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5-HT_1B/1D receptor agonists have been widely used for the treatment of moderate-to-severe migraine attacks. Sumatriptan canadian was the first triptan that was available on the market; it was followed by zolmitriptan (Zomig, As-traZeneca), naratriptan (Amerge, Glaxo Wellcome Inc), rizatriptan (Maxalt drug, Merck), and almotriptan (Axert, Pharmacia), respectively. Eletriptan (Replax, Pfizer) is pending Food and Drug Administration (FDA) approval. Introduction of the 5-HT₁b/₁d agonists has revolutionized our understanding of the pathophysiology and treatment of migraine headache.

5-HT has long been suspected as a potential mediator in migraines, because its actions on vascular and gastrointestinal smooth muscle are compatible with the clinical features seen during a migraine attack. The addition of 5-HT to peripheral nerve tissue can induce pain. Modulating 5-HT receptors with a 5-HT antagonist, methysergide, results in effective migraine prophylaxis, whereas administering reserpine, which releases 5-HT from nerve endings, often induces a migraine. Various studies re­ported that the intravenous administration of 5-HT often helps during migraine attacks, and it is likely that various 5-HT receptor subtypes exist. Vasodilation has been implicated in the pathogenesis of migraine, and stimulation of 5-HT receptors on blood vessels leads to vasoconstriction. 5-HT receptors on cerebral arteries are predominantly 5-HT1; however, receptors on the temporal arteries tend to be 5-Ш% Therefore, medications that cause vasoconstriction via modulation of 5-HT_rtype receptors should be effective pharmacologic agents in the acute treatment of migraine at-tacks.

Table 4 Comparison of Pharmacokinetics of 5-HT|_b/|d Receptor Agonists

The pharmacokinetic profile of each 5-HT_1B/1D agonist is slightly different, as shown in Table 4. Variability in the adverse-event profiles, onset of action, and patient preference in clinical practice can be partly explained by this variability; however, the clinical significance of such differences is not well delineated. Oral sumatriptan is poorly absorbed; it has an oral bioavailability of 15% and time to maximum concentration (t_max) of 1 to 1.5 hours, resulting in delayed onset of action compared to the in-tranasal and parenteral formulations. Zolmitriptan has better oral bioavail-ability than sumatriptan and a slightly faster onset, but a similar half-life (t1/2) and duration. Conversely, naratriptan is a longer-acting triptan with improved bioavailability and tolerability. However, its advantage is offset by a delayed onset of action. Rizatriptan generic has a faster onset of action because of its fast absorption, but it has a similar duration of action to sumatriptan and zolmitriptan. Almotriptan, which was recently approved by the FDA, is the latest 5-HT1B/1D receptor agonist to be added to the trip-tans. Almotriptan has demonstrated high and specific affinity for human 5-HT receptors in vivo and in vitro. Like other triptans, almotriptan exhibits negligible affinity for histamine, a and в adrenoreceptors, and dopamine receptors. In addition, almotriptan has been shown to have a higher affinity for meningeal artery tissue than pulmonary or coronary artery tissue. The initial pharmacokinetic parameters of almotriptan were investigated in a study involving 24 volunteers. Almotriptan was well absorbed orally, with a bioavailability of approximately 70%. The time to peak plasma level was approximately 2.5 hours and was not affected by dose. The main route of elimination of almotriptan was renal; approximately 40% of the drug was excreted unchanged in the urine and 13% was excreted in feces. The elimination half-life did not vary with different doses and ranged from 3.19 to 3.69 hours. Unlike sumatriptan, the newer triptans are able to better penetrate the blood-brain barrier and access the central component of the trigeminal system; however, the clinical relevance of this effect has not been established. The triptans have different pathways of metabolism, resulting in different drug interaction profiles and contraindications. Sumatriptan, zolmitriptan, and rizatriptan canadian are metabolized by monoamine oxidase-A to inactive compounds. Consequently, they interact with monoamine oxidase inhibitors (MAOIs); concomitant use and use within 14 days of stopping the MAOI is con-traindicated. Until recently, naratriptan was the only triptan that did not interact with MAOIs, because it is mainly metabolized by cytochrome P-450 enzymes. Naratriptan is renally excreted and is contraindicated in patients with severe renal impairment; a lower dose should be considered in patients with mild-to-moderate renal impairment. Almotriptan is metabolized by monoamine oxidase A and cytochrome P-450 3A4 and 2D6 isoenzymes to five inactive metabolites. However, no clinically relevant change in the pharmacokinetic profile of almotriptan was observed during coadministration with canadian fluoxetine, medication verapamil, canadian propranolol, or mo-clobemide. All triptans interact with ergot derivatives and selective serotonin reuptake inhibitors (SSRIs). Concurrent use of triptans and ergot derivatives within a 24-hour period is contraindicated because of the increased risk of vasospasm. Finally, the concomitant use of SSRIs and triptans should be undertaken with great caution, as serotonin syndrome has been reported in patients using this combination.

Clinical Efficacy

Sumatriptan is the prototype for the 5-HT1b/1d agonists, and its therapeutic efficacy is well established (Table 5). In placebo-controlled, clinical trials, subcutaneous sumatriptan was significantly more effective than place­bo in relieving migraine headache as well as associated symptoms of nausea, vomiting, photophobia, and phonophobia.

