, myocardial ischemia, itch and renal injury. Sumatriptan, a 5-HT1B/1D agonist, has anti-inflammatory and anti-oxidative stress effects on animal models. This study was aimed to assess the effects of sumatriptan on kidney injury, the levels of pro-inflammatory cytokines and the percentage of survival in (CLP)-induced sepsis were examined.Cecal ligation and puncture (CLP) model was done on adult C57BL/6 male mice to induce Polymicrobial sepsis. Sumatriptan was injected intraperitoneally 1 h after the sepsis induction by CLP at doses of 0.1, 0.3, and 1 mg/kg in 3 treatment groups. To study the effect of sumatriptan on short-term survival, septic animals were detected 72 h after CLP. Serum levels of TNF-α, IL-1β, IL-6 and IL-10 were evaluated. To study sepsis-induced acute renal failure, kidney functional biomarkers and histopathological alterations were evaluated.Sumatriptan (0.3 mg/kg) administration significantly enhanced survival rate (PAnti-inflammatory effects of sumatriptan lead to decrease mortality rate and inflammatory cytokines in CLP induction sepsis in C57BL/6 mice.

In this case study, we explore a case of bilateral acute angle closure (AAC) attack detected in a 52-year-old female patient with no other ophthalmic background or predisposition to angle closure, following an increase of her regular sumatriptan dose used for migraine relief. Even though the initial presentation was misinterpreted as migraine attack, it nevertheless alerted the treating physicians to immediate cessation of the drug, allowing for the pertinent ocular symptomatology to be unveiled. Drug-induced bilateral AAC is a rare occurrence and can lead to significant ocular morbidity if not detected and treated early. Clinicians of emergency care should be aware of this uncommon association, as prompt ophthalmology input is vital. Interestingly, although it would be anticipated that people prone to angle closure attack after sumatriptan intake would exhibit symptoms after initiation of the drug, our patient suffered an attack while on long-term treatment and following dose increase.

The most comfortable and choicely path of drug administration is oral route. Orodispersible tablets bring a revolution among all routes of drug administration as well as oral route of drug administration also. Orodispersible tablets are unit dosage form but it has unique characteristics. It disintegrates in the mouth within a minute for the presence of saliva where the presence of super disintegrates in the preparation. Especially, old and child have no chance to swallow as a result it is very acceptable for them. Migraine is a very well-known irritating condition for adult and female. Migraine is a debilitating and common neurovascular illness associated with symptoms of one-sided headache, nausea with or without vomiting, photophobia and/or phonophobia. But these symptoms are subjective and vary from patient to patient. Orodispersible tablets are most important solution of migraine like emergency condition and helping human by transferring from hell to heaven. Very short half-life, quick disintegration, quick onset of action and better bioavailability brings the orodispersible tablets into the top position of the management of migraine. Sumatriptan, zolmitriptan like drugs are helping their hands to reduce migraine. Lastly, there are lots of drugs are investigating for this purpose and our hope that the orodispersible tablet can give the pioneer and will give the migraine free era to us and our futures. Keywords: Orodispersible tablet, migraine, sumatriptan, super disintegrate, fast dissolving

AIM To describe the clinical characteristics and therapeutic options available to paediatric patients with cluster headache. METHOD Based on a literature search of the medical databases PubMed, LILACS, and Web of Science and using selected descriptors, we carried out a systematic review of case reports on cluster headache in paediatric patients published from 1990 to 2020. RESULTS Fifty-one patients (29 males, 22 females) with a mean (SD) age of 9 years 7 months (3y 10mo; range 2-16y) were diagnosed with cluster headache. The mean (SD) diagnosis was made 27.8 months (26.2mo) after the onset of cluster headache. Pain occurred at night or on waking up (76.5%) and consisted of 1 to 3 attacks per day (62.7%) lasting 30 to 120 minutes (68.6%). Headaches were unilateral (90.2%), had a pulsatile character (64.7%), and severe intensity (100%). There were autonomic manifestations (90.2%) predominantly ipsilateral to pain, in this order: lacrimation; conjunctival injection; nasal congestion; ptosis; eyelid oedema; and rhinorrhoea. Sumatriptan and oxygen inhalation were the most effective treatments for acute manifestation. Prophylaxis, corticosteroids, verapamil, and gabapentin were the most effective drugs. INTERPRETATION Due to the small number of published studies, this review could not provide reliable data; however, it appears that cluster headache in children and adolescents is similar to adults, both in clinical characteristics and treatment. What this paper adds Cluster headache in children and adolescents is poorly studied. Cluster headache is uncommon before 10 years of age and diagnosis is difficult in the first few years of life. Treatment of cluster headache in children and adolescents is similar to that used in adults. The notion of the effectiveness of prophylactic treatment is based only on authors' experience.

Background: Migraine is a common neurological disorder that affects the quality of life and causes several health problems. Preventive migraine treatment can reduce migraine frequency, headache severity, and health care costs. This study aimed to estimate the utilization of migraine preventive therapy and associated factors in eligible patients. Methods: We studied 534 patients with migraine who were eligible for migraine preventive therapy using 2017 National Patient Sample (NPS) data from the Health Insurance Review and Assessment Service (HIRA). We estimated the migraine days by calculating the monthly average number of defined daily dose (DDD) of migraine-specific acute drug. Patients with a monthly average number of DDD of 4 or more were considered as subjects for preventive treatment. Chi-square test and multiple logistic regression analysis were used to determine the association between the preventive therapy and the influencing variables. Results: Less than half of the eligible patients for prophylaxis (n=234, 43.8%) were prescribed preventive therapy. Multiple logistic regression results show that migraine preventive therapy was influenced by age, the type of migraine, and some comorbidities. Patients over the age of 50 tend to receive less prophylactic treatment than under the age of 40. On the other hand, migraine patients with epilepsy or depression were more likely to receive preventive therapy. Sumatriptan was the most preferred medication for acute treatment, and propranolol was the most commonly prescribed drug for prevention. Conclusions: More than half of the patients who were candidates for migraine prophylaxis were not receiving suitable preventive treatment. Positive factors affecting the use of migraine prevention were the presence of comorbidities such as epilepsy and depression.

Background The efficacy of triptans as the main acute treatment strategy for migraine headache at the population-wide level needs to be understood to inform clinical decision-making. We summarise key trends in triptan use using more than 25 years of Danish nationwide data. Methods We conducted a nationwide register-based cohort study based on all Danish residents with access to public healthcare between 1 January 1994 and 31 October 2019 and summarise informative trends of all purchases of triptans in Denmark in the same period. Complete purchase records of Sumatriptan, Naratriptan, Zolmitriptan, Rizatriptan, Almotriptan, Eletriptan, and Frovatriptan were used. Findings Over a 25-year period, triptan use increased from 345 to 945 defined daily doses (DDD) per 1000 inhabitants per year and the yearly prevalence of triptan use increased from 5.17 to 14.57 per 1000 inhabitants. Between 2014 and 2019, 12.3% of the Danish migraine population purchased a triptan. Following their initial purchase, 43% of patients had not repurchased triptans within 5 years. At most, 10% of patients indicating triptan discontinuation tried more than one triptan. The prevalence of triptan overuse, defined as having purchased at least 20 DDDs of triptans per month for 3 consecutive months, increased in parallel with the prevalence of triptan use, prevalent in 56 of every 1000 triptan users every year between 2014 and 2019. Interpretation In a cohort with access to free clinical consultations and low medication costs, we observed low rates of triptan adherence, likely due to disappointing efficacy and/or unpleasant side effects rather than economic considerations. Triptan success continues to be hindered by poor implementation of clinical guidelines and high rates of treatment discontinuance.

The cost analysis for the relief of migraine attack using selective 5HT1-receptor agonists (frovatriptan, zolmitriptan, risatriptan, sumatriptan) of domestic and imported manufacturers in various dosages and forms of production in the proposed resource online pharmacy chains of Lviv for their efficient and cost effective applications. Among the registered drugs, most dosage forms and trade names are presented for sumatriptan; slightly less for risatriptan and zolmitriptan; for frovatriptan is only one trade name. It has been found that to relieve migraine attack with domestic drugs will be cheaper for patients than imported. Packaging with the same dosage of active ingredient, but with more tablets in the blister is more cost effective for patients. It`s the most economical to stop the migraine attack with Stopmigren (sumatriptan) at a dosage of 50 mg, packing 6 tablets in a blister, and the most valuable drug is Rapimig (zolmitriptan) at a dosage of 50 mg, packing 6 tablets in a blister.

