A new hypothesis linking oxytocin to menstrual migraine.

OBJECTIVE: To highlight the emerging understanding of oxytocin (OT) and oxytocin receptors (OTRs) in modulating menstrual-related migraine (MRM). BACKGROUND: MRM is highly debilitating and less responsive to therapy, and attacks are of longer duration than nonmenstrually related migraine. A clear understanding of the mechanisms underlying MRM is lacking. METHODS: We present a narrative literature review on the developing understanding of the role of OT and the OTR in MRM. Literature on MRM on PubMed/MEDLINE database including clinical trials and basic science publications was reviewed using specific keywords. RESULTS: OT is a cyclically released hypothalamic hormone/neurotransmitter that binds to the OTR resulting in inhibition of trigeminal neuronal excitability that can promote migraine pain including that of MRM. Estrogen regulates OT release as well as expression of the OTR. Coincident with menstruation, levels of both estrogen and OT decrease. Additionally, other serum biochemical factors, including magnesium and cholesterol, which positively modulate the affinity of OT for OTRs, both decrease during menstruation. Thus, during menstruation, multiple menstrually associated factors may lead to decreased circulating OT levels, decreased OT affinity for OTR, and decreased expression of the trigeminal OTR. Consistent with the view of migraine as a threshold disorder, these events may collectively result in decreased inhibition promoting lower thresholds for activation of meningeal trigeminal nociceptors and increasing the likelihood of an MRM attack. CONCLUSION: Trigeminal OTR may thus be a novel target for the development of MRM therapeutics.

Dihydroergotamine and sumatriptan in isolated human coronary artery, middle meningeal artery and saphenous vein.

BACKGROUND: Dihydroergotamine (DHE) and sumatriptan are contraindicated in patients with cardiovascular disease because of their vasoconstricting properties, which have originally been explored in proximal coronary arteries. Our aim was to investigate DHE and sumatriptan in the proximal and distal coronary artery, middle meningeal artery and saphenous vein. METHODS: Blood vessel segments were mounted in organ baths and concentration response curves for DHE and sumatriptan were constructed. RESULTS: In the proximal coronary artery, meningeal artery and saphenous vein, maximal contractions to DHE (proximal: 8 ± 4%; meningeal: 32 ± 7%; saphenous: 52 ± 11%) and sumatriptan (proximal: 17 ± 7%; meningeal: 61 ± 18%, saphenous: 37 ± 8%) were not significantly different. In the distal coronary artery, contractions to DHE (5 ± 2%) were significantly smaller than those to sumatriptan (17 ± 9%). At clinically relevant concentrations, mean contractions to DHE and sumatriptan were below 3% in proximal coronary arteries and below 6% in distal coronary arteries. Contractions in the meningeal artery and saphenous vein were higher (7%-38%). CONCLUSIONS: Contractions to DHE in distal coronary arteries are smaller than those to sumatriptan, while at clinical concentrations they both induce only slight contractions. In meningeal arteries contractions to DHE and sumatriptan are significantly larger, showing their cranioselectivity. Contractions to DHE in the saphenous vein are higher than those in the arteries, confirming its venous contractile properties.

Treatment persistence and switching in triptan users: a systematic literature review.

OBJECTIVE: To conduct a systematic review to evaluate persistence to and switching of triptan therapy for the acute treatment of migraine. BACKGROUND: Migraine affects over 12% of adults in Western countries and an estimated 36 million people in the United States. Triptans are an abortive treatment option in patients with moderate to severe migraine. Despite the safety and efficacy of triptans reported in clinical trials, observational studies have consistently demonstrated low persistence to therapy and frequent switching among products over time. METHODS: The following databases were researched: Medline, CENTRAL, and EMBASE. Detailed inclusion and exclusion criteria were specified a priori before conducting abstract and full-text screening. Included studies were required to: (1) report triptan use for migraine treatment; (2) report measures of persistence and/or switching patterns; (3) study migraineurs aged 18 years or older; and (4) conduct an observational study. Studies were excluded if they (1) incorporated interventional study design; (2) lack information or relevance to outcome of interest; (3) were not original research; (4) did not clearly state the results; and (5) were not written in English. Abstracts and full-text articles were reviewed independently by two investigators. RESULTS: Out of 595 studies identified, 380 studies were included for abstract screening. A total of 12 articles met the eligibility criteria after full-text screening of 44 studies, including four studies from reference search. The proportion of patients that remained persistent up to six refills of an index triptan ranged from 3.2% to 12.6% and the proportion of patients that never refilled their index triptan ranged from 38% to 65.8%. In addition to those patients who discontinued, several studies reported that 5-9% of newly initiating triptan users switch to a different triptan before refilling their original medication. Finally, several studies reported the 1-year probability of discontinuation among a general group of triptan users (not limited to treatment naïve patients) to be between 30% and 60%. CONCLUSIONS: Triptans can be a valuable option for acute treatment of migraine. However, studies have shown that treatment persistence is low. This, along with frequent switching behaviors, suggests that a significant unmet clinical need remains despite the wide availability of triptans.

