Sumatriptan as a First-Line Treatment for Headache in the Pediatric Emergency Department.

BACKGROUND: Headache is a common presenting condition for patients seen in the pediatric emergency department (ED). Intranasal (IN) sumatriptan is a well-tolerated and safe abortive treatment for migraine headache, but it is infrequently administered in pediatric EDs. In this study we characterize an ED migraine pathway that uses IN sumatriptan as a first-line treatment. METHODS: We performed retrospective chart analysis from a single center, reviewing a cohort of patients treated on an ED migraine pathway between October 2016 and February 2020. We reviewed patient demographics, clinical characteristics, treatment patterns, change in pain scores, sumatriptan prescriptions at discharge, length of stay (LOS), ED charges, and unexpected return visits. RESULTS: A total of 558 patients (aged six to 21 years, 66% female) were included in this study. Overall, the median pretreatment pain score was 7 (interquartile range [IQR]: 5 to 8) and the median post-treatment pain score was 2 (IQR: 0 to 4). Forty-eight percent of patients received IN sumatriptan in the ED, and 36% of those who received sumatriptan were prescribed oral sumatriptan at discharge. When intravenous (IV) access was obtained for headache management, this was associated with a significantly longer LOS and higher ED charges. CONCLUSIONS: IN sumatriptan shows promise as a feasible and potentially effective first-line treatment for pediatric migraine in the ED that could reduce the need for IV therapies, shorten LOS, and lower ED charges. Further research is needed to determine the efficacy of IN sumatriptan relative to other common first-line therapies used to treat pediatric migraine in the ED.

PACAP signaling is not involved in GTN- and levcromakalim-induced hypersensitivity in mouse models of migraine.

BACKGROUND: Calcitonin gene-related peptide (CGRP) antagonizing drugs represents the most important advance in migraine therapy for decades. However, these new drugs are only effective in 50-60% of patients. Recent studies have shown that the pituitary adenylate cyclase-activating peptide (PACAP38) pathway is independent from the CGRP signaling pathway. Here, we investigate PACAP38 signaling pathways in relation to glyceryl trinitrate (GTN), levcromakalim and sumatriptan. METHODS: In vivo mouse models of PACAP38-, GTN-, and levcromakalim-induced migraine were applied using tactile sensitivity to von Frey filaments as measuring readout. Signaling pathways involved in the three models were dissected using PACAP-inhibiting antibodies (mAbs) and sumatriptan. RESULTS: We showed that PACAP mAbs block PACAP38 induced hypersensitivity, but not via signaling pathways involved in GTN and levcromakalim. Also, sumatriptan has no effect on PACAP38-induced hypersensitivity relevant to migraine. This is the first study testing the effect of a PACAP-inhibiting drug on GTN- and levcromakalim-induced hypersensitivity. CONCLUSIONS: Based on the findings in our mouse model of migraine using migraine-inducing compounds and anti-migraine drugs, we suggest that PACAP acts via a distinct pathway. Using PACAP38 antagonism may be a novel therapeutic target of interest in a subgroup of migraine patients who do not respond to existing therapies.

Efficacy of Ubrogepant in the Acute Treatment of Migraine With Mild Pain vs Moderate or Severe Pain.

