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Objective Background Methods Results Conclusions Our primary outcome was to determine the feasibility of patients with post‐traumatic headache (PTH) keeping a daily headache diary and using sumatriptan as directed. Secondary outcomes include determining if sumatriptan is effective in aborting PTH and whether headache resolution is dependent on PTH phenotype.PTH is prevalent and persistent after traumatic brain injury, yet there have been few studies evaluating the effects of pharmacological treatments in individuals with PTH.This is a single‐arm, prospective, non‐randomized phase 2 clinical trial registered at Clinicaltrials.gov (NCT01854385) and conducted from 2013 to 2017. Data analysis was completed in 2022. Of the 299 participants screened, 40 were enrolled in the study. Participants kept a headache diary documenting headache characteristics and severity. Headache characteristics were used to determine PTH phenotypes of migraine‐like, probable migraine‐like, or non‐migraine‐like. Participants reported whether sumatriptan was used for their headache, their response to the medication, if a second dose was taken, and their response to the second dose.A total of 15 participants out of the 40 enrolled (mean [SD] age, 41.9 [14.2] years, and 53% [21/40] male), met the criteria for the use of sumatriptan, and completed all assessments. Average headache diary compliance rate for the final month of the study was 80% (372/465). While sumatriptan was used for only 19% (122/654) of all reported headaches, 72% (88/122) of those headaches resolved within 2 h of taking the medication. Resolution of headaches with sumatriptan was not significantly different among headache phenotypes (migraine‐like: 22/38 [58%], probable migraine‐like: 24/29 [83%], non‐migraine‐like: 6/15 [40%]; p = 0.154).A daily headache diary is feasible for tracking headache symptoms. Preliminary results also suggest that sumatriptan, a migraine‐specific medication, may be beneficial for the treatment of PTH of different clinical phenotypes. Future studies, such as a phase 3 clinical trial with a larger sample size, are needed to better understand the efficacy of sumatriptan in the treatment of PTH. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to test whether a combination of sumatriptan with dual enkephalinase inhibitor PL37 would result in an additive or a synergistic effect. Background: Combination treatment is frequently used to improve the therapeutic efficacy of drugs. The co‐administration of two drugs may result in efficacy at lower doses than those needed for either drug alone, thus minimizing side effects. Here, we tested the effect of the co‐administration of two drugs on cutaneous mechanical hypersensitivity (MH), a symptom often affecting cephalic regions in patients with migraine: dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, and sumatriptan, a serotonin 5‐HT1B/1D receptor agonist. Methods: We investigated the effects of oral administrations of sumatriptan, PL37, or their combination on changes in cutaneous mechanical sensitivity induced by a single intraperitoneal administration of the nitric oxide donor, isosorbide dinitrate (ISDN) in male rats. Mechanical sensitivity was assessed using von Frey filaments applied to the face of animals to determine pain thresholds. Isobolographic analysis was performed to determine the nature of the interaction between sumatriptan and PL37. Results: Sumatriptan as well as PL37 each produced a dose‐dependent inhibition of ISDN‐induced cephalic MH. Median effective dose (ED50) values were 0.3 and 1.1 mg/kg for sumatriptan and PL37, respectively. An isobolographic analysis of the effect of combined doses of sumatriptan and PL37 based on their calculated ED50 values demonstrated a synergistic effect of the combination on cephalic MH, with an interaction index of 0.14 ± 0.04. Conclusion: These results suggest that PL37 acts synergistically with sumatriptan to produce an anti‐allodynic effect in a rat model of migraine. Thus, combining PL37 and sumatriptan may be a useful therapeutic strategy in the management of migraine. Plain Language Summary: There have been many advances in migraine treatment, but we still need more options that are effective and have few side effects. Sumatriptan is one available drug for acute treatment of migraine, but it does not work for every patient and is not suitable for some people. We tested a new drug called PL37 (that blocks enkephalinases) together with sumatriptan and the combination minimized side effects and allowed lower doses of the drugs for effective migraine treatment in an animal model. [ABSTRACT FROM AUTHOR]

Objective: We sought to investigate the prevalence of triptan use among patients with migraine who have contraindications to triptan usage, and to explore specifics of the medication prescribed, dosage, and route of administration. Background: Triptan medications are a mainstay of acute migraine therapy, but little is known about prevalence and patterns of triptan prescribing among patients with contraindications in the United States. Methods: In this retrospective cohort study, we used data from the IBM Marketscan database to identify patients aged ≥ 18 years with migraine from January 1, 2016, to December 31, 2017, using International Classification of Diseases, Clinical Modification 10 codes. Contraindications to triptan medications were identified by review of package labels as listed on the US Food and Drug Administration website. Triptan medications were identified from the IBM Micromedex Redbook linked to prescription claims along with route of administration and dosage. Results: Of 1,038,472 individuals diagnosed with migraine, 400,112 (38.5%) were prescribed triptan medication, and of those who were prescribed a triptan, 55,707 (13.9%) had at least one contraindication, with the most common contraindication being cardiac arrhythmia (33,696/400,112 individuals, 8.4%) followed by cerebrovascular disease (14,787/400,112, 3.7%) and coronary artery disease (10,236/400,112, 2.6%). Sumatriptan was the most prescribed triptan (261,736/1,038,472, 25.2%), and the subcutaneous and intranasal routes were more commonly prescribed among those with contraindications compared with those without contraindications. Discussion: A substantial proportion of patients with migraine with contraindications were prescribed triptan medications. These findings call for further research on the outcomes of patients with medical contraindications who are prescribed triptan medications, and for greater clarity in prescribing guidelines about the optimal approach for acute therapy among patients with migraine. [ABSTRACT FROM AUTHOR]

The article presents a case study reporting two instances of severe and transient pain at recent bone fracture sites following subcutaneous sumatriptan (SS) injection in patients with cluster headaches. Topics include the unusual adverse reaction of bone site pain associated with SS injection, the patients' clinical histories, and the proposed hypotheses regarding the pathophysiology, including SS-induced allodynic pain and the stimulation of 5-HT1B and 5-HT1D receptors at the fracture site.

Objective: We used network meta‐analysis (NMA) to characterize the relative effectiveness and harms of acute treatment options for cluster headache. Background: There are few evidence‐based acute treatments available for cluster headache. As most treatments were compared only against placebos in clinical trials, few head‐to‐head comparisons of treatments are available. Methods: An a priori registered scoping review was performed to identify randomized controlled trials evaluating treatments in adult patients (>18 years old) with cluster headache per accepted diagnostic criteria. Bayesian NMAs were performed to compare treatments in terms of headache relief at 15 or 30 min, and also the occurrence of adverse events. We report odds ratios (ORs) of relative treatment effects along with corresponding 95% credible intervals (CrIs), as well as measures of treatment ranking. Results: A total of 13 randomized controlled trials informed NMAs. We found high flow oxygen to be the most effective therapy for headache response at 15 and 30 min (OR 9.0, 95% CrI 5.3 to 15.9 vs. placebo), with injectable sumatriptan demonstrating the next highest effect (OR 6.4, 95% CrI 3.75 to 11.1 vs. placebo). High flow oxygen was also more effective than low flow oxygen (OR 2.55, 95% CrI 1.13 to 5.8), nasal spray zolmitriptan (OR 3.75, 95% CrI 1.72 to 8.4), octreotide (OR 4.5, 95% CrI 1.64 to 12.5), and non‐invasive vagal nerve stimulation (nVNS; OR 5.2, 95% CrI 2.29 to 11.9). Sumatriptan injectable was also effective for headache relief and was found to be better than nasal spray zolmitriptan (OR 2.67, 95% CrI 1.21 to 5.9), octreotide (OR 3.20, 95% CrI 1.17 to 8.8), and nVNS (OR 3.69, 95% CrI 1.63 to 8.4). Octreotide (OR 4.1, 95% CrI 1.71 to 10.5) and sumatriptan (OR 2.40, 95% CrI 1.39 to 4.2) were associated with greater risk of adverse events compared to placebo, while other treatments did not demonstrate increased risk. When focusing on patients with episodic cluster headache, nVNS was significantly better than placebo (OR 4.9, 95% CrI 1.89 to 14.1). Conclusions: Our findings suggest that high flow oxygen is more efficacious when compared to low flow oxygen for headache relief. When low flow oxygen fails in patients who can tolerate oxygen, increased flow rates should be tried. Additionally, high flow oxygen is likely more effective than zolmitriptan nasal spray, nVNS, and octreotide. Sumatriptan injectable is more likely to be effective when compared to zolmitriptan nasal spray, octreotide, and nVNS. [ABSTRACT FROM AUTHOR]

Objective: To investigate the safety and efficacy of intranasal ketamine for the treatment of a single cluster headache (CH) attack. Background: Acute treatment options for patients with CH who have an insufficient response to oxygen and triptans are limited. Intranasal ketamine has anecdotally been successful in treating a CH attack. Methods: We conducted an open‐label pilot study enrolling 23 patients with chronic CH (International Classification of Headache Disorders, 3rd edition), and of these, 20 patients treated a single CH attack with intranasal ketamine. Under in‐hospital observation, patients received 15 mg of intranasal ketamine every 6 min a maximum of five times. The primary endpoint was a 50% reduction in pain intensity within 15 min after initiating treatment. Results: The primary endpoint was not met; 15 min after the first ketamine administration, the mean reduction in pain intensity was 1.1 (95% confidence interval [CI]: −0.6 to 2.7, p = 0.188) on the numeric rating scale (NRS), equivalent to a 15% reduction in pain intensity. However, 30 min after the first application, the pain intensity was reduced by 59% on an 11‐point NRS (mean difference: 4.3, 95% CI: 2.4–6.2, p < 0.001, N = 16) and 11 out of 16 (69%) scored 4 or below on the NRS. Four patients received rescue medication 15 min after the first ketamine application and were therefore excluded from the analysis at 30 min. Half of the patients preferred ketamine to oxygen and/or sumatriptan injection. No serious adverse events were identified during the trial. Conclusion: Intranasal ketamine may be an effective acute treatment for CH at 30 min but should be tested in a larger controlled design. Patients and physicians should be conscious of the abuse potential of ketamine. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: The monoclonal antibodies against calcitonin gene‐related peptide (CGRP) or its receptor are new antimigraine drugs from which many patients already benefit. Very few side effects have been reported from the antibody trials, including very few gastrointestinal (GI) side effects. The current data derive from a double‐blind cross‐over study of CGRP infusion for 2 hours. We present the GI side effects of the infusion and raise the question if underreporting of GI symptoms in CGRP antibody trials has occurred. We also discuss why constipation may be more likely with CGRP receptor blockade than with CGRP neutralizing antibodies. Methods: Thirty healthy volunteers were recruited to receive a 2‐hour infusion of CGRP 1.5 µg/minutes on 2 different days. The participants were pretreated with sumatriptan tablets (2 × 50 mg) 1 day and with placebo the other day. During the infusion, the participants were asked about side effects including a detailed description about their GI symptoms. Clinical observations like flatulence, rumbling, and use of bedpan were also noted. After the infusion, the participants filled out a questionnaire about side effects at home until 12‐hour after the infusion start. The study was conducted at the Danish Headache Center at Rigshospitalet Glostrup in the period February 2018 to July 2018. Results: On both study days 93% (27/29 participants) experienced symptoms from the GI system during the infusion. Rumbling, stomach pain, nausea, diarrhea, and an urge to defecate were the most commonly experienced GI side effects. There was no difference in symptoms between placebo and sumatriptan pretreatment. Conclusion: We conclude that a 2‐hour infusion of CGRP causes frequent and sometimes severe symptoms from the GI system. The symptoms are not antagonized by sumatriptan. More attention should be paid to constipation as a possible side effect of CGRP receptor antagonists. [ABSTRACT FROM AUTHOR]

