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Home , Ciramadol, Ethenzamide, Magnesium salicylate, Talbutal, Ziconotide

US 200901 10724A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0110724 A1 Giordano (43) Pub. Date: Apr. 30, 2009

(54) COMPOSITIONS AND METHODS FOR Publication Classification TREATMENT OF PAN (51) Int. Cl. A6II 3/19 (2006.01) (75) Inventor: John A. Giordano, West Orange, A6II 3/55 (2006.01) NJ (US) A6II 3/522 (2006.01) A69/64 (2006.01) Correspondence Address: A6IP 43/00 (2006.01) DON.J. PELTO (52) U.S. Cl...... 424/456; 514/263.3: 514/270; Sheppard, Mullin, Richter & Hampton LLP 5147568 1300 ISTREET, NW, 11TH FLOOR EAST WASHINGTON, DC 20005 (US) (57) ABSTRACT The present invention relates to compositions and methods (73) Assignee: Everett Laboratories, Inc. for treatment of various forms of . Specifically, the method involves administering to a patient a composition (21) Appl. No.: 11/932,237 comprising , acetaminophen and in the gel cap dosage form, to treat and/or alleviate the occurrence or (22) Filed: Oct. 31, 2007 negative effects of various forms of . US 2009/01 1 0724 A1 Apr. 30, 2009

COMPOSITIONS AND METHODS FOR 0008 Caffeine is used in combination with other drugs for TREATMENT OF PAN the treatment of headaches because of its role as an adjunct. Caffeine on its own does not have any known anal FIELD OF THE INVENTION gesic activity. 0001. The present invention relates to compositions that 0009 Acetaminophen, also known as and may be in a form of a gel caplet (gelcap), comprising a sold under the trade name Tylenol R, is a clinically proven , a non-Salicylate analgesic/, and an analgesic/antipyretic. Acetaminophen produces analgesia by analgesic adjunct, and methods for administering these com elevation of the pain threshold and antipyresis through action positions for treatment of patients suffering from various on the hypothalamic heat-regulating center. forms of pain. 0010 Delivery systems of over the counter or prescription drugs come in a variety of shapes and dosage forms, such as BACKGROUND OF THE INVENTION in a capsule, tablet, caplet, gel caplet (gelcap) or in a syrup form if a pill is impractical. However, due to consumer per 0002 Pain is an unpleasant sensation with a wide range in ception and patient preference, certain dosage forms have severity that can be localized or prevalent throughout the particular advantages over others. Until the 1980's, capsules body. The Merck Manual of Medical Information (M. Beers et were the preferred form for the delivery of active drugs. al., 2"Home ed., Merck Research Laboratories, 2003). Pain Capsules area dosage form in which the drug is housed within is affected by nerve stimulation that carries impulses to the two halves of gelatin shells that are banded together. Due to brain and is a symptom of an underlying disease, disorder, or the ability of taking apart the capsule gelatin shell halves and physical injury. Id. then resealing the halves, tampering of the capsule became a 0003. It is estimated that 75 million Americans currently major problem. For this reason, the pharmaceutical industry suffer with pain. NATIONAL CTR. FOR HEALTH STATISTICS, withdrew many of their capsule products from the market, HEALTH, UNITED STATES, 2006 WITH CHARTBOOKONTRENDS often replacing them with tablets or caplets. IN THE HEALTH OF AMERICANS 68-71 (2006). Pain can be classified into two groups: acute pain or . Accord 0011 Tablets and caplets are compressed solid pills where ing to the National Centers for Health Statistics, more than 50 the dosage forms are cylindrical or the oblong shape similar to million Americans experience chronic pain. Id. Chronic pain capsules. Although both dosage forms are presently used in is a persisting or reoccurring pain that can last for months and the market, tablets and caplets have not reached the same level even years. It is more common for chronic pain to be due to a of consumer acceptance that capsules once had. Consumer disorder Such as sickle cell anemia or a serious physical Surveys Suggest that a dosage form with the like appearance injury. of a gelatin coated capsule is easier to Swallow and that the 0004 Alternatively, acute paintends to come on quickly, drug contained in the capsule form will be more effective. but subsides after a short time. Acute pain serves a useful 0012. The gelcap is a drug product that may itself encom purpose by alerting humans of a physiological hazard or a pass many forms. For example, the gelcap may contain a filler need for treatment. Therefore, acute paintends to be caused containing the active drug in a liquid form that is encapsulated from a sudden physical injury or infection. in a gelatin capsule like shell. Also, a gelcap can contain the 0005 Clinical complaints due to pain come in many vari active drug in a solid form, which has the shape of a caplet and eties. Such complaints may be due to Such ailments as arthri a gelatin coating or covering to create the appearance and tis, , neuropathy, or a . therefore, the consumer acceptability of the capsule. 0006. A headache, also known as cephalalgia, ranks amongst the most common clinical pain complaints and can 0013 There are numerous advantages to a drug being be caused from a wide variety of physiological effects. Such administered in the form of a solid gelcap. The gelcap can be causes range from hormonal changes, muscle tension in the manufactured in a wide variety of sizes, shapes and colors that back of the neck, or from dehydration. Because headaches consumers tend to find aesthetically appealing. Moreover, it come in many forms, they may be treated or prevented by has also been established that patient compliance is improved various methods. These methods may include maintaining a if a gelcap is used to administer the drug because of its soft healthy lifestyle, reducing stress or making use of various and elastic nature, which makes it easierto Swallow compared . Such medications can be antianxiety drugs, to a hard tablet or caplet. or nonsteroidal anti-inflammatories 0014 A liquid gelcap also has numerous advantages. (NSAIDs). However, when these drugs are ineffective or not First, it retains many of the advantages of consumer accep possible to use due to allergic reactions, other drug combina tance and is easier to Swallow due to the outer coating being tions may be prescribed. An effective for treat a soft and elastic gelatin shell. Also, concentrated liquid com ment of headaches is the combination ofbutalbital, acetami positions are well Suited for encapsulation within a softgela nophen and caffeine in the capsule form. McCrory et al., 41 tin shell, creating flexibility that further assists in the capsule HEADACHE 953-967 (2001). Although the role of each com being easier to Swallow. The active drug contained in the pound in the relief of headaches is incompletely understood, liquid form also provides advantages by dispersing the drug the combination of these three compounds due to their syn to the active site. For example, the active drug does not first ergistic effects has been widely accepted as a treatment for have to dissolve in the gastrointestinal tract, thereby facilitat various forms of headache. ing absorption of the pharmacologically active Substance. 0007 Butalbital is a short to intermediate-acting barbitu See, for example, U.S. Pat. No. 6,689.382, which is expressly rate that acts as a of the central nervous system. It incorporated by reference herein. Other formulations take is used in combination with other drugs for its and advantage of the liquid form by creating a Sustained release relaxant effects in the treatment of headaches. gelatin capsule, thereby permitting the delivery of the drug in US 2009/01 1 0724 A1 Apr. 30, 2009

a controlled fashion. See, for example, U.S. Pat. Nos. 5,324. one or more of the group consisting of S (+)-, meto 280 and 6,929.803, which are expressly incorporated by ref clopramide, , Sulfentanil and . erence herein. 0022. In another embodiment, the compositions of the present invention may comprise one or more of about 25 mg SUMMARY OF THE INVENTION to about 75 mg ofbutalbital; about 200 mg to about 600 mg of 0015 The present invention provides compositions and acetaminophen; and about 20 mg to about 60 mg of caffeine. methods of using the compositions for the therapeutic treat 0023. In another embodiment, the compositions of the ment of pain. Specifically, the present invention comprises a present invention may comprise one or more of about 37.5 mg composition of a barbiturate, an analgesic/antipyretic and an to about 62.5 mg ofbutalbital; about 300 mg to about 500 mg analgesic adjunct in the form of a gelcap. of acetaminophen; and about 30 mg to about 50 mg of caf 0016. In another embodiment of the present invention, the feine. compositions may comprise a barbiturate from one or more of 0024. In another embodiment, the compositions of the the group consisting of , butalbital , present invention may comprise one or more of about 45 mg , butethal, , mephobarbital, metho to about 55 mg ofbutalbital; about 360 mg to about 440 mg of hexital, , , , acetaminophen; and about 36 mg to about 44 mg of caffeine. , talbutal, , , thiopental and 0025. In another embodiment, the compositions of the thiopental sodium. present invention may comprise one or more of about 50 mg 0017. In another embodiment of the present invention, the of butalbital, about 400 mg of acetaminophen, and about 40 compositions may comprise an analgesic/antipyretic from mg of caffeine. one or more of the group consisting of acetaminophen, 0026. In another embodiment of the present invention, the , , , , compositions may be administered to a patient to treat and/or , , diamorphine (), hydroc alleviate the occurrence or negative effects from one or more odone, , , , nalbu of the group consisting of chronic pain and acute pain. phine, , , , , 0027. In another embodiment of the present invention, the , acetylsalicylic acid, , , ami compositions may be administered to a patient to treat and/or nophenaZone, , , , alleviate the occurrence or negative effects of headaches. , , acetylsalicylic acid (aspi 0028. In another embodiment, the compositions may be rin), choline salicylate salicylate, sodium salicy administered to a patient to treat and/or alleviate the occur late, , and . rence or negative effects from one or more of the group 0018. In another embodiment of the present invention, the compositions may comprise an analgesic adjunct from one or consisting oftension type headache, migraine headache, clus more of the group consisting of S (+)-ketamine, metoclopra ter headache or chronic daily headache. mide, ciramadol, Sulfentanil, caffeine and remifentanil. 