WO2023059698A1

WO2023059698A1 - Methods and compositions for treating von willebrand's migraine disorder

Info

Publication number: WO2023059698A1
Application number: PCT/US2022/045753
Authority: WO
Inventors: Bradford C. SIPPY
Original assignee: Tremeau Pharmaceuticals, Inc.
Priority date: 2021-10-06
Filing date: 2022-10-05
Publication date: 2023-04-13

Abstract

Disclosed herein are methods of treating migraine in a subject with von Willebrand's migraine disorder. In certain aspects, the methods of treating migraine in a subject with von Willebrand's migraine disorder comprise administering to the subject a pharmaceutical composition comprising an effective amount of a non-opioid migraine therapy.

Description

METHODS AND COMPOSITIONS FOR TREATING VON WILLEBRAND’S MIGRAINE DISORDER

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Number 63/252,842, filed October 6, 2021, titled METHODS AND COMPOSITIONS FOR TREATING VON WILLEBRAND’S MIGRAINE DISORDER, the contents of which are incorporated herewith by reference in their entirety.

BACKGROUND

[0002] Non-selective non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit both types of the cyclooxygenase (COX) enzyme (e.g., COX-1 and COX-2), and opioids are commonly used to treat migraines. See Ghlichloo, I., Gerriets, V., Nonsteroidal Antiinflammatory Drugs (NSAIDs), updated 2020 May 18, StatPearls, Treasure Island, Florida: StatPearls Publishing, 2021, and Levin, M., Opioids in Headache, The Journal of Headache and Face Pain, 2014, 54, 12-21. However, using opioids for migraine treatment can result in more frequent and severe headaches. Non-selective NSAIDs have numerous contraindications, including renal insufficiency, peptic ulcer disease, gastritis, pregnancy, hypersensitivity, hypertension, and bleeding. See The Nonsteroidal Anti-Inflammatory Drugs: Treating Osteoarthritis and Pain. Comparing effectiveness, safety, and price, updated 2013 August 9, Consumer Reports Health Best Buy Drugs, Yonkers, New York: Consumer Reports, 2014. In particular, non-selective NSAIDS are contraindicated for persons with von Willebrand disease (VWD) due to bleeding risk, e.g., gastrointestinal bleeding. See COX-2 Selective (includes Bextra, Celebrex, and Vioxx) and Non-Selective Non-Steroidal Anti- Inflammatory Drugs (NSAIDs), updated 2018 February 6, Postmarket Drug Safety Information for Patients and Providers, U.S. Food and Drug Administration, 2018.

SUMMARY OF THE INVENTION

[0003] Disclosed herein are methods of treating von Willebrand’s migraine disorder, a new disorder discovered by the inventors.

[0004] In one aspect, the present disclosure provides a method of treating migraine in a subject with von Willebrand’s migraine disorder, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of a non-opioid migraine therapy. [0005] In another aspect, the present disclosure provides the use of a non-opioid migraine therapy in the manufacture of a medicament for treating migraine in a subject with von Willebrand’s migraine disorder.

[0006] In another aspect, the present disclosure provides a pharmaceutical composition comprising an effective amount of a non-opioid migraine therapy for use in treating migraine in a subject with von Willebrand’s migraine disorder.

[0007] In another aspect, the present disclosure provides a method of treating migraine in a subject with von Willebrand’s migraine disorder, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of rofecoxib.

[0008] In another aspect, the present disclosure provides the use of rofecoxib in the manufacture of a medicament for treating migraine in a subject with von Willebrand’s migraine disorder.

[0009] In another aspect, the present disclosure provides a pharmaceutical composition comprising an effective amount of rofecoxib for use in treating migraine in a subject with von Willebrand’s migraine disorder.

[0010] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, Figures, and Claims. It should be understood that the aspects disclosed herein are not limited to specific embodiments, methods, or configurations, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.

DEFINITIONS

[0011] The following are definitions of terms used in the present specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0012] The terms “composition” and “formulation” are used interchangeably.

[0013] A “subject” to which administration is contemplated refers to a human (z.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. In some embodiments, the non-human animal is a male or female at any stage of development. In some embodiments, the non-human animal is a transgenic animal or genetically engineered animal.

[0014] As used herein, the term “patient” refers to a subject that is a human or animal. In some embodiments, the patient is a healthy patient who is in a generally healthy condition. In some embodiments, the patient is a health patient who is in a generally healthy condition and is eligible to participate as a healthy volunteer in a Phase 1 pharmacokinetic study of a compound or pharmaceutical composition disclosed herein.

[0015] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound disclosed herein, or a composition thereof, in or on a subject.

[0016] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease disclosed herein. In some embodiments, treatment is administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment is administered in the absence of signs or symptoms of the disease. For example, in some embodiments, treatment is administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). In some embodiments, treatment is continued after symptoms have resolved, for example, to delay or prevent recurrence of a disease or condition.

[0017] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0018] An “effective amount” of a compound disclosed herein refers to an amount sufficient to elicit the desired biological response. In some embodiments, an effective amount of a compound disclosed herein varies depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound disclosed herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound disclosed herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0019] A “therapeutically effective amount” of a compound disclosed herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating migraine in a subject with von Willebrand’s migraine disorder.

[0020] A “prophylactically effective amount” of a compound disclosed herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing migraine in a subject with von Willebrand’s migraine disorder.

[0021] As used herein the term “inhibit” or “inhibition” in the context of enzymes, for example, in the context of COX or COX-2, refers to a reduction in the activity of the enzyme. In some embodiments, the term refers to a reduction of the level of enzyme activity, e.g., COX activity or COX-2 activity, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of enzyme activity. In some embodiments, the term refers to a reduction of the level of enzyme activity, e.g., COX activity or COX-2 activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of enzyme activity.

[0022] The term “von Willebrand’s disease” refers to a blood disorder in which the blood does not clot properly due to decreased von Willebrand factor levels or defective von Willebrand factor protein. Type I von Willebrand’s disease is the most common form of von Willebrand’s disease and relates to a reduced level of von Willebrand Factor and/or Factor VIII. Type II von Willebrand’s disease relates to qualitative defects of von Willebrand Factor. Type II von Willebrand’s disease is further characterized into four subtypes (IIA, IIB, IIM, and IIN) according to the defect associated with von Willebrand factor. Type III von Willebrand’s disease is the most severe form in which a person lacks or has very low levels of von Willebrand Factor and low levels of Factor VIII. von Willebrand’s disease is typically inherited, but may arise due to spontaneous mutation or from an underlying medical condition (e.g., medication or another disease) that causes the immune system to destroy von Willebrand factor.

[0023] The term “von Willebrand factor” or “vWF” refers to a blood glycoprotein involved in hemostasis, von Willebrand factor is deficient and/or defective in von Willebrand disease, von Willebrand factor is produced by platelets, megakaryocytes, and endothelial cells. Von Willebrand factor is composed of 220 kDa monomers that associate to form a series of high molecular weight multimers. These multimers normally range in molecular weight from 600- 20,000 kDa. von Willebrand factor participates in coagulation by stabilizing circulating coagulation Factor VIII and by mediating platelet adhesion to exposed subendothelium and to other platelets. See Leebeek, F. W. G.; Eikenboom, J. C. J. von Willebrand’s Disease. The New England Journal of Medicine, 2018, 375, 2067-2080.

[0024] The term “von Willebrand factor corrective agent” refers to an agent administered to correct defective platelet adhesion-aggregation and abnormal coagulation. In some embodiments, the von Willebrand factor corrective agent increases von Willebrand factor levels. In some embodiments, the von Willebrand factor corrective agent increases Factor VIII levels. In some embodiments, the von Willebrand factor corrective agent increases von Willebrand factor levels and Factor VIII levels. In some embodiments, the von Willebrand factor corrective agent increases endogenous production of von Willebrand factor and/or Factor VIII. In some embodiments, the von Willebrand factor corrective agent is von Willebrand factor replacement therapy. In some embodiments, the von Willebrand factor corrective agent is a von Willebrand’s activating agent. In some embodiments, the von Willebrand factor corrective agent is a gene therapy. In some embodiments, the von Willebrand factor corrective agent achieves a hemostatic affect without affecting the von Willebrand factor levels.

[0025] The term “migraine” refers to a paroxysmal headache. In some embodiments, migraine is accompanied by transient neurological symptoms. In some embodiments, the migraine lasts from 2 to 72 hours. In some embodiments, the migraine is accompanied by nausea, vomiting, or sensitivity to light, sound, or smell. In some embodiments, the headache is characterized by unilateral pain, pain on one half of the head, throbbing pain, moderate to severe pain, or pain, aggravated by physical activity. In some embodiments, the migraine is preceded by or coincides with an aura, such as transient visual, sensory, language, or motor disturbance. In some embodiments, migraine with aura can occur with little or no headache. In some embodiments, the migraine is an acute migraine, chronic migraine, migraine with aura, migraine without aura, ocular migraine, silent migraine, hemiplegic migraine, vestibular migraine, menstrual migraine, abdominal migraine, basilar migraine, status migrainosus, transformed migraine, or cyclic migraine. In some embodiments, migraine is diagnosed by one or more of medical history, family history, symptoms, neurological examination, MRI scan, or CT scan. In some embodiments, migraine is diagnosed by a self-administered tool. In some embodiments, the self-administered tool is ID-CM, which is described in Lipton, R. B., et al. Improving the detection of chronic migraine: Development and validation of Identify Chronic Migraine (ID-CM), Cephalalgia, 2016, 36, 203-215, the contents of which are hereby incorporated by reference in their entirety. In some embodiments, migraine is diagnosed by a neurologist, headache specialist, primary care physician, or hematologist.

[0026] The term “acute migraine” refers to a single headache attack in a patient with migraine. In some embodiments, an acute migraine refers to a single occurrence of episodic migraines.

[0027] The term “chronic migraine” refers to a migraine headache occurring on 15 or more days per month for more than three months in the absence of medication, as defined by the International Classification of Headache Disorders. Clinical guidelines for the diagnosis of chronic migraine can be found, for example, in the ICHD-3, Cephalalgia, 2018, 38(1): 1-211, the contents of which are hereby incorporated by reference in their entirety. In some embodiments, chronic migraine is diagnosed by a self-administered tool. In some embodiments, the self-administered tool is ID-CM. In some embodiments, chronic migraine is diagnosed by ID-CM based on symptoms and frequency. In some embodiments, chronic migraine is diagnosed by ID-CM based on medication use, activities, or making plans. In some embodiments, chronic migraine is diagnosed by ID-CM based on frequency and symptoms criteria and medication use, activities, and making plans criteria.

[0028] The term “von Willebrand’s migraine disorder” refers to the increased prevalence (e.g., several-fold higher prevalence) of migraines in people having von Willebrand’s disease relative to the estimated prevalence of migraine in the general population. In some embodiments, the von Willebrand’s migraine disorder is diagnosed. In some embodiments, the von Willebrand’s migraine disorder is undiagnosed.

[0029] The term “pain” includes, but is not limited to, pain associated with migraine or von Willebrand’s migraine disorder. In some embodiments, pain is measured through any clinically-validated pain assessment measurement. In some embodiments, pain is measured through the Pain Intensity Numerical Rating Scale. In some embodiments, pain is measured by use of a visual analogue scale (“VAS,” such as a 10 cm scale with 0 representing no pain and 10 representing maximal pain). In some embodiments, the pain is mild, moderate, or severe pain associated with von Willebrand’s migraine disorder.

[0030] Unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular. The singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise. The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0031] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. It will be understood that when a range is recited in the application, the ends of the range are specifically disclosed as if specifically recited. For example, a range of about 19% to about 99% specifically include a disclosure separately of 19% and separately of 99%.

[0032] Other than in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, or more typically, within 5%, 4%, 3%, 2%, or 1% of a given value or range of values. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0033] The inventors have unexpectedly discovered that certain patients having von Willebrand’s disease may suffer from a previously uncharacterized migraine disorder. In particular, the inventors unexpectedly discovered a significantly higher prevalence of migraine diagnosis in patients having von Willebrand’s disease as compared to the general population, with a similar prevalence between subtypes of von Willebrand’s disease, i.e. subtypes I, II, and III. Surprisingly, rates did not vary significantly by gender, even though migraines are three-fold more common in females than in males in the general population. On average, patients with von Willebrand’s disease were diagnosed with migraines at a relatively early age and suffer from general migraine, rather than chronic migraine. This migraine disorder will be referred to herein as “von Willebrand’s migraine disorder.” The present application answers the significant need for awareness of von Willebrand’s migraine disorder and for effective therapies to treat von Willebrand’s migraine disorder.

[0034] In particular, disclosed herein are methods of treating von Willebrand’s migraine disorder. The inventors unexpectedly discovered that von Willebrand’s migraine disorder may be effectively treated without the use of an opioid medication and without the use of non-selective NSAIDs, such as ibuprofen, naproxen sodium, aspirin, diclofenac, mefenamic acid, indomethacin, ketoprofen, and piroxicam. As relatively few patients with von Willebrand’s migraine disorder experience chronic migraine, many patients with von Willebrand’s migraine disorder may benefit from acute interventions. Accordingly, such patients may be able to safely use medications for which chronic administration can be problematic. Without wishing to be bound by theory, the inventors posit that non-opioid, non-NSAID, and COX-2 selective NSAID medications may allow for safer and effective methods of treatment for von Willebrand’s migraine disorder, especially as compared to other therapies that may be contraindicated for patients with von Willebrand disease, such as analgesics that affect platelet function or carry a higher risk of gastrointestinal bleeding. For example, celecoxib, a COX-2 selective inhibitor, has poor central nervous system penetration and is therefore likely to be ineffective for the treatment of migraines. See Dembo, G., Park, S. B., Kharasch, E. D., Central Nervous System Concentrations of Cyclooxygenase-2 Inhibitors in Humans, Anesthesiology, 2005, 102, 409-415.