BACKGROUND AND OBJECTIVES: To examine the efficacy of ubrogepant in the treatment of migraine with mild vs moderate or severe pain. METHODS: This was a phase 3, open-label, dose-blinded, 52-week extension trial. Adults with migraine were randomized 1:1:1 (usual care, ubrogepant 50 mg, or ubrogepant 100 mg). Participants treated up to 8 migraine attacks of any pain intensity every 4 weeks. Efficacy outcomes (only collected for ubrogepant) included 2-hour pain freedom (2hPF), freedom from associated symptoms, and from disability. A generalized linear mixed model with binomial distribution and logit link function was used to assess the influence of baseline pain intensity on treatment outcomes in this post hoc analysis. RESULTS: Data for 19,291 attacks from 808 participants were included. 2hPF rates were higher for attacks treated when pain was mild vs moderate or severe: ubrogepant 50 mg (47.1% vs 23.6%; odds ratio [95% CI] 2.89 [2.57-3.24]) and ubrogepant 100 mg (55.2% vs 26.1%; 3.50 [3.12-3.92]; p < 0.0001 both doses). Rates of freedom from photophobia, phonophobia, and nausea 2 hours after treatment were also significantly higher following the treatment of mild vs moderate or severe pain (p < 0.001 all symptoms, both doses). At 2 hours, the proportion of attacks with normal function was more than double for both doses of ubrogepant (p < 0.001). The most common adverse event was upper respiratory tract infection (∼11% both doses). Serious adverse events were reported by 2% in ubrogepant 50 mg and 3% in ubrogepant 100 mg. DISCUSSION: Relative to treatment of attacks with moderate or severe pain, treatment with ubrogepant during mild pain resulted in significantly higher rates of freedom from pain, freedom from associated symptoms, and achieving normal function 2 hours after administration. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov, NCT02873221. CLASSIFICATION OF EVIDENCE: This trial provides Class III evidence that treatment of migraine with ubrogepant when pain is mild vs moderate or severe increases the likelihood of achieving pain freedom, absence of symptoms, and normal function within 2 hours postdose.

Feasibility, Utility, and Interrater Reliability of the Cluster Headache Severity Scale, Cluster Headache Quality of Life, Cluster Headache Index, and 6-Item Headache Impact Test in Pediatric Cluster Headache.

Introduction: Cluster headache is rare in children and only a few clinical studies have systematically evaluated cluster headache in children. Methods: This study was conducted between August 2019 and December 2021 with the primary aim to evaluate the feasibility and utility of the Cluster Headache Severity Scale in determining the severity of cluster headache in patients aged less than 18 years and monitoring response to prescribed treatment. Secondary objectives were to evaluate the feasibility and utility of Cluster Headache Quality of Life, Cluster Headache Index, and 6-item Headache Impact Test in pediatric cluster headache patients to assess the quality of life, severity, and impact of cluster headache. Results: A total of 32 children (age of onset 11.9 ± 2.3 years, age of diagnosis 13.7 ± 2.4 years, 68% boys) were enrolled. Although 30 cases had their headache episodes occurring during nighttime, only 16 children had a Children's Sleep Habits Questionnaire (CSHQ) score >41 at baseline. All children responded to prednisolone as bridging therapy and 23 of 32 showed adequate pain relief after sumatriptan nasal spray for an acute attack. The average time taken for completion of Cluster Headache Index, Cluster Headache Severity Scale, Cluster Headache Quality of Life, and Headache Impact Test-6 scores were 5.2 ± 0.7, 5.1 ± 0.8, 27.4 ± 3.5, and 6.2 ± 0.8 minutes, respectively. The interrater reliability was good for Cluster Headache Severity Scale, Cluster Headache Quality of Life, and Headache Impact Test-6 (Cronbach α 0.93, 0.81, and 0.89, respectively). There was a strong positive correlation between the Cluster Headache Severity Scale score with Headache Impact Test-6 score and Cluster Headache Quality of Life score (correlation coefficient r = 0.90 and 0.98). Conclusion: Majority of pediatric cluster headache patients are likely to respond to prednisolone and sumatriptan. Cluster Headache Severity Scale, Cluster Headache Quality of Life, and Headache Impact Test-6 can be used for pediatric cluster headache patients for treatment monitoring.

Endogenous and exogenous serotonin, but not sumatriptan, ameliorate seizures and neuroinflammation in the pentylenetetrazole-induced seizure model in rats.

