MIGRAINE: SOME TREATMENT OPTIONS

     The Lancet reports that migraine is a largely undertreated disorder with many victims either never seeking professional help or having given up on seeing physicians because of fatalistic expectations, unsatisfactory experiences with medications, misdiagnosis, or lack of physician empathy. New medications and new concepts of the disease itself, though, are providing ample reason to encourage these sufferers to seek evaluation and help with this disabling pain in the head.

Recognizing both classic migraine (preceded by aura) and common migraine (without aura), common migraine affects some 75% of migraine sufferers, while about 33% of sufferers experience both types. Attacks seem to occur as a result of genetic tendencies to exceed a certain threshold of neurological activity in the brain stem that initiates a chain reaction involving neurotransmitter and chemical mediator release, vasoconstriction and rebound vasodilation, and inflammatory processes. As the intricacies of the pathophysiology unfold, treatments are becoming more refined ,specifically focussing on various key elements, both facilitating efficacy and reducing side effects. Treatment of migraine with narcotic analgesics is rapidly becoming frowned upon in favor of other therapeutic options at least as effective and less prone to abuse and addiction.

With bounding strides made in research on serotonin and the disparate types of receptors affected by it, a variety of new prescription medications have recently become available for treating migraine, affording almost immediate relief of many symptoms. Options for administration of these agents are also improving, progressing from the invasiveness of injection to oral tablets, and more recently to various nasal spray formulations. In spite of improvements in acute treatment, though, recurrence and rebound continue to plague many migraine sufferers.

In light of these more high-tech developments, it seems almost a paradox to note that an old standby over-the-counter product has received as much official recognition of both safety and efficacy. Excedrin Migraine is a combination of acetaminophen (250mg per tablet), aspirin (250mg per tablet), and caffeine (65mg per tablet) with FDA approval specifically for the treatment of migraine (the only over-the-counter product with such endorsement) and labeling designed to help guide migraine sufferers in safe, effective self-treatment backed by the extensive research support necessary for FDA approval. The American Medical Association’s Archives of Neurology touts the product as “highly effective in treating migraine pain as well as the associated nausea, sensitivities to light and sound and functional disability.” Over-the-counter availability means ready access to effective relief, early access to treatment to keep symptoms from escalating, and avoidance of the costs and hassles associated with prescription and emergency care.


A Rundown Of The New Prescription Products for Migraine

With a few exceptions, the new products focus on the role of serotonin, (5-hydroxytryptamine or 5HT) in the disease process, capitalizing on the observation that serotonin levels decrease as migraine symptoms worsen during an attack. Ineffective during the aura phase, when serotonin levels may be abnormally high, and unable to correct underlying brain stem pathology that seems to cause recurrence of symptoms, serotonin agonists (triptans) can abort the pain of an acute attack. Since serotonin is involved in producing the gastrointestinal effects of migraine, these agents are often also effective in treating the nausea and gastronintestinal stasis (which can affect oral absorption of medications) associated with an attack.

Amerge® (naratriptan), from Glaxo Wellcome, is available in 1mg and 2.5mg oral tablets with relatively fast onset of action and relatively long duration of action to provide relief for up to four hours. Rebound seems to be less of an issue with Amerge than with other triptans, and it is often used for prophylaxis of severe menstrual migraine as a once-per-day dose for several days during or before the menses.

Imitrex® (Sumatriptan), also from Glaxo Wellcome, is available as injection both in a STATdose Injector and the original “syringe injection”, as 25mg and 50mg tablets, and unit-dose nasal sprays of 5mg and 20mg. Most patients require 50-100mg, but 25mg every 3-4 hours is occasionally effective and a good starter dose to evaluate individual reactions. Without significant adverse side effects, 50-100mg as needed every 3-4 hours with a maximum of 200mg per day is a reasonable oral regimen. One nasal administration is considered approximately equivalent to one injection; and most practitioners limit their patients to one injection or nasal spray and two tablets per day when those combinations are employed