Active Ingredients for the Treatment of von Willebrand’ s Migraine Disorder

[0035] In some embodiments, the non-opioid migraine therapy is not a non-selective NSAID.

In some embodiments, the non-opioid migraine therapy is not ibuprofen, naproxen sodium, aspirin, diclofenac, mefenamic acid, indomethacin, ketoprofen, or piroxicam, or a pharmaceutically acceptable salt thereof. In some embodiments, the non-opioid migraine therapy is not ibuprofen, or a pharmaceutically acceptable salt thereof. In some embodiments, the non-opioid migraine therapy is not naproxen sodium, or a pharmaceutically acceptable salt thereof. In some embodiments, the non-opioid migraine therapy is not aspirin, or a pharmaceutically acceptable salt thereof. In some embodiments, the non-opioid migraine therapy is not diclofenac, or a pharmaceutically acceptable salt thereof. In some embodiments, the non-opioid migraine therapy is not mefenamic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, the non-opioid migraine therapy is not indomethacin, or a pharmaceutically acceptable salt thereof. In some embodiments, the non- opioid migraine therapy is not ketoprofen, or a pharmaceutically acceptable salt thereof. In some embodiments, the non-opioid migraine therapy is not piroxicam, or a pharmaceutically acceptable salt thereof. In some embodiments, the non-opioid migraine therapy is not acetaminophen, or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the non-opioid migraine therapy is a COX-2 inhibitor, a serotonin receptor agonist, or a calcitonin gene-related peptide (CGRP) antagonist. In some embodiments, the non-opioid migraine therapy is a COX-2 inhibitor or a serotonin receptor agonist. In some embodiments, the non-opioid migraine therapy is a COX-2 inhibitor. In some embodiments, the non-opioid migraine therapy is a serotonin receptor agonist. In some embodiments, the non-opioid migraine therapy is CGRP antagonist. In some embodiments, the non-opioid migraine therapy is not a CGRP antagonist.

[0037] In some embodiments, the non-opioid migraine therapy is a selective NSAID. In some embodiments, the non-opioid migraine therapy is a COX-2 selective NSAID. In some embodiments, the COX-2 inhibitor is celecoxib, etoricoxib, rofecoxib, valdecoxib, parecoxib, or a pharmaceutically acceptable salt thereof. In some embodiments, the COX-2 inhibitor is celecoxib, or a pharmaceutically acceptable salt thereof. In some embodiments, the COX-2 inhibitor is etoricoxib, or a pharmaceutically acceptable salt thereof. In some embodiments, the COX-2 inhibitor is rofecoxib, or a pharmaceutically acceptable salt thereof. In some embodiments, the COX-2 inhibitor is valdecoxib, or a pharmaceutically acceptable salt thereof. In some embodiments, the COX-2 inhibitor is parecoxib, or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the CGRP antagonist is a small molecule CGRP antagonist. In some embodiments, the CGRP antagonist is BI 44370 TA (BI 44370), MK-3207, olcegepant (BIBN-4096BS), rimegepant (BMS-927711), SB-268262, telcagepant (MK-0974), or ubrogepant, or a pharmaceutically acceptable salt thereof. In some embodiments, the CGRP antagonist is BI 44370 TA (BI 44370), or a pharmaceutically acceptable salt thereof. In some embodiments, the CGRP antagonist is MK-3207, or a pharmaceutically acceptable salt thereof. In some embodiments, the CGRP antagonist is olcegepant (BIBN-4096BS), or a pharmaceutically acceptable salt thereof. In some embodiments, the CGRP antagonist is rimegepant (B MS-927711), or a pharmaceutically acceptable salt thereof. In some embodiments, the CGRP antagonist is SB-268262, or a pharmaceutically acceptable salt thereof. In some embodiments, the CGRP antagonist is telcagepant (MK-0974), or a pharmaceutically acceptable salt thereof. In some embodiments, the CGRP antagonist is ubrogepant, or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the CGRP antagonist is an antibody. In some embodiments, the CGRP antagonist is erenumab (AMG-334), eptinezumab (ALD403), fremanezumab (TEV-48125), or galcanezumab (LY2951742). In some embodiments, the CGRP antagonist is erenumab (AMG-334). In some embodiments, the CGRP antagonist is eptinezumab (ALD403). In some embodiments, the CGRP antagonist is fremanezumab (TEV-48125). In some embodiments, the CGRP antagonist is galcanezumab (LY2951742).

[0040] In some embodiments, the serotonin receptor agonist is a triptan. In some embodiments, the triptan is a full agonist. In some embodiments, the triptan is a partial agonist. In some embodiments, triptan is an agonist of one or more of the serotonin 5-HTIA, 5-HTIB, 5-HTID, 5-HTIE, or 5-HTIF receptors. In some embodiments, triptan is an agonist of the serotonin 5-HTIA receptor. In some embodiments, triptan is an agonist of the serotonin 5- HTIB receptor. In some embodiments, triptan is an agonist of the serotonin 5-HTID receptor. In some embodiments, triptan is an agonist of the serotonin 5-HTIE receptor. In some embodiments, triptan is an agonist of the serotonin 5-HTIF receptor. In some embodiments, the triptan is sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan, frovatriptan, ergotamine or lasmiditan, or a pharmaceutically acceptable salt thereof. In some embodiments, the triptan is sumatriptan, or a pharmaceutically acceptable salt thereof. In some embodiments, the triptan is zolmitriptan, or a pharmaceutically acceptable salt thereof. In some embodiments, the triptan is naratriptan, or a pharmaceutically acceptable salt thereof. In some embodiments, the triptan is rizatriptan, or a pharmaceutically acceptable salt thereof. In some embodiments, the triptan is almotriptan, or a pharmaceutically acceptable salt thereof. In some embodiments, the triptan is eletriptan, or a pharmaceutically acceptable salt thereof. In some embodiments, the triptan is frovatriptan, or a pharmaceutically acceptable salt thereof. In some embodiments, the triptan is ergotamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the triptan is lasmiditan, or a pharmaceutically acceptable salt thereof.

Methods of Use

[0041] In one aspect, the present disclosure provides a method of treating migraine in a subject with von Willebrand’s migraine disorder, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of a non-opioid migraine therapy.

[0042] In another aspect, the present disclosure provides the use of a non-opioid migraine therapy in the manufacture of a medicament for treating migraine in a subject with von Willebrand’s migraine disorder.

[0043] In another aspect, the present disclosure provides a pharmaceutical composition comprising an effective amount of a non-opioid migraine therapy for use in treating migraine in a subject with von Willebrand’s migraine disorder.

[0044] In another aspect, the present disclosure provides a method of treating migraine in a subject with von Willebrand’s migraine disorder, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of rofecoxib.

[0045] In another aspect, the present disclosure provides the use of rofecoxib in the manufacture of a medicament for treating migraine in a subject with von Willebrand’s migraine disorder.

[0046] In another aspect, the present disclosure provides a pharmaceutical composition comprising an effective amount of rofecoxib for use in treating migraine in a subject with von Willebrand’s migraine disorder.

[0047] In some embodiments, the migraine is acute migraine, chronic migraine, migraine with aura, migraine without aura, ocular migraine, silent migraine, hemiplegic migraine, vestibular migraine, menstrual migraine, abdominal migraine, basilar migraine, status migrainosus, transformed migraine, or cyclic migraine. In some embodiments, the migraine is acute migraine. In some embodiments, the migraine is chronic migraine. In some embodiments, the migraine is migraine with aura. In some embodiments, the migraine is migraine without aura. In some embodiments, the migraine is ocular migraine. In some embodiments, the migraine is silent migraine. In some embodiments, the migraine is hemiplegic migraine. In some embodiments, the migraine is vestibular migraine. In some embodiments, the migraine is menstrual migraine. In some embodiments, the migraine is abdominal migraine. In some embodiments, the migraine is basilar migraine. In some embodiments, the migraine is status migrainosus. In some embodiments, the migraine is transformed migraine. In some embodiments, the migraine is cyclic migraine.

[0048] In some embodiments, the von Willebrand’s migraine disorder is associated with von Willebrand’s sub-type I. In some embodiments, the von Willebrand’s migraine disorder is associated with von Willebrand’s sub-type II. In some embodiments, the von Willebrand’s migraine disorder is associated with von Willebrand’s sub-type III.

[0049] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the treatment described herein is administered to a subject of any age. In some embodiments, the subject is age 2 or older, or age 12 years or older. In some embodiments, the patient is of age 12 to 75 years old, inclusive. In some embodiments, the subject is at least 16 years of age. In some embodiments, the subject is at least 18 years of age. In some embodiments, the subject is at most 65 years of age. In some embodiments, the subject is a human. In some embodiments, the subject is a healthy human subject. In some embodiments, the subject is male. In some embodiments, the subject is female.

[0050] In some embodiments, the subject has been diagnosed with von Willebrand’s migraine disorder. In some embodiments, the subject has failed a prior treatment regimen. In some embodiments, the prior treatment regimen comprised administration of acetaminophen, or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, the subject is contraindicated for a non-selective NSAID due to at least one contraindication. In some embodiments, the contraindication is one or more of renal insufficiency, peptic ulcer disease, gastritis, pregnancy, hypersensitivity, hypertension, and bleeding. In some embodiments, the contraindication is renal insufficiency. In some embodiments, the contraindication is peptic ulcer disease. In some embodiments, the contraindication is gastritis. In some embodiments, the contraindication is pregnancy. In some embodiments, the contraindication is hypersensitivity. In some embodiments, the contraindication is hypertension. In some embodiments, the contraindication is bleeding. In some embodiments, the bleeding is gastrointestinal bleeding.

[0052] In some embodiments, the subject has a history or current symptoms of bleeding. In some embodiments, the subject has a history or current symptoms of gastrointestinal bleeding, ulceration, and perforation. In some embodiments, the subject has a history or current symptoms of gastrointestinal bleeding. In some embodiments, the subject has a history or current symptoms of ulceration. In some embodiments, the subject has a history or current symptoms of perforation. [0053] In some embodiments, the subject is concurrently administered a von Willebrand factor corrective agent. In some embodiments, the subject is not concurrently administered a von Willebrand factor corrective agent. In some embodiments, the von Willebrand factor corrective agent is von Willebrand factor replacement therapy. In some embodiments, the subject is concurrently administered prophylactic von Willebrand factor replacement therapy. In some embodiments, the subject is not concurrently administered prophylactic von Willebrand factor replacement therapy. In some embodiments, the von Willebrand factor corrective agent is a von Willebrand’s activating agent. In some embodiments, the von Willebrand’s activating agent is desmopressin acetate. In some embodiments, the von Willebrand factor corrective agent is a gene therapy.

[0054] In some embodiments, a patient administered treatment for migraine associated with von Willebrand deficiency expresses von Willebrand factor at a level about 50% below normal. In certain embodiments, a patient administered treatment for migraine associated with von Willebrand deficiency expresses von Willebrand factor at a level about 45% below normal. In some embodiments, a patient administered treatment for migraine associated with von Willebrand deficiency expresses von Willebrand factor at a level about 40% below normal. In certain embodiments, a patient administered treatment for migraine associated with von Willebrand deficiency expresses von Willebrand factor at a level about 35% below normal. In some embodiments, a patient administered treatment for migraine associated with von Willebrand deficiency expresses von Willebrand factor at a level about 30% below normal. In certain embodiments, a patient administered treatment for migraine associated with von Willebrand deficiency expresses von Willebrand factor at a level about 25% below normal. In some embodiments, a patient administered treatment for migraine associated with von Willebrand deficiency expresses von Willebrand factor at a level about 20% below normal. In certain embodiments, a patient administered treatment for migraine associated with von Willebrand deficiency expresses von Willebrand factor at a level about 15% below normal. In some embodiments, a patient administered treatment for migraine associated with von Willebrand deficiency expresses von Willebrand factor at a level about 10% below normal. In certain embodiments, a patient administered treatment for migraine associated with von Willebrand deficiency expresses von Willebrand factor at a level about 5% below normal.

[0055] In some embodiments, a patient administered treatment for migraine associated with von Willebrand deficiency exhibits or shows signs of excessive bleeding. In certain embodiments, the excessive bleeding occurs due to slow clotting. In some embodiments, the excessive bleeding is due to missing clotting factors. In certain embodiments, the excessive bleeding is due to damaged clotting factors. In some embodiments, the excessive bleeding occurs from too few platelets. In certain embodiments, the excessive bleeding occurs because of defective platelets. In some embodiments, the patient exhibits excessively long bleeding. In certain embodiments, the patient exhibits excessive loss of blood. In some embodiments, the patient exhibits signs of excessive bleeding. In certain embodiments, the signs of excessive bleeding are cuts that bleed too much, unexpected bruising, petechiae, blood in vomit, black bowel movements, bloody bowel movements, red urine, dizziness, headaches, vision changes, joint pain, gum bleeding, nose bleeding, long menstrual periods, or heavy menstrual periods. In some embodiments, the signs of excessive bleeding are cuts that bleed too much. In certain embodiments, the signs of excessive bleeding are unexpected bruising. In some embodiments, the signs of excessive bleeding are petechiae. In certain embodiments, the signs of excessive bleeding are blood in vomit. In some embodiments, the signs of excessive bleeding are black bowel movements or bloody bowel movements. In certain embodiments, the sign of excessive bleeding is red urine. In some embodiments, the signs of excessive bleeding are dizziness, headaches, or vision changes. In certain embodiments, the sign of excessive bleeding is joint pain. In some embodiments, the sign of excessive bleeding is gum bleeding. In certain embodiments, the sign of excessive bleeding is nose bleeding. In some embodiments, the signs of excessive bleeding are long menstrual periods or heavy menstrual periods

[0056] In some embodiments, the non-opioid migraine therapy is effective at treating the migraine disorder without the co-administration of a von Willebrand factor corrective agent. In some embodiments, the treatment described herein is effective at treating mild, moderate, or severe pain associated with von Willebrand’s migraine disorder in a subject without the co-administration of another pain medication or analgesic. In some embodiments, the treatment described herein results in the subject decreasing or discontinuing the use of another pain medication or analgesic, including rescue medications, during the course of the treatment when compared to before the initiation of the treatment. In some embodiments, the treatment results in the subject decreasing or discontinuing the use of NSAID and/or opioid medications during the treatment during the course of the treatment when compared to before the initiation of the treatment.

