Eletriptan for the treatment of migraine in patients with previous poor response or tolerance to oral sumatriptan

To determine the tolerability and efficacy of eletriptan in patients who had discontinued oral sumatriptan due to lack of efficacy or intolerable adverse events (AEs) during previous clinical treatment (not a controlled trial). Eletriptan is a potent, selective 5-HT1B/1D receptor agonist with beneficial pharmacokinetic properties compared with sumatriptan. In a double-blind, parallel group, placebo-controlled multicentre study, patients with and without aura (n = 446) were randomized to 40 mg eletriptan (E40, n = 188), 80 mg eletriptan (E80, n = 171) or placebo (n = 87) for treatment of up to three migraine attacks. Two-hour headache response, based on first-dose, first-attack data, was 59% for eletriptan 40 mg, 70% for eletriptan 80 mg, and 30% for placebo (P < 0.0001 for both doses of eletriptan vs. PBO; P < 0.05 for E80 vs. E40). Onset of action was rapid, with 1-h headache response rates significantly superior for E40 and E80 vs. placebo (40%, 48%, 15%; P < 0.0005). Both E40 and E80 were significantly superior to placebo, based on first-dose, first-attack data, for 2-h pain-free response (35%, 42%, and 7%; P < 0.0001). Both E40 and E80 demonstrated significant consistency of response, with headache relief rates at 2 h on at least two of three attacks in 66% and 72% vs. 15% on placebo (P < 0.001). AEs were mild to moderate in severity and dose related. The most commonly reported AEs included nausea, vomiting, asthenia, and chest symptoms. E40 and E80 produce an effective response in patients who had previously discontinued treatment with sumatriptan due to lack of efficacy or side-effects.     

Comparative efficacy of eletriptan 40 mg versus sumatriptan 100 mg

OBJECTIVE: To confirm the efficacy advantage of eletriptan 40 mg over sumatriptan 100 mg. Background.-Eletriptan 80 mg has demonstrated significantly greater efficacy when compared to both sumatriptan 50 mg and 100 mg in two studies. Eletriptan 40 mg demonstrated significantly greater efficacy than sumatriptan 100 mg in one previous trial. METHODS: Two thousand one hundred thirteen patients with a diagnosis of migraine according to International Headache Society criteria were randomized using a double-blind, double-dummy, parallel-group design, and treated for a single migraine attack with either eletriptan 40 mg, sumatriptan 100 mg, or placebo. The primary endpoint was 2-hour headache response. Secondary endpoints included headache response rates at 1 hour, pain-free rates, absence of associated symptoms, functional response at 1 and 2 hours, and sustained headache response. RESULTS: Headache response rates at 2 hours postdose were significantly higher for eletriptan 40 mg (67%) than for sumatriptan 100 mg (59%; P <.001) and placebo (26%; P <.0001). Eletriptan 40 mg consistently showed significant (P <.01) efficacy over sumatriptan 100 mg across secondary clinical outcomes, including 1-hour headache response; 2-hour pain-free response; absence of nausea, photophobia, and phonophobia; functional improvement; use of rescue medication; treatment acceptability; and sustained headache response (P <.05). Overall, treatment-related adverse events were low, nausea being the only adverse event with an incidence of 2% or higher (4.9% with eletriptan, 4.2% sumatriptan, 2.8% placebo). CONCLUSION: This trial confirmed that eletriptan 40 mg offers superior efficacy in treating migraine pain and associated symptoms and in restoring patient functioning when compared with sumatriptan 100 mg.     

Efficacy, safety and tolerability of oral eletriptan in the acute treatment of migraine: results of a phase III, multicentre, placebo-controlled study across three attacks

The efficacy, safety and tolerability of the 5-HT1B/D receptor agonist eletriptan (40 mg and 80 mg) in acute treatment of migraine was evaluated in a multinational, randomized, double-blind, parallel-group, placebo-controlled, three-attack study treating 1153 patients. In the initial attack, significantly more eletriptan patients reported headache relief and complete pain relief at 2 h vs. placebo (40 mg 62% and 32%, 80 mg 65% and 34%, placebo 19% and 3%; P < 0.0001). Headache relief occurred faster after eletriptan, with more patients at both doses reporting relief 30 min (P < 0.01) and 1 h (P < 0.0001) after treatment than after placebo. There was a significantly lower recurrence rate with eletriptan 80 mg compared with placebo (P < 0.01). Adverse events for all treatments were generally mild or moderate and self-limiting. Eletriptan 40 mg and eletriptan 80 mg both appear to be effective and well-tolerated acute migraine treatments.     

