Dihydroergotamine mesylate nasal spray: an acute treatment option for migraine in adults.

INTRODUCTION: Although the landscape of migraine symptomatic treatment has been enriched by novel effective drugs, it is mandatory to critically reappraise older molecules to ascertain whether they could still represent reliable alternatives in specific endophenotypes of patients or migraine attacks. Among these, dihydroergotamine (DHE) nasal spray has been shown to be effective and is characterized by greater tolerability and manageability than the parenteral DHE formulation. AREAS COVERED: In this narrative review, the authors describe the pharmacodynamic and pharmacokinetic properties of DHE nasal spray and explore the results of the trials which explored its efficacy, safety and tolerability as migraine symptomatic treatment. They also discuss the limitations of the classically used device and the attempts that several companies are carrying out to generate devices warranting a more reproducible drug absorption. EXPERT OPINION: DHE nasal spray could be considered as rescue treatment in patients who have failed other symptomatic therapeutic strategies. Nevertheless, in the perspective of tailored therapy, the intranasal route of administration and the consequent rapid onset of action may represent benefits putatively making DHE a treatment of choice for challenging migraine attacks such as those with nocturnal onset or quickly reaching the climax of both headache and neurovegetative associated symptoms.

Development and Evaluation of an Integrated Outpatient Infusion Care Model for the Treatment of Pediatric Headache.

BACKGROUND: Care for pediatric patients with headache often occurs in high-cost settings such as emergency departments (EDs) and inpatient settings. Outpatient infusion centers have the potential to reduce care costs for pediatric headache management. METHODS: In this quality improvement study, we describe our experience in creating the capacity to support an integrated outpatient pediatric headache infusion care model through an infusion center. We compare costs of receiving headache treatment in this model with those in the emergency and inpatient settings. Because dihydroergotamine (DHE) is a costly infusion, encounters at which DHE was administered were analyzed separately. We track the number of ED visits and inpatient admissions for headache using run charts. As a balancing measure, we compare treatment efficacy between the infusion care model and the inpatient setting. RESULTS: The mean percentage increase in cost of receiving headache treatment in the inpatient setting with DHE was 61% (confidence interval [CI]: 30-99%), and that without DHE was 582% (CI: 299-1068%) compared with receiving equivalent treatments in the infusion center. The mean percentage increase in cost of receiving headache treatment in the ED was 30% (CI: -15 to 100%) compared with equivalent treatment in the infusion center. After the intervention, ED visits and inpatient admissions for headache decreased. The mean change in head pain was similar across care settings. CONCLUSIONS: Our findings demonstrate that developing an integrated ambulatory care model with infusion capacity for refractory pediatric headache is feasible, and our early outcomes suggest this may have a favorable impact on the overall value of care for this population.

Dihydroergotamine affects spatial behavior and neurotransmission in the central nervous system of Wistar rats.

INTRODUCTION: Dihydroergotamine (DHE) is a derivative of an ergot alkaloid used as an antimigraine medication. Nowadays, ergot alkaloids may still endanger the safety of humans and animals as food or medicine pollutants, but the outcomes of long-term DHE administration on the behaviour and neurotransmission remain undescribed. MATERIAL AND METHODS: Adult male Wistar Albino Glaxo rats pre-treated orally with DHE for six weeks were investigated to assess the relationship between concentration of neurotransmitters and behavioural response. The behavioural effects of the drug administered at doses of either 30 µg/kg b.w. (group DHE30, n = 11) or 100 µg/kg b.w. per day (group DHE100, n = 10) were evaluated in the Morris Water Maze. It is known that monoaminergic neurotransmitters (serotonin, noradrenaline and dopamine) in some brain structures (prefrontal cortex, hippocampus, striatum, cerebellum, spinal cord) play a role in the control of cognitive and motor functions. The concentration of neurotransmitters was determined by High Performance Liquid Chromatography (HPLC). RESULTS: Administration of DHE influenced neither the learning processes nor memory in rats. Nevertheless, an increased motor activity of the DHE-administered animals was observed in both the cued and non-cued behavioural tasks. In HPLC examination, changes in the concentration of monoaminergic neurotransmitters and their metabolites were noted in all tested structures, except for the hippocampus. CONCLUSIONS: DHE is able to modulate noradrenergic, serotonergic and dopaminergic neurotransmission that may support the increase in locomotion.