[0057] In some embodiments, the therapeutically effective amount is administered to the subject once daily. In some embodiments, the therapeutically effective amount is administered to the subject twice daily. In some embodiments, the therapeutically effective amount is administered to the subject two times or more daily. In some embodiments, the therapeutically effective amount is administered to the subject three times daily. In some embodiments, the method further comprises administering a loading dose of the compound and a maintenance dose of the compound. In some embodiments, the therapeutically effective amount is administered with food. In some embodiments, the therapeutically effective amount is administered under fasted conditions.

[0058] In some embodiments, about 10 mg to about 2500 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 10 mg, about 15 mg, about 17.5 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 1000 mg, or about 2500 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 10 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 15 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 17.5 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 20 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 25 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 50 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 75 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 100 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 150 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 200 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 250 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 300 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 350 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 400 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 450 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 500 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 550 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 600 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 650 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 700 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 750 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 800 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 850 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 900 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 1000 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day. In some embodiments, about 2500 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day.

[0059] In some embodiments, the effective amount is about 0.1 mg to about 2,500 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 0.1 mg to about 1,000 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 0.1 mg to about 500 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 1 mg to about 2,500 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 1 mg to about 1,000 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 1 mg to about 500 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 1 mg to about 300 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 5 mg to about 300 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 5 mg to about 250 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 5 mg to about 200 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 5 mg to about 150 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 5 mg to about 140 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 5 mg to about 130 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 5 mg to about 120 mg of the non-opioid migraine therapy.

[0060] In some embodiments, the effective amount of the non-opioid migraine therapy is about 1 mg, 2mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 110 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, or 300 mg. In certain embodiments, the effective amount is about 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 110 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, or 300 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 5 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 7.5 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 10 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 12.5 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 15 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 17.5 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 20 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 22.5 mg of the non- opioid migraine therapy. In some embodiments, the effective amount is about 25 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 27.5 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 30 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 35 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 40 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 45 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 50 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 55 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 60 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 65 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 70 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 75 mg of the non- opioid migraine therapy. In some embodiments, the effective amount is about 80 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 85 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 90 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 100 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 110 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 120 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 140 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 160 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 180 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 200 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 220 mg of the non- opioid migraine therapy. In certain embodiments, the effective amount is about 240 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 260 mg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 280 mg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 300 mg of the non-opioid migraine therapy.

[0061] In some embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 25 mg to about 400 mg. In certain embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 50 mg to about 400 mg. In some embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 25 mg. In certain embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 50 mg. In some embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 75 mg. In certain embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 100 mg. In some embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 125 mg. In certain embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 150 mg. In some embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 175 mg. In certain embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 200 mg. In some embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 225 mg. In certain embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 250 mg. In some embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 275 mg. In certain embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 300 mg. In some embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 325 mg. In certain embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 350 mg. In some embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 375 mg. In certain embodiments, the non-opioid migraine therapy is celecoxib, and the effective amount is about 400 mg.

[0062] In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 5 mg to about 300 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 30 mg to about 120 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 5 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 7.5 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 10 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 12.5 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 15 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 17.5 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 20 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 22.5 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 25 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 27.5 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 30 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 35 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 40 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 45 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 50 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 55 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 60 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 65 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 70 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 75 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 80 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 85 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 90 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 100 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 110 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 120 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 140 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 160 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 180 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 200 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 220 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 240 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 260 mg. In certain embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 280 mg. In some embodiments, the non-opioid migraine therapy is etoricoxib, and the effective amount is about 300 mg.

[0063] In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 0.5 mg to about 500 mg. In some embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 5 mg to about 500 mg. In some embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 12.5 mg to about 500 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 12.5 mg to about 50 mg. In some embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 0.5 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 1.0 mg. In some embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 1.5 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 2.0 mg. In some embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 2.5 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 5.0 mg. In some embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 7.5 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 10.0 mg. In some embodiments, the non- opioid migraine therapy is rofecoxib, and the effective amount is about 12.5 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 15.0 mg. In some embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 17.5 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 20.0 mg. In some embodiments, the non- opioid migraine therapy is rofecoxib, and the effective amount is about 22.5 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 25.0 mg. In some embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 30 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 35 mg. In some embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 40 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 45 mg. In some embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 50 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 75 mg. In some embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 100 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 125 mg. In some embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 150 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 175 mg. In some embodiments, the non- opioid migraine therapy is rofecoxib, and the effective amount is about 200 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 225 mg. In some embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 250 mg. In some embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 275 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 300 mg. In some embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 400 mg. In certain embodiments, the non-opioid migraine therapy is rofecoxib, and the effective amount is about 500 mg.

[0064] In some embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 5 mg to about 50 mg. In certain embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 10 mg to about 40 mg. In some embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 5 mg. In certain embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 7.5 mg. In some embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 10.0 mg. In certain embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 12.5 mg. In some embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 15.0 mg. In certain embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 17.5 mg. In some embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 20.0 mg. In certain embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 22.5 mg. In some embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 25.0 mg. In certain embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 30 mg. In some embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 35 mg. In certain embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 40 mg. In some embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 45 mg. In certain embodiments, the non-opioid migraine therapy is valdecoxib, and the effective amount is about 50 mg.

[0065] In certain embodiments, the non-opioid migraine therapy is parecoxib, and the effective amount is about 1 mg to about 100 mg. In certain embodiments, the non-opioid migraine therapy is parecoxib, and the effective amount is about 5 mg to about 50 mg. In some embodiments, the non-opioid migraine therapy is parecoxib, and the effective amount is about 5 mg. In certain embodiments, the non-opioid migraine therapy is parecoxib, and the effective amount is about 7.5 mg. In some embodiments, the non-opioid migraine therapy is parecoxib, and the effective amount is about 10.0 mg. In certain embodiments, the non- opioid migraine therapy is parecoxib, and the effective amount is about 12.5 mg. In some embodiments, the non-opioid migraine therapy is parecoxib, and the effective amount is about 15.0 mg. In certain embodiments, the non-opioid migraine therapy is parecoxib, and the effective amount is about 17.5 mg. In some embodiments, the non-opioid migraine therapy is parecoxib, and the effective amount is about 20.0 mg. In certain embodiments, the non-opioid migraine therapy is parecoxib, and the effective amount is about 22.5 mg. In some embodiments, the non-opioid migraine therapy is parecoxib, and the effective amount is about 25.0 mg. In certain embodiments, the non-opioid migraine therapy is parecoxib, and the effective amount is about 30 mg. In some embodiments, the non-opioid migraine therapy is parecoxib, and the effective amount is about 35 mg. In certain embodiments, the non- opioid migraine therapy is parecoxib, and the effective amount is about 40 mg. In some embodiments, the non-opioid migraine therapy is parecoxib, and the effective amount is about 45 mg. In certain embodiments, the non-opioid migraine therapy is parecoxib, and the effective amount is about 50 mg.

[0066] In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 0.5 mg to about 150 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 3 mg to about 100 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 0.5 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 1.0 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 1.5 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 2.0 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 2.5 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 3.0 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 3.5 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 4.0 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 4.5 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 5.0 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 5.5 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 6.0 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 6.5 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 7.0 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 7.5 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 8.0 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 8.5 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 9.0 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 9.5 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 10.0 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 10.5 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 11.0 mg. In some embodiments, the non- opioid migraine therapy is sumatriptan, and the effective amount is about 11.5 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 12.0 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 12.5 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 15.0 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 17.5 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 20.0 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 22.5 mg. In certain embodiments, the non- opioid migraine therapy is sumatriptan, and the effective amount is about 25.0 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 30 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 35 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 40 mg. In certain embodiments, the non- opioid migraine therapy is sumatriptan, and the effective amount is about 45 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 50 mg. In certain embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 75 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 100 mg. In certain embodiments, the non- opioid migraine therapy is sumatriptan, and the effective amount is about 125 mg. In some embodiments, the non-opioid migraine therapy is sumatriptan, and the effective amount is about 150 mg.

[0067] In some embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 0.25 mg to about 10 mg. In certain embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 1 mg to about 5 mg. In some embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 0.25 mg. In certain embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 0.50 mg. In some embodiments, the nonopioid migraine therapy is zolmitriptan, and the effective amount is about 0.75 mg. In certain embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 1.0 mg. In some embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 1.25 mg. In certain embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 1.5 mg. In some embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 1.75 mg. In certain embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 2.0 mg. In some embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 2.25 mg. In certain embodiments, the non- opioid migraine therapy is zolmitriptan, and the effective amount is about 2.5 mg. In some embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 2.75 mg. In certain embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 3.0 mg. In some embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 3.5 mg. In certain embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 4.0 mg. In some embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 4.5 mg. In certain embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 5.0 mg. In some embodiments, the non- opioid migraine therapy is zolmitriptan, and the effective amount is about 5.5 mg. In certain embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 6.0 mg. In some embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 6.5 mg. In certain embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 7.0 mg. In some embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 7.5 mg. In certain embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 8.0 mg. In some embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 8.5 mg. In certain embodiments, the non- opioid migraine therapy is zolmitriptan, and the effective amount is about 9.0 mg. In some embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 9.5 mg. In certain embodiments, the non-opioid migraine therapy is zolmitriptan, and the effective amount is about 10 mg.

[0068] In some embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 0.25 mg to about 10 mg. In certain embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 1 mg to about 2.5 mg. In some embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 0.25 mg. In certain embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 0.50 mg. In some embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 0.75 mg. In certain embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 1.0 mg. In some embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 1.25 mg. In certain embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 1.5 mg. In some embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 1.75 mg. In certain embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 2.0 mg. In some embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 2.25 mg. In certain embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 2.5 mg. In some embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 2.75 mg. In certain embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 3.0 mg. In some embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 3.5 mg. In certain embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 4.0 mg. In some embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 4.5 mg. In certain embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 5.0 mg. In some embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 5.5 mg. In certain embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 6.0 mg. In some embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 6.5 mg. In certain embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 7.0 mg. In some embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 7.5 mg. In certain embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 8.0 mg. In some embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 8.5 mg. In certain embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 9.0 mg. In some embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 9.5 mg. In certain embodiments, the non-opioid migraine therapy is naratriptan, and the effective amount is about 10 mg. [0069] In certain embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 2.5 mg to about 25 mg. In some embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 5 mg to about 10 mg. In certain embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 2.5 mg. In some embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 3.0 mg. In certain embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 3.5 mg. In some embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 4.0 mg. In certain embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 4.5 mg. In some embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 5.0 mg. In certain embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 5.5 mg. In some embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 6.0 mg. In certain embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 6.5 mg. In some embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 7.0 mg. In certain embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 7.5 mg. In some embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 8.0 mg. In certain embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 8.5 mg. In some embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 9.0 mg. In certain embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 9.5 mg. In some embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 10.0 mg. In certain embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 10.5 mg. In some embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 12.5 mg. In certain embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 15.0 mg. In some embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 17.5 mg. In certain embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 20.0 mg. In some embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 22.5 mg. In certain embodiments, the non-opioid migraine therapy is rizatriptan, and the effective amount is about 25.0 mg.

[0070] In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 2.5 mg to about 25 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 6.25 mg to about 12.5 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 0.5 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 1.0 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 1.5 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 2.0 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 2.5 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 3.0 mg. In some embodiments, the non- opioid migraine therapy is almotriptan, and the effective amount is about 3.5 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 4.0 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 4.5 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 5.0 mg. In some embodiments, the non- opioid migraine therapy is almotriptan, and the effective amount is about 5.5 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 5.75 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 6.0 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 6.25 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 6.5 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 6.75 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 7.0 mg. In certain embodiments, the non- opioid migraine therapy is almotriptan, and the effective amount is about 7.25 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 7.5 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 8.0 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 8.5 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 9.0 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 9.5 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 10.0 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 10.5 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 11.0 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 11.5 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 11.75 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 12.0 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 12.25 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 12.5 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 12.75 mg. In some embodiments, the non- opioid migraine therapy is almotriptan, and the effective amount is about 13.0 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 13.5 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 14.0 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 15.0 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 17.5 mg. In certain embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 20.0 mg. In some embodiments, the non-opioid migraine therapy is almotriptan, and the effective amount is about 22.5 mg. In certain embodiments, the non- opioid migraine therapy is almotriptan, and the effective amount is about 25.0 mg.