Objective: Previous attempts to develop a pragmatic human model for testing new anti‐migraine drugs, have failed. Calcitonin gene‐related peptide (CGRP) induces a mild headache in healthy volunteers and migraine‐like headache in migraine patients. The induced headache must respond to already established migraine treatment for validation. Thus, the objective of the study was to test the effect of sumatriptan against CGRP‐induced symptoms in an attempt to validate CGRP‐induced headache as a model for drug testing. Methods: Thirty healthy volunteers were recruited to receive a 2‐hour infusion of CGRP on 2 separate days. The participants were pretreated with sumatriptan 1 day and with placebo the other day in a randomized double‐blind cross‐over fashion. During the infusion, a questionnaire about headache and side effects was administered. Electrocardiography, heart rate, blood pressure, dermal blood flow, and diameter of peripheral arteries were monitored during the infusion. Participants were carefully instructed to fill out a headache questionnaire at home until 12 hours after the infusion start. Primary endpoints are difference between the sumatriptan day and the placebo day in area under the headache score curve (AUC) 0‐2 hours after infusion start and in headache intensity 2 hours after infusion start. The study was conducted at the Danish Headache Center in Glostrup, Denmark. Results: CGRP‐induced headache in 86% (25/29) of the participants on the sumatriptan day and in 96% (28/29) of the participants on the placebo day. There was no difference in AUCheadache, 0‐2 hours between the days (P =.794). There was a statistically significant decrease in mean atrial pressure (MAP) over time on both days with a16.2% reduction on the sumatriptan day and a 14.8% reduction on the placebo day (P <.001) and a statistically significant increase in heart rate (HR) over time on both days (from mean 57.5 at baseline to mean 105.4 at 120 minutes on the sumatriptan day and from mean 60.2 at baseline to 105.8 at 120 minutes on the placebo day, P <.001). The diameter of peripheral arteries increased statistically significant on both days (P <.001). Conclusion: Sumatriptan does not influence headache score, accompanying symptoms or other symptoms induced by CGRP. Furthermore, a 2‐hour CGRP infusion causes a wide range of side effects and does not induce more headache than the usual 20‐minute infusion. Thus, the prolonged infusion of CGRP in healthy volunteers is not a valid and pragmatic model for testing new anti‐migraine drugs. [ABSTRACT FROM AUTHOR]

There are many new treatment options available for migraine and more are coming. Three calcitonin gene‐related peptide (CGRP) antagonist monoclonal antibodies have been approved and a 4th is due in early 2020. Small molecule CGRP receptor‐blocking oral compounds, both for acute care and prevention, are also coming. Four neurostimulators are available, with others on the way. New acute treatments coming soon include the 5HT1F agonist lasmiditan, a zolmitriptan intradermal micro‐needle patch, and a nasal mist sumatriptan with a permeability enhancer. Farther out, three novel dihydroergotamine delivery systems, and a liquid‐filled capsule of celecoxib show early promise. A new, safer form of methysergide is in the works, as is a longer‐duration onabotulinumtoxinA. As always with new products, questions regarding safety, tolerability, cost, and insurance coverage will need to be addressed. Despite these concerns and uncertainties, a robust headache treatment pipeline is good for patients who are not satisfied with the results of their treatment and/or cannot tolerate existing treatments. [ABSTRACT FROM AUTHOR]

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 < .0001). The MMA dilation lasted over 5 hours during observational period. We found a significant association between headache and MMA dilation (P < .0001). The superficial temporal artery (STA) circumference was significantly larger after levcromakalim compared with placebo (P = .03) over the initial period (110 minutes). Over the entire observational period, there was no difference in circumference of the STA and the middle cerebral artery (MCA) between levcromakalim and placebo. Conclusion: Levcromakalim dilated the MMA but not MCA. The MMA dilation was associated with headache. Future studies should investigate whether opening of KATP channels can activate and sensitize the perivascular nociceptors. [ABSTRACT FROM AUTHOR]

Objective: To provide evidence‐based recommendations for the acute symptomatic treatment of children and adolescents with migraine. Methods: We 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. Results: There 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. Recommendations: Recommendations 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 counselling on lifestyle factors that can exacerbate migraine, including trigger avoidance and medication overuse. [ABSTRACT FROM AUTHOR]

Background: Consistency of response across multiple attacks is typically measured as the proportion of study participants who achieve a categorical endpoint over a specified number of attacks (ie, 2‐hour pain‐free response in 2 of 3 attacks). We applied a novel analytic approach for measuring consistency of response in the acute treatment of episodic migraine using data from the COMPASS study. Methods: The COMPASS study (NCT01667679) was a multiple attack crossover study which compared AVP‐825, a Breath Powered® intranasal delivery system for low‐dose sumatriptan powder (22 mg), with 100‐mg oral sumatriptan tablets in the acute treatment of migraine. Participants were 18–65 years old, met ICHD‐2 criteria for migraine with or without aura, and had migraine for ≥1 year prior to screening. They were instructed to treat up to 5 migraine attacks with each treatment and recorded migraine pain intensity and disability data at pre‐dose and 10, 15, 30, 45, 60, 90, and 120 minutes post‐dose for each attack. We explored the mean level and within‐person variability (WPV; a measure of consistency) in migraine pain intensity and migraine‐related disability across multiple attacks after treatment with AVP‐825 (22 mg) vs oral sumatriptan (100 mg) using location scale mixed‐effects models (LSMEMs). LSMEMs controlled for pre‐dose pain/disability, demographics, treatment sequence, and treatment period. Results: The mean age was 40 and the sample was 84.6% women. Participants (N = 259) treated an average of 6.8 attacks each during the course of the study. Attacks treated with AVP‐825 showed significantly lower mean pain intensity and mean disability from 10 to 90 minutes post‐dose (effect sizes ranged from −0.09 to −0.29 and P values ranged from P <.0001 to P =.01). WPV was significantly greater at 10–15 minutes (WPV ratios ranged from 1.20 to 1.58 and P values ranged from P <.0001 to P =.04) but significantly reduced from 45 to 120 minutes for attacks treated with AVP‐825 compared to oral sumatriptan (WPV ratios ranged from 0.67 to 0.81 and P values ranged from P <.0001 to P =.03). Conclusions: LSMEMs demonstrate that treatment with AVP‐825 is associated with lower average migraine pain intensity and disability from 10 to 90 minutes and greater within‐person consistency across multiple migraine attacks (reduced WPV) from 45 to 120 minutes post‐dose compared to oral sumatriptan. These findings may reflect the more rapid and consistent absorption of sumatriptan using AVP‐825. Increased WPV with AVP‐825 in the first 15 minutes likely reflects the earlier onset of treatment effects with the device compared to oral sumatriptan. LSMEMs show promise as a novel approach for assessing and comparing consistency of treatment response in migraine trials. [ABSTRACT FROM AUTHOR]

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 [11C]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. [ABSTRACT FROM AUTHOR]

The article focuses on two small molecule Calcitonin gene-related peptide (CGRP) receptor antagonists, ubrogepant, and rimegepant. The main results of large Phase 3 trials of the drugs were reportedly presented as abstracts at several medical conferences in the first half of 2018. It adds that pain-free at 2 hours has been used as the primary efficacy outcome measure in most randomized controlled trials of newer treatments for migraine.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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‐β‐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). [ABSTRACT FROM AUTHOR]

Objective: To present results from the United States Cluster Headache Survey comparing the clinical presentation of tobacco nonexposed and tobacco‐exposed cluster headache patients. Background: Cluster headache is uniquely tied to a personal history of tobacco usage/cigarette smoking and, if the individual cluster headache sufferer did not smoke, it has been shown that their parent(s) typically did and that individual had significant secondary smoke exposure as a child. The true nontobacco exposed (no personal or secondary exposure) cluster headache sufferer has never been fully studied. Methods: The United States Cluster Headache Survey consisted of 187 multiple choice questions related to cluster headache including: patient demographics, clinical headache characteristics, family history, triggers, smoking history (personal and secondary), and headache‐related disability. The survey was placed on a website from October through December 2008. Results: One thousand one hundred thirty‐four individuals completed the survey. One hundred thirty‐three subjects or 12% of the surveyed population had no personal smoking/tobacco use history and no secondary smoke exposure as an infant/child, thus a nontobacco exposed population. In the nonexposed population, there were 87 males and 46 females with a gender ratio of 1.9:1. Episodic cluster headache occurred in 80% of nonexposed subjects. One thousand and one survey responders or 88% were tobacco‐exposed (729 males and 272 females) with a gender ratio of 2.7:1. Eighty‐three percent had a personal smoking history, while only 17% just had parents who smoked with secondary smoke exposure. Eighty‐five percent of smokers had double exposure with a personal smoking history and secondary exposure as a child. Significant highlights from the survey: Nonexposed cluster headache subjects are significantly more likely to develop cluster headache at ages 40 years and younger, while the exposed sufferers are significantly more likely to develop cluster headache at 40 years of age and older. Nonexposed patients have a statistically significant higher frequency of a migraine family history. The exposed population is statistically significantly more likely to have a history of head trauma 19% vs the nonexposed population 10% (P = .02). Tobacco exposed are significantly more likely to transition from episodic to chronic cluster headache (23% vs 14%, P = .02). Cranial autonomic symptoms as well as agitation are more common in tobacco exposed. Nonexposed are less likely to have specific cluster headache triggers. Exposed are significantly more likely to be triggered by alcohol. Tobacco exposed are significantly heavier caffeine users than nonexposed. Nonexposed are significantly more likely to have cluster headache cycles that vary throughout the year than exposed (52% vs 40%, P = .02). Exposed are much more likely to develop cluster headache from 12 am to 6 am than non exposed. Exposed experience significantly more frequent attacks per day and longer duration cycles than nonexposed. A significantly larger percent of the exposed population (57%) has suicidal ideations with their syndrome than nonexposed (43%) (P = .003). In regard to disability, both subtypes are disabled by their headaches, but exposed have more work related disability and lost home‐days from headache. Both subgroups have a poor overall response to preventive and abortive medication outside of inhaled oxygen and injectable sumatriptan. Conclusion: Cluster headache sufferers who were never exposed to tobacco (personal or secondary as a child) appear to present uniquely compared to the tobacco exposed subgroup. The tobacco exposed clinical phenotype appears to have a more severe syndrome based on attack frequency, cycle duration, and headache related disability. Tobacco exposure is associated with cluster headache chronification. The nonexposed subtype appears to have an earlier age of onset, higher rate of familial migraine, and less circadian periodicity and daytime entrainment, suggesting a possible different underlying pathology than in the tobacco exposed sub‐form. [ABSTRACT FROM AUTHOR]