Comparative efficacy of eletriptan and zolmitriptan in the acute treatment of migraine

Eletriptan 40 mg and 80 mg have shown greater efficacy in acute migraine than oral sumatriptan 100 mg and naratriptan 2.5 mg. This study continues the systematic series of active comparator trials in the eletriptan clinical development programme. In a multicentre double-blind, double-dummy, parallel-groups trial, 1587 outpatients with migraine by IHS criteria were randomised in a 3: 3 : 3: 1 ratio to eletriptan 80 mg, eletriptan 40 mg, zolmitriptan 2.5 mg or placebo. Of these, 1312 treated a single migraine attack and recorded baseline and outcome data to be included in the intention-to-treat population. The primary analysis was between eletriptan 80 mg and zolmitriptan. For the primary efficacy end-point of 2-h headache response, rates were 74% on eletriptan 80 mg, 64% on eletriptan 40 mg, 60% on zolmitriptan (P < 0.0001 vs. eletriptan 80 mg) and 22% on placebo (P < 0.0001 vs. all active treatments). Eletriptan 80 mg was superior to zolmitriptan on all secondary end-points at 1, 2 and 24 h, in most cases with statistical significance. Eletriptan 40 mg had similar efficacy to zolmitriptan 2.5 mg in earlier end-points, and significantly (P < 0.05) lower recurrence rate and need for rescue medication over 24 h. All treatments were well tolerated; 30-42% of patients on active treatments and 40% on placebo reported all-causality adverse events that were mostly mild and transient. On patients' global ratings of treatment, both eletriptan doses scored significantly better than zolmitriptan.     

Efficacy,safety, and tolerability of oral eletriptan for treatment of acute migraine: a multicenter,double-blind,placebo-controlled study conducted in the United States

OBJECTIVE: To investigate the efficacy, consistency, safety, and tolerability of oral eletriptan in the acute treatment of three migraine attacks. BACKGROUND: Eletriptan is a selective 5-HT1B/1D agonist member of a class of agents known to be effective in the acute treatment of migraine. METHODS: Thirteen hundred thirty-four patients were randomized to 20 mg, 40 mg, or 80 mg of eletriptan, or placebo and could treat up to three attacks. The primary efficacy endpoint was 2-hour headache response for the first attack. Secondary endpoints included associated symptom relief, and pain-free, sustained pain-free, and consistency of response. RESULTS: Eletriptan 20 mg, 40 mg, and 80 mg achieved significantly (P <.0001) better headache response rates than placebo at 2 hours (47%, 62%, and 59%, respectively, versus 22%) and 4 hours (64%, 76%, and 79%, respectively, versus 25%). Headache response was observed to be rapid, showing improvement at 0.5 hour and 1 hour. Two-hour pain-free response rates for eletriptan 20 mg, 40 mg, and 80 mg were 14%, 27%, and 27%, respectively, compared with 4% for placebo. Sustained pain-free response rates were significantly (P <.001) better for eletriptan 20 mg (10%), 40 mg (20%), and 80 mg (18%) compared with placebo (3%). Eletriptan had a higher consistency of intrapatient response than placebo in two of three (68% to 82%) and three of three attacks (32% to 60%) versus 16% and 8%, respectively. All eletriptan doses yielded significant functional improvement at 2 hours. Adverse events were generally mild or moderate and transient, with eletriptan 20 mg having an adverse event profile comparable to placebo. CONCLUSIONS: Eletriptan is efficacious, displaying high consistency of response over multiple attacks, and is well tolerated for the acute treatment of migraine.     