STOP 301: A Phase 3, open-label study of safety, tolerability, and exploratory efficacy of INP104, Precision Olfactory Delivery (POD® ) of dihydroergotamine mesylate, over 24/52 weeks in acute treatment of migraine attacks in adult patients.

OBJECTIVE: To report the safety, tolerability, exploratory efficacy, and patient acceptability of INP104 for the acute treatment of migraine from the Phase 3 STOP 301 trial. BACKGROUND: Dihydroergotamine (DHE) has long been used to treat migraine, but intravenous administration is invasive, frequently associated with adverse events (AEs), and not suitable for at-home administration. INP104 is an investigational drug device that delivers DHE mesylate to the upper nasal space using a Precision Olfactory Delivery technology and was developed to overcome the shortcomings of available DHE products. METHODS: STOP 301 was an open-label, 24-week safety study, with a 28-week extension period. After a 28-day screening period where patients used their "best usual care" to treat migraine attacks, patients were given INP104 (1.45 mg) to self-administer nasally with self-recognized attacks. The primary objective of this study was to assess safety and tolerability, with a specific focus on nasal mucosa and olfactory function. Exploratory objectives included efficacy assessments of migraine measures and a patient acceptability questionnaire. RESULTS: A total of 360 patients entered the 24-week treatment period, with 354 patients dosing at least once. INP104-related treatment-emergent AEs were reported by 36.7% (130/354) of patients, and 6.8% (24/354) discontinued treatment due to AEs over 24 weeks. No new safety signals were observed following delivery to the upper nasal space. Pain freedom, the most bothersome symptom freedom, and pain relief at 2 h post-INP104 were self-reported by 38.0% (126/332), 52.1% (173/332), and 66.3% (167/252) of patients, respectively. A low recurrence rate at 24 and 48 h was observed (7.1% [9/126] and 14.3% [18/126], respectively). Most patients found INP104 easy to use and preferred it over their current therapy. CONCLUSIONS: INP104 has the potential to deliver rapid symptom relief, without injection, that is well tolerated and suitable for outpatient use. Results suggest INP104 may be a promising treatment for patients with migraine.

Dihydroergotamine infusion for pediatric refractory headache: A retrospective chart review.

BACKGROUND: Headaches are a common symptom in children. Children with refractory headaches may be admitted for inpatient treatment with intravenous dihydroergotamine mesylate (DHE). However, very few studies have characterized these patients and their treatment outcomes using validated, self-reported, pain scales. OBJECTIVE: The objective of this study was to describe demographic and clinical characteristics of children admitted for DHE infusion, determine DHE treatment outcomes by means of numeric pain scale ratings, and explore associations between treatment outcomes and clinical characteristics. METHODS: Retrospective chart review was completed in patients ages 5-21 admitted for DHE infusion from January 2013 to July 2018 at a large, pediatric academic medical center and community-based satellite center. All primary headache types were included. RESULTS: A total of 200 unique admissions for DHE were available for analysis. Overall, patients were predominantly White (87.5%, 175/200) and female (80.0%, 160/200) with an average age of 15.4 years (SD 2.3). Common comorbidities included obesity (42.0%, 81/193), anxiety (41.0%, 82/200), and depression (20.0%, 40/200). The mean length of stay was 2.4 days (SD 1.10; range 1-8 days). Most headaches (65.0%, 130/200) met the International Classification of Headache Disorders, 3rd edition criteria for migraine, followed by new daily persistent headache (25.5%, 51/200). Mean DHE maximum dose was 5.3 (SD 2.17; range 0.5-14.5 mg) with most patients requiring 3.5-6.5 mg. DHE was typically terminated at six doses (range 1-15). The most frequently reported adverse event was nausea (5.5%, 11/200). There was no difference in pain severity at admission across headache types, with an average baseline pain score of 8.1 (SD 1.6). Posttreatment reduction in pain score was statistically significant (range: -3.2 to -4.9; each p < 0.001) across all headache types. Overall, 84.0% (168/200) of the patients had some improvement in pain. More than half of the patients (53.5%, 107/200) showed at least moderate improvement (≥50.0% reduction in pain score), and 18.0% (36/200) had full headache resolution. Limited patients (16.0%, 32/200) experienced no improvement in pain. CONCLUSIONS: Treatment with DHE resulted in at least some improvement for most patients regardless of headache type or number of doses. Clinical trials stratified by headache type and comorbid factors could help clarify treatment algorithms to optimize patient outcomes.

