USOO8703823B2
(12) United States Patent (10) Patent No.: US 8,703,823 B2 Salehani (45) Date of Patent: Apr. 22, 2014
(54) METHODS FORTREATMENT OF MIGRAINE Aube (Neurology, 53, S26-28, 1999).* AND SYMPTOMIS THEREOF Anonymous (2004). “Migraine.” located at
(56) References Cited The Robert Wood Johnson Foundation (1999). “Education for Phy sicians on End-Of-Life Care.” Powerpoint Presentation by American Medical Association's Institute for Ethics, pp. 1-45. OTHER PUBLICATIONS Wadibia, E.C. (Feb. 1999). “Antiemetics' Southern Medical Journal 92(2):162-165. Nelson, T.P. (2002). “Postoperative Nausea and Vomiting: Under Weisz, M.A. et al. (Jun. 1994). “Home Administration of Intramus standing the Enigma. Continuing Education Articles Online by cular DHE for the Treatment of Acute Migraine Headache.” Head ache 34(6):371-373 (Abstract Only). American Society of PeriAnesthesia Nurses located at
O
N N 5 1- N'- . es r X- C 1N1N
10 dimenhydrinate orphenadrine 15 () phenyltoloxamine
bietanautine
25 r) C setastine
Cl carbinoxamine
Br 35
clemastine
N-1-1 40
embramine 45
diphenylpyraline
ON-1a N1 50 Anti-Migraine Compositions The present invention encompasses compositions consist ing essentially of a therapeutically effective amount of a Substituted benzamide antiemetic and an ethanolamine anti moxastine histamine. A therapeutically effective amount is one that pro 55 vides effective treatment of migraines. For example, upon administration of a therapeutically effective amount to an individual Suffering from migraines, the symptoms disappear within less than about 1 hour, less than about 30 minutes, less than about 20 minutes, less than about 15 minutes, less than 60 about 10 minutes, or less than about 5 minutes following the administration of the therapeutically effective amount. 1)N-N In one embodiment of the invention, the substituted ben Zamide antiemetic is trimethobenzamide and the ethanola mine antihistamine is doxylamine, diphenhydramine, bromo 65 diphenhydramine, dimenhydrinate, clemastine, bietanautine, p-methyldiphenhydramine carbinoxamine, diphenylpyraline, embramine, medrylamine, moXastine, p-methyldiphenhydramine, orphenadrine, phe US 8,703,823 B2 13 14 nyltoloxamine, or setastine. In another embodiment of the The compounds can be formulated for parenteral delivery, invention, the substituted benzamide antiemetic is tri Such as intra Venous (IV), intra muscular (IM) injection, or methobenzamide and the ethanolamine antihistamine is intra peritoneal (IP) injection, or for non-parenteral delivery, doxylamine, diphenhydramine, bromodiphenhydramine, Such as oral (e.g. tablet, capsule, gel, etc.), topical (e.g., trans dimenhydrinate, bietanautine, carbinoxamine, embramine, dermal, etc.), nasal, inhaler, or Suppository. The term "injec medrylamine, moXastine, p-methyldiphenhydramine, tion' can refer to both IM and IP delivery. When administered orphenadrine, phenyltoloxamine, or setastine. In another separately, the trimethobenzamide can be formulated for embodiment of the invention, the substituted benzamide anti parenteral delivery or non-parenteral delivery and the etha emetic is trimethobenzamide and the ethanolamine antihista nolamine antihistamine can be formulated independently for mine is doxylamine, diphenhydramine, bromodiphenhy 10 parenteral delivery or non-parenteral delivery. Any combina dramine, or dimenhydrinate. In another embodiment of the tion of delivery of a therapeutically effective amount may be invention, the compositions consist essentially of a therapeu co-administered, such as parenteral delivery of both com tically effective amount of trimethobenzamide and diphenhy pounds, non-parenteral delivery of both compounds, dramine. parenteral delivery of trimethobenzamide with non The invention also encompasses a composition comprising 15 parenteral delivery of the ethanolamine antihistamine, or a therapeutically effective amount of trimethobenzamide and non-parenteral delivery of trimethobenzamide with diphenhydramine, including any salt forms, Solvates, or Ste parenteral delivery of the ethanolamine antihistamine. In cer roisomers thereof. tain embodiments, the therapeutically effective amounts of All compositions discussed herein encompass pharmaceu trimethobenzamide and the ethanolamine antihistamine are tical compositions of the two compounds, whether formu formulated as a mixture for parenteral (e.g., injection, etc.) or lated separately or as a mixture. For example, a pharmaceu non-parenteral (e.g., oral, etc.) delivery. In particular embodi tical composition of trimethobenzamide and diphenydramine ments the