ELETRIPTAN VERSUS COMPETITORS

Eletriptan 40 mg and 80 mg have shown greater efficacy in acute migraine than oral sumatriptan 100 mg and naratriptan 2.5 mg. This study continues the systematic series of active comparator trials in the eletriptan clinical development programme. In a multicentre double-blind, double-dummy, parallel-groups trial, 1587 outpatients with migraine by IHS criteria were randomised in a 3:3:3:1 ratio to eletriptan 80 mg, eletriptan 40 mg, zolmitriptan 2.5 mg or placebo. Of these, 1312 treated a single migraine attack and recorded baseline and outcome data to be included in the intention-to-treat population. The primary analysis was between eletriptan 80 mg and zolmitriptan. For the primary efficacy end-point of 2-h headache response, rates were 74% on eletriptan 80 mg, 64% on eletriptan 40 mg, 60% on zolmitriptan ( P < 0.0001 vs. eletriptan 80 mg) and 22% on placebo ( P < 0.0001 vs. all active treatments). Eletriptan 80 mg was superior to zolmitriptan on all secondary end-points at 1, 2 and 24 h, in most cases with statistical significance. Eletriptan 40 mg had similar efficacy to zolmitriptan 2.5 mg in earlier end-points, and significantly ( P < 0.05) lower recurrence rate and need for rescue medication over 24 h. All treatments were well tolerated; 30-42% of patients on active treatments and 40% on placebo reported all-causality adverse events that were mostly mild and transient. On patients' global ratings of treatment, both eletriptan doses scored significantly better than zolmitriptan.     

Tolerability and safety of eletriptan in the treatment of migraine: a comprehensive review

OBJECTIVE: To provide a comprehensive review of the tolerability and safety of eletriptan. Background.-Eletriptan is a potent and selective 5-HT1B/1D agonist that has demonstrated significant efficacy in the acute treatment of migraine in doses of 20 mg, 40 mg, and 80 mg. DESIGN: This review reports the tolerability and safety of eletriptan across a broad spectrum of preclinical studies and clinical trials that collectively included treatment of more than 11 000 subjects and more than 74 000 migraine attacks. RESULTS: In clinical trials, eletriptan was well tolerated and safe across its dosing range of 20 mg to 80 mg. The adverse event profile of eletriptan 20 mg was similar to placebo, while the most commonly used dose, eletriptan 40 mg, has an adverse event profile that is only marginally higher than placebo. Eletriptan was safe and well tolerated regardless of age or gender, and for both short- and long-term treatment. Eletriptan is metabolized primarily by the CYP3A4 enzyme. Coadministration of potent CYP3A4 inhibitors was not associated with clinically meaningful change in eletriptan tolerability or safety in the population included in these clinical trials. The margin of cardiovascular safety for eletriptan was also confirmed by a well-controlled clinical study in which intravenous eletriptan in excess of an 80-mg dose was rapidly infused in patients undergoing coronary angiography; nonetheless, it is recommended that eletriptan not be coadministered with a limited list of 7 potent CYP3A4 inhibitors; in addition, the triptan class in general (including eletriptan) is contraindicated in patients with symptoms or findings consistent with ischemic heart disease or other significant underlying cardiovascular disease. CONCLUSIONS: This comprehensive review found that eletriptan is safe and well tolerated, and that relatively large changes in dose and plasma concentration result in minimal changes in tolerability.     

Eletriptan for the acute treatment of migraine in adolescents: results of a double-blind, placebo-controlled trial

BACKGROUND: Eletriptan is a potent 5-HT(1B/1D) agonist with proven efficacy in the acute treatment of migraine in adults. OBJECTIVE: To evaluate the efficacy and tolerability of eletriptan 40 mg versus placebo in adolescent patients (aged 12-17). METHODS: A multicenter, double-blind, parallel-group, placebo-controlled trial was conducted comparing 40 mg of oral eletriptan with placebo for the treatment of migraine in adolescent patients. The primary efficacy endpoint was 2-hour headache response, and a number of secondary endpoints were also evaluated. An exploratory analysis evaluated which clinical and demographic characteristics might be correlated with high placebo response. RESULTS: Of 274 patients who treated a migraine attack, 267 were evaluated for efficacy (n = 138 eletriptan; n = 129 placebo) at 2 hours post-dose. There was no significant difference in 2-hour headache response for eletriptan 40 mg versus placebo (57% vs 57%), and no significant improvements were observed for any of the outcomes at 1 or 2 hours post-dose. By contrast, there was a significant advantage for eletriptan 40 mg in reducing headache recurrence within 24 hours post-dose (11% vs 25%, P= .028), and post hoc analyses showed statistically significant differences for sustained headache response rates (52% vs 39%; P= .04) and sustained pain-free response rates (22% vs 10%; P= .013). The strongest clinical predictor of placebo response was triptan-na?ve status (i.e., no previous use of any triptan). Eletriptan 40 mg was well tolerated in this population, and the profile of adverse events was similar to that observed in Phase III trials in adult patients. CONCLUSIONS: The high placebo response rates reported here for 1- and 2-hour outcomes are in accordance with other studies of triptans in adolescent patients. The evaluation of treatment effect in adolescent migraine might benefit from use of more stringent outcome measures, such as headache recurrence, sustained headache response, and sustained pain-free response at 24 hours post-dose.     