Implementation of an Intravenous Dihydroergotamine Protocol for Refractory Migraine in Children.

OBJECTIVE: Retrospective chart review to assess the effectiveness of an institutional intravenous (IV) dihydroergotamine (DHE) therapy protocol for refractory migraine in the pediatric population. BACKGROUND: Limited high-quality evidence exists to guide the approach to treatment of refractory migraine with IV DHE, particularly in the pediatric population. This study reviews our institutional experience in implementing an IV DHE protocol in children to identify areas for improvement. We specifically sought to determine whether the outcome differed at follow-up between children who completed the full course of DHE (8 or 9 doses) as specified in our institutional protocol and those who did not. In addition, given the limited Food and Drug Administration-approved treatments for chronic migraine (CM) in the pediatric population, re-evaluating the response rate in this group of patients was of particular interest. METHODS: A retrospective cohort based on a chart review of 159 consecutive pediatric patients who received IV DHE while inpatient at University of Virginia Children's Hospital over a 9-year period (January 2011-January 2019) was identified. Patients were classified according to the International Classification of Headache Disorders, 3rd edition criteria as having CM, status migrainosus, or, in a small number of patients, Other headache with migrainous features. To investigate any benefit of completing the full course of DHE, patients were categorized as having completed the DHE protocol ("Protocol Complete" 8 or 9 doses) or not completing the protocol ("Protocol Incomplete" <8 doses). Patient-reported pain scores upon admission and discharge were recorded, and follow-up outcomes were categorized as headache freedom, >50% relief, <50% relief, or no relief. Pain outcomes were analyzed with respect to DHE protocol complete status and headache classification. RESULTS: A total of 159 patients were included in the analysis. The headache diagnosis was CM in 49% (78/159), status migrainosus in 44% (70/159), and Other headache with migrainous features in 7% (11/159). At discharge, 60% (96/159) of patients achieved headache freedom, and no statistically significant difference was found in relative change in headache among the CM, status migrainosus, and Other headache groups. Patients who completed the full 8 or 9 dose IV DHE protocol were more likely to have persistent headache at discharge, with a median pain score of 1.0 (IQR 0.0-4.0) compared to a score of 0.0 (IQR 0.0-1.0) in the DHE incomplete group (P < .001). No difference was found in pain relief outcomes at follow-up in the DHE protocol complete and DHE protocol incomplete groups. CONCLUSIONS: Although limited by the absence of a control group, our data support repetitive IV DHE as an abortive therapy for pediatric patients with status migrainosus or CM, with no evidence of differential efficacy in these groups. A higher rate of headache at discharge in the DHE protocol complete group reflects in large part the common decision to discontinue treatment once headache freedom was achieved, resulting in nonresponders being more likely to complete the full course of DHE. In our cohort, there was no difference in pain relief at follow-up between patients who completed the full 8 or 9 doses of DHE and those that did not. Discontinuing DHE once the patient has achieved headache freedom would therefore achieve the therapeutic goal while shortening the hospital stay. To potentially impact longer term pain relief, incorporation of a comprehensive treatment approach into the IV DHE admission is of interest for future study and quality improvement initiatives.

A Phase 1, Randomized, Open-Label, Safety, Tolerability, and Comparative Bioavailability Study of Intranasal Dihydroergotamine Powder (STS101), Intramuscular Dihydroergotamine Mesylate, and Intranasal DHE Mesylate Spray in Healthy Adult Subjects.

