Migraine is a common form of pulsating or throbbing headache that is usually severe and even disabling, unilateral in more than half of patients, often associated with feeling ill, and sometimes preceded by visual or other neurologic symptoms. It affects more than 28 million Americans, and three times as many women as men. Migraine attacks generally begin during the early teen years and persist throughout adulthood.

Complex migraine occurs in about 15% of cases, in which an aura consisting of lightning-bolt shaped flashes of light, blind spots or limb tingling warns of imminent headache. Migraines with or without aura are often accompanied by nausea, vomiting and extreme sensitivity to light and sound, and usually last from four to 72 hours if untreated. Frequency varies from once or twice a year to several times monthly.

Although the mechanism underlying migraine is complex and incompletely understood, the culprit may be imbalances in serotonin and other neurotransmitters affecting pain perception in the trigeminal nerve system. Decreasing serotonin levels cause the trigeminal nerve to release neuropeptides which dilate and inflame dural blood vessels, thereby intensifying and prolonging headache pain. Magnesium levels may also decrease immediately before or during migraine.

Migraine triggers vary among sufferers, but may include hormonal changes, especially those related to the menstrual cycle; alcohol or caffeine; foods including aged cheese, chocolate, fermented or pickled products; aspartame; monosodium glutamate; and nitrates or other preservatives. Fasting, stress, bright sun, unusual odors, intense exercise, changes in sleep pattern or in the environment, and certain medications can also bring on or aggravate migraine headache. Family history is positive for migraine in about 80% of patients.

Diagnosis is usually based on typical history, after consideration and exclusion of other, more ominous types of headache associated with head trauma, subarachnoid hemorrhage, meningitis, brain tumor, or temporal arteritis.

Although over-the-counter analgesics such as aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) may be effective on occasion, they may predispose to stomach ulcers, gastrointestinal bleeding and even rebound headaches. Currently available prescription medications for migraine are either preventive, designed to reduce headaches in patients that have frequent attacks, or pain- relieving, designed for use once the headache has started. The U.S. prescription market for treatment of migraine headaches is approximately $2.1 billion.

NSAIDs such as ibuprofen may help relieve mild migraines, as may Excedrin Migraine, a combination of acetaminophen, aspirin and caffeine. Sumatriptan (Imitrex), the first drug specifically developed for migraine, binds to serotonin receptors, leading to blood vessel constriction. The injected form is effective within 15 minutes in 70%-80% of cases, but injections may be inconvenient and painful.

Imitrex is also available in oral and nasal formulations, and other available triptans include rizatriptan (Maxalt), naratriptan (Amerge), zolmitriptan (Zomig), almotriptan (Axert), frovatriptan (Frova) and eletriptan (Relpax). These relieve pain within two hours in about 60% to 90% percent of patients. Compared with Imitrex, adverse effects are generally fewer but may include nausea, dizziness, muscle weakness and, rarely, stroke and heart attack.

Ergots, including ergotamine (Ergomar), dihydroergotamine (D.H.E 45) and dihydroergotamine nasal spray (Migranal) relieve pain by constricting blood vessels, but may have more adverse effects than triptans. Metoclopramide (Reglan) helps relieve nausea and vomiting accompanying migraine and improves gastric emptying, allowing better absorption and more rapid action of many oral drugs. Prochlorperazine (Compazine) and chlorpromazine (Thorazine) help relieve nausea but have no effect on gastric emptying.

Avoiding triggers, following a healthy lifestyle, relaxation techniques, and support groups may all play a role in migraine management. Complementary and alternative medicine therapies showing some promise include acupuncture, biofeedback, massage, herbal therapies and other supplements, and cervical manipulation.

CenterWatch has identified a pipeline of 14 drugs, many of which are triptans, in various stages of development for migraine. Others are beta-blockers, antiepileptic drugs, or analgesics.

Pozen has submitted a new drug application (NDA) for MT 100, a combination of metoclopramide hydrochloride and naproxen sodium developed as an oral first-line therapy for migraine pain and associated symptoms. However, Pozen received non-approvable notification from the Food and Drug Administration (FDA) in June 2004. The combination is designed to release metoclopramide hydrochloride initially, allowing relief of nausea and faster absorption of the NSAID naproxen, with fewer adverse effects than other available treatments. In Phase II, Phase III, and Phase IIIb studies enrolling a total of more than 7,700 patients, MT 100 was effective in treating migraine pain and statistically superior to either of its component drugs given alone.

In two Phase III trials, a single tablet dose of MT 100 was as effective as oral Imitrex 50 mg with less risk of cardiovascular side effects. In one of these studies but not the other, MT 100 was superior for relief of pain, nausea, photophobia, and phonophobia. In its nonapproval letter, the FDA also cited the apparent lack of superiority of MT 100 over naproxen for sustained pain relief, and the potential risk of tardive dyskinesia or carcinogenicity associated with metoclopramide.