BACKGROUND: Epilepsy has neuropsychiatric comorbidities such as depression, bipolar disorder, and anxiety. Drugs that target epilepsy may also be useful for its neuropsychiatric comorbidities. OBJECTIVE: To investigate the effects of serotonergic modulation on pro-inflammatory cytokines and the seizures in pentylenetetrazole (PTZ)-induced seizure model in rats. METHODS: Male Wistar rats were injected intraperitoneally with serotonin, selective serotonin reuptake inhibitor fluoxetine, 5-HT1B/D receptor agonist sumatriptan, or saline 30 min prior to PTZ treatment. Behavioral seizures were assessed by the Racine's scale. Concentrations of IL-1ß, IL-6, and TNF-α in serum and brain tissue were determined by ELISA. RESULTS: Serotonin and fluoxetine, but not sumatriptan, alleviated PTZ-induced seizures by prolonging onset times of myoclonic-jerk and generalized tonic-clonic seizures. The anti-seizure effect of fluoxetine was greater than that of serotonin. Likewise, serotonin and fluoxetine, but not sumatriptan, reduced PTZ-induced increases in the levels of IL-1ß and IL-6 in both serum and brain tissue. None of the administered drugs including PTZ affected TNF-α concentrations. CONCLUSIONS: Our findings suggest that endogenous and exogenous serotonin exhibits anticonvulsant effects by suppressing the neuroinflammation. It seems that 5-HT1B/D receptors do not mediate anticonvulsant and anti-neuroinflammatory effects of serotonin.

Endogenous and exogenous serotonin, but not sumatriptan, ameliorate seizures and neuroinflammation in the pentylenetetrazole-induced seizure model in rats / A serotonina endógena e exógena, mas não o sumatriptano, melhora as convulsões e a neuroinflamação no modelo de convulsão induzida por pentilenotetrazol em ratos

ABSTRACT Background: Epilepsy has neuropsychiatric comorbidities such as depression, bipolar disorder, and anxiety. Drugs that target epilepsy may also be useful for its neuropsychiatric comorbidities. Objective: To investigate the effects of serotonergic modulation on pro-inflammatory cytokines and the seizures in pentylenetetrazole (PTZ)-induced seizure model in rats. Methods: Male Wistar rats were injected intraperitoneally with serotonin, selective serotonin reuptake inhibitor fluoxetine, 5-HT1B/D receptor agonist sumatriptan, or saline 30 min prior to PTZ treatment. Behavioral seizures were assessed by the Racine's scale. Concentrations of IL-1β, IL-6, and TNF-α in serum and brain tissue were determined by ELISA. Results: Serotonin and fluoxetine, but not sumatriptan, alleviated PTZ-induced seizures by prolonging onset times of myoclonic-jerk and generalized tonic-clonic seizures. The anti-seizure effect of fluoxetine was greater than that of serotonin. Likewise, serotonin and fluoxetine, but not sumatriptan, reduced PTZ-induced increases in the levels of IL-1β and IL-6 in both serum and brain tissue. None of the administered drugs including PTZ affected TNF-α concentrations. Conclusions: Our findings suggest that endogenous and exogenous serotonin exhibits anticonvulsant effects by suppressing the neuroinflammation. It seems that 5-HT1B/D receptors do not mediate anticonvulsant and anti-neuroinflammatory effects of serotonin.

RESUMO Antecedentes: A epilepsia apresenta comorbidades neuropsiquiátricas como depressão, transtorno bipolar e ansiedade. Os medicamentos que visam o tratamento da epilepsia podem ser úteis para a epilepsia e suas comorbidades neuropsiquiátricas. Objetivo: Investigar os efeitos da modulação serotonérgica em citocinas pró-inflamatórias e as convulsões no modelo de convulsão induzida por pentilenotetrazol (PTZ) em ratos. Métodos: Ratos Wistar machos foram injetados intraperitonealmente com serotonina, inibidor seletivo da recaptação da serotonina fluoxetina, sumatriptano agonista do receptor 5-HT1B / D ou solução salina 30 min antes do tratamento com PTZ. As crises comportamentais foram avaliadas pela escala de Racine. As concentrações de IL-1β, IL-6 e TNF-α no soro e tecido cerebral foram determinadas por ELISA. Resultados: A serotonina e a fluoxetina, mas não o sumatriptano, aliviaram as convulsões induzidas por PTZ ao prolongar os tempos de início das convulsões mioclônicas e tônico-clônicas generalizadas. O efeito anticonvulsivo da fluoxetina foi maior do que o da serotonina. Da mesma forma, a serotonina e a fluoxetina, mas não o sumatriptano, reduziram os aumentos induzidos por PTZ nos níveis de IL-1β e IL-6 no soro e no tecido cerebral. Nenhum dos medicamentos administrados, incluindo PTZ, alterou as concentrações de TNF-α. Conclusões: Nossos achados sugerem que a serotonina endógena e exógena exibe efeitos anticonvulsivantes por suprimir a neuroinflamação. Aparentemente, os receptores 5-HT1B / D não medeiam os efeitos anticonvulsivantes e anti-neuroinflamatórios da serotonina.