Meta-analysis of the efficacy and safety of zolmitriptan in the acute treatment of migraine

OBJECTIVE: To assess the relative efficacy and safety of zolmitriptan in the treatment of acute migraine attacks. BACKGROUND: Zolmitriptan is a second-generation triptan developed for the treatment of migraine. Numerous randomized controlled trials (RCTs) have been carried out to compare different dosages and formulations of zolmitriptan against other treatments for acute migraine. METHODS: Random effects meta-analysis of 24 RCTs, including 15,408 patients suffering from acute migraine attacks. Subgroup analyses compared differences in response between different dosages and formulations of zolmitriptan, and other triptan comparators. RESULTS: Zolmitriptan 2.5 mg tablet was found to be as effective as almotriptan 12.5 mg, eletriptan 40 mg, sumatriptan 50 mg and 100 mg and more effective than naratriptan 2.5 mg in terms of 2-hour pain-free rates. Likewise, zolmitriptan 5 mg tablet was as effective as sumatriptan 50 mg and 100 mg in 2-hour pain-free rates. Compared against zolmitriptan 2.5 mg tablet, eletriptan 80 mg was more effective in achieving headache relief, pain-free and sustained pain-free responses, and rizatriptan 10 mg was more effective in terms of sustained pain-free rates. Zolmitriptan 2.5 mg tablet was associated with a lower risk of adverse events than eletriptan 80 mg but higher risk than naratriptan 2.5 mg and rizatriptan 10 mg. Zolmitriptan 5 mg tablet was superior to zolmitriptan 2.5 mg tablet in achieving 1- and 2-hour pain-free response. There were no significant differences in 1- and 2-hour headache relief and adverse event rates between the different formulations of zolmitriptan 2.5 mg. CONCLUSIONS: Zolmitriptan 2.5 mg tablet is an effective treatment for acute attacks of migraine showing similar efficacy to almotriptan 12.5 mg, eletriptan 40 mg, and sumatriptan 50 mg, and being more effective than naratriptan 2.5 mg in terms of pain-free response at 2 hours post dose. Zolmitriptan 2.5 mg tablet was also as effective as rizatriptan 10 mg in terms of headache relief and pain-free response but less effective in terms of sustained pain-free response.     

Predictors of migraine headache recurrence: a pooled analysis from the eletriptan database

OBJECTIVE: To identify clinical variables associated with risk of headache recurrence within 22 hours of initial successful treatment of a migraine attack (2-hour headache response), and to analyze the effect of eletriptan in reducing the incidence of recurrence. METHODS: Data were pooled from 10 randomized, double-blind, placebo-controlled trials evaluating eletriptan 40 mg (E40), eletriptan 80 mg (E80), and sumatriptan 100 mg (S100) for acute migraine treatment. Patients who achieved a headache response (improvement from moderate/severe pain at baseline to mild/no pain at 2 hours postdose) were evaluable. A multivariable logistic regression analysis identified significant predictors of headache recurrence (return to moderate/severe pain intensity within 22 hours of initial headache response). Treatment response was assessed in two high-risk subgroups, defined by the presence of significant recurrence predictors. RESULTS: Of 4312 patients responding to acute treatment within 2 hours postdose, 1232 (29%) experienced recurrence. Initial headache response within 2 hours was significantly higher for E40 (62.0%), E80 (67.4%), and S100 (57.9%) compared to placebo (25.1%; all P < .0001). Three clinical variables were significant predictors of recurrence: female gender, age > or = 35 years, and severe baseline headache pain. Among patients with all 3 risk factors (n = 742; 17% of total population), recurrence rates were lower with E40 (35.6%) and E80 (32.9%) than placebo (47.8% P < .01). The same result was observed in the subgroup of patients with 2 risk factors (female gender and age > or = 35 years; P < .0001 vs placebo). Sustained headache and pain-free response rates (a headache/pain-free response at 2 hours postdose with no headache recurrence and no rescue medication use in the subsequent 22 hours) were significantly higher with E40 and E80 than placebo in both high-risk subgroups (P < .05). CONCLUSION: Female gender, age > or = 35 years, and severe baseline headache pain are significant predictors of headache recurrence during a migraine attack. Eletriptan is effective at reducing the incidence of headache recurrence in high-risk subgroups.     

