Treatment of Juvenile Migraine with Subcutaneous Sumatriptan

SYNOPSIS
An open, prospective study was undertaken to assess the efficacy and safety of subcutaneous sumatriptan in 17 children, ages 6 to 16 years, with severe, recurrent migraine. A 6-mg dose was used in 15 patients and relieved headache within I hour in six and by 2 hours in five others. Two smaller children received a 3-mg dose and both were headache-free within 2 hours. Most also reported marked improvement in associated symptoms such as nausea and photophobia. Four subjects had no clinical improvement after a 6-mg dose. Side effects, such as neck pressure, were brief and mild. These findings suggest that subcutaneous sumatriptan can be both effective and safe as an abortive agent in juvenile migraine, but the appropriate dose in smaller children will need further investigation.     

Oral Rizatriptan Versus Oral Sumatriptan: A Direct Comparative Study in the Acute Treatment of Migraine

Rizatriptan is a potent, oral, 5-HT_1B/1D agonist with more rapid absorption and higher bioavailability than oral sumatriptan. It was postulated that this would result in more rapid onset of effect. This randomized, double-blind, triple-dummy, parallel-groups study compared rizatriptan 5 mg, rizatriptan 10 mg, sumatriptan 100 mg, and placebo in 1268 outpatients treating a single migraine attack. Headache relief rates after rizatriptan 10 mg were consistently higher than sumatriptan at all time points up to 2 hours, with significance at 1 hour (37% versus 28%, P =0.010). All active agents were significantly superior to placebo with regard to headache relief and pain freedom at 2 hours ( P ≤0.001). The primary efficacy endpoint of time to pain relief through 2 hours demonstrated that, after adjustment for age imbalance, rizatriptan 10 mg had earlier onset than sumatriptan 100 mg ( P =0.032; hazard ratio 1.21). Rizatriptan 10 mg was also superior to sumatriptan on pain-free response ( P =0.032), reduction in functional disability ( P =0.015), and relief of nausea at 2 hours ( P =0.010). Significantly fewer drug-related clinical adverse events were reported after rizatriptan 10 mg (33%, P =0.014) compared with sumatriptan 100 mg (41%). We conclude that rizatriptan 10 mg has a rapid onset of action and relieves headache and associated symptoms more effectively than sumatriptan 100 mg.     

Subcutaneous Sumatriptan in the Acute Treatment of Migraine in Patients Using Dihydroergotamine as Prophylaxis

SYNOPSIS
The efficacy of sumatriptan, a 5-HT 1 receptor agonist, in patients with migraine attacks occurring despite prophylactic treatment with oral dihydroergotamine, was assessed in a double-blind placebo-controlled study involving 76 patients. Thirty-seven patients were treated with a subcutaneous injection of 6 mg sumatriptan self-administered with an auto-injector and 39 with placebo given by the same route. Patients having inadequate relief were allowed to use a second injection of test medication I hour later and rescue treatment between 2 hours and 24 hours after the first dose. Headache relief was achieved within 2 hours after sumatriptan in 26 patients (70%) compared to 8 patients (21%) in the placebo group (P<0.0001). Of these patients, 19 (51%) and 3 (8%) were, respectively, pain free at this time. A second injection of sumatriptan was used by 8 (22%) patients compared to 30 (77%) patients in the placebo group (P<0.0001), whereas rescue medication was used respectively by 13 (35%) and 22 (58%) patients (P < 0.024). The adverse event profile of sumatriptan was not affected by the concomitant use of dihydroergotamine and side-effects were all minor and transient. Patient satisfaction was significantly higher in the sumatriptan group (75%) compared to patient satisfaction with placebo (16%). These results show that the high efficacy rate of subcutaneous sumatriptan and its safety profile remain unchanged in migraine patients receiving oral dihydroergotamine as pro-phylaxis.     

Sumatriptan in the Acute Treatment of Migraine Without Aura: Efficacy of 50-mg Dose

We conducted an open study on the efficacy of 50 mg of sumatriptan as an acute treatment for migraine without aura. We recruited 200 consecutive patients, with an established history of migraine without aura, presenting at a headache center. The patients were instructed to take half a 100-mg sumatriptan tablet for their next migraine attack, and to record details of their headache in a diary. The primary outcome of the study was headache relief from one migraine attack. Attacks were moderately intense (46%), moderate to severe (7%), or severe (47%). Total or partial benefit at 2 hours from the 50-mg dose was reported by 140 of 200 patients (70%). Thirty-six patients received no benefit from half a tablet, and 24 did not take sumatriptan, preferring their habitual medication. Side effects were few, mild, and short lasting. We conclude that the 50-mg oral dose is generally effective for migraine without aura attacks of both moderate and severe intensity and recommend this dose for all such patients. If, however, sumatriptan is ineffective at that dose it can be increased to a maximum of 100 mg.     