0029. In another embodiment, the compositions may be 0019. In one embodiment of the present invention, the administered to a patient to treat and/or alleviate the occur compositions may comprise butalbital, acetaminophen and rence or negative effects from one or more of the group caffeine. consisting of episodic tension type headache or chronic ten 0020. The compositions of the present invention may be sion type headache. administered to the patient for oral use and may be in the form 0030 The present invention also includes methods of of an elixir, syrup and/or Suspension according to an indi administering the compositions of the invention to a patient to vidual patient’s preferences. In another embodiment of the treat and/or alleviate the occurrence or negative effects of present invention, the compositions may further comprise a pain. Specifically, the methods may include administering to flavorant. a patient a composition comprising a barbiturate, an analge 0021. In another embodiment of the present invention, the sic/antipyretic and analgesic adjunct in the form of a gelcap. compositions may be substantially free of other added active 0031. In another embodiment, the methods may include ingredients. The other added active ingredient may comprise the patient taking the compositions of the invention. another barbiturate, such as one or more of the group consist 0032. In another embodiment of the present invention, the ing of amobarbital, aprobarbital, butabarbital, butethal, methods may utilize a barbiturate selected from one or more cyclobarbital, mephobarbital, , methylphe of the group consisting of amobarbital, butalbital aprobar nobarbital, pentobarbital, phenobarbital, secobarbital, talb bital, butabarbital, butethal, cyclobarbital, mephobarbital, utal, thiobarbital, thiamylal, thiopental and thiopental methohexital, methylphenobarbital, pentobarbital, phenobar Sodium. The other added active ingredient may comprise bital, secobarbital, talbutal, thiobarbital, thiamylal, thiopental another analgesic Such as one or more of the group consisting and thiopental sodium. of buprenorphine, butorphanol, codeine, dextropro 0033. In another embodiment of the present invention, the poxyphene, dihydrocodeine, fentanyl, diamorphine (Heroin), methods may utilize an analgesic/antipyretic selected from , hydromorphone, ketobemidone, morphine, one or more of the group consisting of acetaminophen, , oxycodone, oxymorphone, pentazocine, pethi buprenorphine, butorphanol, codeine, dextropropoxyphene, dine, tramadol, acetylsalicylic acid, diflunisal, ethenZamide, dihydrocodeine, fentanyl, diamorphine (Heroin), hydroc , metamizole, phenaZone, phenacetin, odone, hydromorphone, ketobemidone, morphine, nalbu Ziconotide and tetrahydrocannabinol. The other added active phine, oxycodone, oxymorphone, pentazocine, pethidine, ingredient may comprise another antipyretic Such as one or tramadol, acetylsalicylic acid, diflunisal, ethenZamide, ami more of the group consisting of acetylsalicylic acid (), nophenaZone, metamizole, phenaZone, phenacetin, choline salicylate , , Ziconotide, tetrahydrocannabinol, acetylsalicylic acid (aspi ibuprofen, naproxen and ketoprofen. The other added active rin), choline Salicylate magnesium salicylate, sodium salicy ingredient may comprise another analgesic adjunct Such as late, ibuprofen, naproxen and ketoprofen. US 2009/01 1 0724 A1 Apr. 30, 2009

0034. In another embodiment of the present invention, the 0045. In another embodiment, the methods may include methods may utilize an analgesic adjunct selected from one administering the compositions of the present invention to a or more of the group consisting of S (+)-ketamine, metoclo patient to treat and/or alleviate the occurrence or negative pramide, ciramadol, Sulfentanil, caffeine and remifentanil. effects of headaches. 0035. In one embodiment of the present invention, the 0046. In another embodiment, the methods may include methods may include administering a composition compris administering the compositions of the present invention to a ing butalbital, acetaminophen and caffeine in the form of a patient to treat and/or alleviate the occurrence or negative gelcap. effects from one or more of the group consisting of tension 0036. In one embodiment of the present invention, the type headache, migraine headache, cluster headache or methods may include the patient taking a composition com chronic daily headache. prising butalbital, acetaminophen and caffeine in the form of 0047. In another embodiment, the methods may include a gelcap. administering the compositions of the present invention to a 0037. In another embodiment, the methods may include patient to treat and/or alleviate the occurrence or negative administering the compositions of the present invention to the effects from one or more of the group consisting of episodic patient orally. tension type headache or chronic tension type headache. 0048. In another embodiment of the present invention, the 0038. In another embodiment of the present invention, the methods may utilize compositions that are administered to a methods may utilize compositions in the form of an elixir, patient at a frequency of once a day, twice a day, three times syrup and/or Suspension according to an individual patient's a day, four times a day, five times a day, six times a day, seven preferences. In another embodiment of the present invention, times a day, eighttimes a day, nine times a day, tentimes a day, the methods may utilize compositions comprising a flavorant. eleven times a day and twelve times a day. 0039. In another embodiment of the present invention, the 0049. In another embodiment of the present invention, the methods may utilize compositions substantially free of other methods may utilize compositions that a patient takes at a added active ingredients. The other added active ingredient frequency of once a day, twice a day, three times a day, four may be one or more of another barbiturate. Such as amobar times a day, five times a day, six times a day, seventimes a day, bital, aprobarbital, butabarbital, butethal, cyclobarbital, eight times a day, nine times a day, ten times a day, eleven mephobarbital, methohexital, methylphenobarbital, pento times a day and twelve times a day. , phenobarbital, secobarbital, talbutal, thiobarbital, 0050. In another embodiment of the present invention, the thiamylal, thiopental and thiopental sodium. The other added methods may utilize compositions that are administered to a active ingredient may be one or more of another analgesic patient at a frequency of once every hour, once every two Such as buprenorphine, butorphanol, codeine, dextropro hours, once every three hours, once every four hours, once poxyphene, dihydrocodeine, fentanyl, diamorphine (Heroin), every five hours, once every six hours, once every seven hydrocodone, hydromorphone, ketobemidone, morphine, hours, once every eight hours, once every nine hours, once nalbuphine, oxycodone, oxymorphone, pentazocine, pethi every ten hours, once every eleven hours, once every twelve dine, tramadol, acetylsalicylic acid, diflunisal, ethenZamide, hours, once every thirteen hours, once every fourteen hours, aminophenaZone, metamizole, phenaZone, phenacetin, once every fifteen hours, once every sixteen hours, once every Ziconotide and tetrahydrocannabinol. The other added active seventeen hours, once every eighteen hours, once every nine ingredient may be one or more of another antipyretic Such as teen hours, once every twenty hours, once every twenty one acetylsalicylic acid, choline salicylate magnesium salicylate, hours, once every twenty two hours, once every twenty three Sodium salicylate, ibuprofen, naproxen and ketoprofen. The hours and once every twenty four hours. other added active ingredient may be one or more of another 0051. In another embodiment of the present invention, the analgesic adjunct such as S (+)-ketamine, metoclopramide, methods may utilize compositions that a patient takes at a ciramadol, Sulfentanil and remifentanil. frequency of once every hour, once every two hours, once 0040. In another embodiment, the methods may utilize every three hours, once every four hours, once every five compositions comprising one or more of about 25 mg to about hours, once every six hours, once every seven hours, once 75 mg ofbutalbital; about 200 mg to about 600mg of acetami every eight hours, once every nine hours, once every ten nophen; and about 20 mg to about 60 mg of caffeine. hours, once every eleven hours, once every twelve hours, 0041. In another embodiment, the methods may utilize once every thirteen hours, once every fourteen hours, once compositions comprising one or more of about 37.5 mg to every fifteen hours, once every sixteen hours, once every about 62.5 mg ofbutalbital; about 300 mg to about 500 mg of seventeen hours, once every eighteen hours, once every nine acetaminophen; and about 30 mg to about 50 mg of caffeine. teen hours, once every twenty hours, once every twenty one 0042. In another embodiment, the methods may utilize hours, once every twenty two hours, once every twenty three compositions comprising one or more of about 45 mg to about hours and once every twenty four hours. 