trimethobenzamide and ethanolamine antihista would include separate formulations, e.g. separate capsules, mine are administered orally, either with a single tablet or tablets, gels, etc. for oral delivery or separate solutions for capsule, or simultaneously with separate tablets or capsules. parenteral delivery, such as separate vials for injection. A 25 In other embodiments, the trimethobenzamide and ethanola pharmaceutical composition, for example, of trimethobenza mine antihistamine are administered via injection (e.g., IM, mide and diphenhydramine would also include a mixture of IP), ether as a mixture or via separate injections. the two in the same formulation, e.g. in one capsule, tablet, In certain embodiments of the above described methods, gel, etc. for oral delivery or one solution for parenteral deliv the ethanolamine antihistamine is doxylamine, diphenhy ery, Such as one vial for injection. A mixture of the com 30 dramine, bromodiphenhydramine, dimenhydrinate, clemas pounds is any pharmaceutical composition comprising an tine, bietanautine, carbinoxamine, diphenylpyraline, effective amount of the compounds, wherein the compounds embramine, medrylamine, moxastine, p-methyldiphenhy may be mixed at any point in the process of making the dramine, orphenadrine, phenyltoloxamine, or setastine. In compounds and formulating the pharmaceutical composi certain embodiments of the above described methods, the tion. 35 ethanolamine antihistamine is doxylamine, diphenhy In another aspect of the invention, the therapeutically dramine, bromodiphenhydramine, dimenhydrinate, biet active anti-migraine composition, and methods of using the anautine, carbinoxamine, embramine, medrylamine, moxas composition, encompass where the moieties of the tri tine, p-methyldiphenhydramine, orphenadrine, methobenzamide and ethanolamine antihistamine are com phenyltoloxamine, or setastine. In certain embodiments of bined in a single therapeutically active anti-migraine com 40 the above described methods, the ethanolamine antihistamine pound. is doxylamine, diphenhydramine, bromodiphenhydramine, Such therapeutically active compounds include where the or dimenhydrinate. In certain embodiments of the above trimethobenzamide and ethanolamine antihistamine are described methods, the ethanolamine antihistamine is linked via a frangible linker or a non-frangible linker, as diphenhydramine. known to those of skill in the art. In certain embodiments, the 45 The therapeutically effective amount of trimethobenza anti-migraine compound comprises the trimethobenzamide mide is one that, in combination with a therapeutically effec and diphenhydramine moieties. The moieties so incorporated tive amount of an ethanolamine antihistamine, provides into the anti-migraine compound may include the entire tri effective treatment of migraines, for example where upon methobenzamide or ethanolamine antihistamine molecule administration to an individual Suffering from migraines, the (absent atoms as necessary at the linking site), or the portion 50 symptoms disappear within less than about 1 hour, less than of the trimethobenzamide or ethanolamine antihistamine nec about 30 minutes, less than about 20 minutes, less than about essary for therapeutic activity. 15 minutes, less than about 10 minutes, or less than about 5 Methods of Migraine Treatment minutes after the administration of the therapeutically effec Migraines are effectively treated by the co-administration tive amount. Similarly, the therapeutically effective amount of trimethobenzamide and an ethanolamine antihistamine. A 55 of an ethanolamine antihistamine is one that, in combination therapeutically effective amount of trimethobenzamide and with a therapeutically effective amount of trimethobenza an ethanolamine antihistamine may be co-administered via mide, provides effective treatment of migraines, for example parenteral or non-parenteral delivery. Co-administration is where upon administration to an individual Suffering from defined as administration of the therapeutically effective migraines, the symptoms disappear within less than about 1 amount of each compound simultaneously, or within a certain 60 hour, less than about 30 minutes, less than about 20 minutes, period of time. For example, the compounds may be formu less than about 15 minutes, less than about 10 minutes, or less lated as a mixture that is administered, as separate formula than about 5 minutes after the administration of the therapeu tions administered simultaneously, or as separate formula tically effective amount. tions administered within a time period, Such