Sumatriptan in Acute Migraine Using a Novel Cartridge System Self-Injector

SYNOPSIS
This double-blind. randomized, placebo-controlled, parallel-group, multicenter study assessed the efficacy, acceptability, safety, and tolerability of subcutaneous sumatriptan 6 mg administered using a novel cartridge system self-injector for the acute treatment of migraine.
Eighty-six patients treated one migraine attack at home with sumatriptan or placebo. A second identical injection was available after 1 hour for inadequate relief or if the headache recurred. Rescue medication was available I hour later. The primary end point was headache relief (improvement in headache from moderate or severe to mild or no pain) within 60 minutes of the first injection. Secondary end points included the acceptability of the self-injector, requirement for and efficacy of a second dose, relief of nonheadache symptoms, use of rescue medication, and adverse events.
Significantly more patients taking sumatriptan than placebo reported headache relief I hour after the first injection (88% vs 11%, P <0.001). The device was well accepted by patients; about 90% found it easy to use and wanted to take further medication using it. Significantly fewer patients taking sumatriptan than placebo required a second injection (33% vs 92%, P <0.001) or rescue medication after the second injection (35% vs 67% P <0.05). Significantly more patients taking sumatriptan than placebo reported headache relief after the second injection (83% vs 32%, P <0.01), and resolution of non-headache migraine symptoms (54% vs 23%, P <0.01). Sumatriptan was generally well tolerated.
Subcutaneous sumatriptan 6 mg self-administered using the novel self-injector is an effective, well accepted, and well tolerated acute treatment of migraine.     

Efficacy and Tolerability of Subcutaneous Sumatriptan for Acute Migraine: A Comparison Between Ethnic Groups

OBJECTIVE: To evaluate efficacy and tolerability of subcutaneous sumatriptan 6 mg versus placebo for acute migraine between ethnic groups. BACKGROUND: Patients in previous sumatriptan studies have been predominantly Caucasian and the effects of sumatriptan between different ethnic groups are unknown. METHODS: This was a multicenter, 3-phase, 12-attack study. Phases I and III (inclinic) were randomized, double-blind, placebo-controlled, crossover designs. Phase II (outpatient) was a single-blind design. Sumatriptan was compared to placebo across 2 groups (non-Caucasian and Caucasian) and individual ethnic subgroups (black, Hispanic, and others). Headache response, pain-free response, associated symptoms, and clinical disability were assessed. Tolerability assessments included the incidence of adverse events, physical examinations, vital signs, electrocardiograms, and clinical laboratory data. RESULTS: Two hundred patients treated at least one migraine attack (150 non-Caucasians: 46 blacks, 68 Hispanics, 36 others). Two hours postdose, significantly more inclinic sumatriptan-treated patients reported headache response (non-Caucasians, 81% versus 37% placebo; Caucasians, 87% versus 19% placebo; P<.001) and mild or no clinical disability, compared with placebo (non-Caucasians, 87% versus 50% placebo; Caucasians, 90% versus 38% placebo; P<.001). Blacks (80%), Hispanics (83%), and others (74%) reported similar patterns of headache response at 2 hours. Similar results were reported during the outpatient phase. The incidence of adverse events following sumatriptan during the inclinic phase was similar between ethnic groups (non-Caucasian, 75%; Caucasian, 79%) and higher than placebo (non-Caucasian, 51%; Caucasian, 31%). Overall, adverse events in the outpatient phase of the study were lower than in the inclinic phase. CONCLUSION: Sumatriptan injection is effective and well tolerated in non-Caucasians and Caucasians for the treatment of acute migraine attacks. Only minor differences in efficacy or tolerability were observed between blacks, Hispanics, and others.     