PARACENTRAL ACUTE MIDDLE MACULOPATHY FOLLOWING ORAL INTAKE OF SUMATRIPTAN.

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.

The pathophysiology of Sumatriptan induced non-arteritic anterior ischemic optic neuropathy.

Objective: To report a case of a non-arteritic anterior ischemic optic neuropathy (NAAION) in a patient treated with Sumatriptan. Materials and methods: NAAION represents a severe affection that frequently determines irreversible visual acuity damage. The exact cause is yet to be identified, but is usually connected to the systemic status of the patient. We presented the case of a 53-year-old female patient who complained of visual acuity loss in her right eye, associated with inferior visual field (VF) damage. Patient history revealed migraine attacks, raised arterial blood pressure (BP), mitral valve insufficiency and dyslipidemia. Systemic treatment included Sumatriptan for migraine attacks and Bisoprolol for arterial hypertension. Results: A complete ophthalmologic examination was performed, including a visual field examination and optic coherence tomography. Interdisciplinary consults, along with inflammatory biomarkers, brain scan and cardiovascular Doppler echography were used to establish the final diagnosis. Considering the patient's history, systemic medication, clinical picture, paraclinical findings and interdisciplinary check-ups, NAAION was established as a diagnosis. Discussion: NAAION occurs more frequently after the age of 50 years old and may be associated with systemic factors such as nocturnal hypotension, diabetes, atherosclerosis, sleep apnea. In the present case, the association of medically induced nocturnal hypotension and vasoconstriction led to optic nerve ischemia. Conclusions: In a patient with multiple pathology, we must consider the systemic therapy when performing any clinical examination. Abbreviations: AAION = arteritic anterior ischemic optic neuropathy, AION = anterior ischemic optic neuropathy, BCVA = best corrected visual acuity, BP = blood pressure, CS = corticosteroid, IOP = intraocular pressure, LE = left eye, MRI = magnetic resonance imaging, NAAION = non-arteritic anterior ischemic optic neuropathy, OCT = optical coherence tomography, ON = optic nerve, OU = both eyes, RE = right eye.

Acute coronary syndrome and transient global amnesia with sumatriptan.

Triptans are potent serotoninergic vasoconstrictors. They are generally avoided in elderly patients age greater than 65 or in patients with a history of CAD. Although there are reported cases of Acute Coronary Syndrome (ACS) or Transient Global Amnesia (TGA) in patients after ingesting therapeutic doses of triptan or dihydroergotamine, this is the first case report, up to our knowledge, of a patient, who had no previous cardiac history, that was diagnosed with both ACS and TGA. A 59-year-old woman with a long-standing history of migraine, gastroesophageal reflux disease, and hypothyroidism, presented to the Emergency Department (ED) complaining of amnesia, chest pain, and left arm numbness after ingesting a single dose of oral sumatriptan approximately 1-2 h prior to arrival. She had no recollection of the events that occurred after taking sumatriptan. No acute laboratory abnormalities were found except for an elevated troponin, which continued to trend upwards. Her EKG had no ST-T wave abnormalities. She was diagnosed with Acute Coronary Syndrome (ACS), non-ST elevation MI. She had a negative noncontrast CT head. Neurology was consulted for her amnesia and diagnosed her with Transient Global Amnesia (TGA). They recommended discontinuing sumatriptan and beginning topiramate as a prophylactic therapy. There is an increasing number of reports delineating sumatriptan's adverse effects. Emergency medicine physicians should promptly recognize the toxic effects and adverse reactions from triptans. Sumatriptan-induced vasoconstriction may lead to cardiac and cerebral ischemic events.