55 mg ofbutalbital; about 360 mg to about 440 mg of acetami 0052. In another embodiment, the methods may utilize nophen; and about 36 mg to about 44 mg of caffeine. compositions that are administered in a dose unit of 0.5, 1. 0043. In another embodiment, the methods may utilize 1.5, 1.5, 2, 2.5, 3, 3.5 and 4 dosage forms. compositions comprising one or more of about 50 mg of butalbital; about 400 mg of acetaminophen; and about 40 mg DETAILED DESCRIPTION OF THE INVENTION of caffeine. 0053. It is understood that the present invention is not 0044. In another embodiment, the methods may include limited to the particular methodologies, protocols, fillers, administering the compositions of the present invention to a excipients, etc., described herein, as these may vary. It is also patient to treat and/or alleviate the occurrence or negative to be understood that the terminology used herein is used for effects from one or more of the group consisting of chronic the purpose of describing particular embodiments only, and is pain or acute pain. not intended to limit the scope of the present invention. It US 2009/01 1 0724 A1 Apr. 30, 2009

must be noted that as used herein and in the appended claims, dosage form include, but are not limited to, beads, granules, the singular forms “a,” “an and “the' include the plural pellets, spheroids, particles, tablets, pills, etc. As used herein, reference unless the context clearly dictates otherwise. Thus, the term “gelcap.” otherwise known as “gel caplet” refers to for example, a reference to “a barbiturate' is a reference to a capsule-shaped dosage form where the active ingredients one or more and includes equivalents thereof are dissolved in a liquid that is coated within a gelatin shell for known to those skilled in the art and so forth. easy Swallowing or to have the appearance of easy Swallow 0054. Unless defined otherwise, all technical and scien 1ng tific terms used herein have the same meanings as commonly 0062. Despite many advances in treatment, pain continues understood by one of ordinary skill in the art to which this to be a major healthcare problem in the United States. Dorsey invention belongs. Specific methods, devices, and materials et al., 16 AACN CLIN. ISSUES 277-90 (2005). Pain is a con are described, although any methods and materials similar or dition that affects millions of Americans every day, costing in equivalent to those described herein can be used in the prac excess of S100 billion for treatment-related costs and lost tice or testing of the present invention. work productivity. Id. Pain is an unpleasant sensation with a 0055. The term “patient as used herein, comprises any wide range in severity that can be localized or prevalent and all organisms and includes the term “subject.” “Patient’ throughout the body. The Merck Manual of Medical Informa may refer to a human or any other animal, including mam tion (M. Beers et al., 2"Home ed., Merck Research Labora mals. tories, 2003). Pain is affected by nervestimulation that carries 0056. The term “administrable' defines a composition impulses to the brain and is a symptom of an underlying that is able to be given to a patient. Likewise, “administering disease, disorder, or physical injury. Id. refers to the act of giving a composition to a patient or other 0063 Pain can be classified into two groups: acute pain or wise making Such composition available to a patient or the chronic pain. Id. According to the National Centers for Health patient taking a composition themselves. Statistics, more than 50 million Americans experience 0057 The term “active ingredient as used herein is any chronic pain. NATIONAL CTR. FOR HEALTH STATISTICS, ingredient that is a barbiturate, an analgesic/antipyretic, and HEALTH, UNITED STATES, 2006 WITH CHARTBOOKONTRENDS an analgesic adjunct when taken orally by a patient. IN THE HEALTH OF AMERICANS 68-71 (2006). Chronic pain is 0058 As used herein, the terms “inactive.” “inert, a persisting or reoccurring pain that can last for months and “excipient,” and/or “formulatory” refer to any compound that even years. The Merck Manual of Medical Information (M. is an inactive ingredient of a described composition. The Beers et al. 2". Home ed., Merck Research Laboratories, definition of “inactive ingredient as used herein follows that 2003). It is more common for chronic pain to be due to a of the U.S. Food and Drug Administration, as defined in 21 disorder Such as sickle cell anemia or a serious physical C.F.R. 201.3(b)(8), which is any component of a drug product injury. other than the active ingredient. By “active ingredient, then, is meant any compound intended to furnish pharmacological 0064. Alternatively, acute paintends to come on quickly, activity or other direct effect in the diagnosis, cure, mitiga but subsides after a short time. Acute pain serves a useful tion, treatment and/or prevention of a condition. See 21 C.F. purpose by alerting humans of a physiological hazard or a R. 210.3(b)(7). Further, “active ingredients’ include those need for treatment. Therefore, acute paintends to be caused compounds of the composition that may undergo chemical from a sudden physical injury or infection. change during the manufacture of the composition and be 0065 Clinical complaints due to pain come in many vari present in the final composition in a modified form intended eties. Such complaints may be due to Such ailments as arthri to furnish an activity or effect. Id. tis, back pain, neuropathy, or a headache. Hence, the thera 0059. The term “substantially free,” as used herein, means peutic treatment can be highly dependent on the type of pain. free from therapeutically effective amounts of compounds Such treatments may include acupuncture, change in nutri when administered in Suggested dosages, but may include tion, exercise, or medication. trace amounts of compounds in non-therapeutically effective 0.066 One of the most common sources of pain are head amountS. aches. Headache symptoms may be due to tension type head 0060. The term “dosage form,” as used herein, is the form ache (tension headache), migraine, cluster headache or in which the dose is to be administered to the patient. The drug chronic daily headache. However, tension type headache is by is generally administered as part of a formulation that far the most common form. Nearly 70% of all headaches are includes nonmedical agents, referred to as pharmaceutical attributed to tension type headache and approximately 3% of ingredients. The dosage form has unique physical and phar population suffers from them. Olesen et al., 44.J. CLIN. EPI maceutical characteristics. Dosage forms may be solid, liquid DEMIOL. 1147-57 (1991). or gaseous. Solid forms include, but are not limited to cap 0067 Tension headache is classified into two forms: epi Sules, tablets, caplets, gel caplets (gelcap), lozenges, wafers sodic and chronic. Lipton et al., 279 JAMA 381-3 (1998). etc. Liquid dosage forms include, but are not limited to, These forms distinguish between occasional headaches sepa syrups, elixirs, injectable Solutions, and intravenous solu rated by varying lengths of time between attacks and frequent tions. Gaseous forms include vapors, inhalants, and the like. headaches that occur, in many cases, almost daily. Id. 0061. As used herein the term “tablet” refers to a medica 0068 Episodic tension headache occurs on fewer than 15 tion, usually mixed with a binder powder, which is molded days a month. Juang et al., 66 NEUROLOGY 160-1 (2006). and pressed into the form of a tablet, traditionally circular or These headaches are usually brief, lasting a few minutes to a disk-shaped. As used herein, the term “caplet” refers to a few hours. In one Survey of people with episodic tension Smooth, coated, oval-shaped tablet. As used herein, the term headache, over 60% had scalp and neck muscle tenderness in “capsule’ refers to a solid dosage form in which the drug, in addition to head pain. People with increasingly frequent discrete units, is enclosed in a hard or soft soluble container, attacks of the episodic form may be at higher risk of devel usually of a form of gelatin. The discrete units of the capsule oping the chronic form of the headache over a period of years. US 2009/01 1 0724 A1 Apr. 30, 2009