Crossover comparison of rizatriptan 5 mg and 10 mg versus sumatriptan 25 mg and 50 mg in migraine. Rizatriptan Protocol 046 Study Group

Rizatriptan is a selective 5-HT1B/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.     

Sumatriptan for the treatment of migraine attacks-a review of controlled clinical trials

Sumatriptan, a 5HT₁-like receptor agonist, is a completely new treatment principle for migraine. In an extensive international programme of controlled clinical trials, sumatriptan, 6 mg subcutaneously and 100 mg orally, was superior to placebo in reducing headache and associated symptoms. The response rate for subcutaneous sumatriptan (70–84% after 1 h and 81–87% after 2 h) was higher than for oral sumatriptan (50–67% after 2 h). Additional doses did not increase efficacy. Oral sumatriptan was superior to Cafergot (2 mg ergotamine plus 200 mg caffeine) and somewhat better than aspirin (900 mg) plus metoclopramide (10 mg). Recurrence of migraine occurred in approximately 40% of attacks. Side effects were generally mild and short-lived in the controlled clinical trials. However, in clinical practice sumatriptan has subsequently caused rare cases of heart ischemia and sumatriptan is contraindicated in patients with a history of ischemic heart disease.     

Efficacy and safety of eletriptan 20 mg, 40 mg and 80 mg in Japanese migraineurs

This prospective multicentre, double-blind, randomized, parallel-group, placebo-controlled trial evaluated the efficacy and safety of a single dose of eletriptan 20 mg, 40 mg and 80 mg in Japanese migraineurs. A total of 402 adult Japanese migraineurs were diagnosed using International Headache Society (IHS) criteria. At 2 h after a single dose, the headache response rates of eletriptan 20 mg, 40 mg, 80 mg and placebo were 64%, 67%, 76% and 51%, respectively, with all doses significantly superior to placebo ( P <0.05). Eletriptan had a statistically significant dose response for headache relief and pain-free response at 2 h post-dose ( P =0.0011 and P =0.0291, respectively). Most all-causality adverse events were mild and there were no deaths or discontinuations. Saliva samples were used to assess serum eletriptan levels 2 h post-dose. Pharmacokinetic evaluations showed no clinically significant differences between Japanese and Western subjects. Eletriptan was shown to be efficacious, safe, and well tolerated in Japanese migraineurs.     

Eletriptan in the early treatment of acute migraine: influence of pain intensity and time of dosing

This double-blind, placebo-controlled study was designed to evaluate the efficacy and tolerability of early treatment of a single migraine attack, when headache pain was mild, with two doses (20 mg and 40 mg) of eletriptan. Patients (N = 613; female 79%; mean age 39 years) meeting International Headache Society criteria for migraine were encouraged, but not required, to utilize early treatment, thus providing an opportunity to assess the relative contribution to efficacy of pain severity and timing of dose. For the total patient sample (mild-to-severe headaches), 2-h pain-free rates were significantly higher than placebo (22%) on both eletriptan 20 mg (35%; P < 0.01) and eletriptan 40 mg (47%; P < 0.0001). For the cohort of patients who treated their headache when the pain intensity was mild, the 2-h pain-free rate on eletriptan 40 mg was 68% compared with 25% on placebo (P < 0.0001). Pain intensity at the time of taking eletriptan appeared to influence outcome more than the timing of the dose relative to headache onset. Eletriptan was well-tolerated, with adverse event rates similar to placebo when mild headaches were treated.     