[Sumatriptan 3 mg subcutaneous : Clinical relevance of acute treatment of migraine despite dose reduction]. / Sumatriptan 3 mg subkutan : Klinische Relevanz in der Akuttherapie der Migräne trotz Dosisreduktion.

BACKGROUND: Triptans are a highly effective substance class in the acute treatment of migraine attacks. They contribute to a substantial improvement in the quality of life and help to reduce the socioeconomic burden of the disease. RESULTS: Sumatriptan is the only triptan that is available for subcutaneous administration. It is primarily indicated in patients with the need for rapid relief or insufficient enteral resorption due to nausea and vomiting. In the treatment of migraine attacks with 6 mg subcutaneous sumatriptan the number needed to treat (NNT) is 2.3 for freedom from pain within 2 h and the NNT is 2.1 for pain relief within 2 h; however, the fast resorption of sumatriptan after subcutaneous administration induces more side effects than the oral route, for example dizziness, paresthesia or chest pressure sensation. CONCLUSION: Clinical studies showed that reducing the subcutaneous dose to 3 mg in migraine treatment has significantly better tolerability with high response rates and freedom from pain within 2 h with 66.7% (3 mg) or 50% (6 mg).

Sumatriptan dose increase-induced acute angle closure glaucoma in chronic migraine sufferer.

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.

Vasospasm induced myocardial ischaemia secondary to sumatriptan use.

Certain medications have been implicated in causing acute myocardial infarctions (AMI). Sumatriptan, a medication usually prescribed for acute migraine and cluster headaches has been documented as potentially causing coronary vasospasm, thereby leading to MI. This is usually seen in patients with strong risk factors for coronary artery disease (CAD) or in those with established CAD. Most cases thus far have been reported in patients using the subcutaneous preparation of sumatriptan. Here, we present a case of a patient without prior risk factors for CAD and angiographically unremarkable coronary arteries who presented with evidence of an AMI after oral sumatriptan use for migraines.

Evaluation of the Pharmacokinetic Interaction of Ubrogepant Coadministered With Sumatriptan and of the Safety of Ubrogepant With Triptans.

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.

Safety Problems With a Transdermal Patch for Migraine: Lessons From the Development, Approval, and Marketing Process.

OBJECTIVE: We sought to analyze publicly available information about patient harm associated with an iontophoretic sumatriptan patch, to identify what went wrong and to suggest ways in which similar problems might be prevented in the future. BACKGROUND: The Zecuity® sumatriptan iontophoretic transdermal system was marketed for acute treatment of migraine. The patch was withdrawn less than 10 months after its introduction because of multiple reports of scarring and burning. As of 2018, the FDA Adverse Event Reporting System public dashboard lists a total of 2889 reports of safety problems with the patch, 904 of which were classified as serious. METHODS: For this narrative review, we examined US Food and Drug Administration documents related to the new drug application for this product and its approval. We searched Clinicaltrials.gov, PubMed, Google, Facebook, Twitter, and Instagram public posts for relevant information relating to the patch, its approval, marketing, and complications. RESULTS: The FDA knew about problems with burns and scarring prior to approval of the product, and turned down the initial new drug application for this reason and because of other quality problems with the patch. The reapplication was approved despite continued concerns of several FDA reviewers about safety. The approval required the manufacturer to comply with enhanced postmarketing safety reporting. However, product information and labeling did not mention the possibility of burns or scarring. Approval was based on 1 clinical trial and 2 open label studies in which reporting of adverse events was suboptimal. The clinical trials had been prospectively registered but outcomes had been changed around the time the trial concluded. Aggressive marketing efforts and social media activity may have contributed to inaccurate perceptions of safety and efficacy, but social media also provided a written and photographic record of burns and other harm suffered by patients who used the patch. CONCLUSIONS: Our review identified several problems with the development, testing, approval, and marketing of the Zecuity patch. To improve the process of developing headache treatments, it is important to consider the lessons that can be drawn from an examination of this high-profile failure of the drug development and regulatory system.