Gastric stasis in migraineurs: etiology, characteristics, and clinical and therapeutic implications.

BACKGROUND: Migraine is a disabling neurological disorder often complicated by gastrointestinal conditions such as gastric stasis. The association between migraine and gastric stasis has received very little attention in the literature, but the existing evidence suggests that they may share a common etiology. RESULTS: Patients with migraine and those with gastric stasis exhibit abnormal autonomic nervous system function. Furthermore, empirical studies demonstrate that migraineurs experience significant delays in gastric emptying, both during and outside of attacks, when compared to non-migrainous controls. CONCLUSION: More research is needed to establish the relationship between gastric stasis and migraine burden and to determine the impact of gastric stasis on migraine treatment.

Dihydroergotamine (DHE) use during gestation and the risk of adverse pregnancy outcomes.

BACKGROUND: Dihydroergotamine (DHE) is perceived to be associated with a higher risk of adverse pregnancy events, but it has significantly less vasoconstrictive and uterotonic effects compared with ergotamine, and has demonstrated no teratogenic effect in animals. The objectives of this study were to quantify the risk of major congenital malformations (MCMs), prematurity, low birth weight (LBW), and spontaneous abortions (SAs) associated with gestational use of DHE, triptans, and nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: Four independent case-control analyses were conducted within the Quebec Pregnancy Registry: (1) MCM; (2) prematurity (<37 weeks of gestation); (3) LBW (birth weight <2500 g); (4) clinically detected SA. Exposure was defined dichotomously as use of DHE, triptan, and NSAIDs during pregnancy. RESULTS: Overall, 59,707 pregnant women met the eligibility criteria and were considered (53 [0.08%] used DHE, 139 [0.23%] triptans, and 2990 [5.01%] NSAIDs). Adjusting for potential confounders, gestational use of DHE was not significantly associated with the risk of MCM (odds ratio [OR]: 0.97; 95% confidence interval [CI]: 0.22-4.28), LBW (OR: 1.41; 95%CI: 0.25-7.80), or SA (OR: 1.97; 95% CI: 0.21-18.57). DHE use was, however, increasing the risk of prematurity (OR: 4.18; 95% CI: 1.34-12.99). In users of triptans, the OR for MCM was 1.49 (95% CI: 0.89-2.52), prematurity 0.76 (95% CI: 0.34-1.66), LBW 0.83 (95% CI: 0.31-2.25), and SA 2.65 (95% CI: 1.57-4.48). In users of NSAIDs, the OR for MCM was 1.20 (95% CI: 1.06-1.36), prematurity 1.10 (95% CI: 0.95-1.26), LBW 1.29 (95% CI: 1.08-1.54), and SA 2.97 (95% CI: 2.63-3.36). CONCLUSIONS: This study showed that other than for prematurity, DHE use during pregnancy was similar to that of triptan use and was smaller than the risk associated with NSAID use.

Efficacy and safety of MAP0004, orally inhaled DHE in treating migraines with and without allodynia.

BACKGROUND: Central sensitization develops once migraine attacks become established and can be clinically detected by the development of cutaneous allodynia. The efficacy of triptans for migraine resolution has been shown to be markedly reduced when administered in patients with established cutaneous allodynia. OBJECTIVE: The study aimed to evaluate the efficacy and safety of MAP0004, a novel, orally inhaled, form of dihydroergotamine, in patients with and without cutaneous allodynia at the time of treatment. METHODS: This evaluation was a post hoc subanalysis of a randomized, double-blind, placebo-controlled, 2-arm, phase 3, multicenter study. The presence or absence of baseline cutaneous allodynia at the time of drug administration was based on the response to a standard questionnaire. Treatment efficacy at 2 hours posttreatment was compared in patients with and without baseline allodynia. RESULTS: At the time of treatment, allodynia was present in 216 patients treated with MAP0004 and 202 patients treated with placebo. MAP0004 treatment efficacy was superior to placebo, as measured by 2-hour pain relief for patients with and without allodynia (P < .0001) and as measured by 2-hour pain freedom for patients with (P < .0001) and without (P < .0002) allodynia. No significant within-treatment differences after treatment with MAP0004 in patients with and without allodynia at baseline were observed. Patients were more likely to be allodynia-free after treatment with MAP0004 compared with placebo (73% vs 66%, P = .0013). Furthermore, treatment with MAP0004 prevented the development of allodynia in patients not experiencing allodynia at baseline (P = .0057). MAP0004 was generally well tolerated. CONCLUSIONS: This post hoc subanalysis shows that MAP0004 was similarly effective in patients whether or not allodynia was present at treatment baseline. Patients were also more likely to be allodynia-free following treatment of a migraine with MAP0004.