as within less A unit dose for the treatment of migraines is the combined than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or 30 minutes of 65 therapeutically effective amounts of trimethobenzamide and each other, wherein either compound can be administered an ethanolamine antihistamine, whetherformulated as a mix first. ture or separately. Whena therapeutically effective amount of US 8,703,823 B2 15 16 trimethobenzamide and an ethanolamine antihistamine is for Kits mulated as a mixture, the therapeutically effective amount of The invention also provides kits for the treatment of the mixture is a unit dose of the composition comprising migraines comprising a pharmaceutical composition consist trimethobenzamide and an ethanolamine antihistamine. ing essentially of at least one unit dose of a Substituted ben When the unit dose is not a formulated mixture of the tri Zamide antiemetic and an ethanolamine antihistamine, methobenzamide and the ethanolamine antihistamine, i.e. wherein the pharmaceutical composition further comprises when the therapeutically effective amounts of trimethoben acceptable excipients, adjuvants, diluents, or stabilizers, Zamide and an ethanolamine antihistamine are formulated wherein a kit includes instructions for use in the treatment of and administered independently (including simultaneously), migraines. The unit dose of the substituted benzamide anti 10 emetic and the ethanolamine antihistamine may be formu a unit dose is the therapeutically effective amounts of each lated separately or as a mixture. These can beformulated with compound co-administered (simultaneously or within a cer suitable excipients, adjuvants, diluents or stabilizers for either taintime period of each other). When co-administration is not parenteral (e.g. IV, injection (IM or IP)) or non-parenteral simultaneous, the symptoms disappear within less than about (e.g., oral, topical, nasal, inhaler, or Suppository) delivery. For 1 hour, less thanabout 30 minutes, less than about 20 minutes, 15 example, a unit dose may comprise a formulated mixture of less than about 15 minutes, less than about 10 minutes, or less the substituted benzamide antiemetic and the ethanolamine than about 5 minutes after the administration of the last com antihistamine. Alternatively, the unit dose may comprise the pound administered. Substituted benzamide antiemetic formulation separate from In one embodiment, the method for treatment of migraines the ethanolamine antihistamine formulation. comprises co-administering to an individual in need thereof a The co-administration of these formulations in accordance unit dose of trimethobenzamide and an ethanolamine antihis with the instructions for use provides the desired therapeutic tamine, or administering a unit dose of a composition con treatment of migraines. When the unit dose consists essen sisting essentially of trimethobenzamide and an ethanola tially of separate formulations, these may be independently mine antihistamine. The method may further comprise formulated for parenteral or non-parenteral delivery. For co-administering one or more additional unit doses of tri 25 example, the substituted benzamide antiemetic may be for methobenzamide and an ethanolamine antihistamine, or mulated for parenteral delivery while the ethanolamine anti administering one or more additional unit doses of a compo histamine may beformulated for non-parenteral delivery. For sition consisting essentially of trimethobenzamide and an ease of administration, both compounds may be formulated ethanolamine antihistamine, after a period of time from the for the same type of delivery, including where the substituted initial dose, such as after at least a month. The method of 30 benzamide antiemetic and the ethanolamine antihistamine treatment may be prophylactic, wherein an individual who are formulated as a mixture. suffers from recurring migraines may be administered unit In one embodiment of the invention, the substituted ben doses of trimethobenzamide and an ethanolamine antihista Zamide antiemetic and the ethanolamine antihistamine are mine, or unit doses of a composition consisting essentially of formulated for parenteral delivery, in Some cases as a mixture. trimethobenzamide and an ethanolamine antihistamine rou 35 In Such embodiments, the kit further comprises at least one tinely, for example about once a month. syringe for delivery of the dose. The formulation for In certain embodiments of the methods described herein, parenteral delivery may comprise a multi-dose formulation, the ethanolamine antihistamine is doxylamine, diphenhy