Objective To determine whether early treatment with sumatriptan can prevent PACAP38-induced migraine attacks. Methods A total of 37 patients with migraine without aura were enrolled between July 2018 to December 2019. All patients received an intravenous infusion of 10 picomole/kg/min of PACAP38 over 20 min followed by an intravenous infusion of 4 mg sumatriptan or placebo over 10 min on two study days in a randomised, double-blind, placebo-controlled, crossover study. Results Of 37 patients enrolled, 26 (70.3%) completed the study and were included in analyses. Of the 26 patients, four (15%) developed a PACAP38-induced migraine attack on sumatriptan and 11 patients (42%) on placebo ( p = 0.016). There were no differences in area under the curve for headache intensity between sumatriptan (mean AUC 532) and placebo (mean AUC 779) ( p = 0.35). Sumatriptan significantly constricted the PACAP38-dilated superficial temporal artery immediately after infusion (T30) compared with infusion of placebo ( p

We present 2 cases of rosacea that were successfully managed with off-label treatment. The first is a case of painful, exuding papulopustular lesions of the nose treated with rifaximin, and the other is a case of severe, debilitating and painful flushing treated with sumatriptan. The cases support previous notions that gastrointestinal comorbidities may be related to papulopustular lesions and that flushing may be related to neurogenic inflammation and migraine. The cases also imply that a new approach to rosacea management, based on endotypes and comorbidities, may be warranted.

Aim: The migraine pathology is still not explained effectively. There is a common relationship between anxiety, depression, and migraine. So the aim of the study to illustrate effectively the behavioural and biomarker changes in the migraine condition. Methods: Nitroglycerin (NTG) induced migraine rats model was used the present study. Twenty-five male Wistar rats were randomly divided into five groups. Ergotamine, sumatriptan, and BIBN4096 were used as antimigraine drugs. The behavioural activity was measured by scratching head, body shaking, and social interaction task. ELISA detected biomarkers like interleukin 6 (IL-6), Substance P (SP) and 5-hydroxytryptamine (5-HT) in various rats brain regions such as cortex, brain stem, trigeminal ganglion. Results: A significant reduction in hyperalgesic response and behavioral changes like scratching head, body shaking and social interaction task. Biomarkers like 5-HT, SP and IL-6 were significantly reduced in the various brain regions such as prefrontal cortex, brain stem and trigeminal ganglia of the rats in the BIBN4096 treated groups. Conclusion: The present study showed a good antimigraine efficacy with a calcitonin gene-related peptide (CGRP) antagonistic agent BIBN4096 than ergotamine and sumatriptan but still lack of behavioural pattern, need to explore nonpharmacological intervention along with the drug treatment.

Background: The pathogenesis of migraine pain has not yet been adequately explained. The incidence of cognitive dysfunction and psychological symptoms, as well as their reciprocal relationships in migraine patients, is still under consideration. The study aims to characterise the neurobehavioral and molecular changes that occur during a migraine condition. Methods: For the present study, nitro-glycerine (NTG)- induced rats were treated with antimigraine drugs such as ergotamine, sumatriptan, as well as BIBN4096. The pain was measured by the hot plate method, and the motor activity was assessed using actophotometer. The neurobehavioural activities were tested by using open field, elevated plusmaze and forced swim test. Vasoactive substances such as NO and CGRP were detected in the plasma and CGRP was detected in the isolated parts of the rat’s brain. Analysis of the proinflammatory marker such as TNF-α was carried out in the serum. Histopathological changes of the animal brain were identified using Cresyl violet (Nissl body) staining. Results: A significant analgesic activity was observed with BIBN4096 (p

PURPOSE: The purpose of this report was to describe a case with paracentral acute middle maculopathy after oral intake of sumatriptan. METHODS: Case presentation. RESULTS: One patient showed typical findings on fundoscopic examination and optical coherence tomography consistent with paracentral acute middle maculopathy following oral intake of sumatriptan. CONCLUSION: Sumatriptan may be a trigger for paracentral acute middle maculopathy. ispartof: Retin Cases Brief Rep vol:16 issue:2 pages:180-182 ispartof: location:United States status: published

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by thunderclap headache and reversible constriction of intracranial arteries; it may present with immediate or delayed neurologic deficits related to brain edema, ischemic or hemorrhagic stroke, or seizure.

Purpose A national primary and secondary healthcare-level study in the Czech Republic has not yet been conducted to evaluate the prevalence of migraine. We analyzed the current treatment patterns (acute and prophylactic) in migraine patients and the number of migraine patients potentially eligible for treatment with recent calcitonin gene-related peptide (CGRP) pathway-targeted therapies. Methods This retrospective study utilized the Ministry of the Interior Health Insurance Fund claims database of the Czech Republic wherein every citizen is insured. Migraine patients with or without aura, and potentially on triptan therapy were included in this study (index years 2012-2016). The prevalence approach included all patients (new and old) present in each index year. Prophylactic therapies were followed f0or three and seven years prior to the index year, including the index year, until 2010. The incidence approach included all patients first diagnosed in each index year. Prophylactic therapies were followed for the next three years, including the index year, until 2017 following incidence approach. The primary endpoint of this study was to determine the rate of migraine prevalence and diagnosis for each index year during the period 2012-2016. The study also evaluated prophylactic and acute treatment patterns and comorbidities among patients in 2016. Results The rate of migraine prevalence was 1% and the rate of diagnosis was 0.2-0.4%. By prevalence approach, approximately 39% of the patients were on prophylactics, and 11.2% and 21.6% of the patient population had two prior treatment failures (three- and seven-year recall period, respectively). Antiepileptics (26%) and beta blockers (15.8%) were the most prescribed prophylactics, and sumatriptan was the predominant triptan used (12%) for acute treatment. Conclusion Taking into account the number of inhabitants in the Czech Republic (10.7 million), there could be up to 23,000 adult patients eligible for novel CGRP therapies.

OBJECTIVE This study describes the approaches, medications used, and time of care for migraineurs, who have been in emergency departments (ED) from 2 different regions of Brazil. METHODS Retrospective, cross-sectional, observational, non-randomized study of migraine patients seen at 2 headache centers in Brazil. RESULTS Eighty-four migraine patients (15 men and 69 women) were divided into 2 groups: chronic (19%, n = 16) and episodic migraineurs (81%, n = 68). In the ED, medications were used in the following order of frequency: dipyrone or metamizole (89.3%, 75/84), nonsteroidal anti-inflammatory drugs (57.1%; 48/84) opioids (51.1%; 43/84), metoclopramide (29.8%; 25/84), dexamethasone (28.6%; 24/84), chlorpromazine (13.1%; 11/84), and subcutaneous sumatriptan (7.1%; 6/84). The average time in the care center was 8.2 hours, but only 23 patients (27.4%) left the hospital with greater than 50% relief in headache severity. CONCLUSIONS Dipyrone and nonsteroidal anti-inflammatories were the most used drugs, but nearly half received opioids. More efficient drugs were poorly used. Considering the number of patients leaving the hospital with headache relief, a changing treatment paradigm should be carried out in Brazil.

Migraine is caused by hyperactivity of the trigeminovascular system, where trigeminal ganglia (TG) play an important role. This hyperactivity might originate from an underfunctional GABAergic system in TG. To investigate this possibility, we adapted a mouse model of migraine by inducing migraine-like grimaces in male mice via repeated injections of nitroglycerin (NTG, 10 mg/kg, i.p.), once every 2 days, for up to 5 sessions. Migraine-like facial pain scores were measured using the mouse grimace scale. Repeated NTG treatments in mice caused significant increases in migraine-like grimaces that were aborted and prevented by two anti-migraine agents sumatriptan and topiramate, respectively. After 5 sessions of NTG injections, the GABA-synthesizing enzyme, 65-kDa glutamate decarboxylase (GAD65), but not the GABA transporter 1 (GAT1) or the α6 subunit-containing GABAA receptors (α6GABAARs), was downregulated in mouse TG tissues. Taking advantage of the unaffected TG α6GABAAR expression in NTG-treated mice, we demonstrated that an α6GABAAR-selective positive allosteric modulator (PAM), DK-I-56-1, exhibited both abortive and prophylactic effects, comparable to those of sumatriptan and topiramate, respectively, in this migraine-mimicking mouse model. The brain-impermeable furosemide significantly prevented the effects of DK-I-56-1, suggesting its peripheral site of action, likely via preventing α6GABAAR modulation in TG. Results suggest that a decreased GABA synthesis caused by the reduced GAD65 expression in TG contributes to the trigeminovascular activation in this repeated NTG-induced migraine-mimicking model and that the unaltered α6GABAARs in TG are potential targets for migraine treatment. Thus, α6GABAAR-selective PAMs are potential anti-migraine agents for both abortive and preventive therapies.