Background: Migraine‐related nausea is associated with significant disability, increased burden of disease, and personal distress. Nausea can lead to delays or avoidance of initiating oral migraine treatment, sometimes resulting in treatment failures and poor outcomes. Nausea is often a symptom of migraine, but nausea may also be a consequence of treatment (ie, treatment emergent nausea [TEN]). Relieving nausea and minimizing TEN are important goals in acute migraine therapy. Methods: We analyzed data from the COMPASS study, a randomized, double blind, double‐dummy, comparative efficacy study that contrasted two active treatments, AVP‐825 (breath‐powered intranasal delivery of powdered sumatriptan 22 mg) and oral sumatriptan tablets (100 mg). Three‐level logistic multilevel models were used to examine longitudinal changes in nausea from three distinct perspectives across multiple attacks. Model 1 (Overall Nausea) examined longitudinal change in nausea from pre‐dose through 120 minutes post‐dose for the entire sample, independent of baseline nausea. Model 2 examined TEN from 10 minutes through 120 minutes post‐dose in attacks free of nausea at baseline to investigate whether or not nausea developed following treatment. Model 3 examined Nausea Relief from 10 minutes through 120 minutes post‐dose in eligible attacks with nausea at baseline to examine whether or not nausea was relieved over the first 2 hours post‐dose. Models tested for differences in rate of change in nausea over time and odds of nausea at specific time‐points. Results: Longitudinal nausea trajectories differed for AVP‐825 and oral sumatriptan in the Overall Nausea model (Model 1) and TEN model (Model 2), but were more comparable across treatments for the Nausea Relief (Model 3). More specifically, in the Overall Nausea model (Model 1), an individual treating an attack with AVP‐825 had a significantly faster decrease in nausea through the first 60 minutes post‐dose and reduced odds of nausea at each time‐point from 30 minutes through 120 minutes post‐dose compared to oral sumatriptan. In Model 2, an individual's risk for TEN increased at a significantly faster rate through the first 45 minutes post‐dose when treating an attack with oral sumatriptan, with significantly greater odds of experiencing TEN at 45, 60, and 90 minutes post‐dose compared to AVP‐825. The Nausea Relief model (Model 3) showed similar rates of change in nausea over time for the two treatments, but there was a constant difference in nausea level leading to reduced odds of nausea when treating with AVP‐825 compared to oral sumatriptan. Conclusions: All three longitudinal models showed that AVP‐825 had more favorable nausea outcomes compared to oral sumatriptan. AVP‐825 treatment led to more rapid early reductions in Overall Nausea rates during the first hour, reduced odds of nausea from 30 minutes to 2 hours following treatment and reduced risk of TEN compared to oral sumatriptan. These results highlight the importance of separately assessing TEN and Nausea Relief in acute treatment trials of migraine. [ABSTRACT FROM AUTHOR]

Background Fast relief of migraine pain, associated symptoms, and migraine-related disability are priorities in the acute treatment of migraine. Efforts to improve the pharmacokinetic profiles of acute migraine treatments with the aim of providing faster relief include the development of non-oral routes of administration. AVP-825 (ONZETRA® Xsail®) is a delivery system containing 22 mg sumatriptan powder that uses a patient's own breath to deliver medication intranasally, targeting the upper posterior nasal cavity beyond the narrow nasal valve, an area lined with vascular mucosa conducive to rapid drug absorption into the systemic circulation. While most studies comparing treatments measure differences in proportions of patients achieving a dichotomous endpoint at fixed time intervals, in this study we compare trajectories of migraine pain and disability over time for AVP-825 versus 100 mg oral sumatriptan tablets. Methods We used data from the COMPASS study (NCT01667679, ), a double-blind, double-dummy, active-comparator, cross-over study of people with a diagnosis of migraine. Participants treated up to five qualifying migraine attacks within 1 hour of onset with either AVP-825 plus placebo tablets or 100 mg oral sumatriptan tablets plus placebo delivery system during the first of two 12-week treatment periods, and then switched treatment sequences to treat up to five more attacks in the second treatment period. Patients recorded ordinal migraine pain intensity and migraine-related disability before dosing (predose), and at 10, 15, 30, 45, 60, 90 and 120 minutes. Three-level ordinal multilevel models accounted for unique data structure (repeated measures nested within attacks for each patient) and tested for treatment differences in migraine pain and migraine-related disability through the first 2 hours of attacks post dose. Results Among 259 study participants (mean age 40.0 years, 84.6% female, 78.4% white), there was significant between and within person variability in migraine pain intensity and migraine-related disability. A typical individual showed significantly faster reductions in migraine pain over the first 30 minutes and migraine-related disability over the first 45 minutes when treating with AVP-825 compared with oral sumatriptan. Overall levels of pain and disability also favored AVP-825 over 2 h following treatment. Model-based odds ratios (OR) comparing AVP-825 to oral sumatriptan ranged from 0.38 to 0.76 for pain and 0.37 to 0.65 for disability, with OR <1 indicating reduced pain/disability in the AVP-825 condition. Conclusions Compared with 100 mg oral sumatriptan, treatment with AVP-825 was associated with faster reductions in migraine pain intensity and migraine-related disability starting at 10 minutes postdose and continuing through the first 30 minutes for migraine pain intensity and the first 45 minutes for migraine-related disability, resulting in lower overall pain intensity and disability that lasted through the first 2 h following treatment. Both migraine pain intensity and disability varied substantially both across subjects and within subjects across attacks. [ABSTRACT FROM AUTHOR]

Background Cardiovascular (CV) events, conditions, and procedures (ECPs) are common in persons with migraine and are a contraindication to triptan and ergot use. In a prior study, we estimated that there are 2.6 million American adults with episodic migraine (EM) who have had CV ECPs. However, the prior analysis did not assess persons with migraine without CV ECPs who are at high risk for a first cardiovascular disease (CVD) event. Objectives To use the Framingham nonlaboratory CVD events risk equation to estimate the number of individuals with EM who are at elevated risk for a first CVD event in the next 10 years using data from the American Migraine Prevalence and Prevention Study, and then to extrapolate the findings to the US population to estimate the scope of people with EM for whom triptan and ergot therapies may be problematic. Methods Data from respondents to the 2009 American Migraine Prevalence and Prevention (AMPP) Study questionnaire aged ≥22 who met criteria and headache day frequency for EM were included in this cross-sectional analysis. Ten-year, first CVD event risk was calculated using the nonlaboratory Framingham CV disease risk score (FRS). Variables were collected via respondent self-report and included sex, age, height, and weight to calculate body mass index (BMI), smoking status, and the presence of hypertension and diabetes among other variables. Standard FRS cut scores of ≥21 for women and ≥16 for men were used, which indicate a 30% or greater risk of a first CVD event in the next 10 years. History of CV ECPs was collected via self-report of ever having the ECP and for events and conditions that were diagnosed by a physician. We applied rates of positive ECPs and rates of high FRS to age and sex stratified estimates of the number of people with EM in the US derived from 2015 US Census data to estimate rates of both in the population. Results The AMPP Study analysis sample included 5227 women and 1496 men with EM. Results showed that 69.5% of women and 73.4% of men had at least one CV risk factor from the FRS, 38.9% of women and 41.6% of men had ≥2 risk factors, and 18.6% of women and 19.1% of men had ≥3 risk factors. The proportion of women with high FRS was 0% for those aged 22-39, 0.8% (95%CI: 0.5-1.2%) among 40- to 59-year-olds and 15.2% (95% CI: 13.3-17.4%) among the ≥60 age group. For men, the corresponding proportions were 0, 7.3% (95% CI: 5.7-9.4%), and 53.0% (95% CI: 4.7-58.1%). Projecting to a national US sample, the number of persons with EM and high FRS was 403,000 for women and 510,000 for men. The proportion of women and men at high risk for future CV events based on a prior CV ECP, a high FRS or both increased with age from 20-39 (women 4.5%, men 4.2%), 40-59 (women 11.8%, men 18.6%), and ≥60 (women 31.2%, men 61.8%). An estimated 141,000 men aged 40-59 and 187,000 aged ≥60 and 34,000 women aged 40-59 and 181,000 women aged ≥60 in the US population with EM have not had a CV ECP but are at increased risk for a future CV event within the next 10 years based upon their FRS alone. Conclusion Among people with EM in the US population, the number of women and men with relative contraindications to triptans and ergots based on a high FRS includes over 900,000 women and men. This includes more than half a million individuals with EM who have not had a prior CV ECP. [ABSTRACT FROM AUTHOR]