wherein a new syringe is used to remove a unit dose from the dramine, bromodiphenhydramine, dimenhydrinate, clemas multi-dose formulation. In one embodiment, the substituted tine, bietanautine, carbinoxamine, diphenylpyraline, 40 benzamide antiemetic and the ethanolamine antihistamine embramine, medrylamine, moxastine, p-methyldiphenhy are formulated for non-parenteral delivery, such as oral deliv dramine, orphenadrine, phenyltoloxamine, or setastine. In ery. In certain embodiments, a unit dose is formulated as a certain embodiments of the methods described herein, the mixture of the substituted benzamide antiemetic and the etha ethanolamine antihistamine is doxylamine, diphenhy nolamine antihistamine for oral delivery, such as a capsule or dramine, bromodiphenhydramine, dimenhydrinate, biet 45 pill. anautine, carbinoxamine, embramine, medrylamine, moxas In certain embodiments, the substituted benzamide anti tine, p-methyldiphenhydramine, orphenadrine, emetic is trimethobenzamide and the ethanolamine antihista phenyltoloxamine, or setastine. In certain embodiments of mine is doxylamine, diphenhydramine, bromodiphenhy the methods described herein, the ethanolamine antihista dramine, dimenhydrinate, clemastine, bietanautine, mine is doxylamine, diphenhydramine, bromodiphenhy 50 carbinoxamine, diphenylpyraline, embramine, medrylamine, dramine, or dimenhydrinate. In certain embodiments of the moXastine, p-methyldiphenhydramine, orphenadrine, phe methods described herein, the ethanolamine antihistamine is nyltoloxamine, or setastine. In another embodiment, the Sub diphenhydramine. stituted benzamide antiemetic is trimethobenzamide and the The methods described herein are for the treatment of ethanolamine antihistamine is doxylamine, diphenhy migraines specifically, and are not intended to treat non 55 dramine, bromodiphenhydramine, dimenhydrinate, biet migraine headaches. Non-migraine headaches include ten anautine, carbinoxamine, embramine, medrylamine, moxas sion (i.e. stress) headaches and secondary headaches, i.e. tine, p-methyldiphenhydramine, orphenadrine, headaches that are caused by other conditions, such as sinusi phenyltoloxamine, or setastine. In another embodiment, the tis, toothache, ear infections, etc. For example, compositions substituted benzamide antiemetic is trimethobenzamide and and methods described herein have been used on individuals 60 the ethanolamine antihistamine is doxylamine, diphenhy suffering from sinusitis or ear infections with no effect on the dramine, bromodiphenhydramine, or dimenhydrinate. In cer pain associated with these conditions. While not limiting the tain embodiments, the Substituted benzamide antiemetic is compositions or methods of the invention to any particular trimethobenzamide and the ethanolamine antihistamine is mechanism, it is possible that the combination of tri diphenhydramine. methobenzamide and ethanolamine antihistamine acts to 65 In another embodiment, the invention provides kits for the block the sympathetic nerve, which alleviates migraine head treatment of migraines comprising a pharmaceutical compo aches and all symptoms associated with migraines. sition consisting essentially of at least one unit dose of tri US 8,703,823 B2 17 18 methobenzamide and an ethanolamine antihistamine, pharmaceutical compositions are formulated by methods wherein the pharmaceutical composition further comprises well know to those skilled in the art. The pharmaceutical acceptable excipients, adjuvants, diluents, or stabilizers, and compositions are manufacture with acceptable excipients, wherein the kit includes instructions for use for treatment of adjuvants, diluents or stabilizers to provide the appropriate migraine. The unit dose of the trimethobenzamide and the formulation for the desired administration, Such as parenteral ethanolamine antihistamine may beformulated separately or (e.g., IV, injection (IM or IP)) or non-parenteral (e.g., oral, as a mixture. These can be formulated with suitable excipi topical, nasal, inhaler or Suppository). As the compounds ents, adjuvants, diluents or stabilizers for either parenteral used in the methods and compositions discussed herein are (e.g., IV, injection (IM or IP)) or non-parenteral (e.g., oral, generally commercially available, the Suitable formulations topical, nasal, inhaler, or Suppository) delivery. In another 10 are readily known to those skilled in the art. For example, the embodiment, the ethanolamine antihistamine is doxylamine, compositions and methods discussed herein comprising tri diphenhydramine, bromodiphenhydramine, dimenhydrinate, methobenzamide