Rapid Oral Transmucosal Absorption of Sumatriptan, and Pharmacodynamics in Acute Migraine

Objectives.— (1) To determine whether sumatriptan can be absorbed across the oral mucosa, and, if so; then (2) to describe its pharmacokinetics; and (3) to investigate whether there are pharmacodynamic correlates of such pharmacokinetics in patients experiencing migraine attacks.
Methods.— Two clinical trials. The first, in normal volunteers, compared the pharmacokinetic performance of a lingual spray (LS) formulation of sumatriptan (2 dose sizes, one of which in both the fed and fasted state) with an orthodox 50-mg sumatriptan tablet. The second clinical trial, in a patient population enriched by documenting suboptimal response to an initial 50-mg sumatriptan tablet, was a multiple-attack, crossover, fixed dose-order, open-label comparison of sumatriptan administered by LS (up to 3 different dose sizes) and a 100-mg sumatriptan tablet.
Results.— The LS formulations resulted in double-peaked time-plasma concentration curves that are consistent with absorption of sumatriptan across the oral mucosa. The first T_max was usually about 10-15 minutes. In the enriched patient population, this corresponded with evidence of earlier efficacy for the LS in comparison with a 50-mg tablet; the lower dose size for the former was consistent with oral mucosal drug absorption, and evasion of first-pass metabolism.
Conclusions.— The initial pharmacokinetics of LS approximate to those of a subcutaneous injection, albeit some fraction of these doses is also swallowed. These pharmacokinetics correspond with earlier effectiveness of LS in comparison with a 50-mg sumatriptan tablet, and at lower dose, in an enriched, relevant patient population. These initial studies support further development of this innovative formulation of sumatriptan and this new route of administration.     

Sumatriptan - Nonresponders: A Survey in 366 Migraine Patients

Sumatriptan, notably after subcutaneous administration, is highly effective in the acute treatment of migraine in the majority of patients. The response is consistent within patients and over time. To determine risk factors for nonresponse to sumatriptan, we compared clinical characteristics. In responders and nonresponders and, within patients, between attacks with and without response. We found no differences at the strict level of significance (P<0.001 because of multiple comparisons), but only tendencies for differences (0.001相似文献   

Comparison of Contingent Negative Variation Between Migraine Interval and Migraine Attack Before and After Treatment With Sumatriptan

SYNOPSIS
We compared in a placebo controlled, double blind, cross-over within-subject design, the amplitude and area integral of contingent negative variation (CNV) using a 2 second interstimulus interval in migraine patients between attack and interval before and after treatment. The study was conducted on 14 female subjects suffering from migraine without aura. The measurements were performed in a balanced sequence at four different times on each patient, twice during the migraine interval and once in each of two migraine attacks. The CNV in the patients was measured first (baseline), then medication was administered on a double-blind basis with an auto-injector, using either 6 mg sumatriptan or a placebo solution. Thirty minutes after administration the CNV parameters were measured again and the changes between pre-and post-treatment were taken as dependent variables. CNV amplitude baseline readings did not differ significantly between the four conditions, Neither administration of placebo nor sumatriptan led to a significant change in CNV parameters independent of whether significant clinical improvement of migraine headache occurred or not. According to our findings CNV-mechanisms between attack and interval are not subject to short-term changes, even though a small, not significant tendency towards · decrease in CNV amplitude during migraine attacks appears to exist. Therefore, it can be assumed that changes in the systems which are depicted by CNV readings are not involved in initiating and terminating acute migraine attacks.     

Distinct Pharmacokinetic Profile and Safety of a Fixed‐Dose Tablet of Sumatriptan and Naproxen Sodium for the Acute Treatment of Migraine

(Headache 2010;50:357‐373) Objective.— To describe the pharmacokinetic and safety profiles of sumatriptan 85 mg formulated with RT Technology (RT) and naproxen sodium 500 mg in a fixed‐dose combination tablet (sumatriptan/naproxen sodium) that targets both serotonergic dysmodulation and inflammation in migraine. Methods.— Six open‐label, crossover studies were conducted in healthy volunteers (Studies 1, 2, 3, 4, 5) or patients with migraine (Study 6). Results.— Consistently across studies, naproxen administered as a component of sumatriptan/naproxen sodium demonstrated a delayed‐release profile similar to that of an enteric‐coated product. Naproxen from the combination tablet showed a delayed time to peak plasma concentration and lower peak plasma concentration while exposures (area under the plasma concentration–time curve) were similar. The peak plasma concentration for naproxen was approximately 36% lower and the time to peak plasma concentration approximately 4 hours later when naproxen was administered as sumatriptan/naproxen sodium compared with a single naproxen sodium 550 mg tablet. Sumatriptan peak plasma concentration and area under the plasma concentration–time curve after administration of sumatriptan/naproxen sodium (containing sumatriptan 85 mg) were comparable to those after administration of a commercially available sumatriptan 100 mg (RT) tablet. Sumatriptan time to peak plasma concentration occurred, on average, 30 minutes earlier with sumatriptan/naproxen sodium compared with sumatriptan 100 mg (RT). No clinically significant differences between sumatriptan/naproxen sodium and sumatriptan tablets 100 mg (RT) were identified with respect to electrocardiograms, blood pressure, or heart rate. In addition, food had no significant effect on the bioavailability of naproxen or sumatriptan after administration of sumatriptan/naproxen sodium but slightly delayed the time to peak plasma concentration of sumatriptan by approximately 40 minutes. The pharmacokinetics of sumatriptan and naproxen did not differ according to whether sumatriptan/naproxen sodium was administered during a migraine attack or a migraine‐free period. The pharmacokinetics of 2 sumatriptan/naproxen sodium tablets administered 2 hours apart were consistent with the pharmacokinetic predictions from a single dose of the combination tablet. The adverse‐event profile of the sumatriptan/naproxen sodium combination tablet did not appear to differ from that of the individual components of the same or similar dosage strengths administered alone or in combination. In addition, the incidence of adverse events with 2 sumatriptan/naproxen sodium tablets administered 2 hours apart was lower than that with the single dose. Conclusion.— The combination tablet of sumatriptan/naproxen sodium has unique pharmacokinetic properties. The rapid absorption of sumatriptan with the delayed‐release properties of naproxen sodium from sumatriptan/naproxen sodium might contribute to its therapeutic advantage over monotherapy with either component. No clinically meaningful effects of food, administration during a migraine attack, or administration of a second tablet (2 hours after initial dose) on the pharmacokinetics or safety of sumatriptan/naproxen sodium were observed.     