Objective In a population sample of persons with migraine treating with a single category of acute migraine medication, to identify rates and factors associated with acute treatment outcomes, including 2-hour pain freedom (2hPF), 24-hour pain response (24hPR), and 24-hour sustained pain response (24hSPR). Key predictors include acute treatment type (triptans and other medication categories), the influence of allodynia on response to medication, and the interaction between medication category and presence of allodynia in response to treatment among people with migraine. Background Cutaneous allodynia was previously associated with inadequate 2hPF, 24hPR, and 24hSPR (sustained response at 24 hours among those with adequate 2hPF) among people with migraine in the American Migraine Prevalence and Prevention (AMPP) Study. Methods The AMPP Study obtained data from a representative US sample of persons with migraine by mailed questionnaire. The 2006 survey included 8233 people with migraine aged 18 or over who completed the Migraine Treatment Optimization Questionnaire (mTOQ). mTOQ was used to assess acute treatment outcomes including 2hPF, 24hPR, and 24hSPR. Eligible individuals used only a single category of acute prescription migraine treatments (n = 5236, 63.6%). This sample was stratified into 5 categories of type of acute prescription headache medication used (triptans, nonsteroidal anti-inflammatory drugs, barbiturate-combinations, opioids, and opioid combinations and ergot alkaloids). Separate binary logistic regression models evaluated: (1) triptans vs other medication types; (2) presence of allodynia vs no allodynia; and (3) the interaction of medication category with allodynia. Sociodemographic variables, health insurance status, over-the-counter and preventive medication use were included as covariates. Odds ratios (OR) and 95% confidence intervals (CI) were generated for each acute treatment outcome. Results Among eligible participants, the mean age was 46 years, and 82.5% were women. The triptan use group had better outcomes than other medication groups for 2hPF (OR range: 2.00-2.63, all significant except ergot alkaloids) and 24hPR (OR range: 2.10-6.22, all significant). No significant medication effects were found for the 24hSPR outcome. The presence of allodynia was associated with significantly worse outcomes for both 2hPF (OR range: 1.42-1.55, all significant) and 24hPR (OR range: 1.30-1.32, all significant, except for ergot alkaloids, P = .051). Allodynia effects were not significant for the 24hSPR. The interaction between medication and allodynia was also not significant (OR range for 2hPF: .68-2.02; OR range for 2hPR: .35-1.34; OR range for 24hSPR: 1.21-2.72) in any of the models, suggesting allodynia is an important predictor of treatment response regardless of the medication group prescribed. Conclusions The use of triptan medication was associated with significantly better 2hPF (except vs ergot alkaloids) and significantly better 24hPR outcomes compared with other acute medication categories. The presence of allodynia significantly increased the likelihood of an inadequate treatment response for both of these outcomes. Triptan use was generally associated with the best outcomes. Because allodynia was associated with inadequate outcomes for all medication groups, we suggest that allodynia is an area of unmet treatment need. [ABSTRACT FROM AUTHOR]

Objective To further characterize the clinical utility of AVP-825 based on additional prespecified outcomes and post hoc analyses of COMPASS, a Phase 3 comparative efficacy trial of AVP-825 vs 100 mg oral sumatriptan (NCT01667679). AVP-825 was approved in January 2016 by the US Food and Drug Administration under the name ONZETRA® Xsail® (sumatriptan nasal powder) for the acute treatment of migraine with or without aura in adults. Background AVP-825 is a delivery system that uses a patient's own breath to deliver low-dose sumatriptan powder to the upper posterior regions of the nasal cavity beyond the narrow nasal valve, areas lined with vascular mucosa conducive to rapid drug absorption into the systemic circulation. The recommended dose of AVP-825 is 22 mg sumatriptan powder administered as one 11 mg nosepiece in each nostril, which delivers approximately 15-16 mg of sumatriptan intranasally. The COMPASS trial compared AVP-825 22-100 mg oral sumatriptan across multiple migraine attacks for efficacy, safety, and tolerability endpoints. Design/Methods COMPASS was a randomized, multicenter, double-dummy, crossover, multiattack, comparative efficacy study with two 12-week double-blind periods. Patients with 2-8 migraine attacks/month were randomized 1:1 to AVP-825 (22 mg) plus oral placebo or an identical placebo delivery system plus 100 mg oral sumatriptan for the first period, and then patients switched treatments for the second period. Patients treated up to 5 qualifying migraines per period within 1 h of onset, even if the intensity of the attack was mild. Results from the primary endpoint (SPID-30, defined as the sum of pain intensity differences from dosing to 30 minutes), key secondary efficacy endpoints and safety assessments have been reported in the primary publication (Tepper et al., 2015). This article reports additional prespecified outcomes, including the SPID-30 for attacks treated when baseline severity was mild vs moderate/severe, measures of sustained response and consistency of effect in patients who experienced multiple migraine attacks, and the results of post hoc analyses performed to assess total migraine freedom (defined as no pain and no migraine-associated symptoms, including nausea, vomiting, photophobia, and phonophobia), time to pain freedom, time to meaningful pain relief, and local (occurring at the site of administration in the nose) vs systemic treatment-emergent adverse events (TEAEs). Results A total of 185 patients completed both treatment periods, yielding 1,531 migraine attacks which were treated and assessed (765 AVP-825, 766 oral sumatriptan). Treatment with AVP-825 provided greater reduction in migraine pain intensity which was statistically significant vs oral sumatriptan in the first 30 minutes postdose regardless of whether attacks were treated when pain was mild (least squares mean SPID-30 = 3.90 vs 0.24, P = .0013) or moderate/severe (least squares mean SPID-30 = 13.83 vs 10.07, P = .0002). At every time point from 15 to 90 minutes postdose, the proportion of attacks achieving total migraine freedom was greater and statistically significant after treatment with AVP-825 vs 100 mg oral sumatriptan. AVP-825 treatment resulted in greater odds of achieving pain freedom (odds ratio, OR = 1.29, P < .01) and meaningful pain relief (OR = 1.32, P < .0001), which were also statistically significant compared with oral sumatriptan. In addition, a greater proportion of attacks treated with AVP-825 vs oral sumatriptan was associated with sustained pain freedom, achieving statistical significance when assessed from 1 h postdose through 24 hours postdose (33.3% vs 27.9%; P < .05) and through 48 hours postdose (32.7% vs 27.4%; P < .05). For patients who treated multiple migraine attacks in both treatment periods, a greater proportion had consistent pain relief and pain freedom following treatment with AVP-825 compared to oral sumatriptan across multiple attacks, a difference that achieved statistical significance at 30 minutes postdose. Local TEAEs of abnormal taste and nasal discomfort were more common following AVP-825 treatment. Of the patients experiencing either of these TEAEs, about 90% described the intensity as mild, and only one discontinued treatment because of either of these two TEAEs. Conclusions These results from the COMPASS study further demonstrate that treatment with AVP-825 provides earlier onset and more consistent across-episode improvement of pain and migraine-associated symptoms compared with oral sumatriptan, highlighting the clinical advantages of this newly approved intranasal delivery system for low-dose sumatriptan powder. [ABSTRACT FROM AUTHOR]

Objective A review of treatment options for menstrual migraine. Background Migraine affects ∼30 million people in the US. A subset of female migraineurs have migraines that are mainly associated with menstruation. Menstrual migraine (MM) is divided into pure MM and menstrually related migraine. Pure MM attacks occur only with menstruation and have a prevalence of 1%. Menstrually related migraine has a prevalence of 6-7%, and occurs both during menstruation as well as during the rest of the cycle. MM is usually without aura and is more severe, longer lasting, and more resistant to treatment due to the effects of ovarian hormones, specifically estrogen. MM treatment is divided into acute, short-term prophylaxis, and daily prevention. The best-studied acute treatments are triptans. For short-term prophylaxis, triptans, non-triptans, or combinations are used. Some preventive medications may be used daily to prevent MM. Many anti-epileptic medications used in migraine prevention can affect the efficacy of oral contraceptives and hormonal treatments, so caution is indicated when these are used. Methods PubMed, Scopus, Cochrane, and Embase were searched for MM and treatments. Results Many randomized, placebo-controlled, prospective studies have evaluated the efficacy of sumatriptan, rizatriptan, naratriptan, zolmitriptan, and almotriptan in MM. Reviewing numerous studies with statistically significant results, rizatriptan has the best overall evidence for acute treatment of MM, ranging from pain-free responses of 33-73% at 2 hours. Sumatriptan and rizatriptan have shown similar efficacies of 61-63% in terms of 2 hour pain freedom. Rizatriptan showed sustained pain relief between 2 and 24 hours with an efficacy of 63% and sustained pain freedom for MM between 2 and 24 hours with an efficacy of 32%. For short-term prevention of MM, there were four randomized controlled trials for frovatriptan taken twice daily, one trial for zolmitriptan taken three times daily, and two studies for naratriptan taken twice daily, all of which showed statistically significant results. Among studies on non-triptans for short-term prevention of MM, magnesium, estrogen, naproxen sodium, and dihydroergotamine all had statistically significant results. Many antiepileptic medications taken for prevention of MM can cause enzyme induction affecting oral contraceptives (OCs) and hormonal treatments to different degrees. Topiramate has the least effect on OCs at doses below 200 mg/day. Lamotrigine noticeably decreases oral contraceptive levels; however, the evidence for it as a preventive medication is not strong. Conclusion MM can be very difficult to treat. For acute treatments, rizatriptan has the best overall evidence. For short-term prevention, frovatriptan, zolmitriptan, or naratriptan, as well as magnesium, estrogen, naproxen sodium, or dihydroergotamine may be useful. [ABSTRACT FROM AUTHOR]