Zomig® (zolmitriptan), available in 2.5mg and 5mg tablets, is similar to sumatriptan in both therapeutic response and side effect profile, both medications potentially causing chest heaviness or pressure, pressure in the throat, nausea, shortness of breath, rash, swelling of the face or lips, tingling, heat or sensation of heaviness, tiredness,

drowsiness, and dizziness. Such side effects are generally minimal and short-lived with both medications, but should always be considered as reasons for precluding a second dose of either. Both products are also contraindicated in patients with a history of cardiovascular disease. Zomig is usually given 2.5-5mg every 3-4 hours with a daily maximum of 10mg and a weekly maximum of 10 tablets. It has the distinct advantage of penetrating the blood-brain barrier to act centrally within the trigeminovascular system, where it has greater chance to prevent recurrence.

Migranal Nasal Spray® (dihydroergotamine mesylate), by Novartis Pharmaceuticals Corp, has been compounded from the parenteral (D.H.E.45) for years, but is now available in kits containing four complete migraine headache treatments. Each treatment consists of one spray (0.5 mg) administered into each nostril, followed by an additional spray to each nostril 15 minutes later, for a total of four sprays (2.0 mg). Ergot alkaloids have been used as tablets, suppositories, and injections for many years; but administration via nasal spray affords rapid onset with maximal efficacy, bypassing metabolic inactivation encountered with oral administration.

The ergot alkaloids are serotonin antagonists with high affinity but low selectivity for serotonin receptor sites as well as affinity for dopamine and norepinephrine binding sites. Though the combination of actions is considered an advantage in light of the rather complicated pathophysiology of the disorder, the effectiveness of serotonin antagonism is primarily limited to the aura phase of classic migraine, as the phase in which 5HT activity is elevated. The ergot products are also prone to rebound headache, so usage should be limited in order to minimize the problem.

Other ergot products include:

Generic & Brand Names

Sublingual tablets (ertogamine) Ergomar®, Ergostat®

Oral tablets (ergotamine/caffeine) Cafergot®, Ercaf®, Wigraine®

Suppositories (ergotamine/caffeine) Cafergot®, Cafetrate®, Ergo-Caff®, Migergot®, Wigraine®

Injectable (dihydroergotamine) D.H.E. 45®

Other Valuable Medications In The Treatment Of Migraine

Activation of dopamine receptors during an attack not only plays a role in the control of cerebral blood flow, but also effects decreases in gastric tone, emptying, peristalsis, and gastroduodenal coordination. Thus administration of dopamine antagonists reduce many of these symptoms dramatically and provide valuable adjunctive therapy for acute migraine. These injected dopamine antagonists have shown the corresponding efficacy rates used alone in the emergency setting:

Haloperidol 100%

Chlorpromazine 93%

Droperidol 91%

Methotrimeprazine 82%

Prochloperazine 86%

Flunarzine 76%

Metoclopramide 60%


Intranasal lidocaine can be useful for either migraine or cluster headache. The 4% solution, only available as injectable, can be dispensed in either a spray or dropper bottle and administered in the nostril on the side most affected by the headache. Occasionally this works very well, but it normally helps only marginally with rapid onset and short duration (only a few minutes). Its main value is in short-term, inexpensive relief while waiting for other therapies (notably a triptan) to take effect. It is generally safe, with bad taste, nervousness, and tachycardia only mild and rare side effects as long as usage is limited to a maximum of 8 to 10 sprays per day.

Stadol® (butorphanol), either injectable or nasal spray, as a powerful "mixed agonist-antagonist" very similar to nalbuphine in its actions, can be effective for OCCASIONAL use. Its addictive nature precludes more than occasional use, but it can be very valuable in the emergency situation where other agents have provided no relief. Opiates are believed to act by stimulation of specific opiate receptors designated as µ, kappa, and sigma. Stimulation of µ-receptors, the classic morphine-receptor type, produces supraspinal analgesia, respiratory depression, euphoria, and physical dependence. Butorphanol is an agonist at kappa- and sigma-receptors but a weak antagonist at µ-receptors, mediating spinal analgesia via stimulation at kappa-receptors. Pain relief after IM and intranasal administration can be expected within about 15 minutes and usually lasts for 2-4 hours.