0069 Chronic tension headache occurs on 15 days a tramadol, acetylsalicylic acid, diflunisal, ethenZamide, ami month or more for at least three months. Id. Compared with nophenaZone, metamizole, phenaZone, phenacetin, the episodic form, chronic tension headache is less common, Ziconotide, tetrahydrocannabinol, acetylsalicylic acid (aspi but twice as many women as men have the chronic form. The rin), choline Salicylate magnesium salicylate, sodium salicy duration and the severity of episodic and chronic tension late, ibuprofen or other nonsteroidal anti-inflammatory drugs headaches are similar, although for many people with the (NSAIDs), naproxen and ketoprofen. For example, ibuprofen chronic form, pain is daily and almost continuous. Like the inhibits the role of COX-2 to induce synthesis. episodic form, chronic tension headache can be with or with Although the inhibition of COX-2 primarily inhibits the out scalp tenderness. inflammatory response, ibuprofen and other NSAIDs are 0070 There has been extensive clinical trials that have effective and . tested the collaborative effect of various combinations of drugs towards episodic and chronic tension type headache. 0075 Acetaminophen is an analgesic/antipyretic that is Diserio et al., 10 CLIN. THER. 69-81 (1987). For example, commonly used to reduce and headaches. Acetami clinical trials have researched the combination of a barbitu nophen is also used in a combination with other active drugs rate, an analgesic/antipyretic and an analgesic adjunct such as in managing severe pain. The chemical name is N-(4-hydrox butalbital, acetaminophen and caffeine. Id. yphenyl)acetamide. Research Suggests that acetominophen's 0071. In another embodiment, the compositions and meth analgesic/antipyretic activity is due to its ability to inhibit ods of the present invention may comprise a barbiturate com prostaglandin synthesis. Prostaglandin synthesis, a pathway prising one or more of amobarbital, butalbital, aprobarbital, that is directly linked to the symptoms of pain and fever, is butabarbital, butethal, cyclobarbital, mephobarbital, metho induced by isozymes (COX ). hexital, methylphenobarbital, pentobarbital, phenobarbital, Clottes et al., 71 MOL. PHARMACOL. 407-15 (2007): Botting, secobarbital, talbutal, thiobarbital, thiamylal, thiopental and 31 CLIN. INFECT. DIS. S202-10 (2000). The discovery and thiopental sodium. For example, methohexital binds to the research on various isoforms of COX enzymes, such as COX GABAA and therefore has anesthetic properties that 3, demonstrate a strong inhibition by acetaminophen. Sim may be beneficial in the treatment of various forms of head mons et al., 99 PROC. NATL. ACAD. SCI. 13371-73 (2002). The ache. Wennberg et al., 286.J. PHARMACOL. EXP. THER. 1177 role of various COX isozymes, and their effect on prostag 82 (1998). landin synthesis, is currently the prevailing theory on how 0072 Butalbital is a short to intermediate acting central acetaminophen reduces pain and fever. nervous system depressant and is a derivative of barbituric 0076. In another specific embodiment, the compositions acid. Butalbital (5-allyl-5-isobutylbarbituric acid) is a white and methods of the present invention may comprise acetami odorless powder that is slightly soluble in cold water. Medi nophen. Specifically, the amounts may range from about 200 cations containing butalbital have been extensively studied in mg to about 600 mg. In another specific embodiment, the clinical trials for treatment of tension type headache. compositions and methods of the present invention may com McCrory et al., 41 HEADACHE 953-67 (2001). Butalbital acts prise acetaminophen in amounts ranging from about 300 mg as an allosteric modulator by binding at a site associated with to about 500 mg. In another specific embodiment, the com the GABAA receptor. The GABAA receptor is a pentameric positions and methods of the present invention may comprise transmembrane chloride that binds GABA. acetaminophen in amounts ranging from about 360 mg to Because of the binding to butalbital, the duration time is about 440 mg. In another specific embodiment, the compo increased for which the Cl ionophore on the GABAA recep sitions and methods of the present invention may comprise tor is open. This opening allows chloride ions to enter the acetaminophen in an amount of about 400 mg. postjunctional terminal which results in inhibition of the 0077. In another embodiment, the compositions and meth postsynaptic neuron. Goadsby et al., 134 B. J. PHARMACOL. ods of the present invention may comprise an analgesic 896-904 (2001). Inhibition of the postsynaptic neuron there adjunct comprising one or more of caffeine, S (+)-ketamine, fore explains butalbital’s central nervous system depressant metoclopramide, ciramadol, remifentanil and an anal effects. gesic Such as Sulfentanil. For example, Sulfentanil is effective 0073. In one specific embodiment, the compositions and in aiding pain relief where pain is severe and the relief is only methods of the present invention may comprise butalbital. required for a short period of time. Nahata et al., 10 CLIN. Specifically, the amounts may range from about 25 mg to PHARM. 581-93 (1991). Therefore, sulfentanil may be effec about 75 mg. In another specific embodiment, the composi tive as an adjunct for cluster headache, which is known for its tions and methods of the present invention may comprise severity and for symptoms that usually do not last longer than butalbital in amounts ranging from about 37.5 mg to about 30 minutes. 62.5 mg. In another specific embodiment, the compositions 0078 Caffeine is most commonly used as a central ner and methods of the present invention may comprise butalbital vous stimulant due to its effect of warding off drowsiness. The in amounts ranging from about 45 mg to about 55 mg. In chemical name of caffeine is 1,3,7-trimethyl-1H-purine-2,6 another specific embodiment, the compositions and methods (3H,7H)-dione. Caffeine is also used in combination for the of the present invention may comprise butalbital in an amount treatment of headaches because of its role as an analgesic of about 50 mg. adjunct. Caffeine on its own does not have any known anal 0074. In another embodiment, the compositions and meth gesic activity. When caffeine is combined with an analgesic ods of the present invention may comprise an analgesic/anti Such as acetaminophen, caffeine's analgesic adjunct activity pyretic comprising one or more of acetaminophen, buprenor provides a synergistic effect that enhances pain relief and phine, butorphanol, codeine, dextropropoxyphene, provides the option of lowering the dosage of the analgesic. dihydrocodeine, fentanyl, diamorphine (Heroin), hydroc Engelhardt et al., 39 NEUROPHARMACOLOGY 2205-13 odone, hydromorphone, ketobemidone, morphine, nalbu (2000). Research indicates that caffeine's role as an analgesic phine, oxycodone, oxymorphone, pentazocine, pethidine, adjunct is due to its ability to induce the constriction of US 2009/01 1 0724 A1 Apr. 30, 2009

cerebral blood vessels, which leads to a decrease in cerebral I0085. The composition and methods of the present inven blood flow and in the oxygen tension of the brain. tion provide the patient with the option of various dosage 0079. In another specific embodiment, the compositions forms for the prevention or treatment of headaches. and methods of the present invention may comprise caffeine. I0086. In another specific embodiment of the present Specifically, the amounts may range from about 20 mg to invention, the compositions may have a dosage form shape about 60 mg. In another specific embodiment, the composi comprising no sharp edges and a smooth and uniform surface. tions and methods of the present invention may comprise Among other dosage forms apparent to the skilled artisan, the caffeine in amounts ranging from about 30 mg to about 50 solid oral dosage form may be a tablet, a discrete unit-filled mg. In another specific embodiment, the compositions and capsule, a gelcap or a caplet. methods of the present invention may comprise caffeine in I0087. In another specific embodiment, the compositions amounts ranging from about 36 mg to about 44 mg. In another of the present invention may be a solid dosage form which has specific embodiment, the compositions and methods of the a coating or gelatin covering and therefore, the appearance of the capsule, and are often referred to as a Solid gelcap. Such present invention may comprise caffeine in an amount of gelcaps may consist of a solid caplet or tablet that is covered about 40 mg. in opposite ends in a soft gelatin shell of different colors to 0080. In another specific embodiment, the methods and simulate a capsule-like dosage form. See, for example, U.S. compositions of the present invention may be free of other Pat. Nos. 5,824,338, 5,415,868, 5,317,849, 5,089,270,4966, added active ingredients. The addition of other active ingre 771 and 4,820.524, which are expressly incorporated by ref dients can produce adverse side effects that can inhibit or erence herein. outweigh the benefits of the methods and compositions of the I0088. In another specific embodiment, the compositions present invention. For example, codeine is an that can of the present invention may be in the form of a liquid gelcap be used for its analgesic and antitussive properties. However, which may consist of a filler comprising one or more phar moderate use of codeine has been associated with a high maceutically active materials dissolved or dispersed in an number of gastrointestinal adverse effects including , appropriate liquid vehicle encapsulated in a