Some patients will experience other symptoms before, after, or during the development of a full-fledged migraine. These symptoms of migraine can also be difficult and distressing for the patient and may occur with or without headache.

Some estimate that 20 million or more Americans have migraine. Migraine usually begins between the ages of 10 and 40, but it can begin at any age between infancy and the seventh decade. Most studies show a female preponderance of 60- 70%. Migraine often remits or changes character during the sixth decade of life.

Greater than one-half of afflicted individuals have a positive family history of migraine. The mechanism for migraine has not been well defined, although a number of theories have been advanced. Migraine may result from the response of a patient to. the interaction of a number of factors including inherited susceptibility. Predisposing factors may include increasing or remitting stress (or emotional upset), hormonal factors including estrogen, certain medications, glare, skipped meals, and numerous dietary factors.

There is no reliable, economically practical laboratory test available to aid the clinician in the diagnosis of migraine. However, there are some characteristic features of migraine headache which are often helpful. Some 5 to 30 minutes before the headache begins (a period called the aura or prodrome), symptoms of a change in mood, irritability, restlessness, nausea, or a change in appetite occur in about 20

percent of patients. A similar percentage of patients lose vision in a specific area (called a blind spot or scotoma) or see jagged, shimmering, or flashing lights. Less commonly, images are distorted; for instance, objects appear smaller or larger than they are. Some patients experience tingling sensations or, rarely, weakness in an arm or leg. Usually these symptoms disappear shortly before the headache begins, but sometimes they merge with it. The pain of a migraine may be felt on either side of the head or over the entire head. Occasionally, the hands and feet may become cold and turn blue. In most of those who have a prodrome, the pattern and headache location remain essentially the same with each migraine. Migraine headaches may occur frequently for long periods in some patients. On the other hand, in some patients the migraine may remit for weeks, months or even years.

Migraine attacks may last for a period of four hours to several days if not treated. For some, the headaches are mild and easily relieved with nonprescription analgesics. Quite often, migraine headaches are severe and temporarily disabling, especially when accompanied by nausea, vomiting, and discomfort from bright light.

A variety of abortive drugs are used for the acute treatment of migraines. For example, one class of drugs that activate serotonin receptors (5-hydroxytryptamine agonists or 5-HT agonists) mediate vasoconstriction and can abort migraine pain in about 70% of patients. The drug sumatriptan is available in oral, nasal spray and subcutaneous injection forms. Subcutaneous dosing is more effective but has greater potential adverse effects, which include flushing, nausea, esophageal constriction, and, rarely, coronary artery constriction. Other known 5-HT agonists include eletriptan, naratriptan, rizatriptan and zolmitriptan. These oral agents may be less effective in the relief of acute migraine, however, the side effects of these agents are potentially less severe. The drug naratriptan is available in tablet form. Ergot alkaloid derivatives, such as ergotamine tartrate and dihydroergotamine, in oral and parenteral preparations have been used. Dopamine antagonist antiemetics, such as metoclopramide and prochlorperazine, may also be effective. It has been reported that analgesics should be used sparingly. They are effective in some patients but cause rebound headache with dose escalation in others. Rebound headache may be induced by repetitive and on- going overuse of acute headache medication. Some nonsteroidal anti-inflammatory

agents (NSAIDs) may be suitable for mild to moderate headaches. Opioids are generally avoided except under special circumstances and strict control.

Currently available abortive agents are often associated with recurrent migraine (triptans), rebound migraine (analgesics), or lack of sufficient efficacy when used with a convenient and practical method of administration (non-injected triptans). A need exists for a targeted prophylactic, acute, or subacute treatment of migraine that can substantially and reliably, with few or no side effects, diminish the likelihood of a patient being affected by disabling migraine symptoms during an important period of time and/or activity for that individual.

Some drugs taken every day may prevent migraine attacks from recurring. A beta-blocker, propranolol, provides long-term relief for about half the people who have frequent migraine headaches. The calcium channel blocker, verapamil, is effective for a few people. Recently, the antisiezure drug, divalproex, has been found to reduce the frequency of migraine headaches when taken daily. Methysergide is another preventive drug, but it must be taken intermittently because is can unpredictable cause a serious complication called retroperitoneal fibrosis, a formation of scar tissue deep within the abdomen, which can block blood supply to vital organs. Therefore, the use of this drug must be closely supervised by a medical provider.