Toradol® (ketorolac), the only injectable NSAID (60mg/dose), is also available in 10mg oral tablets and is appropriately dosed every 3 to 4 hours as needed. It can be very effective in migraine, especially when injected, without narcotic side effects; so the patient generally remains “functional” after administration. GI and kidney side effects can be a problem with overuse or prolonged daily use, so it should be used on a short-term basis.; and it is appropriately given with anti-nausea medications to treat the GI symptoms of migraine as well as the GI side effects of Toradol.

Ultram® (tramadol), though mildly addictive, has lower potential for addiction than the opiates and appears to be relatively safe and effective for mild to moderate pain with side effects similar to the opiates, nausea and drowsiness being relatively common. It is unique in its dual mechanism, exerting agonistic action at opiate receptors and interfering with neurotransmitter reuptake, interfering with the perception of pain that involves one descending pathway from the midbrain that releases serotonin and another descending pathway in the pons that releases norepinephrine. Tramadol also binds weakly to µ-opiate receptors blocking the transmission of pain signals to the brain. It may be used in conjunction with the usual migraine medications without significant drug interactions at a dosage of 1-2 tablets every 3-4 hours as needed and a maximum of 4 tablets per day. Though addiction is rare, dependence is not; and rebound headache is common with Ultram. Thus, daily or frequent use should be discouraged; but Ultram provides a valuable measure of pain relief that lies between the NSAID’s and the narcotic analgesics when analgesia is a necessary adjunct to triptan therapy.


MIGRAINE PROPHYLAXIS

Sansert® (methysergide) is considered a prophylactic agent of last resort, with its serious potential side effect of "fibrosis" (thickening around the heart, lung, or kidneys). Though associated with higher doses and long-term therapy, fibrosis remains a valid concern with today’s lower doses (1-4mg daily). Methysergide is a synthetic ergot alkaloid related to methylergonovine (an oxytocic agent) and to LSD. A weak vasoconstrictor and oxytocic, methysergide is a more potent antagonist of peripheral serotonin receptors than other ergot alkaloids, acting on serotonin receptors centrally. It acts as a highly competitive antagonist of serotonin in the periphery and yet a serotonin agonist in the CNS. Peripherally, it inhibits the serotonin-induced platelet aggregation, inflammation, and vasoconstriction.that characterize migraine. It also inhibits histamine release from mast cells. With its similarity to LSD, “strange” feelings are not uncommon, but usually short-lived, as are GI pain or severe stomach upset, nausea, and leg cramps. It is more effective against migraine than cluster and occasionally works well at reducing both frequency and severity of headache attacks when other agents have been unsuccessful.


Beta-Blockers are frequently employed in prophylaxis and enjoy a high success rate with minimal disruption of quality of life because of side effects. Nonetheless, they do frequently cause fatigue, insomnia, diarrhea, dizziness, bradycardia and depression. They block sympathetic stimulation mediated by beta1-adrenergic receptors in the heart and vascular smooth muscle which decreases both resting and exercise heart rate and cardiac output, systolic and diastolic blood pressure. Propranolol is currently under investigation in a nasal spray formulation for migraine prophylaxis.

Generic Brand Name

Propranolol Inderal

Atenolol Tenormin

Metoprolol Lopressor

Timolol Blocadren

Nadalol Corgard

Antidepressants are also commonly used in migraine prophylaxis, with their roles in neurotransmitter regulation. Comorbidity of migraine and depression is not uncommon, and some of the antidepressants (amitriptyline, for instance) have some efficacy as adjunctive analgesia. The tricyclic antidepressants amitriptyline, doxepin, nortriptyline, and protriptyline have all been used with success in this application; and Serzone® (Nefazodone) has recently shown some promise as well.


Depakote® (divalproex sodium), the anticonvulsant, is FDA-approved for migraine prophylaxis. The mechanism by which it is effective is unclear, but it increases brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS. It may also inhibit enzymes that catabolize GABA or block the reuptake of GABA into glia and nerve endings. Suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels is also an important mechanism in migraine prophylaxis..