Zelrix™: A Novel Transdermal Formulation of Sumatriptan

Objective.— This study evaluated the pharmacokinetic and tolerability profiles of Zelrix? (NuPathe Inc., Conshohocken, PA, USA), the novel formulation of sumatriptan (formerly known as NP101). Background.— Migraine is an episodic headache disorder characterized by a combination of neurological, gastrointestinal, and autonomic symptoms. Gastrointestinal disturbances, including nausea, vomiting, and gastric stasis are common and can result in significant impact on treatment. Triptans are 5‐hydroxytriptanime_1B/1D agonists that work on the trigeminal nerve that is activated during migraine. All triptans approved for use in the US are currently available as oral formulations; however, this may not be the ideal route of administration for many migraineurs. Sumatriptan is also available as a nasal spray and subcutaneous (sc) injection. Therefore, the need to develop improved methods for noninvasive parenteral delivery of triptans remains high. Methods.— This was a Phase I, single‐center, open‐label, crossover study that assessed the pharmacokinetic properties of a single dose of sumatriptan delivered using an iontophoretic transdermal patch in comparison with oral, injection, and nasal delivery. Subjects were healthy male and female volunteers who received each of 5 treatments: sumatriptan 100 mg oral tablets, sumatriptan 6 mg sc, sumatriptan 20 mg nasal spray, Zelrix I (transdermal patch with 3 g of gel solution delivering 6 mg of sumatriptan transdermally), or Zelrix II (transdermal patch containing 2.6 g of gel solution delivering 6 mg of sumatriptan). Results.— The C_max for Zelrix was reduced to 30% and 28% of the sumatriptan sc dose, thereby reducing the risk of triptan‐like sensations associated with high peak plasma concentrations. Plasma concentrations for Zelrix I and Zelrix II were intermediate between those for oral and nasal sumatriptan doses tested. Transdermal patch delivery of sumatriptan to the systemic circulation reached plasma concentrations of 10 ng/mL within about 30 minutes. The mean drug delivery of Zelrix I and II was 6.11 mg (confidence intervals [CI] 5.33‐6.88) and 6.09 mg (CI 5.52‐6.66), respectively. The AUC_0‐inf was approximately 99% for the Zelrix I patch and 100% for the Zelrix II patch as compared with sumatriptan 6 mg sc dose. Both doses of sumatriptan transdermal patches were well tolerated. Skin reactions at the patch site were mild and erythema resolved in most subjects within 48‐72 hours. Conclusions.— The results from this study show that sumatriptan administration using a novel iontophoretic transdermal technology delivers plasma levels within the range for nasal spray, tablet, and injectable sumatriptan. Zelrix I and II were well tolerated and adverse events were mild and transient. Transdermal delivery of sumatriptan using the SmartRelief iontophoretic technology may prove beneficial for a large segment of the migraine population based upon fast, consistent delivery of drug and avoidance of common gastrointestinal disturbances associated with migraine.     