gelatin shell gen vomiting and abdominal . McCrory et al., 41 HEADACHE erally comprising gelatin together with a plasticizer Such as 953-67 (2001). In a specific embodiment, the compositions glycerin or sorbitol. The filler material may comprise, for and methods of the present invention may be free of added example, polyethylene glycols. See, for example, U.S. Pat. codeine. Nos. 4,780,316; 5,419,916; 5,641,512; and 6,589,536 which 0081. Secobarbital and pentobarbital are short acting bar are expressly incorporated by reference herein. biturates that when administered to patients in various doses, I0089. A liquid gelcap has numerous advantages. First, it result in severe withdrawal syndrome. Id. Such symptoms retains many of the advantages of consumer acceptance and is related to withdrawal include delirium, and halluci easier to Swallow due to the outer coating being a soft and nations. Id. In a specific embodiment, one or more of the elastic gelatin shell. Also, concentrated liquid compositions compositions and methods of the present invention may be are well Suited for encapsulation within a soft gelatin shell, free of added secobarbital and pentobarbital. creating flexibility that further assists in the capsule being 0082) Non-steroidal anti-inflammatory drugs (NSAIDs) easierto Swallow. The active drug contained in the liquid form Such as ibuprofen or aspirin are widely used for their analge also has advantages in dispersing the drug to the active site. sic and anti-inflammatory effects. However, current evidence For example, the active drug does not first have to dissolve in Suggests that adverse side effects, such as gastrointestinal and the gastrointestinal tract, thereby facilitating absorption of the other bleeding risks with NSAIDs, probably outweigh its pharmacologically active substance. See, for example, U.S. potential benefits. Kim et al., 58. J. PHARM. PHARMACOL. Pat. No. 6,689.382 which is expressly incorporated by refer 1295-1304 (2006). In a specific embodiment, the composi ence herein. Other formulations take advantage of the liquid tions and methods of the present invention may be free of form by creating a Sustained release gelatin capsule, thereby added non-steroidal anti-inflammatory drugs such as ibupro permitting the delivery of the drug in a controlled fashion. fen or aspirin. See, for example, U.S. Pat. Nos. 5,324.280 and 6,929,803, 0083 Pemoline is a central nervous system stimulant that which are expressly incorporated by reference herein. Many was commonly used to treat attention-deficit hyperactivity shell and fill formulations are discussed in "Advances in disorder (ADHD). Although pemoline is a stimulant that has Softgel Formulation Technology'. M. S. Patel, F. S. S. Mor various benefits such as in treating learning disorders, exces ton and H. Seager, Manufacturing Chemists, July 1989: “Soft sive intake of the drug has been linked to severe hepatotox Elastic Gelatin Capsules: A Unique Dosage Form'. William icity. Gardner et al., 40 J. AM. ACAD. CHILD. ADOLESC. PSY R. Ebert, Pharmaceutical Technology, October 1977; and CHLATRY 622-29 (2001). In a specific embodiment, the “Soft gelatin capsules: a solution to many tableting prob compositions and methods of the present invention may be lems”. H. Seager, Pharmaceutical Technology, September free of added pemoline. 1985. 0084. Remifentanil is an analgesic that is commonly 0090. To prepare the compositions of the present inven administered to patients as an analgesic adjunct after Surgery. tion, each of the active ingredients may be combined in inti Moreover, remifentanil has strong sedative effects and there mate admixture with a suitable carrier according to conven fore is also useful as a general anesthetic. However, the seda tional compounding techniques. In a specific embodiment of tive effects are linked to severe dizziness shortly after admin the compositions of the present invention, the surface of the istering the drug, which has presently limited the drugs use to compositions may be coated with a polymeric film. Such a surgery related . Verbrugge et al., 101 ANESTH. film coating has several beneficial effects. First, it reduces the ANALG. 365-70 (2005). In a specific embodiment, the com adhesion of the compositions to the inner surface of the positions and methods of the present invention may be free of mouth, thereby increasing the patient’s ability to swallow the added remifentanil. compositions. Second, the film may aid in masking the US 2009/01 1 0724 A1 Apr. 30, 2009 unpleasant taste of certain drugs. Third, the film coating may particular instance will generally be within the capability of protect the compositions of the present invention from atmo the person skilled in the art. Details concerning any of the spheric degradation. Polymeric films that may be used in excipients of the invention may be found in WADE & preparing the compositions of the present invention include WALLER, Supra. All active ingredients, fillers and excipients vinyl polymers such as polyvinylpyrrolidone, polyvinyl alco are commercially available from companies such as Sigma hol and acetate, cellulosics Such as methyl and ethylcellulose, Aldrich, St. Louis, Mo.; FMC Corp., Philadelphia, Pa.; Bayer, hydroxyethyl cellulose and hydroxylpropyl methylcellulose, Germany; BASF, Germany; Mallinckrodt, Hazelwood, Mo.; acrylates and methacrylates, copolymers such as the vinyl Rhodia, France: ISP. Wayne, N.J.; and others. maleic acid and styrene-maleic acid types, and natural gums 0097. A specific embodiment of the present invention may and resins such as Zein, gelatin, shellac and acacia. Pharma comprise compositions packaged in blister packs. Blister ceutical carriers and formulations for swallowable com packs as packaging for compositions are well known to those pounds are well known to those of ordinary skill in the art. See of ordinary skill in the art. Blister packs may be made of a generally, Handbook of Pharmaceutical Excipients (2nd ed. transparent plastic sheet which as been formed to carry a Wade and Waller eds., 1994). matrix of depression or blisters. One or more compositions 0091. In addition to those described above, any appropri are received in each depression or blister. A foil or plastic ate fillers and excipients may be utilized in preparing the backing is then adhered across the plane of the sheet sealing compositions of the present invention so long as they are the compositions in their respective blisters. Examples of consistent with the objectives described herein. For example, materials used for the blister packs include, but are not limited binders are substances used to cause adhesion of powder to, aluminum, paper, polyester, PVC, and polypropylene. particles in granulations. Such compounds appropriate for Alternative materials are known to those of ordinary skill in use in the present invention include, by way of example and the art. To remove a composition, the depression material is without limitation, acacia, compressible Sugar, gelatin, pressed in and the composition is pushed through the backing Sucrose and its derivatives, maltodextrin, cellulosic polymers, material. Multiple blister packs may be placed in an outer Such as ethylcellulose, hydroxypropylcellulose, hydroxypro package, often a box or carton for sale and distribution. pylmethyl cellulose, carboxymethylcellulose sodium, and 0098. Another specific embodiment of the present inven methylcellulose, acrylic polymers, such as insoluble acrylate tion may comprise compositions packaged in bottles. The ammoniomethacrylate copolymer, polyacrylate or poly bottle may be glass or plastic inform with a pop or screw top methacrylic copolymer, povidones, copovidones, polyviny cap. Bottle packaging for Such compositions are well known lalcohols, alginic acid, sodium alginate, starch, pregelati to those of ordinary skill in the art. nized Starch, guar gum, polyethylene glycol, and others 0099. Additionally, the unit dose forms may be individu known to those of ordinary skill in the art. ally wrapped, packaged as multiple units on paper strips or in 0092. Diluents also may be included in the compositions vials of any size, without limitation. The compositions of the of the present invention in order to enhance the granulation of invention may be packaged in unit dose, rolls, bulk bottles, the compositions. Diluents can include, by way of example blister packs and combinations thereof, without limitation. and without limitation, microcrystalline cellulose. Sucrose, 0100. In other embodiments, the composition may be an dicalcium phosphate, starches, and polyols of less than 13 elixir, syrup and/or Suspension. As used herein, the term carbonatoms, such as mannitol. Xylitol, Sorbitol, maltitol, and "syrup refers to a concentrated, aqueous preparation of a pharmaceutically acceptable amino acids. Such as glycin, and Sugar or Sugar Substitute with or without an added flavoring their mixtures. agent. As used herein, the term "elixir refers to a clear, 0093 Lubricants are substances used in composition for Sweetened, hydroalcoholic solution intended for oral use, and mulations that reduce friction during composition compres may or may not have an added flavoring agent. As used Sion. Lubricants that may be used in the present invention herein, a “suspension' is a preparation containing finely include, by way of example and without limitation, Stearic divided drug particles distributed somewhat uniformly acid, calcium