OBJECTIVE: To investigate and compare the safety and the pharmacokinetics of dihydroergotamine (DHE) after administration of intranasal DHE powder (STS101), intranasal DHE spray (Migranal® ), and intramuscular (IM) DHE injection in healthy subjects. METHODS: This was a 2-part, active-controlled, 3-period crossover study over 3 weeks, separated by 1-week washout periods. In part 1, 3 ascending dosage strengths of STS101 (1.3, 2.6, and 5.2 mg) were administered to 15 healthy subjects with no history of migraine. In part 2, 27 healthy subjects were administered 1 dose each of STS101 5.2 mg, Migranal DHE Mesylate Liquid Nasal Spray 2.0 mg, and IM DHE Mesylate 1.0 mg in a randomized order. Liquid chromatography, tandem mass spectrometry was used to determine plasma levels of DHE and its major metabolite, 8'OH-DHE. Pharmacokinetic parameters (Cmax , Tmax , AUC0-2 h , AUC0-48 h , AUC0-inf , and t1/2 ) for DHE and metabolite were calculated. Geometric means and 90% confidence intervals of log-transformed data were calculated and the ratio of means compared. Safety was evaluated by monitoring adverse events, vital signs, electrocardiograms, subjective and objective assessments of nasal signs and symptoms, and changes in laboratory parameters. The study is registered as NCT03874832. RESULTS: Forty-three subjects were enrolled and received study medication. Forty completed all study activities, 14 in part 1 and 26 in part 2. In part 1, DHE plasma levels showed a dose-dependent increase, with STS101 5.2 mg reaching a mean Cmax of 1870 pg/mL with a Tmax of 23 minutes. In part 2, STS101 5.2 mg showed rapid absorption, achieving mean DHE plasma concentrations of 1230 and 1850 pg/mL at 10 and 15 minutes after administration, respectively. In comparison to Migranal, STS101 5.2 mg showed approximately 2-fold higher Cmax (2175 vs 961 pg/mL), AUC0-2 h (2979 vs 1316 h × pg/mL), and AUC0-inf (12,030 vs 6498 h × pg/mL), respectively. The mean AUC0-inf of STS101 5.2 mg was comparable to IM DHE (12,030 vs 13,650 h × pg/mL). STS101 5.2 mg showed substantially lower variability compared to Migranal for Cmax (41% vs 76%), AUC0-2 h (39% vs 75%), and AUC0-inf (39% vs 55%). The incidence of treatment emergent AEs (TEAEs), all mild and transient, reported in parts 1 and 2 combined was 9/15 (60%), 5/15 (33%), and 16/41 (39%) of the subjects after 1.3, 2.6, and 5.2 mg STS101, respectively, and 4/26 (15%) and 5/27 (19%) of the subjects after IM DHE and Migranal, respectively. CONCLUSION: STS101 showed rapid absorption, achieving effective DHE plasma concentrations within 10 minutes. It achieved substantially higher Cmax , AUC0-2 h and AUC0-inf , compared to Migranal suggesting potentially better efficacy than Migranal. Its variability was better than Migranal, thus offering improved consistency of response. AUC0-inf was comparable to IM DHE, suggesting prolonged action and low recurrence. Additionally, the Cmax was sufficiently low to avoid any significant nausea reported with IV DHE. Thus, STS101 is an easy to administer, non-injected, acute treatment for migraine, with a favorable tolerability profile and is expected to provide rapid and consistent freedom from pain and associated migraine symptoms without recurrence.

Dihydroergotamine (DHE) - Then and Now: A Narrative Review.

OBJECTIVE: To provide a narrative review of clinical development programs for non-oral, non-injectable formulations of dihydroergotamine (DHE) for the treatment of migraine. BACKGROUND: Dihydroergotamine was one of the first "synthetic drugs" developed in the 20th century for treating migraine. It is effective and recommended for acute migraine treatment. Since oral DHE is extensively metabolized, it must be given by a non-oral route. Intravenous DHE requires healthcare personnel to administer, subcutaneous/intramuscular injection is challenging to self-administer, and the approved nasal spray formulation exhibits low bioavailability and high variability that limits its efficacy. Currently there are several attempts underway to develop non-oral, non-injected formulations of DHE. METHOD: A systematic search of MEDLINE/PubMed and ClinicalTrials.gov databases, then narrative review of identified reports, focusing on those published in the last 10 years. RESULTS: Of 1881 references to DHE from a MEDLINE/PubMed search, 164 were from the last 10 years and were the focus of this review. Further cross reference was made to ClinicalTrials.gov for 19 clinical studies, of which some results have not yet been published, or are studies that are currently underway. Three nasal DHE products are in clinical development, reawakening interest in this route of delivery for migraine. Other routes of DHE administration have been, or are being, explored. CONCLUSION: There is renewed appreciation for DHE and the need for non-oral, non-injected delivery is now being addressed.

Enhancing Outpatient Dihydroergotamine Infusion With Interdisciplinary Care to Treat Refractory Pediatric Migraine: Preliminary Outcomes From the Comprehensive Aggressive Migraine Protocol ("CAMP").