MAP0004, orally inhaled DHE: a randomized, controlled study in the acute treatment of migraine.

OBJECTIVE: To evaluate the efficacy and tolerability of MAP0004 compared with placebo for a single migraine in adult migraineurs: The FREEDOM-301 Study. BACKGROUND: Acute treatment of migraine remains a clinical challenge despite the availability of triptans and other agents. Injectable dihydroergotamine, although effective, is considered invasive and inconvenient, and intranasal dihydroergotamine is associated with inconsistent systemic dosage delivery. MAP0004 is an orally inhaled formulation of dihydroergotamine delivered to the systemic circulation. In a phase 2 study, MAP0004 provided significant early onset of pain relief (10 minutes, P < .05) and sustained pain relief for up to 48 hours with a favorable adverse event profile. METHODS: A phase 3, randomized, double-blind, placebo-controlled, parallel-group, single-attack, outpatient study of MAP0004, an inhaled dihydroergotamine was conducted at 102 sites in 903 adults with a history of episodic migraine. Patients were randomized (1:1) to receive MAP0004 (0.63 mg emitted dose; 1.0 mg nominal dose) or placebo, administered after onset of a migraine headache with moderate to severe pain. The co-primary endpoints were patient-assessed pain relief and absence of photophobia, phonophobia, and nausea at 2 hours after treatment. RESULTS: A total of 903 patients (450 active, 453 placebo) were randomized, and 792 (395 active, 397 placebo) experienced a qualifying migraine. MAP0004 was superior to placebo in all 4 co-primary endpoints: pain relief (58.7% vs 34.5%, P < .0001), phonophobia free (52.9% vs 33.8%, P < .0001), photophobia free (46.6% vs 27.2%, P < .0001), and nausea free (67.1% vs 58.7%, P = .0210). Additionally, significantly more patients were pain-free at 2 hours following treatment with MAP0004 than with placebo (28.4% vs 10.1%, P < .0001). MAP0004 was well tolerated; no drug-related serious adverse events occurred. CONCLUSIONS: In this study, MAP0004 was effective and well tolerated for the acute treatment of migraine with or without aura, providing statistically significant pain relief and freedom from photophobia, phonophobia, and nausea in adults with migraine compared with placebo.

A randomized, double blind, placebo-controlled study of MAP0004 in adult patients with migraine.

BACKGROUND: Dihydroergotamine mesylate (DHE) is an effective treatment for acute migraine, but its effective use is often limited by the inconvenience and inconsistency of intranasal, intramuscular, or subcutaneous routes of administration. A new formulation of DHE delivered through the lungs by the novel Tempo inhaler is being developed and is designed to offer fast onset, consistent dosing, and sustained response. OBJECTIVE: This proof of principle and dose setting study evaluated the efficacy and tolerability of inhaled DHE delivered by a breath-synchronized, plume-controlled inhaler (Tempo) in adult migraineurs. METHODS: This was a randomized, double blind, placebo-controlled, 2-period study conducted at 9 headache centers in the United States. Adult men and women with a documented history of acute migraine for at least 12 months, with an average of 2 to 8 attacks per month in the preceding 6 months were treated with MAP0004 0.5 or 1.0 mg systemic equivalent dose (1.0 or 2.0 mg nominal dose) or matching placebo during Treatment Period 1 (TP1). Patients who responded to treatment during TP1 were re-randomized in Treatment Period 2 (TP2) to receive MAP0004 0.25 mg systemic equivalent dose or placebo. RESULTS: Of 86 patients randomized to treatment, 69 were included in the As-Treated population in TP1. Pain relief at 2 hours was greater for MAP0004 0.5 mg (72%, P = .019) and 1.0 mg (65%, P = .071) than for placebo (33%). Pain relief at 10 (32%), 15 (46%), and 30 (55%) minutes was significantly (P < .05) greater with MAP0004 0.5 mg than with placebo (0%, 7% and 14%, respectively). Pain-free at 2 hours was significantly greater with MAP0004 0.5 mg (44%, P = .015) and 1.0 mg (35%, P = .050) than with placebo (7%). Total migraine relief at 2 hours was significantly (P = .019) greater with MAP0004 0.5 mg (72%) than with placebo (33%). Sustained pain relief and pain-free rates exhibited a therapeutic gain of 30% (P = .066) and 31% (P = .037) at 24 hours and 28% (P = .096) and 30% (P = .057) at 48 hours with MAP0004 0.5 mg vs placebo. MAP0004 was well tolerated with no serious or severe adverse events. Dysgeusia was reported as treatment-related in 2 patients on placebo, 0 patients on MAP0004 0.5 mg, and 6 patients on MAP0004 1.0 mg. No clinically relevant changes were noted in spirometry, vital signs, electrocardiogram, or clinical laboratory values. No significant differences between treatments were observed in TP2. CONCLUSIONS: In this study MAP0004 0.5 mg and 1.0 mg were well tolerated and effective at delivering clinically significant, rapid, and sustained pain relief in adult migraine patients. No additional benefit was observed with the higher dose, thus the MAP0004 0.5 mg systemic equivalent dose has been selected as the dose for further clinical study.