and diphenhydramine were prepared from clemastine, bietanautine, carbinoxamine, diphenylpyraline, commercially available pharmaceutical compositions. A embramine, medrylamine, moxastine, p-methyldiphenhy commercially available composition of trimethobenzamide dramine, orphenadrine, phenyltoloxamine, or setastine. In 15 for oral delivery, such as a capsule, may contain 250 mg to another embodiment, the ethanolamine antihistamine is 300 mg of trimethobenzamide hydrochloride as well as inac doxylamine, diphenhydramine, bromodiphenhydramine, tive ingredients such as D&C Red No. 28, FD&C Blue No. 1, dimenhydrinate, bietanautine, carbinoxamine, embramine, lactose, magnesium Stearate, starch, and titanium oxide. A medrylamine, moXastine, p-methyldiphenhydramine, commercially available composition of trimethoxybenza orphenadrine, phenyltoloxamine, or setastine. In another mide in single dose ampules for injection may contain 200 mg embodiment, the ethanolamine antihistamine is doxylamine, trimethobenzamide hydrochloride in 2 mL, along with inac diphenhydramine, bromodiphenhydramine, or dimenhydri tive ingredients such as 0.2% methyl and propyl parabens nate. In certain embodiments, the ethanolamine antihistamine (preservatives), 1 mg Sodium citrate and 0.4 mg citric acid as is diphenhydramine. buffers, pH adjusted to approximately 5.0 with sodium In certain embodiments, the invention provides kits for the 25 hydroxide. Similarly, multi-dose vials for injection may con treatment of migraines comprising a pharmaceutical compo tain 100 mg/mL trimethobenzamide hydrochloride, along sition comprising at least one unit dose of trimethobenzamide with inactive ingredients such as 0.45% phenol (preservative) and diphenhydramine, wherein the pharmaceutical composi 0.5 mg/mL sodium citrate and 0.2 mg/mL citric acid as buff tion further comprises acceptable excipients, adjuvants, dilu ers, pH adjusted to approximately 5.0 with sodium hydroxide. ents, or stabilizers, wherein a kit includes instructions for use 30 Similarly, diphenhydramine is commercially available as a for the treatment of migraines. The unit dose of trimethoben composition for injection containing 50 mg/mL diphenhy Zamide and diphenhydramine may be formulated separately dramine hydrochloride, adjusted to pH 5.0 or 6.0 with either or as a mixture. These can be formulated with suitable excipi sodium hydroxide or hydrochloric acid, where multi-dose ents, adjuvants, diluents or stabilizers for either parenteral vials may contain additional inactive ingredients, such as 0.1 (e.g., IV, injection (IM or IP)) or non-parenteral (e.g., oral, 35 mg/mL benzethonium chloride as a germicidal agent. Cap topical, nasal, inhaler, or Suppository) delivery. Sules are also commercially available, typically containing 25 The unit dose may comprise a formulated mixture of tri mg or 50 mg of diphenhydramine hydrochloride. methobenzamide and diphenhydramine. Alternatively, the While the trimethobenzamide and ethanolamine antihista unit dose may comprise a trimethobenzamide formulation mines discussed herein are generally commercially available, separate from a diphenhydramine formulation. The co-ad 40 Such that appropriate doses can be readily prepared from ministration of these formulations provides the desired thera existing pharmaceutical compositions, the compositions, peutic treatment of migraines (i.e. unit dose). When the unit methods and kits discussed herein encompass any Suitable dose comprises separate formulations, these may be indepen pharmaceutical formulation of the desired dose of com dently formulated for parenteral or non-parenteral delivery. pounds, either formulated as a mixture or separately. Such For example, the trimethobenzamide may be formulated for 45 formulations are known to those skilled in the art, and parenteral delivery while the diphenhydramine may be for examples of suitable excipients, adjuvants, diluents or stabi mulated for non-parenteral delivery. For ease of administra lizers can be found, for example, in Gennaro, ed., Reming tion, both compounds may beformulated for the same type of ton's The Science and Practice of Pharmacy, 20' edition, delivery, where the trimethobenzamide and the diphenhy Lippincott Williams &Wilkins. dramine may be formulated as a mixture. 