A randomized, double-blind, placebo-controlled trial using sumatriptan in the emergency setting reported that sumatriptan-treated patients had a significantly higher rate of meaningful relief (75% vs. 35% for placebo, P<0.001), decreased median time to discharge (60 vs. 96 minutes), decreased migraine-associated symptoms, and improved clinical disability. However, 52% of patients in the sumatriptan group reported untoward adverse events, compared with 27% in the placebo group. Dose-range-finding studies suggested that 10- and 20-mg intranasal sumatriptan, administered as a single dose in one nostril or as a divided dose in two nostrils, is safe and effective. The two-hour response rate ranged from 43% to 78% in the sumatriptan group compared to 29% to 42% in the placebo group. Significant improvement was reported as early as 30 minutes after treatment, and the response rate at two hours was comparable to the response rate of oral sumatriptan at four hours. canadian antibiotics

The administration of oral sumatriptan at the dose of 25 to 100 mg significantly reduced the severity of migraine headache from moderate or severe to mild or none two hours after drug administration. The response rate ranged from 50% to 57% at two hours and 65% to 78% at four hours, compared to the placebo response rate of 17% to 38%. Oral sumatriptan also improved associated symptoms (nausea, vomiting, photophobia, phonophobia) and clinical disability. Pfaffenrath et al. and Rederich et al. demonstrated that repeated use of oral sumatriptan was well-tolerated and provided consistent efficacy for up to 12 migraine attacks. Sumatriptan 100 mg seemed to be more effective but was associated with a higher incidence of adverse reactions compared to the 25-mg dose.

A dose-range-finding study demonstrated a clear dose-response relationship between efficacy and tolerability for zolmitriptan. The 2.5-mg dose of zolmitriptan was recommended as the optimal initial dose. However, the use of higher doses of zolmitriptan was associated with a slightly decreased rate of headache recurrence and a longer time to recurrence, but a higher incidence of adverse effects. Moreover, a long-term, open-label study in 2,058 patients demonstrated consistent efficacy and tolerability to zolmitriptan use over a period of one year.

Table 5 Clinical Trials for Comparison of 5-HT|_b/|d Receptor Agonists¹

Two multicenter, randomized, double-blind, placebo-controlled trials reported that the 1- and 2.5-mg naratriptan doses significantly relieved the severity of the migraine headache at four hours after administration in 50% to 57% and 60% to 68% of patients, respectively, and that response was maintained for at least 12 hours. Furthermore, only 27% to 28% of the 2.5-mg group had headache recurrence, compared with 33% to 39% of those in the 1-mg group and 36% to 38% in the placebo group.

Rizatriptan at the 5- and 10-mg doses was effective and well-tolerated. The 10-mg dose was preferred, however, because it was more efficacious and had a faster onset of action. The efficacy was consistent for long-term use up to one year. Rizatriptan is available as an oral tablet and an orally disintegrating tablet, which dissolves rapidly under the tongue or may be swallowed without liquid. The 10-mg wafer was shown to be superior to the 5-mg wafer and placebo in relieving the migraine headache and its associated symptoms, and therefore improving quality of life. The orally disintegrating tablet is not a sublingual formulation, so it does not have a quicker onset of action.
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The Almotriptan Study Group conducted a dose-finding, double-blind, parallel-group, multicenter, placebo-controlled study of oral almotriptan in the acute treatment of migraine. The doses tested were 2, 6.25, 12.5, and 25 mg of oral almotriptan in 742 evaluable patients. Migraine pain intensity was graded by patients in a self-assessment booklet using a four-point verbal scale (0 [no pain] to 3 [severe pain]). The primary efficacy end-point of this study was headache relief at two hours after medication administration without the use of rescue medications. Headache relief at two hours was reported by 30%, 56%, 59%, and 67% of patients in the 2-, 6.25-, 12.5-, and 25-mg groups, respectively, compared with 33% in the placebo group. This study indicated that almotriptan 6.25 mg is the minimum effective treatment dose and that almotriptan 12.5 mg offered the optimal ratio of efficacy to tolerability. Moreover, associated symptoms— nausea, vomiting, phonophobia, photophobia, and the need for escape medication decreased dose dependently. Single doses of almotriptan 6.25 and 12.5 mg were evaluated in 722 patients who treated three consecutive moderate-to-severe migraine attacks. Across all migraine attacks, pain relief at two hours was 60% with almotriptan 6.25 mg, 70% with almotriptan 12.5 mg, and 38% with placebo (P<0.001), and the proportion pain-free at two hours was 38.8% with almotriptan 12.5 mg, 29.9% with almotriptan 6.25 mg, and 15.5% with placebo (P<0.001). Recurrence rates were 28.7% and 30.1% with almotriptan 6.25 and 12.5 mg, respectively, and 23.3% with placebo. Almotriptan 12.5 mg provided the optimal balance of efficacy and tolerability.

In summary, all triptans are effective agents in the treatment of migraine attacks and additional comparative efficacy trials are outlined in Table 5. Nonetheless, variability in patients’ responses to different triptans is seen clinically. A single randomized, placebo-controlled trial comparing all of the triptans would be ideal to better delineate the difference in response observed in the clinical setting.

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