The headache management trial: a randomized study of coordinated care.

CONTEXT: Headache is a common, disabling disorder that is frequently not well managed in general clinical practice. OBJECTIVE: To determine if patients cared for in a coordinated headache management program would achieve reduced headache disability compared with patients in usual care. DESIGN: A randomized controlled trial of headache management vs usual care. SETTING: Three distinctly different practice sites: an academic internal medicine practice located in a major east coast city, a staff-model managed care organization located in a major west coast city, and a community practice in a medium-sized city in the southeast. Patients.- Individuals 21 years of age or older with chronic tension-type, migraine, or mixed etiology headache and a Migraine Disability Assessment (MIDAS) score greater than 5, not receiving treatment from a neurologist or headache clinic currently or within the previous 6 months and with an intention to continue general medical care at their current location and to continue their present health insurance coverage for the next 12 months. INTERVENTIONS: Active intervention is a headache management program consisting of: (1) a class specifically designed to inform patients about headache types, triggers, and treatment options; (2) diagnosis and treatment by a professional especially trained in headache care (based on US Headache Consortium guidelines); and (3) proactive follow-up by a case manager. Participation lasted 6 months. Control patients received usual care from their primary care providers. MAIN OUTCOME MEASURES: The primary efficacy measure reported in this article is a comparison of MIDAS scores of headache disability between the intervention group and the control group at 6 months. Secondary measures were response at 12 months, general health and quality of life, and satisfaction with headache care. RESULTS: The intervention improved (ie, decreased) MIDAS scores by 7.0 points (95% confidence interval 2.9 to 11.1) more than the control (P = .008) at 6 months. The difference was not affected by site (P = .59 for clinic by intervention interaction), and a trend toward persistent benefit at 12 months (mean difference in improvement 6.8 points, 95% confidence interval -.3 to 13.9, P = .06) was observed. Quality of life and satisfaction with headache treatment were similarly improved. CONCLUSIONS: Coordinated headache management significantly improved outcomes for patients who, despite contact with the healthcare system for headache, had substantial unmet needs. The intervention in this trial can be implemented practically in a wide range of settings with the expectation that meaningful improvements will accrue.

Twelve-month tolerability and safety of sumatriptan-naproxen sodium for the treatment of acute migraine.

OBJECTIVES: To evaluate the long-term safety and tolerability of sumatriptan-naproxen sodium for the treatment of moderate to severe acute migraines and to assess the safety of administration of an optional second dose. PATIENTS AND METHODS: A 12-month, multicenter, open-label safety study was conducted in adults treated for migraine attacks of moderate to severe intensity from April 14, 2004, to August 18, 2005. Safety evaluations included adverse events and laboratory tests. RESULTS: Of 600 patients enrolled, 565 (94%) were treated for at least 1 migraine. Of treated patients, 414 (73%) and 362 (64%) completed 6 and 12 months of treatment, respectively. Of the 24,485 attacks treated, 17,144 (70%) were treated with only 1 dose. On average, patients treated 5 migraine attacks per month, with a median of 6 days between attacks. The most common treatment-related adverse events were nausea, muscle tightness, and dizziness. Fourteen patients reported 1 or more serious adverse event with only 1 judged probably related to treatment. No deaths occurred. Eight percent of patients discontinued participation in the study because of adverse events or pregnancy. The rates of adverse events reported were no higher after treatment with 2 tablets (at least 2 hours apart) compared with 1 tablet. CONCLUSIONS: In this 12-month data set of more than 24,000 migraine attacks in 565 patients, sumatriptan-naproxen sodium formulated in a single tablet was well tolerated when used episodically for the treatment of acute migraine. The adverse events did not differ from those expected for the individual components alone, and no new or unexpected findings occurred.