Aim Development and characterization of a novel injury-free preclinical model of migraine-like pain allowing mechanistic assessment of both acute and preventive treatments. Methods A “two-hit” hyperalgesic priming strategy was used to induce vulnerability to a normally subthreshold challenge with umbellulone, a transient receptor potential ankyrin 1 (TRPA1) activator, in uninjured female and male C57BL/6 mice. Priming (i.e. the first hit) was induced by three consecutive daily episodes of restraint stress; repeated umbellulone was also evaluated for potential priming effects. Sixteen days after the first restraint stress, mice received inhalational umbellulone (i.e. the second hit) to elicit migraine-like pain. Medications currently used for acute or preventive migraine therapy including propranolol (a beta blocker) and sumatriptan (5HT1B/D agonist), as well as olcegepant, an experimental calcitonin gene related peptide (CGRP) receptor antagonist and nor-Binaltorphimine (nor-BNI), an experimental long-acting kappa opioid receptor (KOR) antagonist, were investigated for their efficacy to block priming and prevent or reverse umbellulone-induced allodynia in primed animals. To assess migraine-like pain, cutaneous allodynia was determined by responses to periorbital or hindpaw probing with von Frey filaments. Results Repeated restraint stress, but not umbellulone exposure, produced transient cutaneous allodynia that resolved within 16 d. Restraint stress produced long-lasting priming that persisted beyond 16 d, as demonstrated by reinstatement of cutaneous allodynia following inhalational umbellulone challenge. Pretreatment with propranolol or nor-BNI prior to restraint stress prevented both transient cutaneous allodynia and priming, demonstrated by a lack of umbellulone-induced cutaneous allodynia. Following establishment of restraint stress priming, olcegepant, but not propranolol or nor-BNI, prevented umbellulone-induced cutaneous allodynia. When administered 1 h after umbellulone, sumatriptan, but not olcegepant, reversed umbellulone-induced cutaneous allodynia in restraint stress-primed rats. Conclusion We have developed a novel injury-free model with translational relevance that can be used to study mechanisms relevant to migraine-like pain and to evaluate novel acute or preventive treatments. Restraint stress priming induced a state of vulnerability to a subthreshold stimulus that has been referred to as “latent sensitization”. The development of latent sensitization could be prevented by blockade of stress pathways with propranolol or with a kappa opioid receptor antagonist. Following establishment of latent sensitization, subthreshold stimulation with umbellulone reinstated cutaneous allodynia, likely from activation of meningeal TRPA1-expressing nociceptors. Accordingly, in restraint stress-primed animals, sumatriptan reversed umbellulone-induced cutaneous allodynia, supporting peripheral sites of action, while propranolol and nor-BNI were not effective. Surprisingly, olcegepant was effective in mice with latent sensitization when given prior to, but not after, umbellulone challenge, suggesting time-dependent contributions of calcitonin gene-related peptide receptor signaling in promoting migraine-like pain in this model. Activation of the calcitonin gene-related peptide receptor participates in initiating, but has a more limited role in maintaining, pain responses, supporting the efficacy of small molecule calcitonin gene-related peptide antagonists as preventive medications. Additionally, the effectiveness of sumatriptan in reversal of established pain thus suggests modulation of additional, non-calcitonin gene-related peptide receptor-mediated nociceptive mechanisms. Kappa opioid receptor antagonists may represent a novel preventive therapy for stress-related migraine.

Background Migraine patients want acute treatment to provide complete relief of the migraine attack within 30 minutes. Traditionally, “speed of onset of effect” is evaluated by estimating the time-point for first statistical separation of drug and placebo. The estimated onset of effect can be a few percent difference of patients being pain free in very large randomised, controlled trials. This difference, however, can be clinically irrelevant. Methods Placebo-controlled randomised, controlled trials with pain freedom results from 30 min to 2–4 hours were retrieved from the literature. For each time-point, the therapeutic gain (drug minus placebo) (TG) was calculated. Therapeutic gain for being pain free of 5% was chosen for the definition of “onset of action”, since this is approximately 1/3 of the 16% TG and 1/4 of 21% of TG for sumatriptan 50 mg and 100 mg, respectively. Results A total of 22 time-effect curves based on randomised, controlled trials were analysed. Based on the “onset of action” of 5% pain freedom, the evaluated drugs and administration forms can be classified as follows: i) Early time to onset, ≤30 min (three randomised, controlled trials); ii) medium time to onset, 60 min (nine randomised, controlled trials); iii) delayed time to onset, 90–120 min (10 randomised, controlled trials). Conclusion Only three non-oral administration forms with a triptan (subcutaneous sumatriptan and nasal zolmitriptan) resulted in an “onset of action” at ≥30 min; in the future, early onset of action should be a priority in the development of new drugs or new administration-forms for the treatment of acute migraine attacks.

Introduction Subcutaneous sumatriptan, a 5HT1B/1D agonist, is the most effective drug in cluster headache acute treatment. About 25% of the patients do not respond to subcutaneous sumatriptan; the reasons for this are unknown. In this study, we compare clinical characteristics of cluster headache patients responding and non-responding to subcutaneous sumatriptan. Methods We retrospectively investigated the clinical records of 277 cluster headache patients. Patients reporting repeated satisfactory response to subcutaneous sumatriptan within 15 minutes were considered responders. Results Of 206 cluster headache patients who had used subcutaneous sumatriptan (mean age 45.6, 16% females, 48% chronic), 91% were responders, and 9% non-responders. Compared to responders, non-responders had longer and more frequent attacks: 60 (median; IQR 38–90) vs. 100 (60–120) minutes ( p = 0.028), 4 (2.5–5) vs. 3 (2–4) attacks/day ( p = 0.024). No other difference was found. Conclusions In cluster headache attacks with long duration and high frequency, pain mechanisms not involving 5HT1B/1D receptors may play a more relevant role.

A 9-year-old female reported left-sided, excruciatingly severe, stabbing orbital pain with cranial autonomic symptoms. The attacks continued for 1 year with a remission period of 2 months. Each attack duration was approximately 120 minutes with a frequency of two to three times a day. The patient was diagnosed with chronic cluster headache (CCH) according to the third edition of the International Classification of Headache Disorders. A combination of low-dose verapamil and lomerizine once a week decreased the frequency of the attacks, and oral sumatriptan became an effective abortive therapy. No case reports of pediatric CCH have been previously published in Japan.

Cortical spreading depolarisation (CSD), the neural mechanism underlying migraine aura, may cause headache by sensitising the trigeminal system. Photophobia, the most bothersome accompanying symptom during migraine attacks, is more prevalent in migraine with aura than in migraine without aura. Whether CSD plays a role in developing photophobia remains unknown. Moreover, migraine-induced physical hypoactivity contributes to loss of productivity. We aimed to investigate the development of trigeminal sensitisation, photophobia and locomotive abnormality after KCl-induced CSD using 86 male C57BL/6 mice. Sham-operated mice were used as controls. We confirmed the presence of trigeminal sensitisation and photophobia at 24 h after CSD. CSD-subjected mice also exhibited significantly reduced locomotive activity in both light and dark zones. Hence, the CSD-induced hypomobility was likely to be independent of photophobia. The 5-HT1B/1D agonist, sumatriptan, corrected all these CSD-induced abnormalities. Moreover, dose dependency was demonstrated in the ameliorating effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, olcegepant, on these abnormalities. Sumatriptan and olcegepant improved mouse locomotion with therapeutic lags ranging from 20 to 30 min. Collectively, CSD caused trigeminal sensitisation, photophobia and hypomobility that persisted for at least 24 h by a mechanism involving the 5-HT1B/1D and CGRP activity.