Objective/Background Intranasal sumatriptan (Imitrex®) may be an alternative for patients who refuse injections and cannot tolerate oral agents, but due to low bioavailability and slow absorption, the clinical utility of the currently marketed formulation is limited, highlighting an unmet need for an effective non-oral migraine medication with a rapid onset of action. To overcome the slow absorption profile associated with intranasal administration, we evaluated the impact of 1-O-n-Dodecyl-β-D-Maltopyranoside (DDM, Intravail A-3™), a permeation enhancer, on sumatriptan's pharmacokinetic profile by comparing the pharmacokinetic characteristics of two commercial sumatriptan products, 4 mg subcutaneous and 6 mg subcutaneous in healthy adults, with DFN-02 - a novel intranasal agent comprised of sumatriptan 10 mg plus 0.20% DDM. We also determined the pharmacokinetic characteristics of DDM and evaluated its safety and tolerability. Methods We conducted two studies: a randomized, three-way crossover study comparing monodose and multidose devices for delivery of single doses of DFN-02 with commercially available intranasal sumatriptan 20 mg in 18 healthy, fasted adults, and an open-label, randomized, single-dose, three-way crossover bioavailability study comparing DFN-02 with 4 mg and 6 mg subcutaneous sumatriptan in 78 healthy, fasted adults. In the study comparing DFN-02 with IN sumatriptan, subjects received a single dose of DFN-02 (sumatriptan 10 mg plus DDM 0.20%) via monodose and multidose delivery systems with at least 5 days between treatments. In the comparison with SC sumatriptan, subjects received a single dose of each treatment with at least 3 days between treatments. In both studies, blood was sampled for pharmacokinetic evaluation of sumatriptan and DDM through 24 hours post-dose; safety and tolerability were monitored throughout. Results In the comparison with commercially available intranasal sumatriptan 20 mg, DFN-02 had a more rapid absorption profile; tmax was 15 minutes for DFN-02 monodose, 10.2 minutes for DFN-02 multidose, and 2.0 hours for commercially available intranasal sumatriptan 20 mg. Compared with 4 and 6 mg subcutaneous sumatriptan, DFN-02's median tmax (10 minutes) was significantly earlier (15 minutes; P < .0001). Mean sumatriptan exposure metrics were similar for DFN-02 and 4 mg sumatriptan: AUC0-2: 35.12 and 44.82 ng*hour/mL, respectively; AUC0-∞: 60.70 and 69.21 ng*hour/mL, respectively; Cmax: 51.79 and 49.07 ng/mL, respectively. With 6 mg subcutaneous sumatriptan, these exposure metrics were about 50% larger (AUC0-2: 67.17 ng*hour/mL; AUC0-∞: 103.78 ng*hour/mL; Cmax: 72.75 ng/mL). Inter-subject variability of AUC0-2, AUC0-∞, and Cmax was 42-58% for DFN-02, 15-22% for 4 mg subcutaneous sumatriptan, and 15-25% for 6 mg subcutaneous sumatriptan. DDM exposure was low (mean Cmax: 1.63 ng/mL), tmax was 30 minutes, and it was undetectable by 4 hours. There were no serious adverse events, discontinuations due to adverse events, or remarkable findings for vital signs, physical examinations (including nasal and injection site examinations), or clinical laboratory assessments. The overall incidence of adverse events was comparable across treatments, and all treatment-related events were mild in severity. Adverse events occurring in ≥10% of subjects were dysgeusia (19%), headache (18%), nausea (15%), paresthesia (15%), and dizziness (12%). Conclusions In healthy subjects, DFN-02, an intranasal spray containing 10 mg sumatriptan plus DDM, had a more rapid absorption profile than commercially available intranasal sumatriptan 20 mg, and systemic exposure from a single-dose administration of DFN-02 was similar to 4 mg SC sumatriptan and two-thirds that of 6 mg SC sumatriptan. With DFN-02, plasma sumatriptan peaked 5 minutes earlier than with both subcutaneous formulations. Systemic exposure to sumatriptan was similar with DFN-02 and 4 mg subcutaneous sumatriptan; both yielded lower systemic exposure than 6 mg subcutaneous sumatriptan. Systemic exposure to DFN-02's excipient DDM was short-lived. DFN-02's safety and tolerability appear to be comparable to subcutaneous sumatriptan. Addition of a permeation enhancer improved the absorption profile compared with commercially available intranasal sumatriptan 20 mg. [ABSTRACT FROM AUTHOR]

The article present a case study of a 25-year old nonsmoker female during her first pregnancy, with a history of Cluster headache (CHs). It mentions Magnetic Resonance Imaging performed at the disease onset ruled out secondary etiologies; and also mentions before pregnancy she usually took subcutaneous sumatriptan 6 mg for the acute treatment and cyclic oral steroid therapy.

Objective To evaluate the safety, tolerability, and pharmacokinetics of sumatriptan delivered by the iontophoretic transdermal system (TDS) in adolescent patients. Background Since nausea can be a prominent and early symptom of migraine, nonoral treatment options are often required. Sumatriptan iontophoretic TDS is approved for the acute treatment of migraine in adults. The present study evaluates the pharmacokinetics of sumatriptan administered via the iontophoretic TDS in adolescents, contrasting the findings with historical data from adults. Design Patients aged 12-17 years (inclusive) with acute migraine were treated with sumatriptan iontophoretic TDS for 4 hours. Blood samples for pharmacokinetic profiling of sumatriptan were obtained prior to dosing and at predetermined time points covering the 12 hours postonset of treatment. Key pharmacokinetic endpoints included Cmax (peak plasma drug concentration), tmax (time to Cmax), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and t½ (terminal elimination half-life). Safety was evaluated by monitoring of adverse events in addition to laboratory and clinical assessments. Results The sample consisted of 37 patients, and 36 were included in the PK evaluable population. Cmax, tmax, AUC0-∞, and t½ values were all similar between male and female patients and between younger (12-14 years) and older (15-17 years) adolescents. When compared with historical adult data, adolescent patients demonstrated similar systemic exposures to those observed in adults (mean Cmax 20.20 (±6.43) ng/mL in adolescents vs 21.89 (±6.15) ng/mL in adults; mean AUC0-∞ 98.1 (±28.1) ng·h/mL in adolescents vs 109.7 (±26.1) ng·h/mL in adults). All adverse events were mild or moderate, with application-site paresthesia being the most common (32%). No clinically relevant changes in laboratory values, vital signs, or electrocardiogram findings were observed. Conclusions The iontophoretic TDS produced mean systemic exposures to sumatriptan in younger and older adolescents, in line with what was seen in adult subjects. It was generally well tolerated. [ABSTRACT FROM AUTHOR]

Background Cluster headache (CH), the most common trigeminal autonomic cephalalgia, is an extremely debilitating primary headache disorder that is often not optimally treated. New evidence-based treatment guidelines for CH will assist clinicians with identifying and choosing among current treatment options. Objectives In this systematic review we appraise the available evidence for the acute and prophylactic treatment of CH, and provide an update of the 2010 American Academy of Neurology (AAN) endorsed systematic review. Methods Medline, PubMed, and EMBASE databases were searched for double-blind, randomized controlled trials that investigated treatments of CH in adults. Exclusion and inclusion criteria were identical to those utilized in the 2010 AAN systematic review. Results and Recommendations For acute treatment, sumatriptan subcutaneous, zolmitriptan nasal spray, and high flow oxygen remain the treatments with a Level A recommendation. Since the 2010 review, a study of sphenopalatine ganglion stimulation was added to the current guideline and has been administered a Level B recommendation for acute treatment. For prophylactic therapy, previously there were no treatments that were administered a Level A recommendation. For the current guidelines, suboccipital steroid injections have emerged as the only treatment to receive a Level A recommendation with the addition of a second Class I study. Other newly evaluated treatments since the 2010 guidelines have been given a Level B recommendation (negative study: deep brain stimulation), a Level C recommendation (positive study: warfarin; negative studies: cimetidine/chlorpheniramine, candesartan), or a Level U recommendation (frovatriptan). Conclusions This AHS guideline can be utilized for understanding which therapies have superiority to placebo or sham treatment in the management of CH. In clinical practice, these recommendations should be considered in concert with other variables including safety, side effects, patient preferences, clinician experience, cost, and the invasiveness of the intervention. Given the lack of Class I evidence and Level A recommendations, particularly for a number of commonly used preventive therapies, further studies are warranted to demonstrate safety and efficacy for established and emerging therapies. [ABSTRACT FROM AUTHOR]

Abstracts related to headache are presented including "Neurorestoration After Traumatic Brain Injury Through Angiotensin II Receptor Blockage" by S. Villapol et al, "Headache in Acute Ischaemic Stroke: A Lesion Mapping Study" by CL Seifert et al and "The Migraine Brain In Transition: Girls vs Boys" by V. Faria, N. Erpelding and A. Lebel.

Objective To compare the efficacy of ketorolac nasal spray (NS) vs placebo and sumatriptan NS for the acute treatment of migraine. Methods This was a randomized, double-blind, placebo and active-comparator, crossover study. Adult migraineurs were randomized to ketorolac NS 31.5 mg, sumatriptan NS 20 mg, or placebo to treat three moderate to severe migraine attacks and switched treatments with each attack. Patients seeking headache care at a headache center or in response to community advertisement were recruited. Adult participants with episodic migraine who experienced ≥2 migraine attacks per month were eligible for the Ketorolac vs Sumatriptan vs Placebo Nasal Spray migraine study. Participants were randomized to treatment arms by a research pharmacist, in a 1:1:1 ratio using computer-generated lists. The primary outcome was 2-hour pain relief. Secondary outcomes included 2-hour pain freedom and absence of migraine associated symptoms, and 24-hour sustained pain relief and pain freedom. Results Of the 72 randomized participants, 54 (75%) treated at least one attack and 49 (68%) completed all three treatments, for a total of 152 treated migraine attacks. Both ketorolac NS (72.5%, P < .001) and sumatriptan NS (69.4%, P = .001) were more effective than placebo (38.3%) for 2-hour pain relief and 2-hour pain freedom (ketorolac: 43.1%, P = .004; sumatriptan: 36.7%, P = .046; placebo: 18.4%). Ketorolac NS, but not sumatriptan NS, was more effective than placebo in 2-hour absence of nausea. Both ketorolac NS and sumatriptan NS were more effective than placebo for 24-hour sustained pain relief (ketorolac: 49%, P < .001; sumatriptan: 31%, P = .01, placebo: 20%). Only ketorolac NS was superior to placebo for 24-hour (ketorolac: 35.3%, P = .003; sumatriptan: 22.4%, P = .18, placebo: 12.2%) sustained pain freedom. Nasal burning and dysgeusia were the most common adverse effects for active treatments. Conclusions This study supports that ketorolac NS is superior to placebo and that it is non-inferior to sumatriptan NS for the acute abortive treatment of migraine. [ABSTRACT FROM AUTHOR]

Objective We sought to conduct a qualitative systematic review to evaluate the safety and efficacy of available treatments for pediatric patients with migraine or benign primary headache in the emergency department, in an effort to inform future practice. Methods Scopus, Medline, and PubMed databases were searched for randomized controlled trials retrospective reviews, review articles, and case studies discussing migraine or benign primary headache management that were conducted in the emergency room or outpatient acute care setting in pediatric patients (less than 18-years old). Meeting abstracts and cited references within articles were also evaluated. Multiple variables were recorded, including type of treatment, study design, dosing, primary outcome, and side effects. Therapeutic gain was calculated in studies with a placebo arm. Treatments were subjectively assessed based on methodology and number of trials for a particular therapy. Results Thirty-one studies were included in the final analysis. Of these, 17 were randomized controlled trials, 9 were retrospective reviews, and 5 were prospective chart review studies. One pertained to IV fluids, 2 to nonspecific analgesic use, 5 to dopamine receptor antagonists, 2 to valproic acid, 1 to propofol, 1 to magnesium, 1 to bupivicaine, 13 to triptan medications, and 3 to dihydroergotamine (DHE). Treatments considered effective for acute migraine or benign primary headache in the analgesic category include ibuprofen, and to a lesser degree acetaminophen. Ketorolac was not compared to other NSAIDs, but was found to be less effective than prochlorperazine. Of the phenothiazines, prochlorperazine was considered most effective. Of the triptan medications, almotriptan, rizatriptan, zolmitriptan nasal spray, sumatriptan nasal spray, and combination sumatriptan/naproxen are effective agents for acute treatment. Treatments considered probably effective included IV fluids, chlorpromazine, valproate sodium, injectable sumatriptan, and IV DHE. Treatments with oral zolmitriptan showed inconsistent results, while treatments considered ineffective included isolated oral sumatriptan and oral DHE. There is insufficient evidence to comment on propofol, magnesium, and bupivicaine efficacy. Conclusions Of the available evidence, ibuprofen, prochlorperazine, and certain triptan medications are the most effective and safe agents for acute management of migraine and other benign headache disorders in the pediatric population. Additional studies in this population are needed, and should take into consideration variables such as dosing, co-administered medications, treatment duration, and length of treatment effect. [ABSTRACT FROM AUTHOR]