OBJECTIVE: To determine preliminary outcomes of a treatment for refractory pediatric migraine that integrates outpatient dihydroergotamine (DHE) infusion with interdisciplinary adjunctive care. BACKGROUND: Limited data are available to inform treatment of refractory migraine in children. Intravenous DHE therapy has shown promise but has been implemented in costly inpatient settings and in isolation of nonpharmacological strategies shown to enhance analgesia and functional improvement. METHODS: We conducted a retrospective chart review of 36 patients ages 11-18 with refractory migraine who underwent a pilot treatment program in an outpatient neurology clinic. The treatment integrated up to 5 days of outpatient DHE infusion with adjunctive nonpharmacological care (pain coping skills training, massage, aromatherapy, and school reintegration support). Changes in headache, healthcare utilization, and functional limitations were assessed as indicators of treatment response through 3-month follow-up. RESULTS: On average, headache intensity declined (M = 5.8 ± 2.5 to M = 2.4 ± 2.7; P < .0001) during the treatment period and remained statistically significantly improved through 3-month follow-up. Headache frequency decreased by a mean of 1.5 days per week (M = 6.7 ± 1.0 vs M = 5.2 ± 2.7, P = .012) through 3-month follow-up, with a 27% reduction (from 0.91 to 0.66) in the proportion of patients reporting a continuous headache (P = .009). Over this same follow-up period, there was a reduction in school days missed per month (median [25th, 75th percentile]: 4.5 [0, 21.0] vs 0 [0.0, 0.5]). There also were reductions in headache-related visits per month to the emergency department and medical providers. Adverse effects were common but typically minor and transient. CONCLUSIONS: Combining outpatient DHE infusion with interdisciplinary adjunctive care has promise as an effective treatment option for adolescents with refractory migraine.

Development and in vitro/in vivo evaluation of dihydroergotamine mesylate loaded maltodextrin-pullulan sublingual films.

Dihydroergotamine mesylate (DHE), ergotamine derivative, has been offered for clinical use to stop or treat symptoms of an emerging migraine as injection for more than a half century. It is shown that bioavailability of DHE greatly changes between the subjects and up to 99% of the orally absorbed dose may be cleared by first pass metabolism. The aim of this study was to design and optimize DHE fast-dissolving sublingual films for migraine treatment. For this purpose pullulan and maltodextrin was chosen as film-forming polymers and propylene glycol as plasticizer. For optimization process Box Behnken design was used. The formed films were free from air bubbles, cuttings, or cracks. Disintegration, mechanical strength and dissolution of films were compared. It is found that pullulan and maltodextrin formed films with the most desired properties at the concentration of 1.5% and 2%. The application of optimum formulation to rabbits showed that bioavailability of formulation is about 23.35% with a tmax 20 min. Due to this fast onset of action and higher bioavailability than oral administration, it is suggested that the polymer combinations of pullulan and maltodextrin formed successful films and were considered as an alternative dosage form for DHE in migraine therapy.

STOP 101: A Phase 1, Randomized, Open-Label, Comparative Bioavailability Study of INP104, Dihydroergotamine Mesylate (DHE) Administered Intranasally by a I123 Precision Olfactory Delivery (POD® ) Device, in Healthy Adult Subjects.

