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.

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.

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.

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.

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.

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.

Gastric stasis in migraine: more than just a paroxysmal abnormality during a migraine attack.

OBJECTIVE: The aim of this article is to evaluate gastric motility and emptying in the ictal and interictal period in migraine. BACKGROUND: Nausea is a predominant symptom of migraine and the basis of it is thought to be gastric stasis. Objective methods to establish this are however lacking. We utilized gastric scintigraphy studies to determine gastric motility in the ictal and interictal period of migraine. METHODS: Ten migraine subjects were compared to equal number of age and sex matched controls. Gastric scintigraphy using a standard meal was performed in all control subjects once and in all 10 migraine subjects in the interictal period and nine studies were performed in the ictal period migraine. RESULTS: The time to half emptying was delayed in migraine ictally (78%) and interictal period (80%) using normative data at this institution. Gastric stasis was less pronounced ictally (149.9 minutes) compared to interictal period (188.8 minutes). There was a significant delay compared to nonmigrainous controls (migraine 188.8 minutes vs normal controls 111.8 minutes; P < .05). These data were replicated in percentage of radioactive material remaining in the stomach at 2 hours. CONCLUSIONS: Contrary to previous belief, this study has demonstrated that migraineurs suffer from gastric stasis both during and outside an acute migraine attack. This may suggest that migraineurs may have an abnormal autonomic function compared to nonmigrainous controls. The potential role of this in pathophysiology of migraine is discussed and avenues for further investigations are explored.