Objectives To test the hypothesis that sumatriptan iontophoretic transdermal system ( TDS) is associated with lower rates of treatment-emergent nausea ( TEN) relative to placebo, as well as to compare the efficacy of sumatriptan TDS in migraineurs with or without nausea at baseline. Methods Participants of a double-blind, randomized, parallel-group, single-attack, placebo-controlled study conducted at 38 sites in the United States were analyzed. Participants who treated their migraine attacks while nausea-free were identified. The primary endpoint was TEN over 24 hours post-treatment contrasting both treatment groups and it was assessed by regression analyses using generalized estimating equations. Secondary endpoint was headache response as a function of presence of nausea, assessed by generalized linear model. Results A total of 130 participants free of nausea at baseline were treated with sumatriptan TDS, while 109 participants free of nausea at baseline were treated with placebo TDS. The occurrence of TEN over 24 hours post-treatment was significantly lower with the sumatriptan TDS than with placebo ( P = .0011). These differences were statistically significant at 1 hour (13.8% vs 9.2%, P < .01), 2 hours (13.8% vs 4.6% P < .001) and 3 hours (13.8% vs 8.5% P < .01). The efficacy of sumatriptan TDS was similar regardless of the presence or absence of nausea at baseline for all clinical parameters. Conclusion Sumatriptan TDS is not associated with the emergence of nausea in migraineurs without nausea. It is equally effective in participants with or without nausea at the time of treatment. [ABSTRACT FROM AUTHOR]

Objectives/Background We herein investigated the role of polymorphisms in calcitonin gene-related peptide ( CGRP)-related genes looking at the association of rs3781719 ( T > C) in the calcitonin gene-related polypeptide-alpha ( CALCA) gene and of rs3754701 ( T > A) and rs7590387 ( C > G) at the receptor activity modifying 1 ( RAMP 1) locus with triptan response in patients with migraine without aura ( MwoA). In addition, their role was evaluated as risk factors for transformation of episodic migraine into medication overuse headache ( MOH). The CGRP has a central role in the pathogenesis of migraine; however, little information is currently available concerning the role of polymorphisms in CGRP-related genes as determinants of clinical response to anti-migraine drugs or as risk factors for migraine chronification. Methods Genotyping was conducted retrospectively by real-time polymerase chain reaction allelic discrimination assay in 219 patients with MwoA and 130 with MOH in whom migraine was the primary headache type. Gene variants association was evaluated by logistic regression analysis adjusted by confounding factors. The threshold of statistical significance was set according to the total number of polymorphisms analyzed in the current study and in previous publications arising from overlapping datasets. Results No evidence of association was found between the three polymorphisms tested and triptan response in MwoA patients. Conversely, carriers of RAMP 1 rs7590387 GG displayed a lower risk of episodic migraine transformation into MOH (vs C allele carriers, odds ratio [ OR]: 0.27, 95% confidence interval [ CI]: 0.13-0.57, P = 0.0002; threshold of significance set at P < 0.0029). When genotype distribution for RAMP 1 rs7590387 was compared between healthy controls (n = 209) and MOH patients, carriers of rs7590387 GG were found at lower risk of developing MOH ( OR: 0.43, 95% CI: 0.22-0.85, P = 0.011). Conclusion These results suggest that RAMP 1 rs7590387 may have a role in the transformation of episodic migraine into MOH. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to compare the efficacy, tolerability, and safety of AVP-825, an investigational bi-directional breath-powered intranasal delivery system containing low-dose (22 mg) sumatriptan powder, vs 100 mg oral sumatriptan for acute treatment of migraine in a double-dummy, randomized comparative efficacy clinical trial allowing treatment across multiple migraine attacks. Background In phases 2 and 3, randomized, placebo-controlled trials, AVP-825 provided early and sustained relief of moderate or severe migraine headache in adults, with a low incidence of triptan-related adverse effects. Methods This was a randomized, active-comparator, double-dummy, cross-over, multi-attack study ( COMPASS; NCT01667679) with two ≤12-week double-blind periods. Subjects experiencing 2-8 migraines/month in the past year were randomized 1:1 using computer-generated sequences to AVP-825 plus oral placebo tablet or an identical placebo delivery system plus 100 mg oral sumatriptan tablet for the first period; patients switched treatment for the second period in this controlled comparative design. Subjects treated ≤5 qualifying migraines per period within 1 hour of onset, even if pain was mild. The primary end-point was the mean value of the summed pain intensity differences through 30 minutes post-dose ( SPID-30) using Headache Severity scores. Secondary outcomes included pain relief, pain freedom, pain reduction, consistency of response across multiple migraines, migraine-associated symptoms, and atypical sensations. Safety was also assessed. Results A total of 275 adults were randomized, 174 (63.3%) completed the study (ie, completed the second treatment period), and 185 (67.3%) treated at least one migraine in both periods (1531 migraines assessed). There was significantly greater reduction in migraine pain intensity with AVP-825 vs oral sumatriptan in the first 30 minutes post-dose (least squares mean SPID-30 = 10.80 vs 7.41, adjusted mean difference 3.39 [95% confidence interval 1.76, 5.01]; P < .001). At each time point measured between 15 and 90 minutes, significantly greater rates of pain relief and pain freedom occurred with AVP-825 treatment compared with oral sumatriptan. At 2 hours, rates of pain relief and pain freedom became comparable; rates of sustained pain relief and sustained pain freedom from 2 to 48 hours remained comparable. Nasal discomfort and abnormal taste were more common with AVP-825 vs oral sumatriptan (16% vs 1% and 26% vs 4%, respectively), but ∼90% were mild, leading to only one discontinuation. Atypical sensation rates were significantly lower with AVP-825 than with conventional higher dose 100 mg oral sumatriptan. Conclusions AVP-825 (containing 22 mg sumatriptan nasal powder) provided statistically significantly greater reduction of migraine pain intensity over the first 30 minutes following treatment, and greater rates of pain relief and pain freedom within 15 minutes, compared with 100 mg oral sumatriptan. Sustained pain relief and pain freedom through 24 and 48 hours was achieved in a similar percentage of attacks for both treatments, despite substantially lower total systemic drug exposure with AVP-825. Treatment was well tolerated, with statistically significantly fewer atypical sensations with AVP-825. [ABSTRACT FROM AUTHOR]

A multi-centered, randomized, placebo-controlled, early intervention, cross-over study was conducted to evaluate the consistency of response of sumatriptan/naproxen sodium 85/500 mg ( S/ NS) over 4 attacks in the acute treatment of migraine in adolescents. Inclusion of subjects was dependent on their age of 12-17 years, frequency, and history of migraine headaches (1-8 per month) over the previous 6 months prior to screening and generally healthy males and females of non-childbearing potential that were not on excluded medications. Subjects were instructed to treat within 1 hour of pain onset, including when the pain was still mild. Subjects were randomized in a double-blind fashion using a computer-generated randomization list in which the study drug was prepared prior to study start, and subjects were allocated to a number in sequential order for each site. Each site was allocated number blocks in sets of 10 depending of the rate of enrollment. The objective of this study was to examine the efficacy of S/ NS vs placebo in the primary end-points of pain-free response at 2 hours (2h PF), 24-hour sustained pain-free response (24hPF), and pain-free response at 2 hours with early intervention (2h PFE) calculated as percentage out of all attacks. In the study, 94 subjects treated 347 attacks in total: treating 277 with S/ NS and 70 with placebo. Compared with placebo, S/ NS produced higher 2hPF rates ( S/ NS 37%, placebo 18%; P < .004), and 2h PFE with rates ( S/ NS 32%, 18% placebo; P < .03). Compared with placebo, 24h PF rates were S/ NS 86%, placebo 78%, P < .17, which were higher than placebo but not clinically significant. 2h PF was reported in at least 2 of the 3 migraines treated with S/ NS in 40.4% of subjects. 24h PF was reported in at least 2 of the 3 migraine treated with S/ NS in 86.2% subjects. Adverse reactions were generally low and comparable between S/ NS and placebo. [ABSTRACT FROM AUTHOR]

Objective To evaluate the efficacy and safety of AVP-825, a drug-device combination of low-dose sumatriptan powder (22 mg loaded dose) delivered intranasally through a targeted Breath Powered device vs an identical device containing lactose powder (placebo device) in the treatment of migraine headache. Background Early treatment of migraine headaches is associated with improved outcome, but medication absorption after oral delivery may be delayed in migraineurs because of reduced gastric motility. Sumatriptan powder administered with an innovative, closed-palate, Bi- Directional, Breath Powered intranasal delivery mechanism is efficiently absorbed across the nasal mucosa and produces fast absorption into the circulation. Results from a previously conducted placebo-controlled study of AVP-825 showed a high degree of headache relief with an early onset of action (eg, 74% AVP-825 vs 38% placebo device at 1 hour, P < .01). Methods In this double-blind, placebo-controlled, parallel-group study in adults with a history of migraine with or without aura, participants were randomized via computer-generated lists to AVP-825 or placebo device to treat a single migraine headache of moderate or severe intensity. The primary endpoint was headache relief (defined as reduction of headache pain intensity from severe or moderate migraine headache to mild or none) at 2 hours post-dose. Results Two hundred and thirty patients (116 AVP-825 and 114 placebo device) were randomized, of whom 223 (112 and 111, respectively) experienced a qualifying migraine headache (their next migraine headache that reached moderate or severe intensity). A significantly greater proportion of AVP-825 patients reported headache relief at 2 hours post-dose compared with those using the placebo device (68% vs 45%, P = .002, odds ratio 2.53, 95% confidence interval [1.45, 4.42]). Between-group differences in headache relief were evident as early as 15 minutes, reached statistical significance at 30 minutes post-dose (42% vs 27%, P = .03), and were sustained at 24 hours (44% vs 24%, P = .002) and 48 hours (34% vs 20%, P = .01). Thirty-four percent of patients treated with AVP-825 were pain-free at 2 hours compared with 17% using the placebo device ( P = .008). More AVP-825 patients reported meaningful pain relief (patient interpretation) of migraine within 2 hours of treatment vs placebo device (70% vs 45%, P < .001), and fewer required rescue medication (37% vs 52%, P = .02). Total migraine freedom (patients with no headache, nausea, phonophobia, photophobia, or vomiting) reached significance following treatment with AVP-825 at 1 hour (19% vs 9%; P = .04). There were no serious adverse events ( AEs), and no systemic AEs occurred in more than one patient. Chest pain or pressure was not reported, and only one patient taking AVP-825 reported mild paresthesia. No other triptan sensations were reported. Conclusions Targeted delivery of a low-dose of sumatriptan powder via a novel, closed-palate, Breath Powered, intranasal device ( AVP-825) provided fast relief of moderate or severe migraine headache in adults that reached statistical significance over placebo by 30 minutes. The treatment was well tolerated with a low incidence of systemic AEs. [ABSTRACT FROM AUTHOR]