OBJECTIVE: Investigate the safety and pharmacokinetics (PK) of INP104, intranasal dihydroergotamine mesylate (DHE) administered via a Precision Olfactory Delivery (POD® ) device, (Impel NeuroPharma, Seattle, WA) vs intravenous (IV) DHE and DHE nasal spray (Migranal® ) in healthy adult subjects. METHODS: This was a Phase 1, open-label, randomized, single-dose, 3-period, 3-way crossover study. Subjects received a single dose of A) INP104 1.45 mg (a drug-device combination product composed of DHE and the I123 POD device); B) DHE 45® Injection (IV) 1.0 mg; and C) DHE by Migranal® Nasal Spray 2.0 mg. Plasma levels of DHE and the major bioactive metabolite, 8'OH-DHE, were measured, and PK parameters were determined for both. Comparative bioavailability (BA) was assessed by calculating the ratio of the geometric means between treatments for Cmax and AUC0-inf on the ln-transformed data. Safety was assessed from adverse events, vital signs, electrocardiograms, and clinical laboratory values. RESULTS: Thirty-eight subjects were enrolled, 36 were dosed with at least 1 IP and 27 were included in the evaluation of PK and comparative BA. DHE plasma levels following INP104 1.45 mg administration reached 93% of Cmax by 20 minutes and were comparable to IV DHE 1.0 mg by 30 minutes (1219 ng/mL for INP104 vs 1224 ng/mL for IV DHE), which was the Tmax for INP104. From 30 minutes onward, DHE levels for INP104 closely matched those of IV DHE to 48 hours, the last time point measured. In comparison, the Cmax for Migranal was 299.6 pg/mL (approximately 4-fold less than INP104) and occurred at 47 minutes, 17 minutes later than INP104. Plasma DHE AUC0-inf were 6275, 7490, and 2199 h*pg/mL for INP104, IV DHE, and Migranal, respectively. Variability (coefficient of variation [CV%]) for Cmax and AUC0-inf for INP104 compared to Migranal indicated more consistent delivery with INP104. In the BA comparison using the PK population (subjects who had received all 3 treatments), the ratios of geometric means (percent) for Cmax and AUC0-inf were 7.9% and 74.2%, respectively, for INP104: IV DHE, and 445% and 308% for INP104: Migranal. Mean plasma concentration profiles for 8'-OH-DHE were proportionately lower and followed a similar profile to the parent compound, regardless of route of administration (IN vs IV) or delivery system (Migranal vs INP104). Treatment emergent AEs (TEAEs), of mostly mild intensity, were reported by 15/31 (48.4%), 21/32 (65.6%), and 14/34 (41.2%) subjects after INP104, IV DHE, and Migranal, respectively. Treatment-related TEAEs occurred in 6/31 (19.4%), 16/32 (50.0%), and 4/34 (11.8%) subjects after INP104, IV DHE, and Migranal, respectively. CONCLUSION: INP104 met the predefined statistical criteria for comparative bioavailability with IV DHE and Migranal. The shorter time to reach Cmax and at 4 times the plasma concentration of DHE in comparison to Migranal combined with a favorable tolerability profile support further investigation of INP104 as an effective, well tolerated, and non-invasive treatment for acute episodic migraine.

Dihydroergotamine mesylate-loaded dissolving microneedle patch made of polyvinylpyrrolidone for management of acute migraine therapy.

Migraine is a widespread neurological disease with negative effects on quality of life and productivity. Moderate to severe acute migraine attacks can be treated with dihydroergotamine mesylate (DHE), an ergot derivative that is especially effective in non-responders to triptan derivatives. To overcome limitations of current DHE formulations in subcutaneous injection and nasal spray such as pain, adverse side effects and poor bioavailability, a new approach is needed for DHE delivery enabling painless self-administration, quick onset of action, and high bioavailability. In this study, we developed a dissolving microneedle patch (MNP) made of polyvinylpyrrolidone, due to its high aqueous solubility and solubility enhancement properties, using a MNP design previously shown to be painless and simple to administer. DHE-loaded MNPs were shown to have a content uniformity of 108±9% with sufficient mechanical strength for insertion to pig skin ex vivo and dissolution within 2min. In vivo pharmacokinetic studies were carried out on hairless rats, and DHE plasma levels were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The area under curve (AUC) value after DHE delivery by MNP (1259±917ng/mL min) was not significantly different (p>0.05) as compared to subcutaneous injection, with a relative bioavailability of 97%. Also, appreciable plasma levels of DHE were seen within 5min for both delivery methods and tmax value of MNPs (38±23min) showed no significant difference (p>0.05) compared to subcutaneous injection (24±13min). These results suggest that DHE-loaded MNPs have promise as an alternative DHE delivery method that can be painlessly self-administered with rapid onset and high bioavailability.

Increased rate of venous thrombosis may be associated with inpatient dihydroergotamine treatment.