A randomized, double-blind, placebo-controlled trial of the efficacy and tolerability of a 4-mg dose of subcutaneous sumatriptan for the treatment of acute migraine attacks in adults.

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of a single 4-mg dose of sumatriptan SC for the acute treatment of adult patients experiencing a migraine attack with moderate to severe pain. METHODS: In this randomized, double-blind, placebo-controlled study, subjects included men and women aged 18 to 60 years who had migraine with or without aura, as defined by the 1988 International Headache Society criteria. Subjects received either sumatriptan 4 mg SC or placebo SC for a migraine attack with headache pain of moderate to severe intensity. The primary efficacy measurement was pain relief at 2 hours. Secondary efficacy measures included the severity of headache pain at 10, 20, 30, 40, 50, 60, and 90 minutes postadministration. Clinical assessments of pain severity and adverse events were made by way of questioning and observation of subjects and were completed at 10, 20, 30, 40, 50, 60, 90, and 120 minutes postadministration. RESULTS: Five hundred seventy-seven subjects (87% female and 94% white) participated in this study. Three hundred eighty-four received sumatriptan and 193 received placebo. At 120 minutes postadministration, sumatriptan 4 mg SC was associated with greater proportions of patients who experienced pain relief (70% vs 22%; P<0.001) or were pain free (50% vs 11%; P<0.001). In addition, there were statistically significant differences between sumatriptan 4 mg SC and placebo for multiple secondary end points, including pain relief as early as 10 minutes postadministration (11% vs 6%; P=0.039), pain-free status as early as 30 minutes postadministration (10% vs 3%; P<0.001), nausea as early as 30 minutes postadministration (39% vs 49%; P=0.021), and photophobia as early as 10 minutes postadministration (80% vs 87%; P=0.046). The most common adverse events in the sumatriptan 4-mg SC and placebo groups, respectively, were injection-site reactions (43% and 15%), tingling (12% and 3%), dizziness or vertigo (10% and 5%), and warm or hot sensation (8% and 2%). Treatment groups were not statistically compared for adverse events. CONCLUSIONS: Sumatriptan 4 mg SC was effective for the acute treatment of migraine attacks and was generally well tolerated in these patients.

Prevalence of migraine and response to sumatriptan in patients self-reporting tension/stress headache.

OBJECTIVE: This study was conducted to evaluate the prevalence of migraine and its responsiveness to migraine-specific therapy in patients with self-reported tension-type headache. METHODS: Patients were adults (n = 423) consulting one of 54 North American study sites including primary care clinics, neurology clinics, and headache clinics. The study comprised an initial diagnosis phase to determine the headache diagnosis of patients entering the study with self-reported tension/stress headache, including that previously diagnosed by a health care provider. Patients reporting tension/stress headache were evaluated and diagnosed as having migraine with or without aura, probable migraine, tension-type headache, or another headache type. Exclusion criteria included prior diagnosis of migraine or probable migraine and the presence of headache for at least 15 days monthly during either of the 2 months before screening. The initial phase was followed by a randomized, double-blind treatment phase to evaluate the efficacy of sumatriptan 100 mg tablets for the treatment of a single migraine attack in those meeting International Headache Society (IHS) criteria for migraine during the diagnosis phase. RESULTS: Of 423 patients reporting tension/stress headache at study entry, 84% (n = 357) were diagnosed at the clinic visit as fulfilling IHS criteria for migraine without aura or migraine with aura, and 65% (n = 276) were diagnosed with migraine only (i.e., with no other concurrent headache diagnosis). Three hundred thirty-two (332) patients entered the double-blind treatment phase. Headache relief rates 2h post-dose, the primary efficacy endpoint, did not significantly differ between sumatriptan and placebo (p = 0.099). However, improvements were significantly (p < 0.05) greater with sumatriptan than placebo on several other headache-related efficacy measures. CONCLUSIONS: Migraine headache may go unrecognized in patients with self-reported tension headache. Among patients having self-reported tension headache and diagnosed with migraine during the study, response to acute treatment with sumatriptan was inconclusive. Improvement with sumatriptan versus placebo was observed for some measures and not for others. The results should be interpreted in the context of study limitations including use of patient self-reports to assess headache diagnosis and possible lack of representativeness arising from the predominantly white sample.