Survey Analysis of the Use, Effectiveness, and Patient-Reported Tolerability of Inhaled Oxygen Compared With Injectable Sumatriptan for the Acute Treatment of Cluster Headache.

OBJECTIVE: In this secondary analysis of the Clusterbusters® Medication Use survey, the use, effectiveness, and tolerability of inhaled oxygen were investigated and compared with injectable sumatriptan. We also sought to understand the predictors of medication response. BACKGROUND: Inhaled oxygen is a mainstay abortive intervention in cluster headache but is not approved by the Food and Drug Administration (FDA). Unlike injectable sumatriptan, the only FDA-approved pharmacologic intervention for cluster headache, oxygen can be used multiple times a day, which is highly relevant for a condition with numerous daily attacks. In addition to obstacles in obtaining oxygen therapy, optimal oxygen delivery (ie, mask, flow rate) is not uniformly employed in cluster headache. These factors lead to underuse and imprecise therapeutic response rates. METHODS: A secondary analysis was conducted using deidentified data from the Clusterbusters® Medication Use survey, which was modeled after previously published surveys and available online. Subjects were recruited from headache clinics and cluster headache websites. Most responses were chosen from a list; others were free-texted. The final analysis included responses from 493 adult participants with a validated diagnosis of cluster headache. This analysis of deidentified data from the Clusterbusters® Medication Use survey received institutional approval. RESULTS: The most commonly used delivery system used by subjects was a non-rebreather-type mask. The use of oxygen flow rates >10 L/min was a positive predictor of medication response (OR = 2.36, P = .016). Among those who used flow rates >10 L/min, both inhaled oxygen (81.5%) and injectable sumatriptan (80.5%) were efficacious and did not differ significantly from each other in any specific group examined. At flow rates >10 L/min, positive predictors of oxygen response were male gender (OR = 2.07, P = .031) and cigarette smoking (current or historical; OR = 2.25, P = .017). Among the groups examined, there were no predictors of sumatriptan response. Most comments about side effects and concerns were directed at triptans. CONCLUSION: Therapeutic response to inhaled oxygen at sufficiently high flow rates (>10 L/min) had comparable efficacy to that of injectable sumatriptan for the acute treatment of cluster headache. Other factors in oxygen delivery (ie, flow rate changes) should be explored for optimization of therapy. The reasons for improved oxygen response in males and those with a cigarette smoking history require further exploration. While both oxygen and sumatriptan can be effective in the management of cluster headache, patient-reported side effects and concerns were more commonly directed at triptan medications. Current restrictions on access to inhaled oxygen, which exist at many levels, limit the therapeutic options available for patients with cluster headache, thereby doing a disservice to this patient population and the providers who deliver their care.

Efficacy and safety of DFN-11 (sumatriptan injection, 3 mg) in adults with episodic migraine: a multicenter, randomized, double-blind, placebo-controlled study.