Identification of negative predictors of pain-free response to triptans: analysis of the eletriptan database

Thirty to forty percent of migraineurs do not respond to any given triptan treatment. We identified clinical variables that significantly predict therapeutic non-response and evaluated the efficacy of eletriptan (20, 40 and 80 mg) and sumatriptan (100 mg) vs. placebo in a subgroup of patients with all predictor variables. First-attack data were pooled from 10 randomized, double-blind, placebo-controlled migraine trials ( n  = 8473). Multivariate regression analyses identified three significant baseline predictors of failure to achieve 2-h pain-free response: severe headache pain, presence of photophobia/phonophobia and presence of nausea. Time of dosing following headache onset did not influence 2-h pain-free response. Among patients with all three risk factors ( n  = 2010; 24% of total sample), 2-h pain-free response was significantly higher in patients receiving all three doses of eletriptan or sumatriptan vs. placebo (all P  < 0.01). Thus, eletriptan and sumatriptan are efficacious in difficult-to-treat patients at high risk for non-response to triptans.     

Therapeutic benefit of eletriptan compared to sumatriptan for the acute relief of migraine pain--results of a model-based meta-analysis that accounts for encapsulation

A novel model-based meta-analysis was used to quantify the dose-response relationship of sumatriptan and eletriptan for the proportion of patients that achieve migraine pain relief up to 4 h after treatment. The proportion of patients that became pain free was also evaluated. This analysis includes some unique features, allowing comparison of sumatriptan and eletriptan doses that have not been directly compared in a head to head study and also permitting comparison between the two drugs at multiple time points up to 4 h after treatment. Because the analysis allows comparison of response to blinded sumatriptan with that to marketed sumatriptan and contains timepoints as early as 0.5 h, it is especially suited to detection of possible effects of encapsulation on sumatriptan's therapeutic effectiveness and thus was employed to assess this also. Data from 19 randomized placebo controlled clinical trials were jointly analysed using a random-effects logistic regression model. The results of this analysis show a significant clinical benefit of eletriptan 40 mg compared to sumatriptan 100 mg at any point in time up to 4 h after treatment. The benefit of eletriptan 40 mg is greatest around 1.5-2 h after treatment with an absolute difference at 2 h of 9.1% (7.4-11.5%) more patients achieving pain relief and 7.3% (5.8-8.6%) more patient achieving pain free when compared to sumatriptan 100 mg. An absolute benefit of more than 5% of patients is maintained from 45 min up to 4 h after treatment for pain relief and from 1.5 h up to 4 h for pain free. Eletriptan 20 mg was superior to sumatriptan 50 mg and similar to sumatriptan 100 mg for pain relief while it was similar to sumatriptan 50 mg for pain free. The benefit of eletriptan 20 mg when compared to sumatriptan 50 mg is greatest around 1.5-2 h after treatment with an absolute difference at 2 h of 5.0% (2.9-8.1%) more patients achieving pain relief. An absolute benefit of more than 3% of patients was maintained from 1 h up to 3 h after treatment. No significant difference was found between eletriptan 20 mg and sumatriptan 50 mg for the fraction of patients that became pain free. No significant effect of encapsulation of sumatriptan was found on the time course of response up to 4 h after treatment when compared to commercial sumatriptan.     

Comparative aspects of triptans in treating migraine

Triptans, beginning with sumatriptan, have revolutionized the treatment of migraine. New triptans in several formulations will soon become available in the United States. Although the similarities of these 5-hydroxytryptamine (5-HT) 1B/1D receptor agonists outweigh their differences, important differences in pharmacokinetics and clinical responses do exist. Subcutaneous sumatriptan has the most rapid onset of action and greatest efficacy but the most adverse effects. Intranasal sumatriptan also has rapid onset of action, but at 2 hours its efficacy is comparable to that of oral zolmitriptan. Of the oral triptans, rizatriptan seems to have the greatest early efficacy. Both rizatriptan and zolmitriptan are now available as rapidly dissolving wafers. Almotriptan, the newest of the triptans, has a response rate similar to that of oral sumatriptan and may produce fewer adverse effects. Naratriptan and frovatriptan, with their slow onset, high tolerability, and long half-lives, may have a role in aborting prolonged migraine attacks and in headache prevention. Eletriptan at higher doses (80 mg) has a response rate approaching that of rizatriptan but may be limited by potential side effects. The many triptans available offer the opportunity to individualize migraine treatment, depending on the patient's attack characteristics, tolerance, and preferences.     

Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials

The triptans, selective serotonin 5-HT1B/1D agonists, are very effective acute migraine drugs. Soon, seven different triptans will be clinically available at 13 different oral doses, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis. We wished to provide an evidence-based foundation for using triptans in clinical practice, and to review the methodological issues surrounding triptan trials. We asked pharmaceutical companies and the principal investigators of company-independent trials for the 'raw patient data' of all double-blind, randomized, controlled, clinical trials with oral triptans in migraine. All data were cross-checked with published or presented data. We calculated summary estimates across studies for important efficacy and tolerability parameters, and compared these with those from direct, head-to-head, comparator trials. Out of 76 eligible clinical trials, 53 (12 not yet published) involving 24089 patients met the criteria for inclusion. Mean results (and 95% confidence intervals) for sumatriptan 100 mg, the first available and most widely prescribed oral triptan, are 59% (57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2-24 h post-dose), and 67% (63-70) for consistency (response in at least two out of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) are 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7). Compared with these data: rizatriptan 10 mg shows better efficacy and consistency, and similar tolerability; eletriptan 80 mg shows better efficacy, similar consistency, but lower tolerability; almotriptan 12.5 mg shows similar efficacy at 2 h but better sustained pain-free response, consistency, and tolerability; sumatriptan 25 mg, naratriptan 2.5 mg and eletriptan 20 mg show lower efficacy and better tolerability; zolmitriptan 2.5 mg and 5 mg, eletriptan 40 mg, and rizatriptan 5 mg show very similar results. The results of the 22 trials that directly compared triptans show the same overall pattern. We received no data on frovatriptan, but publicly available data suggest substantially lower efficacy. The major methodological issues involve the choice of the primary endpoint, consistency over multiple attacks, how to evaluate headache recurrence, use of placebo-subtracted proportions to control for across-study differences, and the difference between tolerability and safety. In addition, there are a number of methodological issues specific for direct comparator trials, including encapsulation and patient selection. At marketed doses, all oral triptans are effective and well tolerated. Differences among them are in general relatively small, but clinically relevant for individual patients. Rizatriptan 10 mg, eletriptan 80 mg and almotriptan 12.5 mg provide the highest likelihood of consistent success. Sumatriptan features the longest clinical experience and the widest range of formulations. All triptans are contra-indicated in the presence of cardiovascular disease.     

Oral sumatriptan: effect of a second dose, and incidence and treatment of headache recurrences

Oral sumatriptan in a dose of 100 mg aborts about 60% of migraine attacks within 2 h, but the headache may recur within 24 h. We investigated: (i) the incidence of headache recurrence after oral sumatriptan, (ii) whether a second tablet of sumatriptan at 2 h increases initial efficacy and/or (iii) prevents headache recurrence and (iv) whether a further tablet of sumatriptan treats headache recurrence. In a randomized, parallel-group clinical trial, 1246 patients treated one to three migraine attacks (with or without aura) with 100 mg oral sumatriptan. Two hours later they all took a double-blind randomized second tablet of sumatriptan (group I) or placebo (group II). Patients who initially improved, but then experienced headache recurrence took a further double-blind randomized tablet of sumatriptan or placebo. Proportions of patients who improved from moderate/severe headache to mild/none were similar in groups I and II at 2 h (55 vs 56%) and 4 h (80 vs 77%). Incidences of headache recurrence (moderate/severe-any grade of headache) and median times to headache recurrence were also similar: 22-32% at 16 h in group I and 25-33% at 16.5 h in group II. Sumatriptan was superior to placebo in treating headache recurrence: 74 vs 49% ( p = 0.017) in group I and 70 vs 30% ( p = 0.0001) in group II. Thus, one-fourth of patients experience headache recurrence at about 16 h after successful treatment of a migraine attack with 100 mg oral sumatriptan. A second tablet of sumatriptan at 2 h does not increase initial efficacy and neither prevents nor delays headache recurrence. A further tablet of sumatriptan is, however, highly effective in treating headache recurrence. All dose regimens were well tolerated.     