Background Ubrogepant, a small-molecule calcitonin gene-related peptide receptor antagonist, was recently approved as an oral medication for the acute treatment of migraine. This study aimed to determine whether ubrogepant shows efficacy in a preclinical model of migraine-like pain and whether repeated oral administration of ubrogepant induces latent sensitization relevant to medication overuse headache in rats. Methods A “two-hit” priming model of medication overuse headache was used. Female Sprague-Dawley rats received six oral doses of sumatriptan 10 mg/kg over 2 weeks to induce latent sensitization (i.e. “priming”). Cutaneous allodynia was measured periodically over 20 days in the periorbital and hindpaw regions using von Frey filaments. The rats were then subjected to a 1-hour bright light stress challenge on two consecutive days. At the start of the second bright light stress exposure, oral sumatriptan 10 mg/kg, oral ubrogepant 25, 50, or 100 mg/kg, or vehicle was administered; thereafter, cephalic and hindpaw sensory thresholds were monitored hourly over 5 hours to determine the efficacy of ubrogepant in reversing bright light stress-induced cutaneous allodynia. A dose of ubrogepant effective in the medication overuse headache model (100 mg/kg) was then selected to determine if repeated administration would produce latent sensitization. Rats were administered six oral doses of ubrogepant 100 mg/kg, sumatriptan 10 mg/kg (positive control), or vehicle over 2 weeks, and cutaneous allodynia was evaluated regularly. Testing continued until mechanosensitivity returned to baseline levels. Rats were then challenged with bright light stress on days 20 and 21, and periorbital and hindpaw cutaneous allodynia was measured. On days 28 to 32, the same groups received a nitric oxide donor (sodium nitroprusside 3 mg/kg, i.p.), and cutaneous allodynia was assessed hourly over 5 hours. Results Sumatriptan elicited cutaneous allodynia in both cephalic and hindpaw regions; cutaneous allodynia resolved to baseline levels after cessation of drug administration (14 days). Sumatriptan priming resulted in generalized and delayed cutaneous allodynia, evoked by either bright light stress (day 21) or nitric oxide donor (day 28). Ubrogepant dose-dependently blocked both stress- and nitric oxide donor-induced cephalic and hindpaw allodynia in the sumatriptan-induced medication overuse headache model with a 50% effective dose of ∼50 mg/kg. Unlike sumatriptan, ubrogepant 100 mg/kg in repeated effective doses did not produce cutaneous allodynia or latent sensitization. Conclusions Both ubrogepant and sumatriptan demonstrated efficacy as acute medications for stress- and nitric oxide donor-evoked cephalic allodynia in a preclinical model of medication overuse headache, consistent with their clinical efficacy in the acute treatment of migraine. However, in contrast to sumatriptan, repeated treatment with ubrogepant did not induce cutaneous allodynia or latent sensitization. These studies suggest ubrogepant may offer an effective acute treatment of migraine without risk of medication overuse headache. Trial Registration Number: Not applicable

Migraine is one of the most disabling disorders worldwide but the underlying mechanisms are poorly understood. Stress is consistently reported as a common trigger of migraine attacks. Here, we show that repeated stress in mice causes migraine-like behaviors that are responsive to a migraine therapeutic. Adult female and male mice were exposed to 2 hours of restraint stress for 3 consecutive days, after which they demonstrated facial mechanical hypersensitivity and facial grimace responses that were resolved by 14 days after stress. Hypersensitivity or grimace was not observed in either control animals or those stressed for only 1 day. After return to baseline, the nitric oxide donor sodium nitroprusside (SNP; 0.1 mg/kg) elicited mechanical hypersensitivity in stressed but not in control animals, demonstrating the presence of hyperalgesic priming. This suggests the presence of a migraine-like state, because nitric oxide donors are reliable triggers of attacks in migraine patients but not controls. The stress paradigm also caused priming responses to dural pH 7.0 treatment. The presence of this primed state after stress is not permanent because it was no longer present at 35 days after stress. Finally, mice received either the calcitonin gene-related peptide monoclonal antibody ALD405 (10 mg/kg) 24 hours before SNP or a coinjection of sumatriptan (0.6 mg/kg). ALD405, but not sumatriptan, blocked the facial hypersensitivity due to SNP. This stress paradigm in mice and the subsequent primed state caused by stress allow further preclinical investigation of mechanisms contributing to migraine, particularly those caused by common triggers of attacks.

Herein, we report on a 44-year-old man who presented with cluster headache (CH)-like pain triggered by polycythemia vera (PV). He had severe unilateral head pain attacks lasting about 30 min not associated with cranial autonomic symptoms. After the exclusion of secondary etiologies, the patient was screened for a neoplastic process through biological markers, and the diagnosis of PV was established. The results of the initial laboratory examination showed hemoglobin at 18.1 g/L and Hct at 54%. JAK2 mutation analysis was positive at 54%, and marrow biopsy confirmed the hematopoietic clonal expansion, without myelofibrosis. He was treated with aspirin and ruxolitinib due to intolerance to interferon and the ineffectiveness of hydroxyurea. The treatment by venesection improved substantially the headaches. Oxygen inhalation was very effective in treating the CH attacks. In contrast, sumatriptan was inefficient at the very beginning of the disease. Among the pathophysiological mechanisms that we can propose to explain these cluster-like headaches are the prolonged hypoxia involving nitric oxide and calcitonin gene-related peptide release.

Objective To evaluate the potential for pharmacokinetic interaction and the safety and tolerability when ubrogepant and sumatriptan are coadministered in a Phase 1 study in healthy participants, and to inform the safety and tolerability of ubrogepant alone and in combination with triptans in Phase 3 trials in participants with migraine. Background Calcitonin gene-related peptide is a potent vasodilatory neurotransmitter believed to play a key role in the pathophysiology of migraine. Ubrogepant (UBRELVY™) is a potent and selective antagonist of the human calcitonin gene-related peptide receptor approved for the acute treatment of migraine. Sumatriptan is a serotonin receptor agonist and the most commonly used triptan for the acute treatment of migraine. Ubrogepant could be prescribed with triptans. Design The Phase 1 study was a single-center, open-label, randomized, 3-way crossover, single-dose, pharmacokinetic interaction study, where participants received each of 3 oral treatments with a 7-day washout period between treatments: single dose of ubrogepant 100 mg, single dose of sumatriptan 100 mg, and ubrogepant 100 mg plus sumatriptan 100 mg. Pharmacokinetic parameters were calculated using a model-independent approach. The ACHIEVE I and II trials were 2 multicenter, single-attack, randomized, Phase 3 trials in adults with a history of migraine with or without aura. Participants had the option to take a second dose of study medication or rescue medication to treat a nonresponding migraine or a migraine recurrence from 2 to 48 hours after the initial dose of study medication. Rescue medication options included acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, anti-emetics, or triptans. Treatment-emergent adverse events were evaluated up to 30 days after the last dose in the Phase 1 and Phase 3 studies. Results Ubrogepant median time to maximum plasma concentration was delayed (3 hours [range: 1-5 hours] vs 1.5 hours [range: 1-4 hours]), mean maximum plasma concentration was reduced by 24% (coefficient of variation: 37.4%) when ubrogepant was coadministered with sumatriptan (n = 29) compared with ubrogepant administered alone (N = 30). No significant effect was observed on the area under the plasma concentration-time curve of ubrogepant. Sumatriptan area under the curve and maximum plasma concentration showed no significant change when sumatriptan was coadministered with ubrogepant (n = 29), but the sumatriptan time to maximum plasma concentration was delayed (1 hour [range: 0.5-5 hours] vs 3 hours [range: 0.5-6 hours]. No treatment-emergent adverse events were reported with the coadministration of ubrogepant 100 mg and sumatriptan 100 mg in the Phase 1 study. The pooled safety data from ACHIEVE trials (N = 1938) showed similar rates of treatment-related treatment-emergent adverse events between participants who took ubrogepant alone and participants who took ubrogepant and a triptan as a rescue medication (14.9% [53/355] vs 12.8% [5/39] in the ubrogepant 100 mg treatment group, respectively). Conclusions Although there were slight alterations in ubrogepant pharmacokinetic parameters when coadministered with sumatriptan, such changes are expected to have minimal clinical relevance, especially because no changes were seen in sumatriptan area under the curve and maximum plasma concentration when coadministered with ubrogepant. Coadministration of ubrogepant with sumatriptan was well tolerated in healthy participants in the Phase 1 study, and coadministration of ubrogepant with triptans was well tolerated in participants with migraine in the Phase 3 trials. No new safety concerns for ubrogepant were identified across all trials.