Stearate, magnesium Stearate, Zinc Stearate, throughout a vehicle in which the drug exhibits a minimum talc, mineral and vegetable oils, benzoic acid, poly-( degree of solubility. Although water itself may make up the glycol), glyceryl behenate, Stearyl fumarate, and others entire carrier, typical formulations may contain a co-solvent, known to those of ordinary skill in the art. for example and without limitation, propylene glycol and/or 0094 Glidants improve the flow of powder blends during glycerin, to assist Solubilization and incorporation of water manufacturing and minimize composition weight variation. insoluble ingredients, flavorants and the like into the compo Glidants that may be used in the present invention include by sition. Any Such ingredients may be included as desired or way of example and without limitation, silicon dioxide, col needed within the compositions and methods of the present loidal or fumed silica, magnesium Stearate, calcium Stearate, invention as long as they are consistent with the objectives Stearic acid, cornstarch, talc and others known to those of herein defined. For example, it is contemplated that when ordinary skill in the art. desirable, flavoring, preserving, Suspending, thickening and/ 0095. If desired, compositions may be sugar coated or or emulsifying agents may be included in the compositions enteric coated by Standard techniques. and methods of the present invention. Formulations for orally 0096. The compositions of the present invention may be administered medications are well known in the art. Descrip prepared using conventional methods and materials known in tions of suitable formulations may be found in Remington, the pharmaceutical art. For example, U.S. Pat. Nos. 5.215,754 The Science and Practice of Pharmacy (A. Gennaro ed., 20" and 4.374,082 relate to methods for preparing such compo ed., Lippincott, Williams & Wilkins, 2000). sitions, which are expressly incorporated by reference herein. 0101 Flavorants that may be used in accordance with the Further, all pharmaceutical carriers and formulations present invention include those known to those skilled in the described herein are well known to those of ordinary skill in art. These flavorants may include, for example and without the art, and determination of workable proportions in any limitation, natural, artificial and synthetic flavor oils and fla US 2009/01 1 0724 A1 Apr. 30, 2009

Voring aromatic and/or oils, oleoresins and extracts derived compositions of the present invention results in a rapid from plants, animals, leaves, flowers, fruits, and so forth, and improvement of the symptoms of tension type headache. combinations thereof. Non-limiting representative flavor oils 0106. A double-blind, placebo controlled study is con include anise oil, cinnamon oil, peppermint oil, spearmint oil ducted over a 4 hour period. A total of 120 subjects, all of wintergreen, clove oil, bay oil, anise oil, eucalyptus oil, presenting for treatment of symptoms of tension type head thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of ache, are chosen for the study. The patients range in age from bitter almonds, cassia oil, lemon oil, orange oil, lime oil, 18 to 65 years old. grapefruit oil, and grape oil. Also useful flavorants include 0107 An initial assessment of the symptoms of each fruit essences including apple essence, pear essence, peach patient is conducted when the patients initially present for essence, berry essence, wildberry essence, date essence, blue treatment. The patient rates the severity of the symptoms on a berry essence, kiwi essence, Strawberry essence, raspberry 4-point scale (0: absent; 1: mild: 2: moderate; 3: severe). For essence, cherry essence, plum essence, pineapple essence, inclusion in the study, a patient must be rated with a score of and apricot essence. Other useful flavorants include alde two or above for tension type headache. hydes and esters such as benzaldehyde (cherry, almond), 0108. The 120 subjects chosen for the study are separated citral, i.e., alpha-citral (lemon, lime), neural, i.e., beta-citral into four separate groups of 30. The characteristics of the (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus symptoms between the four groups are comparable. The first fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus group is administered a 2 gelcap dose of the composition of fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanal the present invention at the onset of the symptoms oftension (green fruit), and 2-dodecenyl (citrus, mandarin), mixtures type headache where the severity has reached at least a score thereof and the like. Honey and artificial honey flavor, as well of 2 as scored by the patient. The second group is adminis as natural mixed berry flavor, citric acid, malic acid, Vanilla, tered a placebo medication at the onset of the symptoms of Vanillin, cocoa, chocolate, and may also be used in tension type headache that is similar in all respects to the accordance with the present invention. Flavorants appealing administered composition except for the exclusion of the to non-human patients may also be included in the composi active ingredients butalbital, acetaminophen and caffeine. tion of the invention, including but not limited to, yeast The third group is administered a placebo medication at the extract, meat extract, fish extract, poultry extract, cheese and onset of the symptoms oftension type headache that is similar other dairy flavors, and the like. in all respects to the administered composition except for the 0102 Other objectives, features and advantages of the exclusion of the active ingredient butalbital. The fourth group present invention will become apparent from the following is administered a placebo medication at the onset of the symp specific examples. The specific examples, while indicating toms oftension type headache that is similar in all respects to specific embodiments of the invention, are provided by way the administered composition except for the exclusion of the of illustration only. Accordingly, the present invention also active ingredients butalbital and caffeine. The various symp includes those various changes and modifications within the toms of tension type headache are evaluated by the patient spirit and scope of the invention that may become apparent to 0.5, 1, 2, 3 and 4 hours after ingestion of the study medication those skilled in the art from this detailed description. The using the same 4-point Scale. The symptoms evaluated are invention will be further illustrated by the following non pain severity, tense and uptight feeling, and muscle stiffness. limiting examples. 0109 The assessment of the relief for pain severity, tense and uptight feeling, and muscle stiffness is conducted for EXAMPLES each Subject group. The data is evaluated using multiple lin ear regression analysis and a standard t-test. In each analysis, 0103 Without requiring further elaboration, it is believed the baseline value of the outcome variable is included in the that one skilled in the art, using the preceding description, can model as a covariant. Treatment by covariant interaction utilize the present invention to the fullest extent. The follow effects is tested by the method outlined by Weigel & Narvaez, ing examples are illustrative only, and not limiting of the 12 CONTROLLED CLINICAL TRIALS378-94 (1991). If there are remainder of the disclosure in any way whatsoever. no significant interaction effects, the interaction terms are removed from the model. The regression model assumptions Example 1 of normality and homogeneity of variance of residuals are evaluated by inspection of the plots of residuals versus pre 0104. A composition of the following formulation is pre dicted values. Detection of the temporal onset of effects is pared in gelcap form, including the appropriate excipients, by done sequentially by testing for the presence of significant standard methods known to those of ordinary skill in the art: treatment effects at 0.5, 1, 2, 3 and 4 hours, proceeding to the earlier time in sequence only when significant effects have been identified at each later time period. Changes from the Butalbital 50 mg baseline within each group are evaluated using paired t-tests. Acetaminophen 400 mg In addition, analysis of variance is performed on all baseline Caffeine 40 mg measurements and measurable Subject characteristics to assess homogeneity between groups. All statistical proce dures are conducted using the Statistical Analysis System Example 2 (SAS Institute Inc., Cary, N.C.). An alpha level of 0.05 is used in all statistical tests. 0105. A study is undertaken to evaluate the effectiveness 0110. This study will demonstrate the efficacy of the com of the compositions of the present invention in the treatment position of the present invention in treating the symptoms of of patients. The objective of the study is to determine whether tension type headache. Regarding potential adverse effects of oral intake of the compositions and the combination of the taking the medication, if there are no significant differences US 2009/01 1 0724 A1 Apr. 30, 2009 between the four therapeutic groups, this study will demon using paired t-tests. In addition, analysis of variance is per strate that the administration of the composition of the present formed on all baseline measurements and measurable subject invention is effective at treating symptoms of tension type characteristics to assess homogeneity between groups. All headache, in addition to being well-tolerated by the patients. statistical procedures are conducted using the Statistical Analysis System (SAS Institute Inc., Cary, N.C.). An alpha Example 3 level of 0.05 is used in all statistical tests. 