EEG and Topographic Frequency Analysis in Migraine Attack Before and After Sumatriptan Infusion

Electroencephalographic changes occurring in patients with migraine have received much attention. Although in migraineurs a number of studies have been done after nitroglycerin-induced attacks, there is no reported EEG study before and after nitroglycerin-induced sumatriptan-treated attacks. We, therefore, studied the EEG topographic frequency analysis in 19 symptom-free, otherwise healthy, unmedicated patients with common migraine and in 19 age and sex-matched controls before nitroglycerin, at the time of maximum pain, and 30 minutes after sumatriptan. During headache attacks, an increase of slow rhythmic activity of the theta and delta range and a decrease of activity in the alpha and beta range were observed. These abnormalities disappeared 30 minutes after a sumatriptan injection. This suggests that common migraine is associated with disturbances of cortical electrogenesis and may provide insight into the causes of migraine and aid in the development of effective therapies.     

Subcutaneous Sumatriptan in the Clinical Setting: The First 50 Consecutive Patients With Acute Migraine in a Pediatric Neurology Office Practice

An open prospective study was undertaken to assess the efficacy and safety of subcutaneous sumatriptan in 50 consecutive children ages 6 to 18 years with severe migraine. There were 28 females and 22 males. The dose of sumatriptan was 0.06 mg/kg. Parameters included overall efficacy, time to relief, recurrence rate, adverse events, and objective global rating. Overall efficacy, defined by headache reduction from severe or moderate to mild or none, was 78%. Twenty-six percent responded within 30 minutes, 46% responded in 60 minutes, and 6% responded between I to 2 hours. Twenty-two percent had no response or a suboptimal response. Recurrence rate was only 6%. There was a difference in efficacy between male and female, as 91% of the males responded, while only 68% of the females responded. The males had more migraine alone while the females had migraine often with a coexistent tension-type headache. Eighty percent of all the patients had some adverse event which was usually mild and transient; however, one patient developed a transitory confusional state which resolved in 2 hours. Eighty-four percent reported a global rating of good to excellent, while 16% rated the treatment only fair to poor. These findings suggest that subcutaneous sumatriptan can be both effective and safe in childhood migraine, especially in dealing with migraine alone,     

Sumatriptan and Cerebral Blood Flow Velocity Changes During Migraine Attacks

Transcranial Doppler studies on the effects of sumatriptan on cerebral hemodynamics have shown conflicting results. We evaluated blood flow velocity changes in 21 patients suffering from migraine with (n = 4) or without aura (n = 17) during a spontaneous attack, before and after treatment with sumatriptan. Flow velocity in the internal and external carotid, middle cerebral, and basilar arteries was measured by means of transcranial Doppler. During the attack, measurements were taken before subcutaneous sumatriptan injection, then after 30 minutes, 2 hours, and 24 hours. An additional measurement was taken 1 week later, in a headache-free state. We found a significant reduction of flow velocity during the attack in the middle cerebral artery on both sides (P < 0.05). After sumatriptan administration, flow velocity increased in the internal carotid artery on both sides (P < 0.05) and in the middle cerebral artery on the headache side (P = 0.0001), but not in the external carotid and basilar arteries (P > 0.05). Flow velocity changes may reflect the vasodilation present at the onset of the migraine attack followed by vasoconstriction in the internal carotid and middle cerebral arteries after sumatriptan treatment. Since vasoconstriction occurs in responders and nonresponders to treatment, it is unlikely to be the primary mechanism by which sumatriptan relieves headache.     

Crossover Comparison of Rizatriptan 5 mg and 10 mg Versus Sumatriptan 25 mg and 50 mg in Migraine

Rizatriptan is a selective 5-HT_1B/1D receptor agonist with rapid oral absorption and early onset of action in the acute treatment of migraine. This double-blind, placebo-controlled, crossover study compared rizatriptan 5 mg versus sumatriptan 25 mg, and rizatriptan 10 mg versus sumatriptan 50 mg. A total of 1329 patients were allocated to one of five groups for treatment of two attacks: rizatriptan 5 mg/sumatriptan 25 mg; sumatriptan 25 mg/rizatriptan 5 mg; rizatriptan 10 mg/sumatriptan 50 mg; sumatriptan 50 mg/rizatriptan 10 mg; placebo/placebo. For each attack, patients rated headache severity, presence of associated symptoms, and functional disability prior to dosing and at intervals through 4 hours thereafter. Patients also rated their satisfaction with medication. Rizatriptan 5 mg and 10 mg provided faster relief of headache pain and greater relief of migraine symptoms than the 25-mg and 50-mg doses of sumatriptan, respectively. The response to rizatriptan was better than sumatriptan on additional measures including functional disability and satisfaction with medication. All active treatments were highly effective compared to placebo and acted as early as 30 minutes after dosing. All active treatments were well-tolerated and showed comparable safety profiles.