[0071] In some embodiments, the non-opioid migraine therapy is eletriptan, and the effective amount is about 5 mg to about 50 mg. In certain embodiments, the non-opioid migraine therapy is eletriptan, and the effective amount is about 20 mg to about 40 mg. In some embodiments, the non-opioid migraine therapy is eletriptan, and the effective amount is about 5 mg. In certain embodiments, the non-opioid migraine therapy is eletriptan, and the effective amount is about 7.5 mg. In some embodiments, the non-opioid migraine therapy is eletriptan, and the effective amount is about 10.0 mg. In certain embodiments, the non- opioid migraine therapy is eletriptan, and the effective amount is about 12.5 mg. In some embodiments, the non-opioid migraine therapy is eletriptan, and the effective amount is about 15.0 mg. In certain embodiments, the non-opioid migraine therapy is eletriptan, and the effective amount is about 17.5 mg. In some embodiments, the non-opioid migraine therapy is eletriptan, and the effective amount is about 20.0 mg. In certain embodiments, the non- opioid migraine therapy is eletriptan, and the effective amount is about 22.5 mg. In some embodiments, the non-opioid migraine therapy is eletriptan, and the effective amount is about 25.0 mg. In certain embodiments, the non-opioid migraine therapy is eletriptan, and the effective amount is about 30 mg. In some embodiments, the non-opioid migraine therapy is eletriptan, and the effective amount is about 35 mg. In certain embodiments, the non-opioid migraine therapy is eletriptan, and the effective amount is about 40 mg. In some embodiments, the non-opioid migraine therapy is eletriptan, and the effective amount is about 45 mg. In certain embodiments, the non-opioid migraine therapy is eletriptan, and the effective amount is about 50 mg.

[0072] In some embodiments, the non-opioid migraine therapy is frovatriptan, and the effective amount is about 0.25 mg to about 10 mg. In certain embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 1 mg to about 2.5 mg. In some embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 0.25 mg. In certain embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 0.50 mg. In some embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 0.75 mg. In certain embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 1.0 mg. In some embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 1.25 mg. In certain embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 1.5 mg. In some embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 1.75 mg. In certain embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 2.0 mg. In some embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 2.25 mg. In certain embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 2.5 mg. In some embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 2.75 mg. In certain embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 3.0 mg. In some embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 3.5 mg. In certain embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 4.0 mg. In some embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 4.5 mg. In certain embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 5.0 mg. In some embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 5.5 mg. In certain embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 6.0 mg. In some embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 6.5 mg. In certain embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 7.0 mg. In some embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 7.5 mg. In certain embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 8.0 mg. In some embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 8.5 mg. In certain embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 9.0 mg. In some embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 9.5 mg. In certain embodiments, the non-opioid migraine therapy is fovratriptan, and the effective amount is about 10 mg.

[0073] In some embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 0.25 mg to about 10 mg. In certain embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 1 mg to about 9 mg. In some embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 0.25 mg. In certain embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 0.50 mg. In some embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 0.75 mg. In certain embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 1.0 mg. In some embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 1.25 mg. In certain embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 1.5 mg. In some embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 1.75 mg. In certain embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 2.0 mg. In some embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 2.25 mg. In certain embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 2.5 mg. In some embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 2.75 mg. In certain embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 3.0 mg. In some embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 3.5 mg. In certain embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 4.0 mg. In some embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 4.5 mg. In certain embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 5.0 mg. In some embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 5.5 mg. In certain embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 6.0 mg. In some embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 6.5 mg. In certain embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 7.0 mg. In some embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 7.5 mg. In certain embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 8.0 mg. In some embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 8.5 mg. In certain embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 9.0 mg. In some embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 9.5 mg. In certain embodiments, the non-opioid migraine therapy is ergotamine, and the effective amount is about 10 mg.

[0074] In some embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 25 mg to about 250 mg. In certain embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 50 mg to about 200 mg. In some embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 25 mg. In certain embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 50 mg. In some embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 75 mg. In certain embodiments, the non- opioid migraine therapy is lasmiditan, and the effective amount is about 100 mg. In some embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 125 mg. In certain embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 150 mg. In some embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 175 mg. In certain embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 200 mg. In some embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 225 mg. In certain embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 250 mg. In some embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 275 mg. In certain embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 300 mg. In some embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 325 mg. In certain embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 350 mg. In some embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 375 mg. In certain embodiments, the non-opioid migraine therapy is lasmiditan, and the effective amount is about 400 mg.

[0075] In some embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 25 mg to about 450 mg. In certain embodiments, the non- opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 50 mg to about 400 mg. In some embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 25 mg. In certain embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 50 mg. In some embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 75 mg. In certain embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 100 mg. In some embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 125 mg. In certain embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 150 mg. In some embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 175 mg. In certain embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 200 mg. In some embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 225 mg. In certain embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 250 mg. In some embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 275 mg. In certain embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 300 mg. In some embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 325 mg. In certain embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 350 mg. In some embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 375 mg. In certain embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 400 mg. In some embodiments, the non-opioid migraine therapy is BI 44370 TA (BI 44370), and the effective amount is about 450 mg.

[0076] In some embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 1 mg to about 150 mg. In certain embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 2.5 mg to about 100 mg. In certain embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 1.0 mg. In some embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 1.5 mg. In certain embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 2.0 mg. In some embodiments, the non- opioid migraine therapy is MK-3207, and the effective amount is about 2.5 mg. In certain embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 3.0 mg. In some embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 3.5 mg. In certain embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 4.0 mg. In some embodiments, the non- opioid migraine therapy is MK-3207, and the effective amount is about 4.5 mg. In certain embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 5.0 mg. In certain embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 6.0 mg. In certain embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 7.0 mg. In certain embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 8.0 mg. In certain embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 9.0 mg. In certain embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 10.0 mg. In some embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 12.5 mg. In certain embodiments, the non- opioid migraine therapy is MK-3207, and the effective amount is about 15.0 mg. In some embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 17.5 mg. In certain embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 20.0 mg. In certain embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 25.0 mg. In some embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 30 mg. In some embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 40 mg. In some embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 50 mg. In certain embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 75 mg. In some embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 100 mg. In certain embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 125 mg. In some embodiments, the non-opioid migraine therapy is MK-3207, and the effective amount is about 150 mg.

[0077] In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN- 4096BS), and the effective amount is about 0.1 mg to about 15 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 0.25 mg to about 10 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 0.25 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 0.50 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 0.75 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 1.0 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 1.25 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 1.5 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 1.75 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 2.0 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 2.25 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 2.5 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 2.75 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 3.0 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 3.5 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 4.0 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 4.5 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 5.0 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 5.5 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 6.0 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 6.5 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 7.0 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 7.5 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 8.0 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 8.5 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 9.0 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 9.5 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 10 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 11 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 12 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 13 mg. In certain embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 14 mg. In some embodiments, the non-opioid migraine therapy is olcegepant (BIBN-4096BS), and the effective amount is about 15 mg.

[0078] In some embodiments, the non-opioid migraine therapy is rimegepant (BMS-927711), and the effective amount is about 25 mg to about 150 mg. In certain embodiments, the non- opioid migraine therapy is rimegepant (B MS-927711), and the effective amount is about 25 mg. In some embodiments, the non-opioid migraine therapy is rimegepant (BMS-927711), and the effective amount is about 30 mg. In certain embodiments, the non-opioid migraine therapy is rimegepant (BMS-927711), and the effective amount is about 40 mg. In some embodiments, the non-opioid migraine therapy is rimegepant (BMS-927711), and the effective amount is about 50 mg. In certain embodiments, the non-opioid migraine therapy is rimegepant (BMS-927711), and the effective amount is about 60 mg. In some embodiments, the non-opioid migraine therapy is rimegepant (BMS-927711), and the effective amount is about 70 mg. In certain embodiments, the non-opioid migraine therapy is rimegepant (BMS- 927711), and the effective amount is about 75 mg. In some embodiments, the non-opioid migraine therapy is rimegepant (BMS-927711), and the effective amount is about 80 mg. In some embodiments, the non-opioid migraine therapy is rimegepant (BMS-927711), and the effective amount is about 90 mg. In certain embodiments, the non-opioid migraine therapy is rimegepant (BMS-927711), and the effective amount is about 100 mg. In some embodiments, the non-opioid migraine therapy is rimegepant (BMS-927711), and the effective amount is about 125 mg. In certain embodiments, the non-opioid migraine therapy is rimegepant (BMS-927711), and the effective amount is about 150 mg.

[0079] In some embodiments, the non-opioid migraine therapy is SB -268262, and the effective amount is about 5 mg to about 100 mg. In certain embodiments, the non-opioid migraine therapy is SB-268262, and the effective amount is about 10 mg to about 50 mg. In some embodiments, the non-opioid migraine therapy is SB -268262, and the effective amount is about 5 mg. In certain embodiments, the non-opioid migraine therapy is SB-268262, and the effective amount is about 10 mg. In some embodiments, the non-opioid migraine therapy is SB-268262, and the effective amount is about 15 mg. In certain embodiments, the non- opioid migraine therapy is SB-268262, and the effective amount is about 20 mg. In some embodiments, the non-opioid migraine therapy is SB -268262, and the effective amount is about 30 mg. In certain embodiments, the non-opioid migraine therapy is SB-268262, and the effective amount is about 40 mg. In some embodiments, the non-opioid migraine therapy is SB-268262, and the effective amount is about 50 mg. In certain embodiments, the non- opioid migraine therapy is SB-268262, and the effective amount is about 60 mg. In some embodiments, the non-opioid migraine therapy is SB -268262, and the effective amount is about 70 mg. In certain embodiments, the non-opioid migraine therapy is SB-268262, and the effective amount is about 80 mg. In some embodiments, the non-opioid migraine therapy is SB-268262, and the effective amount is about 90 mg. In certain embodiments, the non- opioid migraine therapy is SB-268262, and the effective amount is about 100 mg.

[0080] In some embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 25 mg to about 800 mg. In certain embodiments, the non- opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 140 mg to about 600 mg. In some embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 300 mg to about 600 mg. In certain embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 25 mg. In some embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 50 mg. In certain embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 75 mg. In some embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 100 mg. In certain embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 110 mg. In some embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 120 mg. In certain embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 130 mg. In some embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 140 mg. In certain embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 150 mg. In some embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is aboutl75 mg. In certain embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 200 mg. In some embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 250 mg. In certain embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 300 mg. In some embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 350 mg. In certain embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 400 mg. In some embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 450 mg. In certain embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 500 mg. In some embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 550 mg. In certain embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 600 mg. In some embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 650 mg. In certain embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 700. In some embodiments, the non-opioid migraine therapy is telcagepant (MK-0974), and the effective amount is about 800 mg.

[0081] In some embodiments, the non-opioid migraine therapy is ubrogepant, and the effective amount is about 20 mg to about 150 mg. In certain embodiments, the non-opioid migraine therapy is ubrogepant, and the effective amount is about 50 mg to about 100 mg. In some embodiments, the non-opioid migraine therapy is ubrogepant, and the effective amount is about 20 mg. In certain embodiments, the non-opioid migraine therapy is ubrogepant, and the effective amount is about 30 mg. In some embodiments, the non-opioid migraine therapy is ubrogepant, and the effective amount is about 40 mg. In certain embodiments, the non- opioid migraine therapy is ubrogepant, and the effective amount is about 50 mg. In some embodiments, the non-opioid migraine therapy is ubrogepant, and the effective amount is about 60 mg. In certain embodiments, the non-opioid migraine therapy is ubrogepant, and the effective amount is about 70 mg. In some embodiments, the non-opioid migraine therapy is ubrogepant, and the effective amount is about 80 mg. In certain embodiments, the non- opioid migraine therapy is ubrogepant, and the effective amount is about 90 mg. In some embodiments, the non-opioid migraine therapy is ubrogepant, and the effective amount is about 100 mg. In certain embodiments, the non-opioid migraine therapy is ubrogepant, and the effective amount is about 110 mg. In some embodiments, the non-opioid migraine therapy is ubrogepant, and the effective amount is about 120 mg. In certain embodiments, the non-opioid migraine therapy is ubrogepant, and the effective amount is about 130 mg. In some embodiments, the non-opioid migraine therapy is ubrogepant, and the effective amount is about 140 mg. In certain embodiments, the non-opioid migraine therapy is ubrogepant, and the effective amount is about 150 mg.

[0082] In certain embodiments, the non-opioid migraine therapy is erenumab (AMG-334), and the effective amount is about 50 mg to 175 mg. In some embodiments, the non-opioid migraine therapy is erenumab (AMG-334), and the effective amount is about 70 mg to 140 mg. In certain embodiments, the non-opioid migraine therapy is erenumab, and the effective amount is about 50 mg. In some embodiments, the non-opioid migraine therapy is erenumab, and the effective amount is about 60 mg. In certain embodiments, the non-opioid migraine therapy is erenumab, and the effective amount is about 70 mg. In some embodiments, the non-opioid migraine therapy is erenumab, and the effective amount is about 80 mg. In certain embodiments, the non-opioid migraine therapy is erenumab, and the effective amount is about 90 mg. In some embodiments, the non-opioid migraine therapy is erenumab, and the effective amount is about 100 mg. In certain embodiments, the non-opioid migraine therapy is erenumab, and the effective amount is about 110 mg. In some embodiments, the non- opioid migraine therapy is erenumab, and the effective amount is about 120 mg. In certain embodiments, the non-opioid migraine therapy is erenumab, and the effective amount is about 130 mg. In some embodiments, the non-opioid migraine therapy is erenumab, and the effective amount is about 140 mg. In certain embodiments, the non-opioid migraine therapy is erenumab, and the effective amount is about 150 mg. In some embodiments, the non- opioid migraine therapy is erenumab, and the effective amount is about 175 mg.