BACKGROUND: In a previous randomized, double-blind, proof-of-concept study in rapidly escalating migraine, a 3 mg dose of subcutaneous sumatriptan (DFN-11) was associated with fewer and shorter triptan sensations than a 6 mg dose. The primary objective of the study was to assess the efficacy and safety of acute treatment with DFN-11 compared with placebo in episodic migraine. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled efficacy and safety study of DFN-11 in the acute treatment of adults with episodic migraine (study RESTOR). The primary endpoint was the proportion of subjects taking DFN-11 who were pain free at 2 h postdose in the double-blind period compared with placebo. Secondary endpoints included earlier postdose timepoints, assessments of pain relief and subjects' freedom from their most bothersome symptom (MBS) (among nausea, photophobia, and phonophobia). Safety and tolerability were assessed. RESULTS: A total of 392 subjects was screened, 268 (68.4%) were randomized, and 234 (87.3% of those randomized) completed the double-blind treatment period. The proportion of subjects who were pain free at 2 h postdose was significantly greater in the DFN-11 group than in the placebo group (51.0% vs 30.8%, P  =  0.0023). Compared with placebo, significantly higher proportions of subjects treated with DFN-11 were also pain free at 30, 60, and 90 min postdose (P  ≤  0.0195). DFN-11 was significantly superior to placebo for pain relief at 60 min, 90 min, and 2 h postdose (P ≤ 0.0179). At 2 h postdose, DFN-11 was also significantly superior to placebo for freedom from photophobia (P  =  0.0056) and phonophobia (P  =  0.0167). Overall, 33.3% (37/111) who received DFN-11 and 13.4% (16/119) who received placebo experienced at least 1 treatment-emergent adverse event (TEAE), the most common of which were injection site swelling (7.2% vs 0.8%) and pain (7.2% vs 5.9%). Chest discomfort was about half as common in the DFN-11 treatment group as it was in the placebo group (0.9% vs 1.7%). CONCLUSIONS: This study met its primary endpoint, pain freedom at 2 h postdose, with DFN-11 significantly better than placebo, and the incidence of TEAEs and triptan sensations with DFN-11 was low. The 3 mg dose of sumatriptan in DFN-11 appears to be an effective alternative to a 6 mg SC dose of sumatriptan, with good safety and tolerability. ( clinicaltrials.gov : NCT02569853; registered 07 October 2015).

Efficacy and safety of DFN-11 (sumatriptan injection, 3 mg) in adults with episodic migraine: an 8-week open-label extension study.

BACKGROUND: DFN-11, a 3 mg sumatriptan subcutaneous (SC) autoinjector for acute treatment of migraine, has not been assessed previously in multiple attacks. The objective of this study was to evaluate the efficacy, tolerability, and safety of DFN-11 in the acute treatment of multiple migraine attacks. METHODS: This was an 8-week open-label extension of multicenter, randomized, double-blind, placebo-controlled US study. Subjects averaging 2 to 6 episodic migraine attacks per month were randomized to DFN-11 or placebo to treat a single attack of moderate-to-severe intensity and then entered the extension study to assess the efficacy, tolerability, and safety of DFN-11 in multiple attacks of any pain intensity. RESULTS: Overall, 234 subjects enrolled in the open-label period, and 29 (12.4%) discontinued early. A total of 848 migraine episodes were treated with 1042 doses of open-label DFN-11 and subjects treated a mean (SD) of 3.9 (2.3) attacks. At 2 h postdose in attacks 1 (N = 216), 2 (N = 186), 3 (N = 142) and 4 (N = 110), respectively, pain freedom rates were 57.6%, 64.6%, 61.6%, and 66.3%; pain relief rates were 83.4%, 88.4%, 84.1%, and 81.7%; most bothersome symptom (MBS)-free rates were 69.0%, 76.5%, 77.7%, and 74.7%; nausea-free rates were 78.1%, 84.6%, 86.5%, and 85.7%; photophobia-free rates were 75.3%, 76.4%, 72.3%, and 77.5%; and phonophobia-free rates were 75.2%, 77.5%, 73.6%, and 76.0%. Overall, 40.6% (89/219) of subjects reported treatment-emergent adverse events (TEAE), the most common of which were associated with the injection site: swelling (12.8%), pain (11.4%), irritation (6.4%), and bruising (6.4%). Most subjects (65.2%, 58/89) had mild TEAEs; severe TEAEs were reported by 1 subject (treatment-related jaw tightness). Five subjects (2.1%) discontinued due to adverse events, which included mild throat tightness (n = 2), moderate hernia pain (n = 1), moderate hypersensitivity (n = 1), and 1 subject with mild nausea and moderate injection site swelling. There were no serious TEAEs and no new or unexpected safety findings. CONCLUSION: DFN-11 was effective, tolerable, and safe in the acute treatment of 4 migraine attacks over 8 weeks, with consistent responses on pain and associated symptoms. Most TEAEs were mild, with a very low incidence of triptan-related TEAEs. DFN-11 is potentially an effective and safe alternative for the acute treatment of migraine. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02569853 . Registered 07 October 2015.