The effects of feedback and contingent reinforcement on the exercise behavior of chronic pain patients.

The purpose of this study was to increase knowledge through research in the area of operant management of chronic back pain, using a strong experimental design. Reinforcement was made contingent on rate of walking, and feedback about progress was provided at certain intervals during each observation session. The changing criterion experimental design for a single subject indicated important systematic increases in walking rate, while the no-reinforcement and non-contingent reinforcement procedures produced no systematic effect. Pre-post ratings showed an average decrease in reported pain.

Health care resource utilization following initiation of a triptan: a retrospective claims analysis.

BACKGROUND: 23 million Americans suffer from migraine headaches, incurring more than $1 billion in direct medical costs each year (with another $13 billion in indirect productivity losses). Triptans are the most common treatment of choice for these patients; however, adherence and persistence to triptans are poor. Partly due to poor adherence to therapy, the ability of triptans to reduce the utilization of other medical services and prescription drugs remains unclear. OBJECTIVES: To (a) assess changes in the utilization of medical services and relevant prescription drugs after patients suffering from episodic migraines begin triptan therapy and (b) further investigate the relationship between concomitant opioid use among triptan-treated migraine patients and further utilization of medical services and prescription drugs. METHODS: A retrospective analysis of pharmacy and medical insurance claims was carried out using a large and nationally representative database. The utilization patterns of episodic migraine patients were observed for 12 to 24 months prior to their first triptan prescription and 12 to 24 months following that prescription. Resource utilization included physician office visits, diagnostic imaging, emergency room use, inpatient hospitalization, opioid prescriptions, migraine prophylaxis prescriptions, and acetaminophen or nonsteroidal anti-inflammatory prescriptions. Results were stratified according to triptan-switching behavior. RESULTS: The analytic sample included 9,521 migraine patients who were followed for a median of 550 days before and after their first triptan fill. 40.9% of these patients filled their triptan prescriptions only once (index fill). Another 40.3% filled a triptan prescription at least twice and never switched their triptan brand. 15.6% of patients switched their triptan prescriptions once, and 3.2% of patients switched their triptan prescriptions twice or more. The only group to display significant reductions in resource utilization following the prescription of a triptan was the cohort that never refilled the medication, potentially suggestive of misdiagnosis. Either no significant change or a significant increase in resource utilization was seen in all other cases. The ability of triptans to reduce resource utilization seemed to be lower among patients who switched triptans more often. Patients that concomitantly used opioid medications in addition to triptans also used significantly more resources than migraine patients who were not treated with opioids. CONCLUSION: Contrary to the findings of some previous research, the initiation of triptan therapy did not significantly reduce the utilization of migraine-related medical services or other relevant prescription drugs in this retrospective claims analysis. This may have been due to higher and more realistic rates of triptan switching and discontinuation. Consistent with previous findings, patients using concomitant opioids used more migraine-related health care resources.

Dihydroergotamine: a review of formulation approaches for the acute treatment of migraine.

Dihydroergotamine (DHE) was first used to treat migraine in 1945 and is currently included among migraine-specific treatments for moderate-severe migraine. DHE may be administered through several routes of delivery, with efficacy and tolerability varying among formulations. We review DHE formulation approaches for the acute treatment of migraine, reviewing pharmacokinetics/dynamics and comparing clinical response among various formulations. Pharmacokinetic properties vary among DHE formulations, with peak concentration occurring in 6 min with intravenous, 34 min with intramuscular, 56 min with intranasal, 12 min with oral inhalation and 75 min with oral administration. DHE is a potent agonist at serotonin 5-HT1B and 5-HT1D receptors. Adverse effects due to binding to select adrenergic and dopaminergic receptors are significantly less with orally inhaled than intravenous DHE when comparing therapeutically effective doses. Among parenteral formulations (including subcutaneous, intramuscular, intravenous and nasal spray), efficacy is superior with injectable dosing. Nasal spray DHE is generally more effective than placebo, but less effective than sumatriptan. Orally inhaled DHE is likewise more effective than placebo, but there are no head-to-head comparisons with triptans available for review. Adverse effects, particularly nausea, may limit use of parenteral DHE. Nausea is generally less frequent with non-injectable dosing.