[0083] In certain embodiments, the non-opioid migraine therapy is eptinezumab (ALD403), and the effective amount is about 50 mg to 150 mg. In some embodiments, the non-opioid migraine therapy is eptinezumab (ALD403), and the effective amount is about 20 mg. In certain embodiments, the non-opioid migraine therapy is eptinezumab (ALD403), and the effective amount is about 30 mg. In some embodiments, the non-opioid migraine therapy is eptinezumab (ALD403), and the effective amount is about 40 mg. In certain embodiments, the non-opioid migraine therapy is eptinezumab (ALD403), and the effective amount is about 50 mg. In some embodiments, the non-opioid migraine therapy is eptinezumab (ALD403), and the effective amount is about 60 mg. In certain embodiments, the non-opioid migraine therapy is eptinezumab (ALD403), and the effective amount is about 70 mg. In some embodiments, the non-opioid migraine therapy is eptinezumab (ALD403), and the effective amount is about 80 mg. In certain embodiments, the non-opioid migraine therapy is eptinezumab (ALD403), and the effective amount is about 90 mg. In some embodiments, the non-opioid migraine therapy is eptinezumab (ALD403), and the effective amount is about 100 mg. In certain embodiments, the non-opioid migraine therapy is eptinezumab (ALD403), and the effective amount is about 110 mg. In some embodiments, the non-opioid migraine therapy is eptinezumab (ALD403), and the effective amount is about 120 mg. In certain embodiments, the non-opioid migraine therapy is eptinezumab (ALD403), and the effective amount is about 130 mg. In some embodiments, the non-opioid migraine therapy is eptinezumab (ALD403), and the effective amount is about 140 mg. In certain embodiments, the non-opioid migraine therapy is eptinezumab (ALD403), and the effective amount is about 150 mg.

[0084] In certain embodiments, the non-opioid migraine therapy is fremanezumab (TEV- 48125), and the effective amount is about 100 mg to 300 mg. In some embodiments, the non- opioid migraine therapy is fremanezumab (TEV-48125), and the effective amount is about 100 mg. In certain embodiments, the non-opioid migraine therapy is fremanezumab (TEV- 48125), and the effective amount is about 125 mg. In some embodiments, the non-opioid migraine therapy is fremanezumab (TEV-48125), and the effective amount is about 150 mg. In certain embodiments, the non-opioid migraine therapy is fremanezumab (TEV-48125), and the effective amount is about 175 mg. In some embodiments, the non-opioid migraine therapy is fremanezumab (TEV-48125), and the effective amount is about 200 mg. In certain embodiments, the non-opioid migraine therapy is fremanezumab (TEV-48125), and the effective amount is about 225 mg. In some embodiments, the non-opioid migraine therapy is fremanezumab (TEV-48125), and the effective amount is about 250 mg. In certain embodiments, the non-opioid migraine therapy is fremanezumab (TEV-48125), and the effective amount is about 275 mg. In some embodiments, the non-opioid migraine therapy is fremanezumab (TEV-48125), and the effective amount is about 300 mg.

[0085] In certain embodiments, the non-opioid migraine therapy is galcanezumab (LY2951742), and the effective amount is about 50 mg to about 150 mg. In some embodiments, the non-opioid migraine therapy is galcanezumab (LY2951742), and the effective amount is about 100 mg to about 120 mg. In certain embodiments, the non-opioid migraine therapy is galcanezumab (LY2951742), and the effective amount is about 50 mg. In some embodiments, the non-opioid migraine therapy is galcanezumab (LY2951742), and the effective amount is about 60 mg. In certain embodiments, the non-opioid migraine therapy is galcanezumab (LY2951742), and the effective amount is about 70 mg. In some embodiments, the non-opioid migraine therapy is galcanezumab (LY2951742), and the effective amount is about 80 mg. In certain embodiments, the non-opioid migraine therapy is galcanezumab (LY2951742), and the effective amount is about 90 mg. In some embodiments, the non-opioid migraine therapy is galcanezumab (LY2951742), and the effective amount is about 100 mg. In certain embodiments, the non-opioid migraine therapy is galcanezumab (LY2951742), and the effective amount is about 110 mg. In some embodiments, the non-opioid migraine therapy is galcanezumab (LY2951742), and the effective amount is about 120 mg. In certain embodiments, the non-opioid migraine therapy is galcanezumab (LY2951742), and the effective amount is about 130 mg. In some embodiments, the non-opioid migraine therapy is galcanezumab (LY2951742), and the effective amount is about 140 mg. In certain embodiments, the non-opioid migraine therapy is galcanezumab (LY2951742), and the effective amount is about 150 mg.

[0086] In some embodiments, the effective amount is about 0.1 mg/mL to about 50 mg/mL of the non-opioid migraine therapy. In some embodiments, the effective amount is about 0.1 mg/mL to about 25 mg/mL of the non-opioid migraine therapy. In some embodiments, the effective amount is about 0.1 mg/mL to about 10 mg/mL of the non-opioid migraine therapy. In some embodiments, the effective amount is about 1 mg/mL to about 25 mg/mL of the non- opioid migraine therapy. In some embodiments, the effective amount is about 1 mg/mL to about 10 mg/mL of the non-opioid migraine therapy. In some embodiments, the effective amount is about 0.1 mg/mL to about 2 mg/mL of the non-opioid migraine therapy. In some embodiments, the effective amount is about 0.1 mg/mL to about 5 mg/mL of the non-opioid migraine therapy. In some embodiments, the effective amount is about 5 mg/mL to about 10 mg/mL of the non-opioid migraine therapy. In some embodiments, the effective amount is about 10 mg/mL to about 15 mg/mL of the non-opioid migraine therapy. In some embodiments, the effective amount is about 15 mg/mL to about 20 mg/mL of the non-opioid migraine therapy. In some embodiments, the effective amount is about 20 mg/mL to about 25 mg/mL of the non-opioid migraine therapy.

[0087] In some embodiments, the effective amount is about 0.1 mg/mL, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, 5 mg/mL, 7.5 mg/mL, 10 mg/mL, 12.5 mg/mL, 15 mg/mL, 17.5 mg/mL, 20 mg/mL, 22.5 mg/mL, or 25 mg/mL. In some embodiments, the effective amount is about 0.1 mg/mL. In some embodiments, the effective amount is about 0.5 mg/mL. In some embodiments, the effective amount is about 1 mg/mL. In some embodiments, the effective amount is about 2 mg/mL. In some embodiments, the effective amount is about 5 mg/mL. In some embodiments, the effective amount is about 7.5 mg/mL. In some embodiments, the effective amount is about 10 mg/mL. In some embodiments, the effective amount is about 12.5 mg/mL. In some embodiments, the effective amount is about 15 mg/mL. In some embodiments, the effective amount is about 17.5 mg/mL. In some embodiments, the effective amount is about 20 mg/mL. In some embodiments, the effective amount is about 22.5 mg/mL. In some embodiments, the effective amount is about 25 mg/mL.

[0088] In certain embodiments, the effective amount is about 0.1 mg/kg to about 25 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 0.1 mg/kg to about 20 mg/kg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 0.1 mg/kg to about 15 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 0.1 mg/kg to about 10 mg/kg of the non- opioid migraine therapy. In certain embodiments, the effective amount is about 0.1 mg/kg to about 5 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 1 mg/kg to about 25 mg/kg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 1 mg/kg to about 20 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 1 mg/kg to about 15 mg/kg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 1 mg/kg to about 10 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 1 mg/kg to about 5 mg/kg of the non-opioid migraine therapy. [0089] In certain embodiments, the effective amount is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, or about 25 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 0.1 mg/kg of the non- opioid migraine therapy. In certain embodiments, the effective amount is about 0.5 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 1 mg/kg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 2 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 3 mg/kg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 4 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 5 mg/kg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 6 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 7 mg/kg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 8 mg/kg of the non- opioid migraine therapy. In some embodiments, the effective amount is about 9 mg/kg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 10 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 11 mg/kg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 12 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 13 mg/kg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 14 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 15 mg/kg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 16 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 17 mg/kg of the non- opioid migraine therapy. In certain embodiments, the effective amount is about 18 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is aboutl9 mg/kg of the non-opioid migraine therapy. In certain embodiments, the effective amount is about 20 mg/kg of the non-opioid migraine therapy. In some embodiments, the effective amount is about 25 mg/kg of the non-opioid migraine therapy.

[0090] In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0091] In some embodiments, the treatment described herein is effective at treating mild, moderate, or severe pain in a subject without the co-administration of another pain medication or analgesic. In some embodiments, the treatment described herein results in the subject decreasing or discontinuing the use of another pain medication or analgesic, including rescue medications, during the course of the treatment when compared to before the initiation of the treatment. In some embodiments, the treatment results in the subject decreasing or discontinuing the use of acetaminophen and/or opioid medications during the treatment during the course of the treatment when compared to before the initiation of the treatment. [0092] In some embodiments, the treatment achieves a reduction of at least 1 from baseline in a Pain Intensity Numerical Rating Scale. In some embodiments, the treatment achieves a reduction of at least 2 from baseline in a Pain Intensity Numerical Rating Scale. In some embodiments, the treatment achieves a reduction of at least 3 from baseline in a Pain Intensity Numerical Rating Scale. In some embodiments, the treatment achieves a reduction of at least 4 from baseline in a Pain Intensity Numerical Rating Scale. In some embodiments, the treatment achieves a reduction of at least 5 from baseline in a Pain Intensity Numerical Rating Scale.

Pharmaceutical Compositions, Kits, and Administration

[0093] In some embodiments, the pharmaceutical composition is an oral, parenteral, inhalation, transdermal, intranasal, rectal, buccal, vaginal, topical, or injectable dosage form. In some embodiments, the pharmaceutical composition is an oral dosage form. In some embodiments, the pharmaceutical composition is a parenteral, topical, buccal, ophthalmic, rectal, transdermal, or vaginal dosage form. In some embodiments, the pharmaceutical composition is a parenteral dosage form. In some embodiments, the pharmaceutical composition is a topical dosage form. In some embodiments the pharmaceutical composition is a buccal dosage form. In some embodiments, the pharmaceutical composition is an ophthalmic dosage form. In some embodiments, the pharmaceutical composition is a rectal dosage form. In some embodiments, the pharmaceutical composition is a transdermal dosage form. In some embodiments, the pharmaceutical composition is a vaginal dosage form. [0094] In some embodiments, the pharmaceutical composition is an injectable dosage form. In some embodiments, the injectable dosage form is an intravenous dosage form.

[0095] In some embodiments, the pharmaceutical composition is a solid dosage formulation. In some embodiments, the solid dosage formulation is a tablet, capsule, granule, powder, sachet, or chewable dosage form.

[0096] In some embodiments, the pharmaceutical composition is a liquid-filled capsule. [0097] In some embodiments, the pharmaceutical composition is a liquid dosage formulation. In some embodiments, the liquid dosage formulation is a solution, suspension, or syrup. In some embodiments, the liquid dosage formulation is a solution. In some embodiments, liquid dosage formulation is a suspension. In some embodiments, the liquid dosage formulation is a syrup.

[0098] Pharmaceutical compositions disclosed herein can be prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include bringing the compound disclosed herein (z.e., the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit. [0099] In some embodiments, pharmaceutical compositions are prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[00100] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition disclosed herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. In some embodiments, the composition comprises between 0.1% and 100% (w/w) active ingredient.

[00101] Pharmaceutically acceptable excipients used in the manufacture of the disclosed pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. In some embodiments, excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents are present in the composition.

[00102] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof. [00103] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[00104] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof. [00105] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly (vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

[00106] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[00107] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[00108] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[00109] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[00110] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. [00111] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, betacarotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[00112] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, NeoIone®, Kathon®, and Euxyl®. [00113] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen- free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[00114] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[00115] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, com, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[00116] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In some embodiments, in addition to the active ingredients, the liquid dosage forms comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates disclosed herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[00117] In some embodiments, injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions are formulated according to the known art using suitable dispersing or wetting agents and suspending agents. In some embodiments, the sterile injectable preparation is a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. In some embodiments, the acceptable vehicles and solvents that are employed include water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. In some embodiments, any bland fixed oil is employed for this purpose, including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[00118] In some embodiments, the injectable formulations are sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions. In some embodiments, such sterilized injectable formulations are dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00119] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. In some embodiments, this is accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. In some embodiments, the rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, depends upon crystal size and crystalline form. Alternatively, in some embodiments, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[00120] Compositions for rectal or vaginal administration are typically suppositories. In some embodiments, compositions for rectal or vaginal administrations are suppositories prepared by mixing the compounds disclosed herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[00121] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In some embodiments, in the case of capsules, tablets, and pills, the dosage form includes a buffering agent.

[00122] In some embodiments, solid compositions of a similar type are employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. In some embodiments, the solid dosage forms of tablets, dragees, capsules, pills, and granules are prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutics. In some embodiments, the solid dosage forms optionally comprise opacifying agents. In some embodiments, the solid dosage forms are of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. In some embodiments, encapsulating compositions include polymeric substances and waxes. In some embodiments, solid compositions of a similar type are employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[00123] In some embodiments, the active ingredient is in a micro-encapsulated form with one or more excipients as noted above. In some embodiments, the solid dosage forms of tablets, dragees, capsules, pills, and granules are prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In some embodiments, in such solid dosage forms the active ingredient is admixed with at least one inert diluent such as sucrose, lactose, or starch. In some embodiments, such dosage forms comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In some embodiments, in the case of capsules, tablets and pills, the dosage forms comprise buffering agents. In some embodiments, the dosage forms optionally comprise opacifying agents and are of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. In some embodiments, the encapsulating agents include polymeric substances and waxes.