Objective To better familiarize the reader with a migraine-related disorder, cyclic vomiting syndrome ( CVS) in adults, and to discuss its diagnosis and treatment. Background CVS is a profoundly disabling disorder characterized by recurrent, stereotypic episodes of incapacitating nausea and vomiting, separated by completely asymptomatic intervals. CVS episodes tend to start at the same time of day, persist for the same duration, and present with the same intensity and associated symptoms. Most patients experience prodromal symptoms and can identify triggers that precipitate attacks, such as menstruation, lack of sleep, certain foods, physical exertion, and stress. The prevalence of CVS in adults is unknown, but since its occurrence in this age group has been little recognized, patients typically experience lengthy delay in diagnosis or misdiagnosis. Method Literature review, case reports, and discussion. Results Given genetic links of CVS to migraine, as well as its comorbidity, typical migraine triggers, and response to similar acute and preventive medications, CVS likely represents a disorder on the migraine spectrum. Conclusion Adult CVS is not only highly comorbid with migraine, but it responds to migraine preventives, and in some cases to injectable sumatriptan even in the absence of headache. [ABSTRACT FROM AUTHOR]

The author reflects on the treatments for headache, including migraine, in the emergency department (ED). Other topics include how non-headache specialists in the ED should treat headache like screening for secondary headache, as well as the various factors affecting acute treatment of migraine like length of attack, severity of migraine, and the presence of other symptoms like allodynia.

Objectives To monitor for a signal of major teratogenicity by determining the risk of all birth major defects following in utero exposure to sumatriptan, naratriptan, and the sumatriptan/naproxen sodium combination product (tablets marketed in the United States as Treximet [GlaxoSmithKline, Research Triangle Park, NC, USA]), and to monitor for unusual patterns of defects that might suggest teratogenicity. Background The prevalence of migraine is highest in women of childbearing age. Coupled with the recurrent nature of migraine attacks and the high proportion of unplanned pregnancies, intentional and inadvertent exposure to anti-migraine drugs in pregnancy is likely. The Sumatriptan, Naratriptan, and Treximet Pregnancy Registry captured data on women exposed to those drugs during pregnancy to monitor for evidence of major teratogenicity. Methods In this primarily prospective, observational study, health care professionals from anywhere in the world enrolled, on a voluntary basis, women exposed to sumatriptan, naratriptan, or the sumatriptan/naproxen sodium combination product during their pregnancies. Only pregnancies with unknown outcomes at the time of enrollment were included in the analysis. The proportion of infants or fetuses with major birth defects was calculated as the total number of infants/fetuses with major birth defects divided by the sum of the number of infants/fetuses with major birth defects + the number of live births without defects. The risk of major birth defects was further stratified by earliest trimester of pregnancy exposure. Results The registry enrolled 680 evaluable exposed pregnant women, which resulted in 689 infants and fetuses (outcomes). Of these outcomes, 626 were exposed to sumatriptan, 57 were exposed to naratriptan (seven were exposed to both sumatriptan and naratriptan), and six were exposed to the sumatriptan/naproxen sodium combination product. Twenty outcomes with major birth defects were reported among 528 outcomes exposed in the first trimester to sumatriptan. The estimated risk of major birth defects following first-trimester sumatriptan exposure is 4.2% (20/478 [95% confidence interval [ CI] 2.6%-6.5%]). Among 52 first-trimester exposures to naratriptan, major birth defects were reported in one outcome, an infant with exposure to both sumatriptan and naratriptan [birth defect risk of 2.2% (1/46 [95% CI 0.1%-13.0%]). No major defects were reported among the five outcomes with first-trimester exposure to the sumatriptan/naproxen sodium combination products. Conclusions The Sumatriptan, Naratriptan, and Treximet Pregnancy Registry detected no signal of teratogenicity associated with major birth defects for sumatriptan. This finding is consistent with results from other observational studies using a variety of control groups. Enrollment in the registry was insufficient to permit definitive conclusions of the risks associated with naratriptan or sumatriptan/naproxen sodium tablets, or to assess the risk of individual birth defects in any of the products studied. Low enrollment and high rates of loss to follow up within the registry over an extended period of time led the registry's scientific advisory committee to conclude that continuation of the registry beyond its 16 years would offer little additional power to rule out more moderate increases in the risk of birth defects. Data from the other ongoing surveillance sources constitute an important element of post-marketing surveillance of these medications. The lack of a signal of major teratogenicity with sumatriptan across these several sources of data is encouraging. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to validate the ease of assembly and application of the sumatriptan iontophoretic transdermal system (sumatriptan TDS, Zecuity®, NuPathe, Inc., Malvern, PA, USA) during a migraine attack. Background Iontophoresis is a noninvasive drug delivery method using low electrical current to move solubilized drugs across the skin to the underlying tissue. With sumatriptan TDS, a pre-programmed dose of sumatriptan is automatically delivered via a transdermal patch, allowing therapeutic drug levels to be reached without mechanical penetration or disruption of the skin. Because migraine attacks can be disabling, with many patients unable to perform their usual activities, it is important for prescribers and their patients to be confident that they will be able to assemble and apply sumatriptan TDS in the middle of an attack. A human factor use study was conducted to evaluate the ease of assembly and application of the sumatriptan TDS among migraineurs and healthcare professionals ( HCPs) who are likely to instruct patients on how to use the patch. Methods This was a single-center, open-label study assessing a single use of sumatriptan TDS in adult migraineurs and HCPs. Subjects were divided into 3 groups: migraineurs trained to use sumatriptan TDS, migraineurs not trained to use sumatriptan TDS, and HCPs not trained to use sumatriptan TDS. Sixteen subjects (trained migraineurs and untrained HCPs) participated in a preliminary usability test, and 48 subjects (16 representing each of the 3 groups) participated in a formal final test. Subjects were 20-64 years old, inclusive, and 83% female. They rated usability on a scale of 1-7, with 1 being difficult and 7 being easy. Results Preliminary testing.-Of the 16 sumatriptan TDS patches assembled and applied, 100% (16/16) were assembled and applied successfully. The mean score for ease of assembly was 6.3, and the mean score for ease of application was 6.8 out of 7, with 1 being difficult and 7 being easy. No modifications were made to patient instructions for use, patient labeling, or patient video for the final phase of testing. Final testing.-Of the 48 sumatriptan TDS patches assembled and applied during final testing, 100% (48/48) were assembled and applied successfully, with no user errors, one close call, and no operational difficulties observed. Across all 3 groups, the mean score for ease of assembly was 6.1, and the mean score for ease of application was 6.8 out of 7, with 1 being difficult and 7 being easy. For migraineurs who were trained and subsequently returned to the testing facility for evaluation of usability while in distress of a mild to severe migraine attack, the number of days between training and testing ranged from 0 to 20, with a mean of 3.6. Among untrained and trained migraineurs, 3.1% had a mild attack, 68.8% had a moderate attack, and 28.1% had a severe attack. Conclusions The results of this study indicate that sumatriptan TDS can be assembled and applied successfully during a mild to severe migraine attack. Across all subject groups in both the preliminary and final testing, including trained and untrained migraineurs in distress of a migraine attack (96.9% moderate to severe) and untrained HCPs not experiencing a migraine attack, patch assembly and application was 100% successful. In the final test, subjects rated sumatriptan TDS very high for ease of assembly (6.1 out of 7, with 7 being easy) and ease of use (6.8 out of 7, with 7 being easy). These results indicate that patients and HCPs can be confident that patients can readily assemble and use sumatriptan TDS during a migraine attack. Short Summary A human factor use study evaluating ease of assembly and application of the sumatriptan transdermal system ( TDS) among 64 migraineurs and HCPs found that patch assembly and application was 100% successful. Sumatriptan TDS scored 6.1 out of 7 for ease of assembly and 6.8 out of 7 for ease of use (with 7 being easy). Patients and HCPs can be confident that patients can assemble and use sumatriptan TDS during a migraine attack. [ABSTRACT FROM AUTHOR]

Objectives To assess the consistency of improved functioning, productivity, and medication satisfaction in migraines treated with a single tablet of sumatriptan 85 mg/naproxen sodium 500 mg ( S/ NS) using an early intervention approach. Methods Two randomized, double-blind, placebo-controlled, 4-period crossover, multi-attack, multi-center, outpatient studies of moderate to severe adult migraineurs were conducted to compare S/ NS with placebo. Participants recorded outcome assessments in a diary during the 24 hours following study medication. Analyses were conducted on the intent-to-treat population who treated at least 1 attack. Statistical significance between treatment groups used analysis of variance repeated measures models and the intent-to-treat population. There were no corrections for multiplicity. Results Almost half (48.5%) of migraineurs treated with S/ NS returned to normal functioning at 2 hours and 73.3% at 4 hours postdose, compared with 28.7% (2 hours) and 43.3% (4 hours) of placebo-treated attacks. Total productivity loss over the 24 hours postdose was significantly reduced following S/ NS treatment (2.5 hours on average) compared with placebo (4.0 hours). Sumatriptan/naproxen treatment resulted in significantly higher medication satisfaction scores on the efficacy, functionality, and total efficacy subscales compared with placebo in all attacks in both studies. Sumatriptan/naproxen treatment also provided significantly greater ease of use in 7 of the 8 attacks. Although tolerability was high in both treatment groups (over 90%), the placebo group was significantly less bothered by side effects in 6 of 8 attacks. Conclusion Results from these 2 randomized, double-blind, placebo-controlled, multi-attack, crossover studies demonstrated the rapid and consistent restoration of patients' functioning, the consistent reduction in productivity loss, and high satisfaction ratings from patients treating multiple migraine attacks with S/ NS using an early intervention approach. [ABSTRACT FROM AUTHOR]