Assessment of the consistency of absorption of dihydroergotamine following oral inhalation: pooled results from four clinical studies.

BACKGROUND: MAP0004 is an investigational orally inhaled dihydroergotamine (DHE) delivered via a TEMPO(®) metered dose inhaler that was effective in the acute treatment of migraine in a large Phase 3 trial. Rapid and consistent absorption of DHE is important for efficacy in the acute treatment of migraine. METHODS: The pharmacokinetic parameters from four recent clinical studies, with doses including the proposed clinical dose of 1.0 mg nominal (0.65 mg emitted) MAP0004, were assessed for the consistency and speed of absorption of DHE. RESULTS: Across these studies, MAP0004 administration resulted in rapid DHE absorption, with a median time of maximum concentration (C(max)) of approximately 10 min. The C(max) and area under the curve from time zero to 2 hr associated with the MAP0004 1.0 mg nominal dose were also similar between the three studies with this dose. C(max) values after 1.0 mg MAP0004 administration were consistently lower than for 1.0 mg intravenous DHE administration, and C(max) appeared to correlate with incidence of nausea. In these studies, DHE absorption through the lung was fast, consistent, and not associated with any unique tolerability issues for this route of administration. CONCLUSIONS: These results provide evidence of the consistency of absorption that can be achieved with the use of an appropriate metered dose inhaler, which may translate into a predictable therapeutic response.

Assessing acute systemic effects of an inhaled drug with serial echocardiography: a placebo-controlled comparison of inhaled and intravenous dihydroergotamine.

OBJECTIVE: MAP0004 is an investigational product which delivers dihydroergotamine (DHE) through the lung via a breath-synchronized metered dose inhaler. The objective of this study was to compare the acute effects of orally inhaled and intravenous (IV) DHE to placebo on maximum change and area under the curve for pulmonary arterial systolic pressure (PASP). RESEARCH DESIGN AND METHODS: A randomized, double-blind, placebo-controlled, 3-period, crossover study of 24 health adults. Trial registration NCT01089062. Study assessments included pharmacokinetics, electrocardiograms (ECG), and validated echocardiographic (Doppler)-derived measures of PASP by echocardiogram. The primary endpoint was the absolute change in calculated PASP using area under the curve, 0 to 2 hours (AUC(0-2h)). RESULTS: The change in PASP with IV DHE was significantly different than MAP0004 and placebo (AUC(0-2h)2857, 2624, and 2453 mmHg*min, respectively). After a second dose of MAP0004, AUC(0-4h) remained lower with MAP0004 than with a single dose of IV DHE. Adverse events were more common with IV DHE than with MAP0004 or placebo. None of the treatments produced clinically significant changes in PASP or other cardiac parameters. Changes in PASP were significantly smaller with MAP0004 compared with IV DHE. CONCLUSION: These results indicate the effects 1 mg of orally inhaled DHE on the cardiovascular system are less than with 1 mg of IV DHE, and that serial echocardiography can be a useful noninvasive means of assessing acute systemic effects.

Effects of a supratherapeutic dose of investigational orally inhaled dihydroergotamine (MAP0004) on QT interval: a randomized, double-blind, active- and placebo-controlled crossover study in healthy volunteers.

BACKGROUND: MAP0004 is an orally inhaled investigational drug containing dihydroergotamine (DHE). Although DHE has been used for 60 years with no reported cardiac arrhythmias, a thorough QT study had not previously been performed with DHE. OBJECTIVE: The objective of this study was to assess the effects of MAP0004 on the QT interval as required for regulatory approval of a new product. METHODS: This randomized, double-blind, placebo-controlled, 3-period crossover study enrolled healthy volunteers. Subjects were assigned to receive, in randomized sequence, MAP0004 at a supratherapeutic dose (3-fold the clinically effective dose) (3.0 mg), moxifloxacin 400 mg, or inactive vehicle, each administered with 1 placebo capsule. Triplicate ECGs were performed continuously at baseline (day 0), before dosing, and over 24 hours after dosing in each treatment period. The effect on the QT interval was assessed using the Fridericia (QTcF) and individualized (QTcI) correction formulas. RESULTS: Fifty-four healthy adults (20 men, 34 women; mean age, 28 years) completed the trial and had measurable plasma levels of DHE after MAP0004 administration. The largest observed mean difference in QTcI between MAP0004 and placebo was 0.08 msec, and the largest 1-sided 95% upper confidence bound was 2.24 msec, both at 30 minutes after dosing. In contrast, moxifloxacin increased the mean QTcI between 9.57 and 11.28 msec relative to placebo, with a 1-sided lower 95% CL between 7.23 and 8.96 msec, confirming that the assay sensitivity was sufficient to detect MAP0004-related effects. Nausea (27.8%) was common following MAP0004 administration but apparently did not influence the QTc interval. CONCLUSIONS: A supratherapeutic dose of MAP0004 was not associated with prolonged QTc intervals. At the proposed clinical dose (1.0 mg), MAP0004 is unlikely to affect the QT interval. MAP0004 and its primary metabolite showed no evidence for prolongation of the QTc interval in healthy subjects according to the criteria required from regulatory agencies. ClinicalTrials.gov identifier: NCT01191723.