50 The unit dose required for the compositions, methods and In one embodiment of the invention, the trimethobenza kits discussed herein can be adjusted as necessary to Suit the mide and the diphenhydramine are formulated for parenteral individual being treated, for example adjusted to the weight, delivery, and may be formulated as a mixture. In Such age or general health of the individual, as is within the skill of embodiments, the kit may further comprise at least one a medical practitioner. For a unit dose of trimethobenzamide Syringe for delivery of a unit dose. In certain embodiments, 55 and an ethanolamine antihistamine Such as diphenhydramine, the mixture is formulated for IM delivery. The formulation for dosage formulated for either parenteral or non-parenteral parenteral delivery may comprise a multi-dose formulation, delivery as discussed herein, comprises trimethobenzamide wherein a new syringe is used to remove a unit dose from the in the range of approximately 10 mg to 1000 mg, also multi-dose formulation. In one embodiment, the tri approximately 25 mg to 500 mg, also approximately 50 mg to methobenzamide and the diphenhydramine are formulated 60 500 mg, also approximately 250 mg to 300 mg and diphen for non-parenteral delivery, such as oral delivery. In certain hydramine in the range of approximately 1 mg to 200 mg, also embodiments, a unit dose is formulated as a mixture of tri approximately 5 mg to 150 mg, also approximately 10 mg to methoxybenzamide and diphenhydramine for oral delivery, 100 mg, also approximately 25 to 50 mg. In certain embodi Such as a capsule, gel or tablet. ments, the dose is formulated for oral delivery to an adult with Formulations and Dosage 65 250 mg of trimethobenzamide and 25 mg diphenhydramine. The compositions discussed herein can be generally In certain embodiments, an adult dose is formulated for injec administered as pharmaceutical compositions, wherein the tion with 200 mg trimethobenzamide and 50 mg diphenhy US 8,703,823 B2 19 20 dramine in 3 mL solution for injection. Trimethobenzamide is by intramuscular injection (Gluteus muscle) to 113 individu contraindicated in children under 7 years of age via injection als (two individuals were enlisted but not treated), where the or oral delivery. Children under 7 years of age may be treated dose delivered was adjusted according to body weight of the instead with a 100 mg Suppository via the rectum, adminis individual. A single dose for delivery by mouth (oral delivery) tered with the ethanolamine antihistamine according to the was prepared from commercially available capsules, contain methods described herein. For the ethanolamine antihista ing 250 mg of trimethobenzamide and 25 mg dipheny mines, pediatric dosages are calculated according to the dramine. The appropriate amount was prepared according to known dosing regimens according to the weight and age of individual body weights and given orally to 5 individuals the individual for the particular antihistamine. For example, (individuals 70, 74,78, 79, and 84 in Table 1). the diphenhydramine pediatric dose for the claimed mixtures 10 is 5 mg/kg/24 hours, where the dose is delivered over 24 hours All individuals showed reduction in symptoms within in 3-4 doses. approximately 10 minutes of injection or ingestion for all The invention discussed herein further encompasses meth individuals. All but 11 of the treated individuals were moni ods of manufacturing a medicament for the treatment of tored over time. In 3 of these 11 individuals, mild headaches migraine headaches. The methods of manufacturing Such 15 were reported approximately 7-10 days after treatment. How medicaments are well known to those skilled in the art. Such ever, there was evidence of possible sinusitis for these indi medicaments are embodied by the compositions, methods viduals at that time and they were not available for later follow and kits discussed herein. up. It was determined in 5 individuals (unrelated to this study) The invention is further illustrated by the following non having sinusitis without migraines that similar treatment with limiting examples. trimethobenzamide and diphenhydramine does not provide significant reduction in the headaches due to the sinusitis. EXAMPLES Table 1 indicates the response to treatment for the remaining 107 individuals (includes 19 and 80, enlisted but not treated). Example 1 In all individuals, the migraine headache Subsided and all 25 symptoms were alleviated. These results, along with the lack Treatment of Migraine Headache with a Single of efficacy for treating sinusitis headache, Suggest that the Injection of Trimethobenzamide and trimethobenzamide and diphenhydramine treatment is Diphenhydramine uniquely and specifically effective for migraine treatment. This is further supported in that headaches did not recur in Individuals with a history of recurrent migraine headaches 