DFN-02 (Sumatriptan 10 mg With a Permeation Enhancer) Nasal Spray vs Placebo in the Acute Treatment of Migraine: A Double-Blind, Placebo-Controlled Study.

OBJECTIVE: The objective of this study was to evaluate the efficacy, safety, and tolerability of DFN-02 - a nasal spray comprising sumatriptan 10 mg and a permeation-enhancing excipient (0.2% 1-O-n-Dodecyl-ß-D-Maltopyranoside [DDM]) - for the acute treatment of migraine with or without aura in adults. BACKGROUND: Prior work has shown that DFN-02, which contains only half the recommended adult dose of sumatriptan found in the original formulation (10 mg vs 20 mg), is more rapidly absorbed than commercial nasal spray of sumatriptan, with favorable pharmacokinetic and safety profiles. The efficacy of DFN-02 in the acute treatment of migraine has not been previously assessed. METHODS: This was a multicenter, randomized, 2-period, double-blind, placebo-controlled efficacy, safety, and tolerability phase 2 study of DFN-02. Subjects with at least a 12 month history of episodic migraine, who averaged 2-8 attacks per month, with no more than 14 headache days per month and a minimum of 48 headache-free hours between attacks, were randomized (1:1) to receive DFN-02 or a matching placebo. Subjects were instructed to treat a single migraine attack of moderate to severe pain intensity. The primary efficacy endpoint, the proportion of subjects who were pain-free at 2 hours postdose in the first double-blind treatment period, was assessed with 2 protocol prespecified primary analyses: last observation carried forward (LOCF) and observed cases (OC). Secondary efficacy endpoints at 2 hours included pain relief; absence of the most bothersome symptom (MBS) among nausea, photophobia, and phonophobia; freedom from nausea, photophobia, and phonophobia. Sustained pain freedom from 2 through 24 hours postdose was also assessed. RESULTS: Of 107 subjects randomized, 86.9% (N = 93 [DFN-02, n = 50; placebo, n = 43]) had data in the first double-blind treatment period. The study met its primary endpoint; the proportion of subjects who were free from headache pain at 2 hours postdose, was statistically significantly higher in the DFN-02 group than in the placebo group in both prespecified primary analyses: LOCF (DFN-02, n = 21/48; placebo, n = 9/40; 43.8% vs 22.5%, P = .044) and OC (DFN-02, n = 21/48; placebo, n = 8/39; 43.8% vs 20.5%, P = .025). For secondary efficacy endpoints, at 2 hours postdose, DFN-02 was also statistically significantly superior to placebo for the proportion of subjects who had pain relief (83.3% vs 55.0%, P = .005); who were free of their MBS (70.7% vs 39.5%, P = .007); and who were free of nausea (78.3% vs 42.1%, P = .026), photophobia (71.8% vs 38.9%, P = .005), and phonophobia (78.1% vs 40.0%, P = .004). Compared with placebo, statistically significantly greater proportions of subjects who were treated with DFN-02 had sustained pain freedom from 2 through 24 hours postdose (38.9% vs 13.8%, P = .029). In total, 9.7% (9/93) of subjects reported a treatment-emergent adverse event during the study: 10.0% (5/50) of DFN-02 subjects in the first double-blind treatment period and 13.5% (5/37) of DFN-02 subjects in the second double-blind treatment period. The most common treatment-emergent adverse event with DFN-02 was dysgeusia (3/37 subjects in the second double-blind treatment period). CONCLUSIONS: DFN-02 was shown to be effective, well tolerated, and safe in the acute treatment of episodic migraine. Additional studies are needed to confirm these preliminary results. (ClinicalTrials.gov Identifier: NCT02856802).