[00124] In some embodiments, dosage forms for topical and/or transdermal administration of a compound disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. In some embodiments, such dosage forms are prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. In some embodiments, alternatively or additionally, the rate is controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.

[00125] Suitable devices for use in delivering intradermal pharmaceutical compositions disclosed herein include short needle devices. In some embodiments, intradermal compositions are administered by devices which limit the effective penetration length of a needle into the skin. In some embodiments, alternatively or additionally, conventional syringes are used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum comeum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable. [00126] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient. In some embodiments, the concentration of the active ingredient is as high as the solubility limit of the active ingredient in the solvent. In some embodiments, formulations for topical administration further comprise one or more of the additional ingredients disclosed herein.

[00127] In some embodiments, a pharmaceutical composition disclosed herein is prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. In some embodiments, such a formulation comprises dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant is directed to disperse the powder and/or using a self- propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. In some embodiments, dry powder compositions include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[00128] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. In some embodiments, the propellant constitutes 50 to 99.9% (w/w) of the composition, and the active ingredient constitutes 0.1 to 20% (w/w) of the composition. In some embodiments, the propellant further comprises additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[00129] In some embodiments, pharmaceutical compositions disclosed herein formulated for pulmonary delivery provide the active ingredient in the form of droplets of a solution and/or suspension. In some embodiments, such formulations are prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. In some embodiments, such formulations further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. In some embodiments, the droplets provided by this route of administration have an average diameter in the range from about 0.1 to about 200 nanometers.

[00130] Formulations disclosed herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition disclosed herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[00131] For example, in some embodiments, formulations for nasal administration comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient. In some embodiments, formulations for nasal administration further comprise one or more of the additional ingredients disclosed herein. In some embodiments, a pharmaceutical composition disclosed herein is prepared, packaged, and/or sold in a formulation for buccal administration. For example, in some embodiments, such formulations are in the form of tablets and/or lozenges made using conventional methods, and contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients disclosed herein. Alternately, in some embodiments, formulations for buccal administration comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. In some embodiments, such powdered, aerosolized, and/or aerosolized formulations, when dispersed, have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and further comprise one or more of the additional ingredients disclosed herein. [00132] In some embodiments, a pharmaceutical composition disclosed herein is prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1 -1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. In some embodiments, such drops further comprise buffering agents, salts, and/or one or more other of the additional ingredients disclosed herein. Other opthalmically- administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.

[00133] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation .

[00134] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions disclosed herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[00135] In some embodiments, the compounds and compositions disclosed herein are administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). [00136] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. In some embodiments, an effective amount is included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject, any two doses of the multiple doses include different or substantially the same amounts of a compound disclosed herein. In certain embodiments, when multiple doses are administered to a subject, the frequency of administering the multiple doses to the subject is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject is one dose per day. In certain embodiments, the frequency of administering the multiples doses to the subject is two times or more daily. In certain embodiments, the frequency of administering the multiple doses to the subject is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject is three doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject is four times per day. In certain embodiments, the frequency of administering the multiple doses to the subject is five times per day. In certain embodiments, the frequency of administering the multiple doses to the subject is six times per day. In certain embodiments, when multiple doses are administered to a subject, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject. [00137] In some embodiments, a first dose (loading dose) of the compound is provided, followed by a second, lower dose (maintenance dose) of the compound. In some embodiments, the maintenance dose is administered for up to 3 days, up to 5 days, up to 7 days, up to 10 days, up to 14 days, or chronically thereafter.

[00138] The treatment regimen may comprise the administration of an initial (or first) dose of the pharmaceutical composition once daily as further described herein. The treatment regimen may further comprise evaluating the subject after administration of the initial dose to determine if the initial dose was fully, partially, or not effective at treating von Willebrand’s migraine disorder. In another aspect, the treatment regimen may comprise determining if the subject could benefit from the administration of a higher dose. The evaluation and determining steps may take place after a single administration of the initial dose (e.g., two days, three days, one week, two weeks, or longer after the first administration of the initial dose), or after multiple administrations of the initial dose. In some embodiments, the evaluation and determining steps are performed by a physician, physician’s assistant, nurse, or other health care provider. In one aspect, the evaluation and determination steps are based on subject-reported outcomes, and may include an assessment of the benefit of a higher dose compared to any potential safety risks associated with that higher dose.

[00139] Dose ranges as disclosed herein provide guidance for the administration of the disclosed pharmaceutical compositions to an adult. In some embodiments, the amount to be administered to, for example, a child or an adolescent is determined by a medical practitioner or person skilled in the art and is lower or the same as that administered to an adult.

[00140] In some embodiments, a compound or composition, as disclosed herein, is administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). In some embodiments, the compounds or compositions are administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and/or in inhibiting the activity of a protein kinase in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition disclosed herein including a compound disclosed herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects.

[00141] In some embodiments, the pharmaceutical composition further comprises one or more additional agents. In some embodiments, the pharmaceutical composition further comprises an additional agent. In some embodiments, the compound or composition is administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents. For example, the one or more additional pharmaceutical agents are useful as combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti-inflammatory agents, immunosuppressants, anti-bacterial agents, antiviral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, antiallergic agents, contraceptive agents, pain-relieving agents, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti-pyretic s, hormones, and prostaglandins.

[00142] In some embodiments, the additional agent is acetaminophen, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof. In certain embodiments, the additional agent is acetaminophen, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is acetaminophen, or an isotopically labeled derivative thereof. In certain embodiments, the additional agent is an isotopically labeled derivative of acetaminophen. In some embodiments, the additional agent is a deuterated form of acetaminophen. In some embodiments, the additional agent is a deuterated form of acetaminophen that is isotopically enriched by at least 0.05%, at least 0.1%, at least 0.5%, at least 1.0, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 10.0%, at least 20.0%, at least 30.0%, at least 40.0%, at least 50.0%, at least 60.0%, at least 70.0%, at least

75.0%, at least 80.0%, at least 85.0%, at least 90.0%, at least 94.0%, at least 95.0%, at least

96.0%, at least 97.0%, at least 98.0%, at least 99.0%, at least 99.5%, at least 99.7%, at least

99.8%, at least 99.9%, or at least 100%.

[00143] In some embodiments, the additional agent is caffeine, or a pharmaceutically acceptable salt or isotopically labeled derivative thereof. In certain embodiments, the additional agent is caffeine, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is caffeine, or an isotopically labeled derivative thereof. In certain embodiments, the additional agent is an isotopically labeled derivative of caffeine. In some embodiments, the additional agent is a deuterated form of caffeine. In some embodiments, the additional agent is a deuterated form of caffeine that is isotopically enriched by at least 0.05%, at least 0.1%, at least 0.5%, at least 1.0, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 10.0%, at least 20.0%, at least 30.0%, at least 40.0%, at least 50.0%, at least 60.0%, at least 70.0%, at least 75.0%, at least 80.0%, at least

85.0%, at least 90.0%, at least 94.0%, at least 95.0%, at least 96.0%, at least 97.0%, at least

98.0%, at least 99.0%, at least 99.5%, at least 99.7%, at least 99.8%, at least 99.9%, or at least 100%.

[00144] In some embodiments, each additional pharmaceutical agent is administered at a dose and/or on a time schedule determined for that pharmaceutical agent. In some embodiments, the additional pharmaceutical agents are administered together with each other and/or with the non-opioid migraine therapy disclosed herein in a single dose or composition or administered separately in different doses or compositions. The particular combination to employ in a regimen will take into account compatibility of the non-opioid migraine therapy disclosed herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[00145] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). In some embodiments, the kits disclosed herein comprise a pharmaceutical composition or compound disclosed herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, the disclosed kits optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound disclosed herein. In some embodiments, the pharmaceutical composition or compound disclosed herein provided in the first container and the second container are combined to form one unit dosage form.

[00146] Thus, in one embodiment, disclosed herein are kits including a first container comprising a compound or pharmaceutical composition disclosed herein. In certain embodiments, the kits are useful for treating von Willebrand’s migraine disorder in a subject in need thereof. In certain embodiments, the kits are useful for preventing von Willebrand’s migraine disorder in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing von Willebrand’s migraine disorder in a subject in need thereof.

[00147] In certain embodiments, a kit disclosed herein further includes instructions for using the kit. In some embodiments, a kit disclosed herein also includes information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating von Willebrand’s migraine disorder in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing von Willebrand’s migraine disorder in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing von Willebrand’s migraine disorder in a subject in need thereof. In some embodiments, a kit disclosed herein includes one or more additional pharmaceutical agents disclosed herein as a separate composition.

EXAMPLES

[00148] In order that the present disclosure may be more fully understood, the following examples are set forth. The examples disclosed in this application are offered to illustrate the methods disclosed herein and are not to be construed in any way as limiting in their scope.

Example 1: Evaluation of von Willebrand’s Migraine Disorder in a Population of von Willebrand’s Disease Patients

[00149] The frequency of von Willebrand’s migraine disorder was evaluated in seventy-five patients ages 18+. Of the evaluated patients, 57% were diagnosed with type I von Willebrand disease, 28% were diagnosed with type II von Willebrand disease, and 15% were diagnosed with type III von Willebrand disease. Sixty-two patients were female, and 7 patients were male. [00150] Overall, 57% of VWD patients evaluated reported that they have been diagnosed with migraine. This rate of incidence is significantly higher than the 6% diagnosed prevalence (11% overall prevalence) in the general population of the United States. See Stovner L., el al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia, 2007, 27, 193-210. Rates of von Willebrand’s migraine disorder did not vary significantly by VWD sub-type: 56% percent of patients with type I VWD, 67% percent of patients with type II VWD, and 46% percent of patients with type III VWD were diagnosed with migraine. Unexpectedly, rates of migraine diagnosis were also similar for males (46% of males with VWD) and females (62% of females with VWD), even though migraines are three times more common in females than in males in the general population. See Atlas of Headache Disorders and Resources in the World 2011, World Health Organization, Geneva: World Health Organization, 2011. Only 4% of surveyed patients met the criteria for Chronic Migraine based on the criteria of the ID-CM (frequency and symptoms, and/or medication use, activities, and making plans), but 71% of patients met the criteria for migraine symptoms. See Lipton, R. B., et al. Improving the detection of chronic migraine: Development and validation of Identify Chronic Migraine (ID- CM), Cephalalgia, 2016, 36, 203-215. The mean age at which VWD patients were diagnosed with migraine was 21.6 years of age, with a median age of diagnosis of 17 years of age.

[00151] Patients having von Willebrand disease surveyed used a wide array of therapies to treat migraine, including, but not limited to, aspirin/paracetamol/caffeine, acetaminophen, celecoxib, topiramate, sumatriptan, rizatriptan, ubrogepant, amitriptyline, botox injections, ibuprofen, oxycodone, rimegepant, ketorolac, tramadol, nortriptyline, eletriptan, steroids, erenumab, metoprolol, promethazine, and hydrocodone/acetaminophen. Of these, non- selective NSAIDs such as ibuprofen and ketorolac are contraindicated in patients prone to bleeding (e.g., gastrointestinal bleeding), including patients with von Willebrand disorder. See COX-2 Selective (includes Bextra, Celebrex, and Vioxx) and Non-Selective Non- Steroidal Anti-Inflammatory Drugs (NSAIDs), updated 2018 February 6, Postmarket Drug Safety Information for Patients and Providers, U.S. Food and Drug Administration, 2018, and Physician's Desk Reference 2017, Montvale, New Jersey: PDR, LLC. 2017, pp. S-474-S- 475. Example 2: Treatment of von Willebrand’s Migraine Disorder with a Trip tan Migraine Therapy (Sumatriptan)

[00152] Inclusion Criteria: A population of subjects is enrolled based on the following inclusion criteria. The subjects are male or female and are 18 to 60 years of age, inclusive, at screening. Similar numbers of male and female subjects are enrolled. The subjects have been diagnosed with von Willebrand disease (type I, type II, or type III) and suffer from migraine. The subjects have a BMI at screening of 18 to 32 kg/m², inclusive, with a minimum weight of 47 kg for women and 66 kg for men and a maximum weight of 80 kg for women and 90 kg for men. The subjects are not smokers. Subjects are considered by the investigators to be in good general health (aside from VWD) as determined by medical history, clinical laboratory tests, vital sign measurements, 12-lead ECG results, and physical examination findings at screening and check-in. All female subjects have a negative pregnancy test at screening. Female subjects of childbearing potential also have a negative pregnancy test at check-in and are using an acceptable method of birth control during the study (z.e., diaphragm with spermicide, intrauterine device, condom with foam or vaginal spermicide, oral contraceptives, or abstinence). Women who are surgically sterile (z.e., hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or postmenopausal (defined as amenorrhea for 12 consecutive months and documented serum follicle-stimulating hormone level >40 lU/mL) are exempt from the adequate contraception requirement. The subjects agree to comply with all protocol requirements. The subjects provide written informed consent.