Unfortunately, many patients experience significant side effects and/or lack of efficacy with the available and commonly prescribed prophylactic medications for migraine. A need exists for a prophylactic and/or targeted prophylactic treatment of migraine that uses active and effective agents or drugs with no or few complications or side effects.

Summary of the Invention The present invention provides a prophylactic, targeted prophylactic, acute or subacute treatment of migraine that significantly reduces undesired risks or overcomes the problems of side effects associated with current methods of treatment and that provides alternative methodologies for patients that cannot be treated or helped with current methods.

In one embodiment of this invention, a patient is regularly given a therapeutically effective amount of a cyclooxygenase-2 inhibitor for prophylactic, targeted prophylactic or acute, or subacute treatment of migraine. In another embodiment of this invention, a patient is co-administered a therapeutically effective amount of a combination of a cyclooxygenase-2 inhibitor and acetylsalicylic acid (aspirin). This combination is effective when given on an acute, subacute, prophylactic or targeted prophylactic basis. Also, a prophylactic low-dose regimen using an alternate day regimen including a cyclooxygenase-2 inhibitor and aspirin is effective in the prophylactic treatment of migraine. In this embodiment, the potential side effects of both medications or agents are reduced when used in combination or on alternate days. Further, this combination may be useful in conditions other than migraine. In yet another embodiment of this invention, a patient is co-administered a therapeutically effective amount of a combination of a cyclooxygenase-2 inhibitor and a 5-HT agonist for the targeted prophylactic or acute treatment of migraine.

Still another embodiment of this invention includes a pharmaceutical composition in unit dosage form that contains a therapeutically effective amount of a cyclooxygenase-2 inhibitor and acetylsalicylic acid as well as a pharmaceutically acceptable carrier. The unit dosage forms of this embodiment may be provided in the form of a kit that includes both a cyclooxygenase-2 inhibitor and acetylsalicylic acid, either as two separate unit dosage forms or combined as a single unit dosage form.

Cyclooxygenase-2 inhibitors that that are suitable for use in the invention include compounds that selectively inhibit cyclooxygenase-2 that are reported in the art or that are obvious variants. One acceptable cyclooxygenase-2 inhibitor includes compounds represented by Formula 1.

Formula 1

In Formula 1, variable Rl represents lower alkylsulfonyl or sulfamy and variable R2 represents alkyl, cycloalkyl, aryl, mono-, di-or trisubstituted heteroaryl or benzoheteroaryl. A representative compound is rofecoxib.

Another acceptable cyclooxygenase-2 inhibitor includes compounds represented by Formula 2.

Formula 2 In Formula 2, variable Rl represents lower alkylsulfonyl or sulfamy, variable R2 represents alkyl, haloalkyl or halogen, variable R3 represents hydrogen, lower alkyl or haloalkyl, and variable R4 represents cycloalkyl, cycloalkenyl, aryl and substituted aryl.

A representative compound is celecoxib.

5-HT agonists that are suitable for use in the present invention include compounds that selectively effect 5-HT (5-hydroxytryptamine or serotonin) receptors of the central nervous and vascular systems. This class of compounds has been recognized as useful in abortive migraine therapy. Representative compounds in this class include sumatriptan, eletriptan, rizatriptan, frovatriptan, almotriptan, zolmitriptan, and naratriptan as well as ergot alkaloids and related compounds such as dihydroergotamine mesylate, ergotamine tartrate, ergonovine maleate, ergoloid mesylates such as dihydroergocornine, dihydroergocristine, dihydroergocryptine, dihydro-. alpha.-ergocryptine, dihydro-. beta.-ergocryptine and dihydroergotamine mesylate.

Detailed Description This invention provides a method for prophylactically (long term), targeted prophylactically, acutely targeted, acutely or subacutely treating migraine. This method of treatment includes administering a therapeutically effective amount of a cyclooxygenase-2 inhibitor, either alone or combined with acetylsalicylic acid, to a

patient. Further, an alternative method includes administering a therapeutically effective amount of a cyclooxygenase-2 inhibitor combined with a HT-5 agonist to a patient.

Compounds that are cyclooxygenase-2 inhibitors and methods for the preparation of these compounds have been reported in the art. See, for example, U. S.