MAP0004, orally inhaled dihydroergotamine for acute treatment of migraine: efficacy of early and late treatments.

OBJECTIVE: To evaluate the efficacy of MAP0004, an orally inhaled dihydroergotamine, for acute treatment of migraine when administered at various time points from within 1 hour to more than 8 hours after migraine onset. PATIENTS AND METHODS: This post hoc subanalysis was conducted using data from 902 patients enrolled in a randomized, double-blind, placebo-controlled, 2-arm, phase 3, multicenter study conducted from July 14, 2008, through March 23, 2009. End points were 2-hour pain relief and pain-free rates in patients who treated a migraine in ≤1 hour, from >1 hour to ≤4 hours, from >4 to ≤8 hours, or in >8 hours after onset of migraine, given that patients may be unwilling or unable to initiate treatment at headache inception. RESULTS: Treatment with MAP0004 was significantly more effective than placebo in relieving pain at all treatment points (≤1 hour after start of migraine: 66% [74/112] for MAP0004 vs 41% [48/118] for placebo, P<.001; >1 to ≤4 hours: 60% [91/153] vs 35% [58/168], P<.001; >4 to ≤8 hours: 53% [36/68] vs 30% [16/54], P=.008; and >8 hours: 48% [25/52] vs 24% [11/46], P=.007). Pain-free rates were also significantly higher with MAP0004 than placebo for treatment within 8 hours after migraine onset (≤1 hour: 38% [43/112] for MAP0004 vs 13% [15/118] for placebo, P<.001; >1 to ≤4 hours: 28% [43/153] vs 10% [17/168], P<.001; >4 to ≤8 hours: 22% [15/68] vs 7% [4/54], P<.025) but not at >8 hours (19% [10/52] vs 9% [4/46], P=.106). CONCLUSION: This post hoc subanalysis shows that MAP0004 was effective in treating migraine irrespective of the time of treatment, even more than 8 hours after onset of migraine pain.

Randomized, double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of MAP0004 (orally-inhaled DHE) in adult asthmatics.

BACKGROUND: MAP0004 (a proprietary formulation of dihydroergotamine mesylate [DHE]) for inhaled delivery is being developed for acute migraine treatment. Because asthma and migraine often occur as co-morbid conditions, it is considered important to study the safety of MAP0004 in a population of asthmatic adults and to confirm that the pharmacokinetics of DHE, when inhaled by asthmatic subjects, were comparable to a population of healthy volunteers. The safety, tolerability, and pharmacokinetics of orally-inhaled MAP0004 administered by the Tempo inhaler were studied in adult asthmatics. SCOPE: This was a randomized, double-blind, placebo-controlled study of two doses of inhaled MAP0004. Eligible subjects were randomized in a 2 : 1 ratio to MAP0004 or placebo and observed for 4 h after each dose. Pharmacokinetic parameters were determined pre-dose and up to 36 h post-dose. FINDINGS: Among 19 subjects, geometric mean AUC(0-36) was 6754 pg.h/mL and geometric mean AUC(0-inf) was 7483 pg.h/mL. Geometric mean t(max) was 9.6 min, geometric mean C(max) was 3174 pg/mL, and geometric mean t((1/2)) was 9.5 h. Overall, 13 of 19 (68%) subjects reported at least one adverse event, most commonly nausea, vomiting, dysgeusia, and headache. CONCLUSION: MAP0004 results in rapid and efficient systemic absorption in asthmatic subjects. Systemic DHE concentrations were similar to those previously reported in healthy subjects, and no clinically relevant safety issues were observed. While this small study was suitable for pharmacokinetic analysis and conclusions, MAP0004 use in migraineurs with concomitant stable asthma should be supported by larger studies of longer duration to confirm that it does not present additional safety risks compared to non-asthmatic migraineurs.