[00153] Exclusion Criteria: The population of subjects excludes the following. Subjects having a history of relevant drug allergy or food allergy/sensitivity (e.g., allergy to sumatriptan, allergy to NSAIDs, or gluten intolerance that could preclude consumption of a standard clinic diet). Female subjects that are pregnant or lactating. Subjects having a history of intolerance or hypersensitivity to any triptan. Subjects having a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus types 1 or 2 antibodies at screening. Subjects having used any prescription (excluding hormonal birth control) or OTC medications including NSAIDs (z.e., ibuprofen, naproxen, and aspirin) or opioids, as well as herbal or nutritional supplements, within 14 days before the study drug dosing. Subjects having any clinically significant abnormalities before dosing on Day 1 or having a history of disease, including: uncontrolled or poorly controlled hypertension; asthma or pulmonary disease; major cardiac ischemic symptoms, events, or interventions such as angina pectoris, myocardial infarction, acute coronary syndrome, decompensated congestive heart failure, coronary stent or bypass; history of cerebrovascular ischemic events (transient ischemic attack or stroke); major vascular ischemic symptoms such as intermittent claudication or vascular bypass or replacement surgery; significant cardiovascular, GI, neurological, endocrine, or renal disease; hepatic impairment; cholecystectomy; other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs; or clinically significant GI events. Subjects having a history or presence of any clinically significant abnormality in vital signs, ECG, or laboratory tests, or having any medical or psychiatric condition that, in the opinion of the investigator, may interfere with the study procedures or compromise subject safety (assessed at Screening and Check-in). Subjects that are cigarette smokers or who have used nicotine or nicotine- containing products (e.g., snuff, nicotine patch, nicotine chewing gum, e-cigarettes) within 6 months before study drug dosing. Subjects having a history of alcohol abuse or drug addiction within the last year or who consume more than 1 unit (1 unit is equal to approximately * pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure [25 mL] of spirits) of alcohol a day. Alcohol is not allowed within 7 days before study drug dosing. Subjects having a positive test result for drugs of abuse, alcohol, or cotinine (indicating active current smoking) at screening. Subjects that are habitual and heavy coffee drinkers (more than 4 cups a day, 28 cups a week). Subjects involved in strenuous activity or contact sports within at least 24 hours before study drug dosing. Subjects that have donated blood or blood products within at least 30 days before the dose of study drug in this study. Subjects having received study drug in another investigational study within at least 30 days (or less than 5 half-lives of the investigational agent) prior to dosing in this study. Subjects otherwise not suitable for entry into the study in the opinion of the investigator. Subjects that are employees or family members of the investigator or clinic staff.

[00154] Dosage: Each subject receives 25 mg, 50 mg, or 100 mg dose of sumatriptan (up to 200 mg per day) on an as-needed basis, for example when a subject experiences migraine pain described as an increase in pain rating of > 1 or a pain rating of >4 to <9 based on the Pain Intensity Numerical Rating Scale. Study drug is co-administered orally with approximately 250 mL of room temperature water, and up to an additional 250 mL of water is allowed, if necessary, to aid in swallowing the study drug. Study staff ensure that at least 250 mL of water is consumed with the dose of study drug and perform a hand and mouth check after dosing to ensure that the tablet has been swallowed.

[00155] Adverse events are assessed from the time of study drug dosing until all end-of-study procedures are complete. [00156] Treatment is assessed via changes in migraine pain via the Pain Intensity Numerical Rating Scale. Treatment achieves a reduction of at least 1 from baseline in the Pain Intensity Numerical Rating Scale, and may achieve a reduction in at least 2, 3, 4, or 5 from baseline in the Pain Intensity Numerical Rating Scale.

Example 3: Treatment of von Willebrand’s Migraine Disorder with a CGRP Migraine Therapy (Ubrogepant)

[00157] Inclusion Criteria: A population of subjects is enrolled based on the following inclusion criteria. The subjects are male or female and are 18 to 60 years of age, inclusive, at screening. Similar numbers of male and female subjects are enrolled. The subjects have been diagnosed with von Willebrand disease (type I, type II, or type III) and suffer from migraine. The subjects have a BMI at screening of 18 to 32 kg/m², inclusive, with a minimum weight of 47 kg for women and 66 kg for men and a maximum weight of 80 kg for women and 90 kg for men. The subjects are not smokers. Subjects are considered by the investigators to be in good general health (aside from VWD) as determined by medical history, clinical laboratory tests, vital sign measurements, 12-lead ECG results, and physical examination findings at screening and check-in. All female subjects have a negative pregnancy test at screening. Female subjects of childbearing potential also have a negative pregnancy test at check-in and are using an acceptable method of birth control during the study (z.e., diaphragm with spermicide, intrauterine device, condom with foam or vaginal spermicide, oral contraceptives, or abstinence). Women who are surgically sterile (z.e., hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or postmenopausal (defined as amenorrhea for 12 consecutive months and documented serum follicle-stimulating hormone level >40 lU/mL) are exempt from the adequate contraception requirement. The subjects agree to comply with all protocol requirements. The subjects provide written informed consent.

[00158] Exclusion Criteria: The population of subjects excludes the following. Subjects having a history of relevant drug allergy or food allergy/sensitivity (e.g., allergy to ubrogepant, allergy to NSAIDs, or gluten intolerance that could preclude consumption of a standard clinic diet). Female subjects that are pregnant or lactating. Subjects having a history of intolerance or hypersensitivity to any CGRP antagonist. Subjects having a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus types 1 or 2 antibodies at screening. Subjects having used any prescription (excluding hormonal birth control) or OTC medications including NSAIDs (z.e., ibuprofen, naproxen, and aspirin) or opioids, as well as herbal or nutritional supplements, within 14 days before the study drug dosing. Subjects having any clinically significant abnormalities before dosing on Day 1 or having a history of disease, including: uncontrolled or poorly controlled hypertension; asthma or pulmonary disease; major cardiac ischemic symptoms, events, or interventions such as angina pectoris, myocardial infarction, acute coronary syndrome, decompensated congestive heart failure, coronary stent or bypass; history of cerebrovascular ischemic events (transient ischemic attack or stroke); major vascular ischemic symptoms such as intermittent claudication or vascular bypass or replacement surgery; significant cardiovascular, GI, neurological, endocrine, or renal disease; hepatic impairment; cholecystectomy; other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs; or clinically significant GI events. Subjects having a history or presence of any clinically significant abnormality in vital signs, ECG, or laboratory tests, or having any medical or psychiatric condition that, in the opinion of the investigator, may interfere with the study procedures or compromise subject safety (assessed at Screening and Check-in). Subjects that are cigarette smokers or who have used nicotine or nicotine-containing products (e.g., snuff, nicotine patch, nicotine chewing gum, e-cigarettes) within 6 months before study drug dosing. Subjects having a history of alcohol abuse or drug addiction within the last year or who consume more than 1 unit (1 unit is equal to approximately * pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure [25 mL] of spirits) of alcohol a day. Alcohol is not allowed within 7 days before study drug dosing. Subjects having a positive test result for drugs of abuse, alcohol, or cotinine (indicating active current smoking) at screening. Subjects that are habitual and heavy coffee drinkers (more than 4 cups a day, 28 cups a week). Subjects involved in strenuous activity or contact sports within at least 24 hours before study drug dosing. Subjects that have donated blood or blood products within at least 30 days before the dose of study drug in this study. Subjects having received study drug in another investigational study within at least 30 days (or less than 5 half-lives of the investigational agent) prior to dosing in this study. Subjects otherwise not suitable for entry into the study in the opinion of the investigator. Subjects that are employees or family members of the investigator or clinic staff.

[00159] Dosage: Each subject receives 50 mg or 100 mg dose of ubrogepant (up to 200 mg per day) on an as-needed basis, for example when a subject experiences migraine pain described as an increase in pain rating of > 1 or a pain rating of >4 to <9 based on the Pain Intensity Numerical Rating Scale. Study drug is co-administered orally with approximately 250 mL of room temperature water, and up to an additional 250 mL of water is allowed, if necessary, to aid in swallowing the study drug. Study staff ensure that at least 250 mL of water is consumed with the dose of study drug and perform a hand and mouth check after dosing to ensure that the tablet has been swallowed.

[00160] Adverse events are assessed from the time of study drug dosing until all end-of-study procedures are complete.

[00161] Treatment is assessed via changes in migraine pain via the Pain Intensity Numerical Rating Scale. Treatment achieves a reduction of at least 1 from baseline in the Pain Intensity Numerical Rating Scale, and may achieve a reduction in at least 2, 3, 4, or 5 from baseline in the Pain Intensity Numerical Rating Scale.

Example 4: Treatment of von Willebrand’s Migraine Disorder with Lasmiditan [00162] Inclusion Criteria: A population of subjects is enrolled based on the following inclusion criteria. The subjects are male or female and are 18 to 60 years of age, inclusive, at screening. Similar numbers of male and female subjects are enrolled. The subjects have been diagnosed with von Willebrand disease (type I, type II, or type III) and suffer from migraine. The subjects have a BMI at screening of 18 to 32 kg/m², inclusive, with a minimum weight of 47 kg for women and 66 kg for men and a maximum weight of 80 kg for women and 90 kg for men. The subjects are not smokers. Subjects are considered by the investigators to be in good general health (aside from VWD) as determined by medical history, clinical laboratory tests, vital sign measurements, 12-lead ECG results, and physical examination findings at screening and check-in. All female subjects have a negative pregnancy test at screening. Female subjects of childbearing potential also have a negative pregnancy test at check-in and are using an acceptable method of birth control during the study (z.e., diaphragm with spermicide, intrauterine device, condom with foam or vaginal spermicide, oral contraceptives, or abstinence). Women who are surgically sterile (z.e., hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or postmenopausal (defined as amenorrhea for 12 consecutive months and documented serum follicle-stimulating hormone level >40 lU/mL) are exempt from the adequate contraception requirement. The subjects agree to comply with all protocol requirements. The subjects provide written informed consent.

[00163] Exclusion Criteria: The population of subjects excludes the following. Subjects having a history of relevant drug allergy or food allergy/sensitivity (e.g., allergy to lasmiditan, allergy to NSAIDs, or gluten intolerance that could preclude consumption of a standard clinic diet). Female subjects that are pregnant or lactating. Subjects having a history of intolerance or hypersensitivity to lasmiditan. Subjects having a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus types 1 or 2 antibodies at screening. Subjects having used any prescription (excluding hormonal birth control) or OTC medications including NSAIDs (/'.<?., ibuprofen, naproxen, and aspirin) or opioids, as well as herbal or nutritional supplements, within 14 days before the study drug dosing. Subjects having any clinically significant abnormalities before dosing on Day 1 or having a history of disease, including: uncontrolled or poorly controlled hypertension; asthma or pulmonary disease; major cardiac ischemic symptoms, events, or interventions such as angina pectoris, myocardial infarction, acute coronary syndrome, decompensated congestive heart failure, coronary stent or bypass; history of cerebrovascular ischemic events (transient ischemic attack or stroke); major vascular ischemic symptoms such as intermittent claudication or vascular bypass or replacement surgery; significant cardiovascular, GI, neurological, endocrine, or renal disease; hepatic impairment; cholecystectomy; other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs; or clinically significant GI events. Subjects having a history or presence of any clinically significant abnormality in vital signs, ECG, or laboratory tests, or having any medical or psychiatric condition that, in the opinion of the investigator, may interfere with the study procedures or compromise subject safety (assessed at Screening and Check-in). Subjects that are cigarette smokers or who have used nicotine or nicotine- containing products (e.g., snuff, nicotine patch, nicotine chewing gum, e-cigarettes) within 6 months before study drug dosing. Subjects having a history of alcohol abuse or drug addiction within the last year or who consume more than 1 unit (1 unit is equal to approximately * pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure [25 mL] of spirits) of alcohol a day. Alcohol is not allowed within 7 days before study drug dosing. Subjects having a positive test result for drugs of abuse, alcohol, or cotinine (indicating active current smoking) at screening. Subjects that are habitual and heavy coffee drinkers (more than 4 cups a day, 28 cups a week). Subjects involved in strenuous activity or contact sports within at least 24 hours before study drug dosing. Subjects that have donated blood or blood products within at least 30 days before the dose of study drug in this study. Subjects having received study drug in another investigational study within at least 30 days (or less than 5 half-lives of the investigational agent) prior to dosing in this study. Subjects otherwise not suitable for entry into the study in the opinion of the investigator. Subjects that are employees or family members of the investigator or clinic staff. [00164] Dosage: Each subject receives 50 mg, 100 mg, or 200 mg dose of lasmiditan (up to 200 mg per day) on an as-needed basis, for example when a subject experiences migraine pain described as an increase in pain rating of > 1 or a pain rating of >4 to <9 based on the Pain Intensity Numerical Rating Scale. Study drug is co-administered orally with approximately 250 mL of room temperature water, and up to an additional 250 mL of water is allowed, if necessary, to aid in swallowing the study drug. Study staff ensure that at least 250 mL of water is consumed with the dose of study drug and perform a hand and mouth check after dosing to ensure that the tablet has been swallowed.

[00165] Adverse events are assessed from the time of study drug dosing until all end-of-study procedures are complete.

[00166] Treatment is assessed via changes in migraine pain via the Pain Intensity Numerical Rating Scale. Treatment achieves a reduction of at least 1 from baseline in the Pain Intensity Numerical Rating Scale, and may achieve a reduction in at least 2, 3, 4, or 5 from baseline in the Pain Intensity Numerical Rating Scale.