Objectives The authors have previously tried to develop a model for the testing of novel drug candidates for migraine, using the headache and migraine provoking agent cilostazol. Previous studies have used sumatriptan tablets as the validating drug, but they were not sufficiently effective. In this study we test the effect of subcutaneous sumatriptan on cilostazol induced headache in patients with migraine without aura. Method Thirty patients with migraine without aura received 200 mg cilostazol on two different study days. The induced headache was treated with subcutaneous sumatriptan in a randomized, double-blind cross-over design. The patients filled out a self-reported headache questionnaire until 12 h after cilostazol. Results All 30 patients experienced headache (range 3–10) on both study days and the headache fulfilled the criteria for a migraine-like attack in 73% on the sumatriptan day and in 77% on the placebo day. Sumatriptan injection reduced the headache score 2 h after treatment ( p = 0.003). The difference between headache intensity on the sumatriptan day and the placebo day was significant at both 2 h ( p = 0.01) and 4 h ( p = 0.0007) after treatment. Conclusion Subcutaneous sumatriptan reduces cilostazol induced headache in migraine patients. The cilostazol model may be useful as a tool to test the potential of new anti-migraine drugs. Trial registration: The study is registered on clinicaltrials.gov (NCT03422796).

PAC1 receptor blockade using a monoclonal antibody inhibits nociceptive neuronal activity in the trigeminocervical complex., Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) may play an important role in primary headaches. Preclinical evidence suggests that PACAP38 modulates trigeminal nociceptive activity mainly through PAC1 receptors while clinical studies report that plasma concentrations of PACAP38 are elevated in spontaneous attacks of cluster headache and migraine and normalize after treatment with sumatriptan. Intravenous infusion of PACAP38 induces migraine-like attacks in migraineurs and cluster-like attacks in cluster headache patients. A rodent-specific PAC1 receptor antibody Ab181 was developed, and its effect on nociceptive neuronal activity in the trigeminocervical complex was investigated in vivo in an electrophysiological model relevant to primary headaches. Ab181 is potent and selective at the rat PAC1 receptor and provides near-maximum target coverage at 10 mg/kg for more than 48 hours. Without affecting spontaneous neuronal activity, Ab181 effectively inhibits stimulus-evoked activity in the trigeminocervical complex. Immunohistochemical analysis revealed its binding in the trigeminal ganglion and sphenopalatine ganglion but not within the central nervous system suggesting a peripheral site of action. The pharmacological approach using a specific PAC1 receptor antibody could provide a novel mechanism with a potential clinical efficacy in the treatment of primary headaches.

Introduction Females are thought to have increased risk of developing post-traumatic headache following a traumatic head injury or concussion. However, the processes underlying this susceptibility remain unclear. We previously demonstrated the development of post-traumatic headache-like pain behaviors in a male rat model of mild closed head injury, along with the ability of sumatriptan and an anti-calcitonin-gene-related peptide monoclonal antibody to ameliorate these behaviors. Here, we conducted a follow-up study to explore the development of post-traumatic headache-like behaviors and the effectiveness of these headache therapies in females subjected to the same head trauma protocol. Methods Adult female Sprague Dawley rats were subjected to a mild closed head injury using a weight-drop device (n = 126), or to a sham procedure (n = 28). Characterization of headache and pain related behaviors included assessment of changes in cutaneous cephalic and extracephalic tactile pain sensitivity, using von Frey monofilaments. Sensitivity to headache/migraine triggers was tested by examining the effect of intraperitoneal administration of a low dose of glyceryl trinitrate (100 µg/kg). Treatments included acute systemic administration of sumatriptan (1 mg/kg) and repeated systemic administration of a mouse anti-calcitonin gene-related peptide monoclonal antibody (30 mg/kg). Serum levels of calcitonin gene-related peptide were measured at baseline and at various time points post head injury in new cohorts of females (n = 38) and males (n = 36). Results Female rats subjected to a mild closed head injury developed cutaneous mechanical hyperalgesia, which was limited to the cephalic region and was resolved 4 weeks later. Cephalic pain hypersensitivity was ameliorated by treatment with sumatriptan but was resistant to an early and prolonged treatment with the anti-calcitonin gene-related peptide monoclonal antibody. Following the resolution of the head injury-evoked cephalic hypersensitivity, administration of glyceryl trinitrate produced a renewed and pronounced cephalic and extracephalic pain hypersensitivity that was inhibited by sumatriptan, but only partially by the anti-calcitonin gene-related peptide treatment. Calcitonin gene-related peptide serum levels were elevated in females but not in males at 7 days post head injury. Conclusions Development of post-traumatic headache-like pain behaviors following a mild closed head injury, and responsiveness to treatment in rats is sexually dimorphic. When compared to the data obtained from male rats in the previous study, female rats display a prolonged state of cephalic hyperalgesia, increased responsiveness to a headache trigger, and a poorer effectiveness of an early and prolonged anti-calcitonin gene-related peptide treatment. The increased risk of females to develop post-traumatic headache may be linked to enhanced responsiveness of peripheral and/or central pain pathways and a mechanism independent of peripheral calcitonin gene-related peptide signaling.

Objective To evaluate whether intraganglionic calcitonin gene-related peptide induced differential migraine-like responses in male and female rats. Methods Calcitonin gene-related peptide was injected in the trigeminal ganglion of male and female rats followed by assessment of periorbital mechanical allodynia with von Frey hairs. The influence of systemic treatment with sumatriptan or intraganglionic treatment with minocycline and propentofylline was determined on the calcitonin gene-related peptide-induced mechanical allodynia in male and female rats. One additional group was exposed to an aversive light 24 h after calcitonin gene-related peptide priming, followed by evaluation of periorbital mechanical threshold, and another group was tested in the elevated-plus maze. Results Intraganglionar calcitonin gene-related peptide-induced periorbital mechanical allodynia in female (0.5 to 6 h) and male rats (0.5 to 4 h). Systemic sumatriptan briefly attenuated the mechanical allodynia, but intraganglionar minocycline or propentofylline injection was effective only in male rats. Calcitonin gene-related peptide induced photic sensitivity in female and male rats (lasting 4 h and 1 h, respectively), as well as anxiety-like behavior. Conclusions Intraganglionar calcitonin gene-related peptide may play a major role in migraine-like responses, including periorbital mechanical allodynia, light sensitivity and anxiety like-behavior. Female rats are likely to be more susceptible to calcitonin gene-related peptide effects and a better understanding of the sexual dimorphism in calcitonin gene-related peptide signaling may help to improve migraine therapy.

La migraña es la cefalea primaria valorada en el primer nivel de atención que más frecuentemente causa discapacidad, es más común en el sexo femenino y especialmente en edades reproductivas. Muestra una relación con los niveles tanto estrogénicos y de progresterona, así como la fluctuación de los mismos. Durante el embarazo, la migraña puede aparecer de novo, empeorar o más comúnmente tender a la mejoría. Su diagnóstico se centra en la detección de banderas rojas en la historia clínica que sugieran entidades de cefalea secundaria. El abordaje terapeútico de la misma puede ser tanto profiláctico como abortiva, así como farmacológico y no farmacológico. La primera línea para tanto la profilaxis como el tratamiento agudo son medidas no farmacológicas, seguidas respectivamente de drogas como betabloqueadores (propranolol y metoprolol) y el acetaminofén. En la profilaxis también es aceptable el uso de amitriptilina. El uso de triptanes, especialmente sumatriptán, parece ser seguro sin embargo se deja como línea terapeútica posterior. Los opioides a pesar de su efectividad no son recomendados. En la lactancia se siguen recomendaciones similares.

Objective Millions of patients present to US emergency departments (ED) annually for the treatment of migraine. First-line treatments, including metoclopramide, prochlorperazine, and sumatriptan, fail to provide sufficient relief in up to one-third of treated patients. In this narrative review, we discuss the evidence supporting the use of injectable (intravenous, intramuscular, or subcutaneous) medications for patients in the ED who fail to improve sufficiently after treatment with first-line medication. Methods We used the American Headache Society's guideline, "Management of Adults with Acute Migraine in the Emergency Department: The American Headache Society Evidence Assessment of Parenteral Pharmacotherapies," published in 2016, to identify first-line medications for migraine. We then conducted a PubMed search to determine whether any evidence supported the use of these medications as second-line therapy and whether any evidence existed to support the use of injectable therapies not discussed in the guideline as second-line therapy. Results We identified only scant high-quality randomized data of second-line therapy. Therefore, we based our recommendations on medications that have reliably demonstrated efficacy as first-line treatment of migraine. These medications include injectable non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. Dihydroergotamine and valproic acid have some data supporting efficacy. More recently, greater occipital nerve blocks (GONBs) have been shown to be efficacious. With the exception of meperidine, opioids have been shown to be not efficacious. Most data published to date demonstrate no role for propofol and ketamine. Conclusions There are no evidence-based second-line treatments of migraine in the ED setting. For patients with migraine, who fail to improve after treatment with a first-line medication, it is reasonable to use an intravenous NSAID or intravenous acetaminophen. Alternatively, clinicians adept at performing a GONB may offer this treatment.