0111. A study is undertaken to evaluate the effectiveness 0116. This study will demonstrate the efficacy of the com of the compositions of the present invention in the treatment position of the present invention in treating the symptoms of of patients. The objective of the study is to determine whether joint pain due to rheumatoid arthritis. Regarding potential oral intake of the compositions and the combination of the adverse effects of taking the medication, if there are no sig compositions of the present invention results in a rapid nificant differences between the fourtherapeutic groups, this improvement of the symptoms of joint pain due to rheumatoid study will demonstrate that the administration of the compo arthritis sition of the present invention is effective at treating Symp 0112 A double-blind, placebo controlled study is con toms of joint pain due to rheumatoid arthritis, in addition to ducted over a 4 hour period. A total of 120 subjects, all being well-tolerated by the patients. presenting for treatment of symptoms of joint pain due to 0117. While specific embodiments of the present inven rheumatoid arthritis, are chosen for the study. The patients tion have been described, other and further modifications and range in age from 18 to 65 years old. changes may be made without departing from the spirit of the 0113. An initial assessment of the symptoms of each invention. All further and other modifications and changes are patient is conducted when the patients initially present for included that come within the scope of the invention as set treatment. The patient rates the severity of the symptoms on a forth in the claims. The disclosures of all publications cited 4-point scale (0: absent; 1: mild: 2: moderate; 3: severe). For above are expressly incorporated by reference in their entire inclusion in the study, a patient must be rated with a score of ties to the same extent as if each were incorporated by refer two or above for joint pain due to rheumatoid arthritis. ence individually. 0114. The 120 subjects chosen for the study are separated 1. A composition comprising a barbiturate, an analgesic/ into four separate groups of 30. The characteristics of the antipyreffe and an analgesic adjunct, wherein said composi symptoms between the four groups are comparable. The first tion is in the fbrm of a gelcap and wherein said composition group is administered a 2 gelcap dose of the composition of is free of other added active ingredients. the present invention at the onset of the symptoms of joint 2. The composition of claim 1, wherein said barbiturate is pain due to rheumatoid arthritis where the severity has selected from one or more of the group consisting of amobar reached at least a score of 2 as scored by the patient. The bital, butalbital, aprobarbital, butabarbital, butethal, cyclo second group is administered a placebo medication at the barbital. mephobarbital. methohexital, methylphenobarbitaL onset of the symptoms of joint pain due to rheumatoid arthri pentobarbital, phenobarbital, secobarbital, talbutal, thiobar tis that is similar in all respects to the administered composi bital, thiamylal. thiopental and thiopental Sodium. tion except for the exclusion of the active ingredients butal 3. The composition of claim 1, wherein said analgesic/ bital, acetaminophen and caffeine. The third group is antipyretic is selected from one or more of the group consist administered a placebo medication at the onset of the Symp ing of acetaminophen, buprenorphine, butorphanol, codeine, toms of joint pain due to rheumatoid arthritis that is similar in dextropropoxyphene, dihydrocodeine, fentanyl, diamorphine all respects to the administered composition except for the (Heroin), hydrocodone, hydromorphone, ketobemidone, exclusion of the active ingredient butalbital. The fourth group morphine, nalbuphine, oxycodone, oxymorphone. pentaZo is administered a placebo medication at the onset of the Symp cine, pethidine, tramadol, acetylsalicylic acid, diflunisal toms of joint pain due to rheumatoid arthritis that is similar in ethenZamide, aminophenaZone, metamizole, phenaZone, all respects to the administered composition except for the phenacetin, Ziconotide, tetrahydrocannabinol, acetylsalicylic exclusion of the active ingredients butalbital and caffeine. acid (aspirin), choline Salicylate magnesium salicriate, The joint pain is evaluated in severity by the patient 0.5, 1, 2, Sodium salicylate, ibuprofen, naproxen and ketoprofen. 3 and 4 hours after ingestion of the study medication using the 4. The composition of claim 1, wherein said analgesic same 4-point Scale. adjunct is selected from one or more of the group consisting 0115 The assessment of the relief for joint pain severity is of S (+)-ketamine, metoclopramide, ciramadol, , conducted for each Subject group. The data is evaluated using caffeine and remifentanil. multiple linear regression analysis and a standard t-test. In 5. The composition of claim 1 wherein said barbiturate is each analysis, the baseline value of the outcome variable is butalbital, said analgesic/antipyretic is acetaminophen and included in the model as a covariant. Treatment by covariant said analgesic adjunct is caffeine, and wherein said compo interaction effects is tested by the method outlined by Weigel sition is administrable to a patient. & Narvaez, 12 CONTROLLED CLINICAL TRIALS378-94 6. The composition of claim 5, wherein said composition is (1991). If there are no significant interaction effects, the inter administrable to aid patient orally. action terms are removed from the model. The regression 7. The composition of claim 1, wherein said composition model assumptions of normality and homogeneity of Vari comprises one or more of the group consisting of elixir, syrup ance of residuals are evaluated by inspection of the plots of and Suspension. residuals versus predicted values. Detection of the temporal 8. The composition of claim 1, wherein said composition onset of effects is done sequentially by testing for the pres further comprises a flavorant. ence of significant treatment effects at 0.5, 1,2,3 and 4 hours, 9. (canceled) proceeding to the earlier time in sequence only when signifi 10. (canceled) cant effects have been identified at each later time period. 11. (canceled) Changes from the baseline within each group are evaluated 12. (canceled) US 2009/01 1 0724 A1 Apr. 30, 2009

13. (canceled) 38. A method comprising a patient taking the composition 14. (canceled) of claim 1, 15. (canceled) 39. The method of claim 37, wherein said barbiturate is 16. The composition of claim 5, wherein said butalbital is selected from one or more of the group consisting of amobar present in the range of about 25 mg to about 75 mg. bital, butalbital, aprobarbital, butabarbital, butethal, cyclo 17. The composition of claim 5, wherein said acetami barbital mephobarbital, methohexital, methylphenobarbital, nophen is present in the range of about 200 mg to about 600 pentobarbital, phenobarbital, secobarbital, talbutal, thiobar ng. bital, thiamylal, thiopental and thiopental Sodium. 18. The composition of claim 5, wherein said caffeine is 40. The method of claim 37, wherein said analgesic/anti present in the range of about 20 mg to about 60 mg. pyretic is selected from one or more of the group consisting of 19. The composition of claim 5, wherein said butalbital is acetaminophen, buprenorphine, butorphanol, codeine, dex present in the range of about 37.5 mg to about 62.5 mg. tropropoxyphene, dihydrocodeine, fentanyl, diamorphine 20. The composition of claim 5, wherein said acetami (Heroin), hydrocodone, hydromorphone, ketobemidone, nophen is present in the range of about 300 mg to about 500 morphine, nalbuphine, oxycodone, oxymorphone, pentaZo ng. cine, pethidine, tramadol, acetylsalicylic acid, diflunisal, 21. The composition of claim 5, wherein said caffeine is ethenZamide, aminophenaZone, metamizole, phenaZone, present in the range of about 30 mg to about 50 mg. phenacetin, Ziconotide, tetrahydrocannabinol, acetylsalicylic 22. The composition of claim 5, wherein said butalbital is acid (aspirin), choline salicylate magnesium salicylate, present in the range of about 45 mg to about 55 mg. Sodium salicylate, ibuprofen, naproxen and ketoprofen. 23. The composition of claim 5, wherein said acetami 41. The method of claim37, wherein said analgesic adjunct nophen is present in the range of about 360 mg to about 440 is selected from one or more of the group consisting of S ng. (+)-ketamine. metoclopramide, ciramadol, Sufentanil, caf 24. The composition of claim 5, wherein said caffeine is feine and remifentanil. present in the range of about 36 mg to about 44 mg. 42. A method comprising administering to a patient the 25. The composition of claim 5, wherein said composition composition of claim 5. comprises about 25 mg to about 75 mg of butalbital; about 200 mg to about 600 mg of acetaminophen: and about 20 mg 43. A method comprising a patient taking the composition to about 60 mg of caffeine. of claim 5. 26. The composition of claim 5, wherein said composition 44. The method of claim 37, wherein said composition is comprises about 37.5 mg to about 62.5 mg ofbutalbital; about administered to th patient orally. 