Sharing a similar fate to that of MT 100, Pozen’s product MT 300, an injectable formulation of dihydroergotamine mesylate (DHE), received FDA notification of non- approvable status in October 2003. MT 300 is designed to provide long-lasting pain relief in convenient, pre-filled syringes suitable for at-home use.

In two double-blinded, placebo-controlled Phase III trials enrolling more than 1,200 patients, MT 300 offered statistically superior sustained pain relief and two-hour pain relief compared with placebo. More patients treated with MT 300 had sustained relief of nausea, sonophobia and photophobia than patients treated with placebo, but overall relief of secondary symptoms at two hours with MT 300 was not statistically superior to placebo.

In collaboration with GlaxoSmithKline, Pozen is in Phase III development of Trexima (MT 400), a single tablet formulation combining sumatriptan and naproxen sodium. In a Phase II, double-blind study of 972 patients with an acute migraine, a combined version of a triptan and an NSAID provided a faster onset and longer duration of pain relief than did the triptan alone or placebo.

Pozen will conduct a long-term, open label safety study, as well as two Phase III trials to determine the effectiveness and safety of Trexima for the acute treatment of migraine. Filing of the NDA for Trexima is anticipated in the second half of 2005.

NovaDel Pharma is in Phase II testing of a lingual spray formulation of Imitrex (sumatriptan). On Oct. 14, the company reported findings from a pilot pharmacokinetic study in nine subjects. The mean time to reach maximal blood concentrations of active drug with a 15 mg lingual spray dose was approximately 20 minutes shorter than with the 50 mg Imitrex tablet. During the first 30 minutes after administration, the total amount of drug delivered was approximately 40% higher than with the oral formulation, and well within therapeutic range. The lingual spray was well tolerated and had a favorable safety profile, and these pharmacokinetics should translate to greater efficacy and faster relief of migraine symptoms.

Another formulation of sumatriptan is a nasal spray, in Phase I testing by Nastech Pharmaceutical. This company is currently seeking licensing partners. Risks of sumatriptan and the other triptans include blood pressure elevation and coronary artery spasm, and they should not be administered together with ergot type migraine medications or MAO inhibitors.

AlgoRx Pharmaceuticals is in Phase I development of ALGRX 2872, a triptan in a novel formulation. In more than 150 patients treated thus far, the drug has been effective and well-tolerated.

ALX-0646 ( http://www.npsp.com/drug_development/dd_alx0646.php) is a novel small molecule being developed by NPS Pharmaceuticals to act selectively on specific serotonin receptor subtypes in the brain, with a lower affinity for serotonin receptors in cardiovascular tissue. This should allow greater efficacy for migraine relief with fewer cardiovascular adverse effects than available triptans. In a Phase I study, ALX-0646 was safe and well tolerated in human volunteers.

NPS 1776, or isovaleramide, is in Phase II development by NPS Pharmaceuticals. This small organic molecule was designed as an antiepileptic drug, but it may also be promising in other neurological and psychiatric disorders including bipolar disorder and migraine. In Phase I clinical trials, the drug was safe and well tolerated. A Phase IIa proof-of-concept study in patients with migraine headache pain is underway.

D-Pharm has completed Phase I testing of DP-VPA, a derivative of valproic acid (VPA), linked to a lipid vector. Like NPS 1776, DP-VPA is being developed for chronic and prophylactic treatment of epilepsy, bipolar disorder and migraine. Although VPA may have serious adverse effects, DP-VPA is a prodrug activated at the site of excitatory or seizure activity in the brain, allowing a superior effect of the drug in the target cells at much lower doses and with less toxicity.

A Phase I safety study in 56 healthy male volunteers showed minimal systemic effects from DP-VPA and no neurological adverse effects, such as dizziness or somnolence. Oral administration resulted in plasma levels within the target dose range.

Other approaches to migraine pain in Phase II development include olcegepant (BIBN 4096), a calcitonin gene-related peptide antagonist by Boehringer Ingelheim; CNS-5161, a non-competitive blocker of the N-methyl-D-aspartate (NMDA) ion-channel complex developed for neuropathic pain by CeNeS Limited; and Zonegran (zonisamide), a sodium and calcium channel blocker by Elan Pharmaceutical Research.

A unique approach is PreHistin (cyanocobalamin), for which Cobalis has completed Phase I testing. By stimulating production of CD8+ suppressor T-cells and inhibiting the synthesis of immunoglobulin E, this product corrects the over-production of histamines and other substances causing allergy symptoms. Although most of the drugs in the pipeline are pain-relieving rather than preventive, Questcor is in Phase II development of Migrastat, a nasal formulation of the beta-blocker propanolol designed to reduce migraine frequency.

Better understanding of the mechanisms underlying migraine has allowed fairly specific treatment targeting serotonin receptors. As further development allows greater selectivity of triptans and related drugs, efficacy and speed in migraine relief should continue to increase as adverse cardiovascular effects decrease.