Migraine headaches affect approximately 12% of the adult population and are more prevalent in women (ranging from 15°% to 18°%) than men (6%). Their occurrence is dependent on age, sex, socioeconomic status, and race. Migraines are recurrent episodes of intense headache pain, often associated with nausea, vomiting, and sensitivity to light and sound. These episodes may last from a few hours to days. A migraine can be an extremely disabling event for its sufferer; the annual cost of labor lost to migraine disability is estimated at $5.6 to $17.2 billion. Every year, decreased productivity and absenteeism contribute to this economic impact.

Although the exact physiological mechanism of a migrane attack is not completely understood, the headache is thought to occur as a result of neuronal dysfunction. Within the trigeminovascular system, trigeminal nerves serve as important initiators and promoters of tissue inflammation. Vasoactive peptides such as calcitonin gene-related polypeptide, substance P, and neu-rokinin A are released after neuronal activation. As a result, vasodilation and plasma protein extravasation occur. A neurogenic inflammatory response is initiated, sensitizing the surrounding tissues and producing a hyperalgesic state. Activity within this system is regulated primarily by serotonergic neurons and, to a lesser extent, by nora-drenergic neurons.

Migraines are typically unilateral at onset, present with pulsating or throbbing pain, and are located in the fron-totemporal region of the head or face. Other common characteristic features are nausea, vomiting, phonophobia, and photophobia. Peak headache pain intensity generally occurs within one hour of onset, and headache duration can last anywhere from four to 72 hours.

With the identification of patient-specific migraine triggers, alterations of neu-rotransmitter levels within the central nervous system can be avoided. For instance, loud noises, glare, caffeine, and certain food additives (e.g., sodium nitrite and monosodium glutamate) often provoke migraine attacks in susceptible individuals. In other patients, changes in temperature, humidity, or hormone levels can trigger a migraine attack.

There are two major pharmacological approaches to migraine treatment. Therapeutic management is targeted at either altering the attack once it is under way or at preventing the attack altogether. The daily administration of prophylactic agents is usually reserved for patients with more frequent and severe headaches.

Traditionally, migraine attacks had been treated with nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, analgesics, narcotic analgesics, and ergot de-rivatives. The introduction of triptans to the pharmaceutical market revolutionized the treatment of migraine. All of the currently available triptan products are 3,5-substituted tryptamine derivatives. They are agonists at the 5-hydroxytryptamine (5-HT1B) receptor sites with varying affinity for the 5-HT1a, 5-HT1b, and 5-HT-[d receptors. Headache pain is relieved as a result of cerebral vasoconstriction. These agents have been responsible for the most effective, complete relief of headache and associated symptoms, and they are re­garded as a mainstay for abortive migraine therapy.
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With the addition of each new drug to this class comes the burden of distinguishing it from other agents. Thus far, the similarities of these agents far outnumber the differences between them. However, the newest addition— frovatriptan succinate (Frova™, Elan)—has displayed remarkable characteristics that may set it apart. Frovatriptan is indicated for acute treatment of migraine attacks, with or without an aura, in adults. It is not indicated as prophylactic treatment of migraine or for management of hemiplegic or basilar migraine.

Several in vitro and in vivo studies have shown that frovatriptan is a potent 5-HT1d/1b receptor agonist, one with a long duration of action and good tolerability. Frovatriptan reverses cerebral vasodila-tion by activating 5-HT1B, and it prevents neurogenic inflammation by activating 5-HT. In other words, frovatriptan and other 5-HT1d/1b agonists constrict dilated cerebral vessels in such a way as to prevent the subsequent neurogenic inflammation.

When frovatriptan was compared (GlaxoSmithKline) and naratriptan (Amerge®, GlaxoSmith-Kline), all three drugs were shown to be full agonists on 5-HT1d/1b in the cerebral vascu-lature; however, frovatriptan was more potent, having a fourfold higher affinity to 5-HT1B. Frovatriptan not only is more potent in cerebral receptors but also, unlike sumatrip-tan, zolmitriptan (Zomig®, AstraZeneca), and naratriptan, does not appear to constrict human coronary and peripheral arteries. Peripheral arterial constriction is the cause of decreased tolerability in patients. In addition to its favorable tolerability and potency, frova-triptan has the potential to be useful in patients with long-lasting or recurrent migraine.

Table 1 Pharmacokinetic Properties of FDA-Approved Oral Triptan Products

Sumatriptan generic

Naratriptan

Zolmitriptan

Almotriptan

Frovatriptan

Parameter (Imitrex canadan)

(Amerge®)

(Zomig®)

(Axert®)

(FrovaTM)

F (%) 14%-15%

~ 63%-75%

~ 45%

~ 49%

~ 70%-80%

24%-30%

T|/2 (hr) ~ 2 hr

~ 6 hr

~ 2 hr

~ 3 hr

3-3.7 hr

25 hr

Tmax(hr) 2-2.5 hr

2-3 hr

0.5- 2.5 hr

2-4 hr

|-4 hr

2-4 hr

Onset |-2 hr

1 hr

< 30 min

< 2 hr

|-2 hr

2 hr

Renal elimination ~ 50%

~ 70%

~ 65%

~ 65%

< 75%

|0%-32%

Metabolism Liver

Liver,

MAO-A

Liver

MAO-A,

Liver,

Cyt. P-450

(active metabolite)

Cyt. P-450

Cyt. P|A2

Frovatriptan is eliminated by both the kidneys and the liver; unlike other trip-tans, however, the drug is not metabolized by monoamine oxidase (MAO) or the cytochrome P-450 (CYP-450) enzyme 3A4. In vitro, CYP-450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan. Frovatriptan is metabolized into hydroxylated frovatriptan, desmethyl frovatriptan, N-acetyl desmethyl frovatriptan, and hydroxylated N-acetyl desmethyl frovatriptan. Desmethyl frovatriptan is active but, compared with the parent compound, has a lower affinity for 5-HT1b/1d.

The elimination half-life of frovatriptan is approximately 26 hours, the longest of any agent in the triptan class (Table 1). Studies have shown no difference in mean terminal half-life between males and females.