Headache is a common cause of emergency department (ED) visits. Migraine is a prevalent neurological disorder that is encountered by emergency physicians in day-to-day practice. However, patients with a known history of migraines should be carefully evaluated when presenting with headaches and serious pathologies of headache should be ruled out. We report the case of a 43-year-old woman, with a known history of classic migraine, who presented to the ED with a severe headache. She described the headache as persistent generalized pain. The headache was worse on awakening and bending. The headache did not improve with the use of oral sumatriptan. She reported that the current episode of headache is more severe than her usual migraine headaches. The patient underwent a cranial CT scan which demonstrated a homogenously hyperdense well-defined round lesion located in the midline at the approximate location of the foramen of Monro with prominent lateral ventricles, conferring the diagnosis of the colloid cyst. The patient underwent a right craniotomy with resection of the cyst using the transcallosal approach. Recognition of this important diagnosis is crucial to prevent serious neurological complications by having timely management.

Objective Determination of possible sex differences in mechanisms promoting migraine progression and the contribution of prolactin and the prolactin long (PRLR-L) and short (PRLR-S) receptor isoforms. Background The majority of patients with chronic migraine and medication overuse headache are female. Prolactin is present at higher levels in women and increases migraine. Prolactin signaling at the PRLR-S selectively sensitizes nociceptors in female rodents, while expression of the PRLR-L is protective. Methods Medication overuse headache was modeled by repeated sumatriptan administration in male and female mice. Periorbital and hindpaw cutaneous allodynia served as a surrogate of migraine-like pain. PRLR-L and PRLR-S isoforms were measured in the trigeminal ganglion with western blotting. Possible co-localization of PRLR with serotonin 5HT1B and 5HT1D receptors was determined with RNAscope. Cabergoline, a dopamine receptor agonist that inhibits circulating prolactin, was co-administered with sumatriptan. Nasal administration of CRISPR/Cas9 plasmid was used to edit expression of both PRLR isoforms. Results PRLR was co-localized with 5HT1B or 5HT1D receptors in the ophthalmic region of female trigeminal ganglion. A single injection of sumatriptan increased serum PRL levels in female mice. Repeated sumatriptan promoted cutaneous allodynia in both sexes but down-regulated trigeminal ganglion PRLR-L, without altering PRLR-S, only in females. Co-administration of sumatriptan with cabergoline prevented allodynia and down-regulation of PRLR-L only in females. CRISPR/Cas9 editing of both PRLR isoforms in the trigeminal ganglion prevented sumatriptan-induced periorbital allodynia in females. Interpretation We identified a sexually dimorphic mechanism of migraine chronification that involves down-regulation of PRLR-L and increased signaling of circulating prolactin at PRLR-S. These studies reveal a previously unrecognized neuroendocrine mechanism linking the hypothalamus to nociceptor sensitization that increases the risk of migraine pain in females and suggest opportunities for novel sex-specific therapies including gene editing through nasal delivery of CRISPR/Cas9 constructs.

Ischemic colitis refers to an inflammatory condition of the large bowel caused by ischemia. It usually presents with an acute onset abdominal pain followed by hematochezia. It can occur as a result of arterial occlusion (embolic or thrombotic), venous thrombosis, or hypoperfusion of mesenteric circulation secondary to dehydration, surgery, or medications. Herein, we present an unusual case of sumatriptan-induced ischemic colitis. Sumatriptan succinate is a selective serotonin (5-hydroxytryptamine-1) receptor agonist that is usually prescribed for refractory migraine headaches. This is a 59-year-old female who presented with acute onset abdominal pain followed by bloody diarrhea after vigorous physical activities. She has a past medical history of non-specific colitis (one time, 15 years ago) and chronic migraine for which she was on low-dose sumatriptan therapy (one tab once or twice a week). On the day of the event, the patient took sumatriptan in the morning and had strenuous activities throughout the day, and overnight she developed abdominal pain. It was followed by bouts of bloody diarrhea. The colonoscopy revealed erythematous mucosa with significant ulceration and necrosis involving the distal transverse colon, splenic flexure, descending colon, and proximal colon, suggestive of ischemic colitis. Unlike previously reported cases, this patient was only on low-dose sumatriptan therapy without frequent dosing. So, her risk of ischemic colitis from triptan therapy could have been accelerated by excessive sweating and strenuous physical activities. The patient was treated with intravenous hydration, bowel rest, intravenous antibiotics, and withdrawal of sumatriptan and her condition improved within the next two to three days.

Headaches are frequently described in progressive multiple sclerosis (PMS) patients, but their mechanism remains unknown. Transient receptor potential ankyrin 1 (TRPA1) was involved in neuropathic nociception in a model of PMS induced by experimental autoimmune encephalomyelitis (PMS-EAE), and TRPA1 activation causes periorbital and facial nociception. Thus, our purpose was to observe the development of periorbital mechanical allodynia (PMA) in a PMS-EAE model and evaluate the role of TRPA1 in periorbital nociception. Female PMS-EAE mice elicited PMA from day 7 to 14 days after induction. The antimigraine agents olcegepant and sumatriptan were able to reduce PMA. The PMA was diminished by the TRPA1 antagonists HC-030031, A-967079, metamizole and propyphenazone and was absent in TRPA1-deficient mice. Enhanced levels of TRPA1 endogenous agonists and NADPH oxidase activity were detected in the trigeminal ganglion of PMS-EAE mice. The administration of the anti-oxidants apocynin (an NADPH oxidase inhibitor) or alpha-lipoic acid (a sequestrant of reactive oxygen species), resulted in PMA reduction. These results suggest that generation of TRPA1 endogenous agonists in the PMS-EAE mouse model may sensitise TRPA1 in trigeminal nociceptors to elicit PMA. Thus, this ion channel could be a potential therapeutic target for the treatment of headache in PMS patients.

Migraine affects ∼15% of the world's population greatly diminishing their quality of life. Current preventative treatments are effective in only a subset of migraine patients, and although cannabinoids seem beneficial in alleviating migraine symptoms, central nervous system side effects limit their widespread use. We developed peripherally restricted cannabinoids (PRCBs) that relieve chronic pain symptoms of cancer and neuropathies, without appreciable central nervous system side effects or tolerance development. Here, we determined PRCB effectiveness in alleviating hypersensitivity symptoms in mouse models of migraine and medication overuse headache. Long-term glyceryl trinitrate (GTN, 10 mg/kg) administration led to increased sensitivity to mechanical stimuli and increased expression of phosphorylated protein kinase A, neuronal nitric oxide synthase, and transient receptor potential ankyrin 1 proteins in trigeminal ganglia. Peripherally restricted cannabinoid pretreatment, but not posttreatment, prevented behavioral and biochemical correlates of GTN-induced sensitization. Low pH-activated and allyl isothiocyanate-activated currents in acutely isolated trigeminal neurons were reversibly attenuated by PRCB application. Long-term GTN treatment significantly enhanced these currents. Long-term sumatriptan treatment also led to the development of allodynia to mechanical and cold stimuli that was slowly reversible after sumatriptan discontinuation. Subsequent challenge with a previously ineffective low-dose GTN (0.1-0.3 mg/kg) revealed latent behavioral sensitization and increased expression of phosphorylated protein kinase A, neuronal nitric oxide synthase, and transient receptor potential ankyrin 1 proteins in trigeminal ganglia. Peripherally restricted cannabinoid pretreatment prevented all behavioral and biochemical correlates of allodynia and latent sensitization. Importantly, long-term PRCB treatment alone did not produce any behavioral or biochemical signs of sensitization. These data validate peripheral cannabinoid receptors as potential therapeutic targets in migraine and medication overuse headache.