Example 5: Treatment of von Willebrand’s Migraine Disorder with Rofecoxib

[00167] Inclusion Criteria: A population of subjects is enrolled based on the following inclusion criteria. The subjects are male or female and are 18 to 60 years of age, inclusive, at screening. Similar numbers of male and female subjects are enrolled. The subjects have been diagnosed with von Willebrand disease (type I, type II, or type III) and suffer from migraine. The subjects have a BMI at screening of 18 to 32 kg/m², inclusive, with a minimum weight of 47 kg for women and 66 kg for men and a maximum weight of 80 kg for women and 90 kg for men. The subjects are not smokers. Subjects are considered by the investigators to be in good general health (aside from VWD) as determined by medical history, clinical laboratory tests, vital sign measurements, 12-lead ECG results, and physical examination findings at screening and check-in. All female subjects have a negative pregnancy test at screening. Female subjects of childbearing potential also have a negative pregnancy test at check-in and are using an acceptable method of birth control during the study (z.e., diaphragm with spermicide, intrauterine device, condom with foam or vaginal spermicide, oral contraceptives, or abstinence). Women who are surgically sterile (z.e., hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or postmenopausal (defined as amenorrhea for 12 consecutive months and documented serum follicle-stimulating hormone level >40 lU/mL) are exempt from the adequate contraception requirement. The subjects agree to comply with all protocol requirements. The subjects provide written informed consent.

[00168] Exclusion Criteria: The population of subjects excludes the following. Subjects having a history of relevant drug allergy or food allergy/sensitivity (e.g., allergy to rofecoxib, allergy to NSAIDs, or gluten intolerance that could preclude consumption of a standard clinic diet). Female subjects that are pregnant or lactating. Subjects having a history of intolerance or hypersensitivity to rofecoxib or any NSAID. Subjects having a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus types 1 or 2 antibodies at screening. Subjects having used any prescription (excluding hormonal birth control) or OTC medications including NSAIDs (z.e., ibuprofen, naproxen, and aspirin) or opioids, as well as herbal or nutritional supplements, within 14 days before the study drug dosing. Subjects having any clinically significant abnormalities before dosing on Day 1 or having a history of disease, including: uncontrolled or poorly controlled hypertension; asthma or pulmonary disease; major cardiac ischemic symptoms, events, or interventions such as angina pectoris, myocardial infarction, acute coronary syndrome, decompensated congestive heart failure, coronary stent or bypass; history of cerebrovascular ischemic events (transient ischemic attack or stroke); major vascular ischemic symptoms such as intermittent claudication or vascular bypass or replacement surgery; significant cardiovascular, GI, neurological, endocrine, or renal disease; hepatic impairment; cholecystectomy; other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs; or clinically significant GI events. Subjects having a history or presence of any clinically significant abnormality in vital signs, ECG, or laboratory tests, or having any medical or psychiatric condition that, in the opinion of the investigator, may interfere with the study procedures or compromise subject safety (assessed at Screening and Check-in). Subjects that are cigarette smokers or who have used nicotine or nicotine- containing products (e.g., snuff, nicotine patch, nicotine chewing gum, e-cigarettes) within 6 months before study drug dosing. Subjects having a history of alcohol abuse or drug addiction within the last year or who consume more than 1 unit (1 unit is equal to approximately * pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure [25 mL] of spirits) of alcohol a day. Alcohol is not allowed within 7 days before study drug dosing. Subjects having a positive test result for drugs of abuse, alcohol, or cotinine (indicating active current smoking) at screening. Subjects that are habitual and heavy coffee drinkers (more than 4 cups a day, 28 cups a week). Subjects involved in strenuous activity or contact sports within at least 24 hours before study drug dosing. Subjects that have donated blood or blood products within at least 30 days before the dose of study drug in this study. Subjects having received study drug in another investigational study within at least 30 days (or less than 5 half-lives of the investigational agent) prior to dosing in this study. Subjects otherwise not suitable for entry into the study in the opinion of the investigator. Subjects that are employees or family members of the investigator or clinic staff.

[00169] Dosage: Each subject receives 12.5 mg, 17.5 mg, 25 mg, or 50 mg dose of rofecoxib (up to 50 mg per day) on an as-needed basis, for example when a subject experiences migraine pain described as an increase in pain rating of > 1 or a pain rating of >4 to <9 based on the Pain Intensity Numerical Rating Scale. Study drug is co-administered orally with approximately 250 mL of room temperature water, and up to an additional 250 mL of water is allowed, if necessary, to aid in swallowing the study drug. Study staff ensure that at least 250 mL of water is consumed with the dose of study drug and perform a hand and mouth check after dosing to ensure that the tablet has been swallowed.

[00170] Adverse events are assessed from the time of study drug dosing until all end-of-study procedures are complete.

Treatment is assessed via changes in migraine pain via the Pain Intensity Numerical Rating Scale. Treatment achieves a reduction of at least 1 from baseline in the Pain Intensity Numerical Rating Scale, and may achieve a reduction in at least 2, 3, 4, or 5 from baseline in the Pain Intensity Numerical Rating Scale.

EQUIVALENTS AND SCOPE

[00171] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[00172] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[00173] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments disclosed herein. The scope of the present embodiments disclosed herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMS What is claimed is:

1. A method of treating migraine in a subject with von Willebrand’s migraine disorder, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of a non-opioid migraine therapy.

2. The method of claim 1, wherein the non-opioid migraine therapy is effective at treating the migraine disorder without the co-administration of a von Willebrand factor corrective agent.

3. The method of claim 1 or 2, wherein the migraine is acute migraine, chronic migraine, migraine with aura, migraine without aura, ocular migraine, silent migraine, hemiplegic migraine, vestibular migraine, menstrual migraine, abdominal migraine, basilar migraine, status migrainosus, transformed migraine, or cyclic migraine.

4. The method of any preceding claim, wherein the migraine is acute migraine.

5. The method of any preceding claim, wherein the migraine is chronic migraine.

6. The method of any preceding claim, wherein the migraine is migraine without aura.

7. The method of any one of claims 1-5, wherein the migraine is migraine with aura.

8. The method of any preceding claim, wherein the non-opioid migraine therapy is not a non-selective NSAID.

9. The method of claim 8, wherein the non-selective NSAID is one or more of ibuprofen, naproxen sodium, aspirin, diclofenac, mefenamic acid, indomethacin, ketoprofen, or piroxicam, or a pharmaceutically acceptable salt thereof.

10. The method of any preceding claim, wherein the non-opioid migraine therapy is not acetaminophen, or a pharmaceutically acceptable salt thereof.

11. The method of any preceding claim, wherein the non-opioid migraine therapy is a COX-2 inhibitor, a serotonin receptor agonist, or a calcitonin gene -related peptide (CGRP) antagonist.

12. The method of claim 11, wherein the non-opioid migraine therapy is a COX-2 inhibitor or a serotonin receptor agonist.

13. The method of any preceding claim, wherein the non-opioid migraine therapy is not a CGRP antagonist.

14. The method of claim 11, wherein the non-opioid migraine therapy is a COX-2 inhibitor.

15. The method of claim 14, wherein the COX-2 inhibitor is celecoxib, etoricoxib, rofecoxib, valdecoxib, parecoxib, or a pharmaceutically acceptable salt thereof.

16. The method of claim 15, wherein the COX-2 inhibitor is rofecoxib, or a pharmaceutically acceptable salt thereof.

17. The method of claim 16, wherein the effective amount is 17.5 mg.

18. The method of claim 11, wherein the CGRP antagonist is a small molecule CGRP antagonist.

19. The method of claim 18, wherein the CGRP antagonist is BI 44370 TA (BI 44370), MK-3207, olcegepant (BIBN-4096BS), rimegepant (BMS-927711), SB-268262, telcagepant (MK-0974), or ubrogepant, or a pharmaceutically acceptable salt thereof.

20. The method of claim 11, wherein the CGRP antagonist is an antibody.

21. The method of claim 20, wherein the CGRP antagonist is erenumab (AMG-334), eptinezumab (ALD403), fremanezumab (TEV-48125), or galcanezumab (LY2951742).

22. The method of claim 11, wherein the serotonin receptor agonist is a triptan.

23. The method of claim 22, wherein the triptan is an agonist of one or more of the serotonin 5-HTIA, 5-HTIB, 5-HTID, 5-HTIE, or 5-HTIF receptors.

24. The method of claim 23, wherein the triptan is a full agonist.

25. The method of claim 23, wherein the triptan is a partial agonist.

26. The method of claim 22, wherein the triptan is sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan, frovatriptan, ergotamine, lasmiditan, or a pharmaceutically acceptable salt thereof.

27. The method of any preceding claim, wherein the subject has been diagnosed with von Willebrand’s migraine disorder.

28. The method of any preceding claim, wherein the subject has failed a prior treatment regimen.

29. The method of claim 28, wherein the prior treatment regimen comprised administration of acetaminophen, or a pharmaceutically acceptable salt thereof.

30. The method of any preceding claim, wherein the subject is contraindicated for a non- selective NSAID due to at least one contraindication.

31. The method of claim 30, wherein the contraindication is one or more of renal insufficiency, peptic ulcer disease, gastritis, pregnancy, hypersensitivity, hypertension, or bleeding.

32. The method of claim 31, wherein the contraindication is bleeding.

33. The method of claim 32, wherein the bleeding is gastrointestinal bleeding.

34. The method of any preceding claim, wherein the subject is concurrently administered a von Willebrand factor corrective agent.

35. The method of one of claims 1-33, wherein the subject is not concurrently administered a von Willebrand factor corrective agent.

36. The method of claim 34 or 35, wherein the von Willebrand factor corrective agent is von Willebrand factor replacement therapy.

37. The method of claim 36, wherein the subject is concurrently administered prophylactic von Willebrand factor replacement therapy.

38. The method of claim 36, wherein the subject is not concurrently administered prophylactic von Willebrand factor replacement therapy.

39. The method of claim 34 or 35, wherein the von Willebrand factor corrective agent is a von Willebrand’s activating agent.

40. The method of claim 39, wherein the von Willebrand’s activating agent is desmopressin acetate.

41. The method of claim 34 or 35, wherein the von Willebrand factor corrective agent is a gene therapy.

42. The method of any preceding claim, wherein the subject is male.

43. The method of any one of claims 1-41, wherein the subject is female.

44. The method of any preceding claim, wherein the subject is a human.

45. The method of claim 44, wherein the subject is at least 16 years of age.

46. The method of claim 44 or 45, wherein the subject is at most 65 years of age.

47. The method of any preceding claim, wherein the von Willebrand’s migraine disorder is associated with von Willebrand’s sub-type I.

48. The method of any one of claims 1-46, wherein the von Willebrand’s migraine disorder is associated with von Willebrand’s sub-type II.

49. The method of any one of claims 1-46, wherein the von Willebrand’s migraine disorder is associated with von Willebrand’s sub-type III.

50. The method of any preceding claim, wherein the effective amount of the non-opioid migraine therapy is about 1 mg to about 300 mg.

51. The method of claim 50, wherein the effective amount of the non-opioid migraine therapy is about 1 mg, 2mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 110 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, or 300 mg.

52. The method of claim 51, wherein the effective amount is about 17.5 mg.

53. The method of any preceding claim, wherein the effective amount of the non-opioid migraine therapy is about 0.1 mg/kg to about 25 mg/kg.

54. The method of claim 53, wherein the effective amount of the non-opioid migraine therapy is about 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, or 25 mg/kg.

55. The method of any preceding claim, wherein about 10 mg to about 2500 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day.

56. The method of claim 55, wherein about 10 mg, about 15 mg, about 17.5 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 1000 mg, or about 2500 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day.

57. The method of claim 56, wherein 17.5 mg of the non-opioid migraine therapy, or a pharmaceutical composition thereof, is administered to the subject per day.

58. The method of any preceding claim, wherein the effective amount of the non-opioid migraine therapy is a therapeutically effective amount.

59. The method of any one of claims 1-57, wherein the effective amount of the non- opioid migraine therapy is a prophylactically effective amount.

60. The method of any preceding claim, wherein the treatment achieves a reduction of at least 1 from baseline in a Pain Intensity Numerical Rating Scale.

61. The method of any preceding claim, wherein the treatment achieves a reduction of at least 2 from baseline in a Pain Intensity Numerical Rating Scale.

62. The method of any preceding claim, wherein the treatment achieves a reduction of at least 3 from baseline in a Pain Intensity Numerical Rating Scale.

63. The method of any preceding claim, wherein the treatment achieves a reduction of at least 4 from baseline in a Pain Intensity Numerical Rating Scale.

64. The method of any preceding claim, wherein the treatment achieves a reduction of at least 5 from baseline in a Pain Intensity Numerical Rating Scale.

65. The method of any preceding claim, wherein the pharmaceutical composition is administered to the subject once daily.

66. The method of any one of claims 1-64, wherein the pharmaceutical composition is administered to the subject two times or more daily.

67. The method of any preceding claim, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

68. The method of any preceding claim, wherein the pharmaceutical composition further comprises an additional agent.

69. The method of claim 68, wherein the agent is acetaminophen, or an isotopically labeled derivative thereof.

70. The method of claim 68, wherein the agent is caffeine, or an isotopically labeled derivative thereof.

71. The method of any preceding claim, wherein the pharmaceutical composition is an oral, parenteral, inhalation, transdermal, intranasal, rectal, buccal, vaginal, topical, or injectable dosage form.

72. The method of claim 69, wherein the pharmaceutical composition is an oral dosage form.

73. The method of any preceding claim, wherein the pharmaceutical composition is a solid dosage formulation.

74. The method of claim 73, wherein the solid dosage formulation is a tablet, capsule, granule, powder, sachet, or chewable dosage form.

75. The method of any one of claims 1-72, wherein the pharmaceutical composition is a liquid-filled capsule.

76. The method of any one of claims 1-72, wherein the pharmaceutical composition is a liquid dosage formulation.

77. The method of claim 76, wherein the liquid dosage formulation is a solution, suspension, or syrup.

78. A method of treating migraine in a subject with von Willebrand’s migraine disorder, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of rofecoxib.

79. The method of claim 78, wherein the effective amount is 17.5 mg.