OBJECTIVE: To review whether the incidence of catheter-associated venous thromboses was higher in patients receiving IV dihydroergotamine compared to lidocaine. METHODS: We retrospectively reviewed all admissions at the University of California, San Francisco Headache Center from February 25, 2008, through October 31, 2014, for age, sex, diagnosis, aura, treatment dose, type of IV line used, days with line, superficial (SVT) or deep venous thrombosis (DVT), and pulmonary embolism (PE). RESULTS: A peripherally inserted central catheter (PICC) or midline catheter was placed in 315 of 589 (53%) admissions. Mean age was 38 years with a range of 6 to 79 years; 121 patients (21%) were ≤18 years old. Seventy-four percent (433 of 589) of patients were female. Of 263 dihydroergotamine admissions using a PICC or midline catheter, 19 (7.2%) had either an SVT or DVT or a PE; 2 patients were diagnosed with both DVT and PE. Of 52 lidocaine admissions using a PICC or midline catheter, none had a thrombotic event (p = 0.05, Fisher exact test). Age, sex, aura, total dihydroergotamine dose, and number of days with line were not significant predictors of venous thrombosis. CONCLUSIONS: IV dihydroergotamine treatment may be associated with an increased risk of catheter-associated venous thrombosis. A low threshold for diagnostic ultrasound investigation is appropriate because anticoagulation therapy was frequently required.

Outcome and Cost of Inpatient Hospitalization for Intravenous Dihydroergotamine Treatment of Refractory Pediatric Headache.

BACKGROUND: To determine the cost and efficacy of admitting patients for intravenous dihydroergotamine treatment and to identify factors associated with a higher likelihood of response to treatment. METHODS: We performed a retrospective review of all pediatric hospitalizations from 2001 to 2010 for intravenous dihydroergotamine therapy for headache. Data were collected using the REDcap database and consisted of multiple variables, including preadmission demographics, headache duration, use of prophylactic medications, inpatient therapies including dihydroergotamine dosing, procedures, consultations, total hospital cost, and headache severity at discharge and at follow-up. RESULTS: Seventy-four percent of the 145 individuals who were hospitalized were female. Mean age was 14.9 years. Headache was described as chronic or daily in almost all patients and 28 (19%) had status migrainosus. Sixty-six percent had a first-degree relative with migraine. The average length of stay was 3.7 days, and the average cost was $7569 per hospitalization. Patients received an average of eight doses of dihydroergotamine. At the time of discharge, 63% of patients reported improvement. Follow-up information was available for 68% of the cohort at a median of 42 days after discharge, and 21 of 99 patients (21%) experienced sustained relief of headache. Response to dihydroergotamine was correlated with a lower rate of comorbid diagnoses, lumbar puncture, and outpatient neuroimaging. Response also correlated to less expensive hospitalizations with an average cost of $5379 per hospitalization versus $7105 per hospitalization without positive response. Response was also correlated with a patient receiving more doses of intravenous dihydroergotamine. CONCLUSIONS: Although intravenous dihydroergotamine is an effective abortive medication for intractable migraine, it may provide only short-term headache relief in many pediatric patients. Hospitalization is relatively costly with only modest long-term benefit, especially in patients with chronic migraine or chronic daily headache.

Safety of domperidone in treating nausea associated with dihydroergotamine infusion and headache.

OBJECTIVE: To determine the safety of domperidone in the treatment of nausea associated with dihydroergotamine (DHE) infusion and headache. METHODS: We audited our use of domperidone for the inpatient management of nausea, focusing on known safety concerns, particularly potential cardiac arrhythmias. RESULTS: We reviewed 103 consecutive admissions of 90 patients admitted for IV DHE by infusion. Most admissions were to treat chronic migraine with (n = 53) or without (n = 46) aura. Domperidone was administered in 85 of 103 encounters and was well-tolerated at doses up to 80 mg/d. A significant side effect, akathisia, was observed in one patient. Baseline ECG with corrected QT interval (QTc) was obtained on all patients. Repeat ECG after domperidone was obtained in 21 patients, whose baseline characteristics did not differ from the group as a whole. ECG was interpreted blindly by a cardiac electrophysiologist. QTc did not differ before and after domperidone administration (Wilcoxon signed-rank test, median [interquartile range] 435.0 [410.5-453.0] at admission and 427.0 [399.0-452.5] after domperidone; p = 0.15). In combination with other antiemetics, domperidone was effective in treating nausea such that no patients had refractory nausea severe enough to limit DHE dose. CONCLUSIONS: This retrospective audit demonstrates that domperidone is safe in the treatment of nausea associated with inpatient DHE infusion and headache. While larger prospective trials are necessary to confirm these results and assess efficacy, current evidence and clinical experience suggests that domperidone is safe and useful for nausea and headache management. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with headache undergoing DHE infusion, domperidone is safe and effective in the treatment of nausea.