Background Gastric accommodation is an essential gastric motor function which occurs following ingestion of a meal. Impaired gastric fundic accommodation (IFA) is associated with dyspeptic symptoms. Gastric accommodation is mediated by the vagal pathway with several important physiologic factors such as duodenal nutrient feedback playing a significant role. IFA has been described as a pathophysiologic factor in several gastrointestinal disorders including functional dyspepsia, diabetic gastropathy, post-Nissen fundoplication, postsurgical gastrectomy, and rumination syndrome. Modalities for gastric accommodation assessment include gastric barostat, intragastric meal distribution via scintigraphy, drinking tests (eg, water load), SPECT, MRI, 2D and 3D ultrasound, and intragastric high-resolution manometry. Several treatment options including sumatriptan, buspirone, tandospirone, ondansetron, and acotiamide may improve symptoms by increasing post-meal gastric volume. Purpose Our aim is to provide an overview of the physiology, diagnostic modalities, and therapies for IFA. A literature search was conducted on PubMed, Google Scholar, and other sources to identify relevant studies available until December 2020. Gastric accommodation is an important gastric motor function which if impaired, is associated with several upper gastrointestinal disorders. There are an increasing number of gastric accommodation testing modalities; however, each has facets which warrant consideration. Evidence regarding potentially effective therapies for IFA is growing.

Medication overuse headache (MOH) usually resolves after the overuse is stopped and starting prophylactic medications. However, it can be challenging to prescribe common prophylactic medications when patients have a history of side effects. As an alternative therapy, traditional Japanese herbal kampo medicine can be used. We herein report a case of a MOH woman with a history of side effects by such common prophylactic medications. A 50-year-old woman presented with a severe migraine attack. She had suffered from migraines for 10 years. She had taken loxoprofen and sumatriptan every day for over eight years. As prophylactic medications, lomerizine, valproic acid, and amitriptyline had been prescribed in the past, but they were discontinued due to side effects. Therefore, she could continue only propranolol as prophylactic medication. She had severe pulsatile headaches and nausea every day. We diagnosed triptan- and non-steroidal anti-inflammatory drug-overuse headache (the International Classification of Headache Disorders 3rd edition code 8.2.2 and 8.2.3.2) and chronic migraine (code 1.3). She was admitted and stopped loxoprofen and sumatriptan. We prescribed three types of Japanese herbal kampo medicines - kakkonto (TJ-1), goreisan (TJ-17), and goshuyuto (TJ-31). Her headache was relieved on day 5, and she was discharged on day 7. In the 40 days after discharge, she had only three times mild headaches with a numeric rating scale (NRS) of 2/10. She did not need any triptans nor anti-inflammatory drugs. We herein presented the MOH woman who was successfully treated using three types of kampo medicine. We should pay attention to their side effects, but kampo medicine may be useful for MOH treatment as acute and prophylactic medications for primary headaches.

Background Naratriptan, marketed in a low oral dose of 2.5 mg, is generally regarded as a less-effective triptan with a slower onset of action than most other triptans in the treatment of migraine attacks. In this review, naratriptan will be compared with sumatriptan, the standard triptan. Methods Papers on pharmacodynamics and pharmacokinetics and results from comparative clinical trials with oral and subcutaneous naratriptan versus other triptans were retrieved from PubMed. Results Naratriptan and sumatriptan have similar effects in relevant animal models. In a randomized controlled trial, oral naratriptan 2.5 mg is less effective than oral sumatriptan 100 mg after both 2 h and 4 h. In contrast, oral naratriptan 10 mg has a similar time-effect curve as oral sumatriptan 100 mg, in both its steepness and the efficacy at 2 h and 4 h. Subcutaneous naratriptan 10 mg (88% pain free at 2 h) was in one trial superior to subcutaneous sumatriptan 6 mg (55% pain free at 2 h). Conclusion Naratriptan was marketed for the treatment of migraine attacks as the “gentle triptan” in a low oral dose of 2.5 mg, a dose with no more adverse events than placebo. This low dose results in the slow onset of action and low efficacy of oral naratriptan, but in high doses oral naratriptan is similar to oral sumatriptan. Based on one randomized controlled trial, subcutaneous naratriptan has probably the greatest effect of any triptan.

Background: The pathogenesis of rosacea is incompletely understood. Signaling neuropeptides, including PACAP, a regulator of vasodilation and edema, are upregulated in rosacea skin. Here, we evaluated PACAP38-induced rosacea features and examined whether a 5-HT1B/1D receptor agonist could reduce these features. Methods: A total of 35 patients with erythematotelangiectatic rosacea received an intravenous infusion of 10 pmol/kg/minute of PACAP38 followed by an intravenous infusion of 4 mg sumatriptan or placebo (saline) on two study days in a double-blind, randomized, placebo-controlled, and cross-over trial. Results: PACAP38 increased facial skin blood flow by 90%, dilated the superficial temporal artery by 56%, and induced prolonged flushing and facial edema. Compared with placebo, sumatriptan reduced PACAP38-induced facial skin blood flow for 50 minutes (P = 0.023), constricted the superficial temporal artery for 80 minutes (P = 0.010), and reduced duration of flushing (P = 0.001) and facial edema (P < 0.001). Conclusions: We established a clinical experimental model of rosacea features and showed that sumatriptan was able to attenuate PACAP38-induced rosacea flushing and edema. Findings support a key role of PACAP38 in rosacea flushing pathogenesis. It remains unknown whether PACAP38 inhibition can improve rosacea. Trial register: The trial was registered at ClinicalTrials.gov NCT03878784 in March 2019.

Background Trigeminal neuralgia (TN) is characterized by brief, unilateral, sharp, stabbing, and shooting pain of the fifth cranial nerve. The objective of this systematic review with meta-analysis was to determine the effect of medications compared to placebo in adult patients with TN. Methods Review authors identified randomized placebo-controlled trials (RCTs) from PubMed, Web of Science, Cochrane, and EMBASE up to February 2021. We assessed the inclusion and exclusion criteria as well as the risk of bias of the studies based on the Cochrane Handbook. A total of 324 unduplicated references were scanned independently and reduced to eight relevant RCTs, with 89 patients included. Medications investigated included oral carbamazepine, subcutaneous sumatriptan, lidocaine (intranasal, 8% spray on the oral mucosa or intravenous), buprenorphine (ganglionic local opioid analgesia), and oral Nav1.7, a selective sodium channel blocker. Results Meta-analyses showed that overall patients receiving lidocaine reported a significantly lower post-treatment intensity of pain -3.8 points on a 0-10 scale (95% Cl = -4.653 to -2.873; P < 0.001). Patients who received lidocaine were 8.62 times more likely to have pain improvement than patients on placebo (P < 0.001). In one RCT, patients receiving oral carbamazepine showed a significant improvement in pain intensity of -32% compared to the placebo (P < 0.001). In one trial, patients receiving 3 mg subcutaneous sumatriptan had a significantly lower intensity of pain on average -6.1 points on a scale of 0-10 compared to placebo (P < 0.001) and a significant improvement in pain intensity of -75% compared to the improvement in the placebo group (P < 0.001). Patients who received subcutaneous sumatriptan were 10 times more likely to have pain improvement than those who received placebo (P = 0.001) in one study. Due to the unclear/high risk of bias and small sample size, the quality of the evidence for lidocaine in the treatment of TN was low. Conclusion Further studies are needed for carbamazepine, sumatriptan, buprenorphine, and oral Nav1.7 sodium channel blockers, as only one study reported outcomes.

Sumatriptan is an effective and well-tolerated medication used for the acute relief of migraines. It blocks nociceptive neurotransmission by binding onto 5-HT1b and 5-HT1d-like serotonin receptors and vasoconstricting cerebral and dural blood vessels.1 It contains a sulfonamide chemical group and hence is considered a sulfa drug. We report a rare report of skin test-proven sumatriptan anaphylaxis in an 18-year-old female.

BACKGROUND ATP-sensitive potassium (KATP ) channel opener levcromakalim induces migraine attacks in migraine patients. Underlying mechanisms responsible for headache and migraine induction after levcromakalim infusion are unknown. OBJECTIVE To investigate the effect of levcromakalim on the cranial arteries and to explore the possible relationship between the middle meningeal artery (MMA) dilation and headache. METHODS In a double-blind, randomized, placebo-controlled study, 20 healthy volunteers were scanned at the baseline and repeatedly after infusion of levcromakalim (n = 14) and placebo (n = 6). All participants received a subcutaneous injection of sumatriptan 6 mg before the last scanning. RESULTS The MMA circumference was significantly larger after levcromakalim compared with placebo (P

ObjectiveTo provide evidence-based recommendations for the acute symptomatic treatment of children and adolescents with migraine.MethodsWe performed a systematic review of the literature and rated risk of bias of included studies according to the American Academy of Neurology classification of evidence criteria. A multidisciplinary panel developed practice recommendations, integrating findings from the systematic review and following an Institute of Medicine–compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence.ResultsThere is evidence to support the efficacy of the use of ibuprofen, acetaminophen (in children and adolescents), and triptans (mainly in adolescents) for the relief of migraine pain, although confidence in the evidence varies between agents. There is high confidence that adolescents receiving oral sumatriptan/naproxen and zolmitriptan nasal spray are more likely to be headache-free at 2 hours than those receiving placebo. No acute treatments were effective for migraine-related nausea or vomiting; some triptans were effective for migraine-related phonophobia and photophobia.RecommendationsRecommendations for the treatment of acute migraine in children and adolescents focus on the importance of early treatment, choosing the route of administration best suited to the characteristics of the individual migraine attack, and providing counseling on lifestyle factors that can exacerbate migraine, including trigger avoidance and medication overuse.