300 mg to about 500 mg of acetaminophen; and about 30 mg 45. The method of claim 37, wherein said composition to about 50 mg of caffeine. comprises one or more of the group consisting of elixir, syrup 27. The composition of claim 5, wherein said composition and Suspension. comprises about 45 mg to about 55 mg of butalbital: about 46. The method of claim 37, wherein said composition 360 mg to about 440 mg of acetaminophen; and about 36 mg further comprises a flavorant. to about 44 mg of caffeine. 47. The method of claim 37, wherein said composition is 28. The composition of claim 27, wherein said butalbital is substantially free of other added active ingredients. present in the amount of about 50 mg. 48. The method of claim 47, wherein said other active 29. The composition of claim 27, wherein said acetami ingredient is another barbiturate. nophen is present in the amount of about 400 mg. 49. The method of claim 47, wherein said other active 30. The composition of claim 27, wherein said caffeine is ingredient is another analgesic/antipyretic. present in the amount of about 40 mg. 50. The method of claim 47, wherein said other active 31. The composition of claim 5, wherein said butalbital is ingredient is another analgesic adjunct. present in the amount of about 50 mg; said acetaminophen is 51. The method of claim 48, wherein said barbiturate is present in the amount of about 400 mg: and said caffeine is selected from one or more of the group consisting of amobar present in the amount of about 40 mg. bital, aprobarbital, butabarbital, butethal, cyclobarbital, 32. The composition of claim 5, wherein said composition mephobarbital, methohexital, methylphenobarbital, pento is administrable to said patient to treat and/or alleviate the barbital, phenobarbital, secobarbital, talbutal, thiobarbital, occurrence or negative effects of pain. thiamylal thiopental and thiopental sodium. 33. The composition of claim 32, wherein said pain is from 52. The method of claim 49, wherein said analgesic/anti one or more of the group consisting of chronic pain or acute pyretic is selected from one or more of the group consisting of pain. buprenorphine, butorphanol, codeine, dextropropoxyphene, 34. The composition of claim 33, wherein said composi dihydrocodeine, fentanyl, diamorphine (Heroin), hydroc tion is administered to said patient to treat and/or alleviate the odone, hydromorphone, ketobemidone morphine, nalbu occurrence or negative effects of headaches. phine, oxycodone, oxymorphone, pentazocine, pethidine, 35. The composition of claim34, wherein said headaches is tramadol, acetylsalicylic acid, diflunisal, ethenZamide, ami from one or more of the group consisting of tension type nophenaZone, metamizole, phenaZone, phenacetin, headache, migraine headache, cluster headache or chronic Ziconotide, tetrahydrocannabinol, acetylsalicylic acid (aspi daily headache. rin), choline Salicylate magnesium salicylate, sodium salicy 36. The composition of claim35, wherein said tension type late, ibuprofen, naproxen and ketoprofen. headaches is from one or more of the group consisting of 53. The method of claim 50, wherein said analgesic adjunct episodic or chronic. is selected from one or more of the group consisting of S 37. A method comprising administering to a patient the (+)-ketamine, metoelopramide, ciramadol, Sufentanil and composition of claim 1. remifentanil. US 2009/01 1 0724 A1 Apr. 30, 2009

54. The method of claim 42, wherein said butalbital is rence or negative effects from one or more of the group present in the range of about 25 mg to about 75 mg. consisting of episodic tension type headache or chronic ten 55. The method of claim 42, wherein said acetaminophenis sion type headache. present in the range of about 200 mg to about 600 mg. 75. The method of claim 42, wherein said composition is 56. The method of claim 42, wherein said caffeine is administered to said patient at a frequency selected from the present in the range of about 20 mg to about 60 mg. group consisting of once a day, twice a day, three times a day, 57. The method of claim 42, wherein said butalbital is four times a day, five times a day, six times a day, seven times present in the range of about 37.5 mg to about 62.5 mg. a day, eight times a day, nine times a day, ten times a day, 58. The method of claim 42, wherein said acetaminophenis eleven times a day and twelve times a day. present in the range of about 300 mg to about 500 mg. 76. The method of claim 42, wherein said patient takes said 59. The method of claim 42, wherein said caffeine is composition at a frequency selected from the group consist present in the range of about 30 mg to about 50 mg. ing of once a day, twice a day, three times a day. four times a 60. The method of claim 42, wherein said butalbital is day, five times a day, six times a day, seven times a day, eight present in the range of about 45 mg to about 55 mg. times a day, nine times a day, ten times a day, eleven times a 61. The method of claim 42, wherein said acetaminophen is day and twelve times a day. present in the range of about 360 mg to about 440 mg. 77. The method of claim 42, wherein said composition is 62. The method of claim 42, wherein said caffeine is administered to said patient at a frequency selected from the present in the range of about 36 mg to about 44 mg. group consisting of once every hour, once every two hours, 63. The method of claim 42, wherein said butalbital is once every three hours, once every four hours, once every five about 50 mg. hours, once every six hours, once every seven hours, once 64. The method of claim 42, wherein said acetaminophen is every eight hours, once every nine hours, once every ten about 400 mg. hours, once every eleven hours, once every twelve hours, 65. The method of claim 42, wherein said caffeine is about once every thirteen hours, once every fourteen hours, once 40 mg. even fifteen hours, once every sixteen hours, once every sev 66. The method of claim 42, wherein said composition is enteen hours, once every eighteen hours, once every nineteen present in the range of about 25 mg to about 75 mg of said hours, once every twenty hours, once every twenty one hours, butalbital; about 200 mg to about 600 mg of said acetami once every twenty two hours, once every twenty three hours nophen: and about 20 mg to about 60 mg of said caffeine. and once every twenty four hours. 67. The method of claim 42, wherein said composition is present in the range of about 37.5 mg to about 62.5 mg of said 78. The method of claim 42, wherein said patient takes said butalbital; about 300 mg to about 500 mg of said acetami composition at a frequency selected from the group consist nophen; and about 30 mg to about 50 mg of said caffeine. ing of once every hour, once every two hours, once every three 68. The method of claim 42, wherein said composition is hours, once every four hours, once every five hours, once present in the range of about 45 mg to about 55 mg of said every six hours, once every seven hours, once every eight butalbital; about 360 mg to about 440 mg of said acetami hours, once every nine hours, once every ten hours, once nophen: and about 36 mg to about 44 mg of said caffeine. every eleven hours, once every twelve hours, once every 69. The method of claim 42, wherein said butalbital is thirteen hours, once every fourteen hours, once every fifteen present in the amount of about 50 mg; said acetaminophen is hours, once every sixteen hours once every seventeen hours, present in the amount of about 400 mg. and s id caffeine is once every eighteen hours once every nineteen hours, once present in the amount of about 40 mg. every twenty hours, once every twenty one hours, once every 70. The method of claim 42, wherein said composition is twenty two hours, once every twenty three hours and once administered to said patient to treat and/or alleviate the occur every twenty four hours. rence or negative effects of pain. 79. The method of claim 42, wherein said composition is 71. The method of claim 42, wherein said composition is administered to said patient in a dose selected from the group administered to said patient to treat and/or alleviate the occur consisting of 0.5, 1, 1.5.2.2.5.3, 3.5 and 4 dosage forms. rence or negative effects from one or more of the group 80. A composition consisting ofbutalbital, acetaminophen, consisting of chronic pain or acute pain. caffeine and one or more inactive ingredients. wherein said 72. The method of claim 42, wherein said composition is composition is in the form of a gelcap. administered to said patient to treat and/or alleviate the occur 81. The composition of claim 80, wherein said composi rence or negative effects of headaches. tion has about 25 mg to about 75 mg butalbital, about 200 mg 73. The method of claim 42, wherein said composition is to about 600 mg acetaminophen and about 20 mg to about 60 administered to said patient to treat and/or alleviate the occur mg caffeine. rence or negative effects from one or more of the group 82. The composition of claim 81, wherein said composi consisting oftension type headache, migraine headache, clus tion has about 50 mg butalbital, about 400 mg acetami ter headache or chronic daily headache. nophen, and about 40 mg caffeine. 74. The method of claim 42, wherein said composition is administered to said patient to treat and/or alleviate the occur c c c c c