Pats. 5,380,738; 5,344,991; 5,393,790; 5,466,823; 5,434,178; 5,474,995; 5,510,368; 5,521,207,5,604,260 and 6,248,745 and international applications W096/06840, W096/03388, W096/03387, W095/15316, W094/15932, W094/27980, W095/00501, W094/13635, W094/20480 and W094/26731. Representative compounds that are commercially available include rofecoxib and celecoxib. These two compounds are sold under the tradenames VIOXX (Merck & Co., Inc., West Point, PA) and CELEBREX (G. D. Searle & Co., Chicago, IL), respectively.

The term"cyclooxygenase-2 inhibitor"includes compounds that selectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Preferably, the compounds have a cyclooxygenase-2 inhibition of less than about 0.5. mu. M, and also have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50, and more preferable of at least 100. Even more preferably, the compounds have a cyclooxygenase-1 IC50 of greater than about 1. mu. M, and more preferable of greater than 20. mu. M. This selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects when used. Use of a cyclooxygenase-2 inhibitor agent is intended to include administration of one or more agents in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to include co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.

Suitable classes of compounds that inhibit cyclooxygenase-2 includes compounds represented by Formulas 1 and 2. Suitable embodiments of cyclooxygenase-2 inhibitors are represented by Formula 1.

Formula 1 wherein Rl is lower alkylsulfonyl or sulfamy; and R2 is alkyl, cycloalkyl, aryl, mono-, di-or trisubstituted heteroaryl or benzoheteroaryl.

Suitable embodiments further include compounds represented by Formula 1 wherein R, is lower alkylsulfonyl ; and R2 is mono-or disubstitued phenyl.

Still other embodiments of cyclooxygenase-2 inhibitors are compounds represented by Formula 2.

Formula 2 wherein RI is lower alkylsulfonyl or sulfamy; R2 is alkyl, haloalkyl or halogen; R3 is hydrogen, lower alkyl or haloalkyl ; and R4 is cycloalkyl, cycloalkenyl, aryl or substituted aryl. Further embodiments include compounds represented by Formula 2 wherein R, is sulfamy ; R2 is haloalkyl ; R3 is hydrogen or lower alkyl ; and R4 is aryl or substituted aryl.

The terms that are used in the formulas have the following definitions: The term"hydrogen"means a single hydrogen atom.

The term"alkyl"means linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. Some alkyl radicals are "lower alkyl"radicals having one to about ten carbon atoms. Others are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl ; isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso- amyl, and hexyl.

The term"cycloalkyl", means saturated carbocyclic radicals having three to twelve carbon atoms. Some cycloalkyl radicals are"lower cycloalkyl"radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term"cycloalkenyl"means partially unsaturated carbocyclic radicals having three to twelve carbon atoms. Some cycloalkenyl radicals are"lower cycloalkenyl"radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl.

The term"halo"means halogen radicals such as fluorine, chlorine, bromine or iodine radicals.

The term"haloalkyl"means radicals wherein any one or more of the alkyl hydrogen atoms is substituted with halogen radical as defined above such as monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodine, bromine, chlorine or fluorine atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halogen radicals or a combination of different halogen radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

The terms"alkoxy"and"alkyloxy"mean linear or branched oxygen-containing radicals each having alkyl portions of one to about ten carbon atoms. Some alkoxy radicals are"lower alkoxy"radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.

The term"alkoxyalkyl"means alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. The"alkoxy"radicals may be further substituted with one or more halogen radicals such as fluorine, chlorine or bromine radicals to provide haloalkoxy radicals.

Some haloalkoxy radicals are"lower haloalkoxy"radicals having one to six carbon atoms and one or more halogen radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term"aryl"means a carbocyclic aromatic system containing one, two or three rings where these rings may be attached together in a pendent manner or may be fused.

For example, the term"aryl"includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from alkyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl,. alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, arylalkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, thioalkyl, alkoxycarbonyl and arylalkoxycarbonyl.

The term"heteroaryl"means unsaturated, saturated, unsubstituted and substituted heterocyclyl radicals.

The term"benzaheteroaryl"means heteroaryl rings fused to a benzene ring.

The term"alkylthio"means radicals containing a linear or branched alkyl radical of one to about ten carbon atoms attached to a divalent sulfur atom. Some alkylthio

radicals are"lower alkylthio"radicals having alkyl radicals of one to six carbon atoms.

Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio.

The term"lower alkylsulfonyl"means radicals having one to six carbon atoms.

Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The"alkylsulfonyl"radicals may be further substituted with one or more halogen radicals such as fluorine, chlorine or bromine radicals atoms to provide haloalkylsulfonyl radicals.

The terms"sulfamyl","aminosulfonyl"and"sulfonamidyl", denotes the radical NH202S-.

The term"acyl"denotes a radical provided by the residue after removal of hydroxyl from an organic acid.

The terms"carboxy"or"carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes-CO2H.

The term"carboxyalkyl"means alkyl radicals substituted with a carboxy radical.

The term"alkoxycarbonyl"means a radical containing an alkoxy radical attached via an oxygen atom to a carbonyl radical.

The term"alkylamino"denotes amino groups which have been substituted with one or two alkyl radicals..

The term"alkylaminoalkyl"means radicals having one or more alkyl radicals attached to an aminoalkyl radical.

The term"pharmaceutically-acceptable salts"means salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds of Formulas 1 and 2 may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclyl, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic,. beta.-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formulas 1 and 2 include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compounds of Formulas 1 and 2 by reacting, for example, the appropriate acid or base with the compounds of Formulas 1 and 2.

5-HT agonists that are suitable for use in the present invention include compounds that selectively effect 5-HT (5-hydroxytryptamine or serotonin) receptors of the central nervous and vascular systems. This class of compounds has been recognized as useful in migraine therapy. Suitable compounds in this class include sumatriptan, eletriptan, rizatriptan, frovatriptan, almotriptan, zolmitriptan, and naratriptan as well as ergot alkaloids and related compounds such as dihydroergotamine mesylate, ergotamine tartrate, ergonovine maleate, ergoloid mesylates such as dihydroergocornine, dihydroergocristine, dihydroergocryptine, dihydro-. alpha.-ergocryptine, dihydro-. beta.-ergocryptine and dihydroergotamine

mesylate.

The term"5-HT agonist"means all types of HT agonists, including but not limited to 5-HTI-like agonists, 5-HTlB agonists, and 5-HTlD agonists. Specific compounds that have been identified for use in migraine therapy are reported in U. S.

Pat. 6,060,499. Representative compounds include sumatriptan succinate and related 5-HT agonist heterocyclic compounds reported in U. S. Pat. 4,816,470 to Dowle et al.

Representative 5-HT agonist compounds that are commercially available include sumatriptan succinate, available under the tradename IMITREX, and naratriptan hydrochloride, available under the tradename AMERGE, both available from GlaxoWellcome Inc., Research Triangle Park, NC.

Other 5-HT agonist compounds include ergot alkaloids and related compounds such as dihydroergotamine mesylate (DHE 45), ergotamine tartrate, ergonovine maleate, ergoloid mesylates such as dihydroergocornine, dihydroergocristine, dihydroergocryptine, dihydro-. alpha.-ergocryptine and dihydro-. beta.-ergocryptine and dihydroergotamine mesylate.

Still other compounds include eletriptan reported in EP Application 0 379 314, Allelix ALX 1323; rizatriptan, frovatriptan, almotriptan, zolmitriptan and naratriptan.

Related pharmacological compounds are also included within the scope of this invention.

Prophylactic or targeted prophylactic regimens are expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, migraine. The indications for preventative treatment of migraine have been published by the American Academy of Neurology. The"targeted prophylactic"approach is especially relevant for persons with frequent, recurring migraine symptoms who anticipate critical activities during which it is very important to prevent or minimize their migraine-related symptoms.

For some of these patients, it is possible that early, premonitory or actual migraine symptoms will be evident at the time of administration of the agent or agents to be used for treatment. In this case, the treatment is actually acute or abortive but may also be termed"acutely targeted"if the goal is to eliminate or substantially reduce the migraine symptoms during a particular time or activity for a patient. In other cases,

there will be no actual or premonitory symptoms of migraine when this agent or agents are used for targeted prophylaxis. This dosing strategy is very useful for those persons with frequent, recurring high demand activities that have frequent migraine symptoms.

Persons at risk of developing a migraine condition generally include those having a family history of migraine, or those diagnosed or identified by a licensed physician to be particularly susceptible to developing migraine.