Aprepitant for the management of nausea with inpatient IV dihydroergotamine.

OBJECTIVE: To assess the efficacy and tolerability of oral aprepitant, a substance P/neurokinin A receptor antagonist, in controlling nausea associated with IV dihydroergotamine (DHE) administered for medically refractory migrainous headache in patients not responding to standard antiemetics or with a history of uncontrolled nausea with DHE. METHODS: This was a retrospective chart review of prospectively collected hourly diary data and clinical notes of patients hospitalized between 2011 and 2015 for inpatient treatment with DHE. Patients were classified using the International Classification of Headache Disorders, 3rd edition (beta version). Peak and average daily nausea scores from hourly diaries, or daily entries of notes, and concurrent antiemetic use were collected and tabulated. RESULTS: Seventy-four patients, of whom 24 had daily diaries, with chronic migraine with or without aura, with or without medication overuse, or new daily persistent headache of a migrainous type, were identified. In 36 of 57 cases in which aprepitant was administered during hospitalization, there was a 50% reduction in the average daily number of as-needed antinausea medications. Of 57 patients, 52 reported that the addition of aprepitant improved nausea. Among 21 of 24 patients with hourly diary data, nausea scores were reduced and in all 12 with vomiting there was cessation of emesis after aprepitant was added. Aprepitant was well tolerated with no treatment emergent adverse events. CONCLUSIONS: Aprepitant can be effective in the treatment of refractory DHE-induced nausea and emesis. Given the broader issue of troublesome nausea and vomiting in acute presentations of migraine, general neurologists may consider what place aprepitant has in the management of such patients. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with medically refractory migraine receiving IV DHE, oral aprepitant reduces nausea.

Is the Generally Held View That Intravenous Dihydroergotamine Is Effective in Migraine Based on Wrong "General Consensus" of One Trial? A Critical Review of the Trial and Subsequent Quotations.

BACKGROUND: The claim that parenteral dihydroergotamine (DHE) is effective in migraine is based on one randomized, placebo-controlled, crossover trial from 1986. The aim of this review was to critically evaluate the original article. It was also found to be of interest to review quotes concerning the results in the more than 100 articles subsequently referring to the article. METHODS: The correctness of the stated effect of intravenous DHE in the randomized clinical trial (RCT) was first critically evaluated. Then, Google Scholar was searched for references to the article and these references were classified as to whether they judged the reported RCT as positive or negative. RESULTS: The design of the RCT, with a crossover within one migraine attack, only allows evaluation of the results for the first period and the effect of DHE and placebo were quite comparable. About 151 references were found for the article in Google scholar. Among the 95 articles with a judgment on the efficacy of intravenous DHE in the RCT, 90 stated that DHE was effective or likely effective whereas only 5 articles stated that DHE was ineffective. CONCLUSIONS: Despite a "negative" RCT, authors of subsequent articles on the efficacy of parenteral DHE overwhelmingly reported this RCT as "positive." This is probably due to the fact that the authors concluded in the abstract that DHE is effective, and to a kind of "wrong general consensus."

Inhaled drug therapy development for the treatment of migraine.

INTRODUCTION: The inhalation of substances, both medicinally and recreationally, is a commonly used method of drug administration but has been underutilized in the treatment of neurologic disorders such as migraine. Three drugs have been studied as potential inhalable treatments for acute migraine: dihydroergotamine (MAP0004), prochlorperazine (Staccato prochlorperazine), and loxapine (Staccato loxapine). AREAS COVERED: This review discusses the available literature describing the pharmacokinetics, tolerability and efficacy of MAP0004, Staccato prochlorperazine and Staccato loxapine, including data from Phase II and Phase III clinical trials. EXPERT OPINION: Inhaled DHE offers rapid absorption with a pharmacokinetic profile similar to IV administration. Improved side effect profile results from more selective binding at antimigraine serotonergic receptors 5-HT1B and 5-HT1D. Inhaled prochlorperazine is rapidly absorbed and resulted in statistically significant migraine pain relief at 2 hours compared to placebo but is not currently being pursued by the manufacturer as a potential migraine abortive. Inhaled loxapine is also rapidly absorbed into systemic circulation but Phase IIb trials did not show statistically improved pain relief or pain freedom compared to placebo. MAP0004 will likely provide a good alternative to patients seeking rapid relief without the need for injection or other invasive routes.