30 other than these three individuals for up to 9 months, includ were selected for treatment. The individuals were queried to ing those individuals who suffered migraines more than 10 assess the Symptoms relating to the migraine headaches. times a month in the 3 months prior to treatment. These symptoms include pulsating or throbbing headache, In some individuals, approximately 30% or less, some photophobia or visual disturbances (e.g. bright flashing drowsiness was observed. However, the side effects normally lights; flickering, colored ZigZag lines; blind spots; loss of 35 associated with administration of either trimethobenzamide vision off to one side), earache or noise disturbances (e.g. or diphenhydramine alone were not observed in any of the phonophobia; buZZing or ringing in ears), nausea or vomiting, individuals. No adverse effects with regard to general health, abdominal discomfort, limpness or numbness in extremities, or blood pressure, were noted by any of the treated individuals tingling (e.g. pins and needles) in extremities, Strange tastes who suffered from migraines. Repeated administration of or Smells, dizziness, and excessive Sweating or irritability. 40 trimethobenzamide and diphenhydramine to non-migraine Dosages of trimethobenzamide and diphenhydramine were individuals caused no discernible effects with regard to blood prepared from commercially available preparations of pressure or general health. Overall, these results suggest that Tigan R and Benadryl(R), respectively. A single dose for injec administering trimethobenzamide and diphenhydramine, tion contained 200 mg of trimethobenzamide in 2 mL mixed either orally or by intra muscular injection, is a safe and with 50 mg of diphenydramine in 1 mL. Injections were given effective treatment for migraines. TABLE 1. Occurrence of migraine headaches pre and post treatment in individuals treated with trimethobenzamide and diphenhydramine. All doses were IM injection with the exception of those with (O) in the dose column (oral dose). Pretreatment condition Post treatment
Individual Headaches Average Headaches # of
i Sex Age per month Severity* Duration Symptoms * per month Months. ** doses 24 3 24 1-2-3-4-6 O 9 1 48 1 8 2.5 24 1-2-4 O 9 1 43 3 24 1-2-4-6 <<1: 6 1 79 3 24 1-2-3-6-7 O 9 1 35 1 2.5 24 1-2-4 O 9.5 1 31 3 24 1-2-3-4 O 8.5 1 37 3 24 1-2-4-6 O 8.5 1 24 3 24 1-2-3-6 O 8.5 1 19 2.5 24 1-3-4 O 8.5 1 47 3 24 1-2-3-4 O 8.5 1 49 2.5 24 1-2-4-7 O 8.5 1 43 2 24 1-2 O 8.5 1 1 3 32 2 24 1-2-4 O 8.5 1 US 8,703,823 B2 21 TABLE 1-continued Occurrence of migraine headaches pre and post treatment in individuals treated with trimethobenzamide and diphenhydramine. All doses were IM injection with the exception of those with (O) in the dose column (oral dose). Pre treatment condition Post treatment
Individual Headaches Average Headaches # of i Sex Age per month Severity Duration Symptoms' per month Months' doses 14 M 24 10 2.5 24 -2-5-6 O 8 15 M 29 10 3 24 -2-4 O 8 16 M 33 2 2.5 24 -2 O 8 17 10 10 2.5 24 -2-3-4 O 8 18 34 10 2.5 24 -2-3-4-6 O 8 19 NA 2O 34 5 3 24 -2-4-7 O 8 21 M 32 1 2.5 24 O 8 22 M 39 1 3 24 -2 O 8 23 35 9 3 24 -2-3-4-6 O 8 24 34 10 3 24 -2-3-5 O 8 25 10 5 2.5 24 -2-4 O 8 26 10 8 2.5 24 -2-3-4 O 8 27 47 9 2.5 24 -2-3-4-7 O 8 28 M 21 4 2.5 24 -2-4 O 8 29 22 10 2.5 24 -2-3-4-6 O 8 30 65 4 2.5 24 -2-3 O 8 31 45 6 3 24 -2-4 O 8 32 27 1 2.5 24 -2 O 7 33 M 69 8 2.5 24 -2-4-7 O 7 34 22 5 3 24 -2-3-6 O 7 35 43 1 3 24 -3 O 7 36 49 6 3 24 -2-3 O 7 37 30 2 3 24 -2-3 O 7 38 M 31 8 3 24 -2-3-6 O 7 39 25 10 2.5 24 -2-3-6-7 O 7 40 35 9 3 24 -2-3-4-6 O 7 41 34 4 2.5 24 -2-6-7 O 7 42 34 8 2.5 24 -2-3-4-7 O 7 43 35 8 2.5 24 -2-3-5-6 O 7 44 26 1 NA 48 NA O NA 45 39 7 2.5 24 -2-3 O 7 46 27 8 2.5 24 -2-3 O 7 47 M 2O 1 2.5 24 -S O 7 48 M 48 9 2.5 24 -2-3-4 O 7 49 38 9 3 24 -2-3-7 O 7 50 M 46 8 2.5 24 -2-3-4 O 7 51 M 15 6 2.5 24 -2-4-6 O 6 52 M 26 2 2.5 24 -2 O 6 53 9 1 2.5 24 -S O 6 S4 23 2 2.5 24 -2 O 5 55 M 14 8 2.5 24 -2-4-6-7 O 5 56 M 16 First Time 1 3 24 -2-4 O 5 57 M 15 First Time 1 3 24 -2-3 O 5 58 M 26 2 2.5 24 -2-3 O 5 59 M 38 9 2.5 24 -2-3-5 O 5 60 28 9 2.5 24 -2-3-4 O 5 61 46 7 2.5 24 -2-3-4 O 5 62 40 8 2.5 24 -2-3-4-6 O 5 63 40 8 2.5 24 -2-3-4 O 5 64 30 8 3 24 -2-3-4-6 O 5 65 51 2 3 24 -2-3 O 5 66 38 8 3 24 -2-3-4 O 5 67 M 15 8 3 24 -2-3-4-5 O 5 68 M 45 8 3 24 -2-3-4 O 5 69 24 8 3 24 -2-3-4 O 5 70 29 1 2.5 24 O 5 1(O) 71 13 4 2.5 24 -2 O 5 72 46 7 3 24 -2-3-4 O 5 73 47 8 3 24 -2-3-4-7 O 5 74 33 4 2.5 24 -2-3-4 O 5 1(O) 75 35 8 3 24 -2-3-4-5 O 5 76 M 64 8 2.5 24 -2-3-4 O 5 77 M 33 6 2.5 24 -2-3-4 O 5 78 52 8 2.5 24 -2-3-4-6 O 5 1(O) 79 44 8 2.5 24 -2-3-4 O 5 1(O) 8O NA 81 M 40 8 2.5 24 -2-3-4 O 5 82 19 8 2.5 24 -2-3-4 O 5 83 57 5 2.5 24 -2-3-5 O 5 US 8,703,823 B2 23 24 TABLE 1-continued Occurrence of migraine headaches pre and post treatment in individuals treated with trimethobenzamide and diphenhydramine. All doses were IM injection with the exception of those with (O) in the dose column (oral dose). Pre treatment condition Post treatment