The phrase"therapeutically effective"is intended to qualify the amount of each active agent or compound for use in a combination therapy which will achieve the goal of improvement in migraine treatment or therapy or reduced frequency or incidence of migraine over treatment of each agent or compound by itself, while avoiding adverse side effects typically associated with alternative therapies.

For appropriate therapeutic indications, the dosage administered will vary with the compound employed, the mode of administration and the treatment desired.

However, in general, satisfactory results are obtained when the compounds are administered at a daily dosage of the solid form of between 1 mg and 2000 mg per day.

A unit dose of about 0.01 to 100 mg/kg body weight, preferably between about 0.1 and about 50 mg/kg body weight and most preferably from about 1 to 20 mg/kg body weight, may be appropriate.

The amount of the compound actually administered will be determined by a physician in light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, the age, weight, and response symptoms, and the chosen route of administration. Therefore the dosage ranges are not intended as a limitation to the scope of the invention.

The agents or compounds of this invention may be used on their own, or preferably as a pharmaceutical composition in which the compounds or derivatives are in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier in a form appropriate for enteral or parenteral administration. The pharmaceutical composition preferably comprises less than 80% and more preferably less than 50% of the agent, compound or derivative. Examples of suitable adjuvants, diluents and carriers are well known and include microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium

bicarbonate and/or gelatin.

Also included within this invention is a class of pharmaceutical compositions comprising the active agents or compounds of this combination therapy in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to as"carrier"materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and composition may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition where, for example, saline, dextrose or water may be used as a suitable carrier. For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered orally, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxy-propylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants

and modes of administration are well and widely known in the pharmaceutical art.

The following examples further describe the method of the present invention.

These examples illustrate alternative embodiments of the invention and do not limit the scope of the appended claims.

Examples Example 1 A patient with an established history of recurrent migraine was treated with a daily oral dose of 25 mg. of VIOXX (rofecoxib tablets, Merck & Co, Inc., West Point, PA). The patient was free of migraine symptoms during the first week of use and noticed a reduced intensity of the symptoms of subsequent migraines as well as a reduced frequency of migraines during the treatment period of three to four weeks while taking the VIOXX tablets.

Example 2 A patient with an established history of recurrent migraine was treated with a daily oral dose of 25 mg of VIOXX (rofecoxib tablets, Merck) and 325 mg of enteric aspirin tablets (over the counter buffered aspirin). The patient noted a lower incidence and intensity of migraine symptoms while taking the combination of VIOXX and aspirin tablets.

Example 3 A patient with an established history of recurrent migraine was treated with a daily oral dose of 12.5 mg of VIOXX (rofecoxib tablets, Merck & Co, Inc., West Point, PA) and 162.5 mg aspirin tablets (over the counter aspirin) for about four weeks.

Then the patient switched to an every other day regimen of 12.5-25 mg VIOXX tablets alternating with 325 mg aspirin tablets. The patient noted a lower incidence and intensity of migraine symptoms during the treatment period of about 52 weeks. He also noted a significant reduction in the use of 5-HT receptor agonists (IMITREX injections and nasal spray, Glaxo Wellcome Inc., Research Triangle Park, NC and AMERGE tablets, Glaxo Wellcome) while taking the combination of VIOXX and aspirin tablets.

Example 4

A patient with an established history of recurrent migraine was treated with a daily oral dose of 200 mg of CELEBREX (celecoxib capsules, G. D. Searle & Co., Chicago, IL). The patient was free of migraine symptoms during the treatment period of ten to fourteen days and noticed a reduced intensity of the symptoms of a subsequent migraine while taking the CELEBREX capsules.

Example 5 A patient with an established history of migraine brought on by glare associated with an opthalmic operating room microscope was treated with 6 mg of IMITREX by injection (Glaxo Wellcome Inc.), and an oral dose of 12.5-25 mg of VIOXX (Merck & Co, Inc.) the night before a scheduled opthalmic operation. The patient was free of migraine symptoms before, during and after the scheduled operation after targeted prophylactic treatment with the combination of IMITREX injection and VIOXX tablet treatment on many occasions. There were other occasions where there were migraine symptoms present at a greatly reduced intensity as compared to a full- fledged migraine, so that he was able to function effectively.