Two replicate randomized, double-blind, placebo-controlled trials of the time to onset of pain relief in the acute treatment of migraine with a fast-disintegrating/rapid-release formulation of sumatriptan tablets

BACKGROUND: The gastric stasis that commonly accompanies migraine headache may impair absorption of conventional oral tablets in the stomach. A fast-disintegrating/rapid-release formulation of sumatriptan has been developed to enhance tablet disintegration and drug dispersion and potentially improve absorption. OBJECTIVE: Two studies were conducted comparing the time to onset of relief from moderate or severe migraine pain with the fast-disintegrating/rapid-release formulation of sumatriptan tablets 50 and 100 mg and placebo. METHODS: These were 2 identically designed randomized, double-blind, parallel-group studies. Sumatriptan 50 or 100 mg or placebo was taken on an outpatient basis to treat a single moderate or severe migraine attack. Using a personal digital assistant, patients recorded the time of dosing and the time at which pain severity reached none or mild (ie, pain relief) or none (ie, pain free) in real time so that the time to onset of relief could be measured as a continuous variable. Onset of relief was defined as the earliest time point at which a statistically significant difference in pain relief compared with placebo was achieved and maintained through 2 hours after dosing. Before dosing and at pre-determined time points after dosing, patients also provided an assessment of migraine pain as none, mild, moderate, or severe. At a clinic visit within 1 week after treatment of the migraine attack, patients were queried about adverse events. For each adverse event, investigators recorded whether study medication was considered the cause. Data analyses were undertaken for each study individually and, in post hoc analyses of the primary and key secondary end points, on pooled data from both studies. RESULTS: The 2 studies comprised 2696 patients: 902 received sumatriptan 50 mg, 902 received sumatriptan 100 mg, and 892 received placebo. Patients' mean age ranged from 40.2 to 40.8 years across treatment groups, and most patients were female (83%-87%) and white (92%-93%). In the analysis of pooled data, sumatriptan tablets provided significantly more effective pain relief compared with placebo as early as 20 minutes after dosing with the 100-mg dose and as early as 30 minutes after dosing with the 50-mg dose (P < or = 0.05). Similar results were observed for the individual studies: in study 1, sumatriptan tablets were significantly more effective than placebo at 25 minutes with the 100-mg dose and at 50 minutes with the 50-mg dose; in study 2, sumatriptan tablets were significantly more effective than placebo at 17 minutes for the 100-mg dose and at 30 minutes for the 50-mg dose (P < or = 0.05). In the pooled data, the cumulative percentages of patients with pain relief by 2 hours after dosing were 72% for the 100-mg dose and 67% for the 50-mg dose, compared with 42% for placebo (P < or = 0.001, both sumatriptan doses vs placebo). The cumulative percentages of patients with a pain-free response by 2 hours were 47% for the 100-mg dose, 40% for the 50-mg dose, and 15% for placebo (P < or = 0.001, both sumatriptan doses vs placebo). In the individual studies, significantly more patients receiving either sumatriptan dose were migraine free 2 hours after dosing and had sustained pain relief and a sustained pain-free response over 24 hours compared with placebo (P < or = 0.001, both sumatriptan doses vs placebo). The only drug-related adverse events reported in >2% of patients in any treatment group in either study were nausea (both studies: 3% sumatriptan 100 mg, 2% sumatriptan 50 mg, 1% placebo) and paresthesia (study 1: <1% sumatriptan 100 mg, <1% sumatriptan 50 mg, 0% placebo; study 2: 3% sumatriptan 100 mg, 1% sumatriptan 50 mg, <1% placebo). CONCLUSIONS: In these studies, sumatriptan tablets in a fast-disintegrating/rapid-release formulation were effective for the acute treatment of moderate to severe migraine pain, were generally well tolerated, and achieved an onset of pain relief as early as 20 minutes for 100 mg and as early as 30 minutes for 50 mg.