Several lines of evidence pointed to an important role for CGRP in migraine. These included the anatomic colocalization of CGRP and its receptor in sensory fibers innervating pain-producing meningeal blood vessels, its release by trigeminal stimulation, the observation of elevated CGRP in the cranial circulation during migraine with normalization concomitant with headache relief by sumatriptan, and translational studies with intravenous (IV) CGRP that evoked migraine only in migraineurs. The development of small molecule CGRP receptor antagonists (CGRP-RAs) that showed clinical antimigraine efficacy acutely and prophylactically in randomized placebo-controlled clinical trials subsequently gave definitive pharmacological proof of the importance of CGRP in migraine. More recently, CGRP target engagement imaging studies using a CGRP receptor PET ligand [11 C]MK-4232 demonstrated that there was no brain CGRP receptor occupancy at clinically effective antimigraine doses of telcagepant, a prototypic CGRP-RA. Taken together, these data indicated that (1) the therapeutic site of action of the CGRP-RAs was peripheral not central; (2) that IV CGRP had most likely evoked migraine through an action at sites outside the blood-brain barrier; and (3) that migraine pain was therefore, at least in part, peripheral in origin. The evolution of CGRP migraine science gave impetus to the development of peripherally acting drugs that could modulate CGRP chronically to prevent frequent episodic and chronic migraine. Large molecule biologic antibody (mAb) approaches that are given subcutaneously to neutralize circulating CGRP peptide (fremanezumab, galcanezumab) or block CGRP receptors (erenumab) have shown consistent efficacy and tolerability in multicenter migraine prevention trials and are now approved for clinical use. Eptinezumab, a CGRP neutralizing antibody given IV, shows promise in late stage clinical development. Recently, orally administered next-generation small molecule CGRP-RAs have been shown to have safety and efficacy in acute treatment (ubrogepant and rimegepant) and prevention (atogepant) of migraine, giving additional CGRP-based therapeutic options for migraine patients.

Headaches are highly disabling and are among the most common neurological disorders worldwide. Despite the high prevalence of headache, therapeutic options are limited. We recently identified the delta opioid receptor (DOR) as an emerging therapeutic target for migraine. In this study, we examined the effectiveness of a hallmark DOR agonist, SNC80, in disease models reflecting diverse headache disorders including: chronic migraine, post-traumatic headache (PTH), medication overuse headache by triptans (MOH), and opioid-induced hyperalgesia (OIH). To model chronic migraine C57BL/6J mice received chronic intermittent treatment with the known human migraine trigger, nitroglycerin. PTH was modeled by combining the closed head weight drop model with the nitroglycerin model of chronic migraine. For MOH and OIH, mice were chronically treated with sumatriptan or morphine, respectively. The development of periorbital and peripheral allodynia was observed in all four models; and SNC80 significantly inhibited allodynia in all cases. In addition, we also determined if chronic daily treatment with SNC80 would induce MOH/OIH, and we observed limited hyperalgesia relative to sumatriptan or morphine. Together, our results indicate that DOR agonists could be effective in multiple headache disorders, despite their distinct etiology, thus presenting a novel therapeutic target for headache.

Ischemic heart disease is a leading cause of death on a global scale, placing major socio-economic burdens on health systems worldwide. Myocardial ischaemia and reperfusion (I/R)-induced tissue injury is associated with alteration in activity of inflammatory system and nitric oxide pathway. Sumatriptan, which is mainly used to relieve migraine headache, has recently been shown to exert anti-inflammatory properties. In this study, we aimed to assess the possible cardioprotective effect of sumatriptan in a rat model of I/R injury. Male Wistar rats were subjected to 30-min ligation of left anterior descending coronary artery and 120-min reperfusion. Animals were randomly divided into five groups: (1) Sham (2) I/R (3) I/R treated with sumatriptan (0.3 mg/kg i.p.) 20 min after induction of I/R rats, (4) GR127935 (a selective antagonist of 5-HT1B/D serotonin receptors; 0.3 mg/kg) 20 min after induction of I/R, and (5) GR127935 (0.3 mg/kg) 15 min before administration of sumatriptan. Post-infarct treatment with sumatriptan increased left ventricular function, which was damaged in I/R animal's heart. Sumatriptan (0.3 mg/kg) decreased lipid peroxidation, CK-MB and lactate dehydrogenase levels; tumor necrosis factor concentration; and Nf-ҡB' protein production. Treatment with sumatriptan significantly increased the endothelial nitric oxide synthase (eNOS) expression consequences nitric oxide metabolites' level in I/R rats. Also, injection of sumatriptan remarkably decreased myocardial tissue injury assessed by histopathological study. These findings suggest that sumatriptan may attenuate I/R injury via modulating the inflammatory responses and endothelial NOS activity. But therapeutic index of sumatriptan is narrow according to the result of this study.

Background The commercial formulation of sumatriptan nasal spray is an effective option for migraine patients requiring or preferring a non-oral route of drug administration, but its utility is limited by poor absorption and tolerability issues. DFN-02, a new formulation of sumatriptan 10 mg nasal spray, is co-formulated with a permeation enhancer that gives it pharmacokinetics comparable to subcutaneous sumatriptan. As reported previously, DFN-02 was significantly better than placebo on multiple efficacy endpoints at 2 h postdose, including pain freedom, absence of the most bothersome symptom, and pain relief, and its safety and tolerability profiles were excellent. Objective The objective of this study was to assess the efficacy of acute treatment of migraine with DFN-02, including its effect on migraine-related functional disability and patient satisfaction with treatment. Methods This was a multicenter, randomized, double-blind, placebo-controlled efficacy and safety study of DFN-02 in adults with episodic migraine. Functional disability and subject satisfaction with treatment were prespecified endpoints, assessed in real-time by subjects, using an electronic diary. Results In total, 107 subjects were randomized. DFN-02 was significantly superior to placebo for the reduction in functional disability score from predose level at 2 h after treatment (− 1.2 vs. − 0.6, p

Exploratory study to investigate the effectiveness of intravenous magnesium as an abortive for status migrainosus in an outpatient infusion center, and characterize the patients who benefit from the therapy.Retrospective analysis of 234 migraine patients who received IV magnesium as a headache abortive, at the headache clinic of University of Southern California. Additional intramuscular (IM) injections for nausea (prochlorperazine, odansetron, metoclopramide) or for refractory pain (ketorolac, dexamethasone, sumatriptan, dihydroergotamine), were administered as necessary. Immediately before and after treatment, self-reported pain levels were recorded using an 11-point numeric pain rating scale (0-10).Our patient sample has a mean age of 44 years and was predominantly female (79%). 36 (19%) had migraine with aura. Overall, pain score decreased from 5.46±2.39 to 3.56 ± 2.75 (P 0.001) after magnesium infusion. One hundred twenty-seven (54%) patients had clinically significant pain reduction, as defined by pain decrease ≥ 30%. One hundred and four patients (44%) received IV magnesium and did not require additional intramuscular (IM) medications for pain. In patients who did not receive additional IM medications for pain, pain score decreased from 4.76 ± 2.41 to 2.95 ± 2.70 (p 0.001), and 61 out of 104 (59%) experienced ≥ 30% pain reduction. Patients with less severe pain tended to have a better response than patients with more severe pain, as patients with ≥30% pain reduction had a significantly lower pre-treatment pain score (p = 0.018).For a subset of patients with status migrainosus, IV magnesium therapy results in clinically significant pain relief without the need for intramuscular pain medications. Therefore, IV magnesium may be useful as a cost-effective first-line parental therapy for status migrainosus, especially for patients who initially present with lower pain intensity.