Individual Headaches Average Headaches # of i Sex Age per month Severity Duration Symptoms per month Months' doses 84 35 4 3 24 -2-3-4 O 5 1(O) 85 M 29 8 3 24 -2-3-4-7 O 5 86 55 8 2.5 24 -2-3-4 O 5 87 M 35 8 2.5 24 -2-3-4 O 5 88 32 11 2.5 24 -2-3-4-6-7 O 4 89 Constant 1-2-3 24 -2-3-4-5- O 4 6-7 90 40 4 2.5 24 -2-3 O 4 91 38 Every Day 1-2-3 24 -2-3-4 O 4 92 53 8 2.5 24 -2-3-4 O 4 93 M 58 8 2.5 24 -2-3-4 O 4 94 9 8 2.5 24 -2-3-4-6 O 4 95 65 6 2.5 24 -2-3-4 O 2 96 M 19 8 2.5 24 -2-3-4-5 O 2 97 M 26 1 2.5 24 -2-3-4 O 2 98 10 2 2.5 24 -2-3 O 2 99 56 8 1-2-3 24 -2-3-4-7 O 2 1OO 37 4 2.5 24 -2-3-4 O 2 101 33 2 3 24 -2-3-4-5-6 O 2 102 14 1 3 24 -2-3-4 O 2 103 13 7 2.5 24 -2-3-4-5 O 2 104 13 8 2.5 24 -2-3-4 O 2 105 27 8 2.5 24 -2-3-4-5 O 1 106 19 8 2.5 24 -2-3-4-5 O 1 107 M 31 6 2.5 24 -2-3-4-6 O 1 108 M 41 8 2.5 24 -2-3-4 O 1 109 23 4 2.5 24 -2-3-4 O 2 wks *Severity 1 = mild, 2 = moderate, 3 = severe Symptoms 1 = throbbing headache, 2 = photophobia or visual disturbance3 = earache or noise disturbance, 4 = nausea or vomiting, 5 = abdominal discomfort, 6 = limpness in extremities, 7 = pins and needles in extremities, ***Months without a headache following a single treatment, ****This individual had one headache in 9 months (at 6 months).
What is claimed as new and desired to be protected by 11. The method of claim 1, wherein the composition is a Letters Patent of the United States is: pharmaceutical composition further comprising one or more 1. A method for the treatment and diminishment of occur 40 pharmaceutically acceptable excipients, adjuvants, diluents rences of migraine headaches comprising administering to an or stabilizers. 12. The method of claim 4, wherein the composition is a individual in need thereof a unit dose of a composition com pharmaceutical composition further comprising one or more prising trimethobenzamide and diphenhydramine, wherein pharmaceutically acceptable excipients, adjuvants, diluents the unit dose comprises 25 mg to 500 mg trimethobenzamide 45 or stabilizers. and 5 mg to 150 mg diphenhydramine, and wherein the 13. The method of claim 7, wherein the composition is a administration diminishes occurrence of migraine headaches pharmaceutical composition further comprising one or more in the individual for at least two weeks. pharmaceutically acceptable excipients, adjuvants, diluents 2. The method of claim 1, wherein the period of time is at or stabilizers. least one month. 50 14. The method of claim 1, wherein the unit dose of tri 3. The method of claim 1, wherein treatment is prophylac methobenzamide and diphenhydramine is provided in sepa tic and wherein the unit dose is administered about one time rate dosage forms. 15. The method of claim 1, wherein the unit dose of tri per month. methobenzamide and diphenhydramine is formulated as a 4. The method of claim 1, wherein the composition is mixture. formulated for non-parenteral delivery. 55 16. The method of claim 1, wherein the trimethobenzamide 5. The method of claim 4, wherein the composition is and diphenhydramine are administered simultaneously. formulated for oral delivery. 17. The method of claim 1, wherein the unit dose comprises 6. The method of claim 5, wherein the unit dose comprises 250 mg to 300 mg trimethobenzamide and 10 mg to 100 mg 250 mg trimethobenzamide and 25 mg diphenhydramine. diphenhydramine. 7. The method of claim 1, wherein the composition is 60 18. The method of claim 9, wherein the injection is intra formulated for parenteral delivery. muscular. 8. The method of claim 7, wherein parenteral delivery is via 19. The method of claim 1, wherein the administration intra Venous delivery or injection. diminishes occurrence of migraine headaches in the indi 9. The method of claim 8, wherein the parenteral delivery vidual for at least five months. is via injection. 65 20. The method of claim 1, wherein the administration 10. The method of claim 9, wherein the unit dose comprises diminishes occurrence of migraine headaches in the indi 200 mg trimethobenzamide and 50 mg diphenhydramine. vidual for at least nine months. US 8,703,823 B2 25 26 21. The method of claim 1, wherein the administration does not cause diarrhea, hypotension, or a combination thereof in the individual.