Objective This pilot study explored the potential for 2 recognized acute migraine medications, 85 mg of sumatriptan plus 500 mg of naproxen sodium in a combination tablet ( SumaRT/ Nap) and 500 mg of naproxen sodium, to treat and modify the disease progression of migraine. In other words, can these medications both abort an acute attack of migraine and reduce the number of future migraine attacks? Background Patients suffering with moderate to severe attacks of migraine desire acute treatment. As migraine frequency increases, so does the need for more frequent relief of acute attacks. This may lead to medication overuse and potentially medication overuse headache ( MOH). Ideally, acute medication would have the ability to abort an attack of migraine and reduce the likelihood of future attacks. Study Design The primary endpoint of this study was a reduction in migraine headache days from baseline through month 3 of the study. Subjects were randomized 1:1 to treat 14 or fewer migraines per month with SumaRT/ Nap (Group A) or naproxen sodium (Group B) for 3 months. Subjects in group A utilized SumaRT/ Nap were encouraged, but not required, to treat migraine headache within 1 hour of onset of headache when the pain was mild. They could re-treat if needed after 2 hours. Subjects in group B utilized the same treatment strategy with 500 mg of naproxen sodium. Tablets of study medication were identical for both groups. Subjects recorded headache days, migraine attacks, duration of attacks, treatment, and treatment results daily on paper diaries. Subjects took the Migraine Disability Assessment Test ( MIDAS) at randomization and 3 months later at the end of study. Results Naproxen sodium was associated with a statistically significant reduction in migraine headache days at month 3 compared to baseline ( P = .0002). SumaRT/ Nap was also associated with a reduction of migraine headache days, but this decrease did not reach statistical significance ( P = .2). In addition, subjects in the naproxen sodium group had a statistically significant reduction of migraine attacks in all 3 months of the study compared to baseline. A greater than 50% reduction in the number of migraine headache days at month 3 occurred in 43% (6/14) of subjects in group B compared to 17% (3/18) of subjects in group A. Consistent with large regulatory studies comparing the efficacy of SumaRT/ Nap with naproxen sodium, SumaRT/ Nap in this study was statistically superior to naproxen sodium at 2 hours in reducing headache severity during months 2 and 3. There was a reduction of acute medication used from baseline to month 3 and improvement in MIDAS scores for both groups. Conclusion Naproxen sodium, when used as a sole acute treatment early in attacks, appears to reduce the frequency of headache days and migraine attacks for a select number of subjects over a 3-month period. SumaRT/ Nap is more effective at 2-hour headache reduction than naproxen sodium alone, but has less impact on reducing attack frequency or the number of headache days. Both treatments were well tolerated, and there was no convincing evidence that either medication led to MOH. [ABSTRACT FROM AUTHOR]

Objective This study was performed to evaluate the efficacy and safety of the combination of sumatriptan (50 mg) plus promethazine ( SPr) (25 mg) compared with sumatriptan (50 mg) plus placebo in patients with migraine attacks. Background Migraine is a chronic, disabling disorder with an estimated worldwide prevalence of 10% in adults imposing substantial social and economic impact. Efficient treatment of migraine attacks could benefit patients by reducing their disability and the need for health care resources, and improving economic productivity. Design and Methods This was a multicenter, randomized, double-blind trial conducted at 5 university-affiliated research centers in Iran. Between January 2013 and April 2013, 350 individuals with a history of migraine were evaluated. Patients were diagnosed with migraine, with or without aura, as defined by the International Headache Society diagnostic criteria. The 242 patients meeting the eligibility criteria were randomly assigned to SPr group (n = 121) or the sumatriptan plus placebo ( SP) group (n = 121). The study medications were taken on an outpatient basis during the moderate to severe phase of migraine attack. Patients recorded details of the treated migraine on a diary card and rated pain severity immediately before dosing and 30 minutes, 1 hour, 2 hours, and 4 hours after dosing using a 4-point scale (0 = none to 3 = severe). Results Of 242 patients randomized, 216 were included in the intention-to-treat efficacy analysis. In the SPr group, 39.6% of subjects experienced 2-hour headache-free response (primary outcome), which was significantly more effective than SP treatment (26.3%, odds ratio: 1.83, 95% confidence interval: 1.03-3.26, P = .038). Significantly more patients receiving SPr treatment (62.2%) had headache improvement compared with SP treatment (37.2%) at 2 hours (odds ratio: 2.77, 95% confidence interval: 1.60-4.81, P < .001). A similar pattern of between-group differences was observed for 4-hour headache-free response ( P = .006) and headache improvement response ( P = .003). The incidence of headache recurrence within 2-48 hours after treatment was lowest in the SPr group (15.0%) compared with SP group (26.6%, P = .041). The only significant drug-related adverse events reported in ≥15% of patients in any treatment group were somnolence (32.2% and 7% in the SPr and SP groups, respectively, P < .001), extrapyramidal symptoms (4.3% and 0%, P = .05), and nausea (1% and 8%, P = .03). Conclusion This is the first prospective clinical trial to demonstrate that multimechanism therapy for migraine, combining a triptan and an antiemetic agent, is well tolerated and offers improved clinical benefits compared with monotherapy. [ABSTRACT FROM AUTHOR]

Objective To compare the use of a combination of 85 mg sumatriptan plus 500 mg naproxen sodium in a combination tablet with 500 mg naproxen sodium in an identically appearing tablet when used as a daily preventative and acute treatment for 1 month and episodic acute treatment for an additional 2 months in patients with chronic migraine. Background To date, there has been minimal study of acute medications for patients with chronic migraine. Consequently, there is a paucity of study methodology or evidence-based guidance on the use of acute treatment medications in patients with chronic migraine. Methods This two-center, double-blind, randomized, parallel-group, comparator pilot trial of 28 subjects, 18 to 65 years of age, with ICHD-II defined chronic migraine, was designed to generate hypotheses about the efficacy of 2 established acute migraine medications used both as a daily preventive treatment (month 1) and episodic acute treatment (months 1, 2, and 3). Subjects were randomized 1:1 to treat daily with SumaRT/ Nap (85 mg sumatriptan + 500 mg naproxen sodium) (group A) or naproxen sodium (500 mg) (group B) in a prophylactic strategy for 1 month followed by 2 months of the same medications used for episodic acute treatment. Results The combination of SumaRT/ Nap used over a 3-month period did not appear to significantly reduce the number of migraine headache days. In the subset of subjects using naproxen sodium and completing the study per protocol, there was a marked reduction in migraine headache days ( P < .02 vs 0.25, respectively). Duration of migraine from treatment to pain free decreased in both groups, but was more robust in group B from baseline to month 3. Subjects in group B completing the study per protocol reported a 56% reduction in headache days vs 8% for group A. Subjects in group A and group B completing the study per protocol had considerably better 2-hour headache relief than subjects withdrawing early from the study. More subjects in group B prematurely withdrew from the study because of lack of efficacy (5 vs 1, respectively). Despite using significant quantities of acute medication during month 1, there was a reduction of acute medication in month 2 and 3 vs baseline vs month 1, particularly in the naproxen group. Conclusion A combination of SumaRT/ Nap (group A) did not appear to reduce migraine headache frequency over a 3-month period. Subjects using naproxen sodium (group B) alone and completing the study per protocol had a marked statistically significant reduction in migraine headache days. Both groups completing the study per protocol had experienced clinically meaningful 2-hour headache relief. This suggests there may be a subset of patients with chronic migraine that are responsive to high doses of naproxen as an acute intervention with a significant prophylactic benefit. Subjects randomized to SumaRT/ Nap experience benefit, primarily as an acute intervention. This hypothesis may warrant future larger scale clinical trials. Frequent dosing of SumaRT/ Nap or naproxen sodium was well tolerated in this study. [ABSTRACT FROM AUTHOR]

Trigeminal autonomic cephalalgias include cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection, tearing, and rhinorrhea ( SUNCT). Conventional pharmacological therapy can be successful in the majority of trigeminal autonomic cephalalgias patients. Most cluster headache attacks respond to 100% oxygen inhalation, or 6 mg subcutaneous sumatriptan. Nasal spray of sumatriptan (20 mg) or zolmitriptan (5 mg) are recommended as second choice. The bouts can be brought under control by a short course of corticosteroids (oral prednisone: 60-100 mg/day, or intravenous methylprednisolone: 250-500 mg/day, for 5 days, followed by tapering off the dosage), or by long-term prophylaxis with verapamil (at least 240 mg/day). Alternative long-term preventive medications include lithium carbonate (800-1600 mg/day), methylergonovine (0.4-1.2 mg/day), and topiramate (100-200 mg/day). As a rule, paroxysmal hemicrania responds to preventive treatment with indomethacin (75-150 mg/day). A short course of intravenous lidocaine (1-4 mg/kg/hour) can reduce the flow of attacks during exacerbations of SUNCT. Lamotrigine (100-300 mg/day) is the preventive drug of choice for SUNCT. Gabapentin (800-2700 mg/day), topiramate (50-300 mg/day), and carbamazepine (200-1600 mg/day) may be of help. [ABSTRACT FROM AUTHOR]

The article presents a case study related to 45-year-old lady was admitted to our tertiary headache center with a history of headache attacks for about 3 years. Topics include the cluster headache patients rarely report an aura has associated directly with the cluster headache attack, and the retinal migraine is a rare condition listed as a specific subtype of migraine with aura in the International Classification of Headache Disorders.

The treatment of migraine was transformed in 1992 with the introduction of the first triptan-based therapy, subcutaneous ( SC) sumatriptan. SC sumatriptan has high efficacy and a rapid onset of action compared with other available triptans and formulations presumably because of its short Tmax, high Cmax, and avoidance of enteral absorption. Because of these characteristics, SC sumatriptan is still considered the most reliably and rapidly effective self-administered medication available for acute migraine. Even so, it is relatively little used possibly in part because of patient 'needle-phobia.' The needle-free sumatriptan injection system ( Sumavel Dose Pro) was developed to address this concern. Clinical trials have shown that the needle-free system is bioequivalent to needle-based injection systems, easy to use, and capable of providing rapid and effective symptom relief for many migraine episodes. Sumavel Dose Pro is an effective treatment for migraine and should be part of the therapeutic armamentarium, particularly in cases where a rapid onset of action is critical or where oral administration is problematic. [ABSTRACT FROM AUTHOR]