US 20140275188A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0275188A1 SCHACHTEL (43) Pub. Date: Sep. 18, 2014

(54) USE OF ANALGESC POTENTATING Publication Classification COMPOUNDS TO POTENTIATE THE ANALGESC PROPERTIES OF AN (51) Int. Cl. ANALGESC COMPOUND A613 L/426 (2006.01) A63L/92 (2006.01) (71) Applicant: SCHABAR RESEARCH (52) U.S. Cl. ASSOCIATES LLC, Jupiter, FL (US) CPC ...... A6 IK3I/426 (2013.01); A61 K3I/192 (2013.01) (72) Inventor: Bernard P. SCHACHTEL, Jupiter, FL USPC ...... S14/365 (US) (57) ABSTRACT (73) Assignee: SCHABAR RESEARCH ASSOCIATES LLC, Jupiter, FL (US) Described herein are methods for effectively and accurately measuring a patient response upon administration of one or (21) Appl. No.: 14/291,037 more drugs to the patient. The methods are more sensitive than current methodologies. Also described herein are com (22) Filed: May 30, 2014 positions comprising an analgesic and a Sufficient amount of an antihistamine to enhance the analgesic properties of the Related U.S. Application Data analgesic. With respect to these compositions, the methods described herein are useful for evaluating qualities of pain, (63) Continuation of application No. 12/811,528, filed on definite improvement, and one or more bodily functions of a Sep. 8, 2010, now Pat. No. 8,771,643, filed as applica subject afflicted with pain. The compositions described tion No. PCT/US2009/030079 on Jan. 5, 2009. herein are useful in improving the quality of pain in a subject (60) Provisional application No. 61/019,025, filed on Jan. or a bodily function of a subject afflicted with pain or definite 4, 2008. improvement of a subject afflicted with pain. Patent Application Publication Sep. 18, 2014 Sheet 1 of 6 US 2014/0275188A1

Rediction in rat Soreness over 6 ors

8 7 8 5 4. 3

1 APA- buprofen Celecoxib Naproxe aceto

FG.

Recities it at Sore ess over 8 iofs

buprofer ibutioratadine but Hydroxyzine bu--Nizaticine Patent Application Publication Sep. 18, 2014 Sheet 2 of 6 US 2014/0275188A1

Reiiction it rcat Soreless over 8 of's

Percent of Patients Achieving Definite in provenient is a Screess

OO 8 6 40 20

AA buprofen Ceiecoxib Naproxer ace

FG, 4. Patent Application Publication Sep. 18, 2014 Sheet 3 of 6 US 2014/0275188A1

Reduction in Difficulty Swallowing over 6 hours

3 8 7 - 6 - 5 4. 3. 2

O buprofen it} +...oratadine bui-hydroxyzine but Nizaticine

F.G. 5

Reduction in ifficity aiking over 6 Hours

8 8 a 2 O 8 6 4. 2 AA buprofen Celecoxib Naproxen Pacebo Patent Application Publication Sep. 18, 2014 Sheet 4 of 6 US 2014/0275188A1

buprofen but-iloratadine buri-Hydroxyzine bui-Nizatidine

G. 7

Reduction is throat Sweig over 6 hours

O 3 8 7 8 4. 3. 2

uprofen but-illoratadine bu-i-Hydroxyzine bui-Nizatione Patent Application Publication Sep. 18, 2014 Sheet 5 of 6 US 2014/0275188A1

Reduction in Throat Sweiling over 6 ours

"*" ibuprofen Placebo

FG. 9

Reduction in Quaity-of-Pain index over 6 ours

14 2O O) 80 80 a. O

buprofen but-iloratidine but Hydroxyzine but Nizaticine

F.G. O. Patent Application Publication Sep. 18, 2014 Sheet 6 of 6 US 2014/0275188A1

AAP buprofen Celecoxib Naproxer Piacebo

F.G. US 2014/0275188A1 Sep. 18, 2014

USE OF ANALGESC POTENTATING SUMMARY OF EMBODIMENTS COMPOUNDS TO POTENTIATE THE ANALGESC PROPERTIES OF AN 0005. Described herein are methods for effectively and ANALGESC COMPOUND accurately measuring a patient response upon administration of one or more drugs to the patient. The methods are more CROSS REFERENCE TO RELATED sensitive than current methodologies. Also described herein APPLICATIONS are compositions comprising an analgesic and a sufficient amount of an antihistamine to enhance the analgesic proper 0001. This application is a continuation application of ties of the analgesic. With respect to theses compositions, the U.S. application Ser. No. 12/811,528, filed on Sep. 8, 2010, methods described herein are useful for evaluating qualities which is a U.S. national phase application under 35 USC 371 of pain, definite improvement, and one or more bodily func of international application number PCT/US2009/030079, tions of a subject afflicted with pain. The compositions filed Jan. 5, 2009, which claims priority to U.S. provisional described herein are useful in improving the quality of pain in application Ser. No. 61/019,025, filed Jan. 4, 2008, which are a subject or a bodily function of a subject afflicted with pain hereby incorporated herein by reference in their entirety for or definite improvement of a subject afflicted with pain. all purposes. 0006. The advantages of the invention will be set forth in part in the description which follows, and in part will be BACKGROUND obvious from the description, or may be learned by practice of 0002. When a patient is administered a drug, the patient the aspects described below. The advantages described below generally produces a response that is perceptible to the will be realized and attained by means of the elements and patient. For example, when a Subject is experiencing pain, the combinations particularly pointed out in the appended Subject will take a medication to relieve the pain symptoms. claims. It is to be understood that both the foregoing general By effectively detecting and measuring the patient response, description and the following detailed description are exem information regarding the effectiveness of the drug can be plary and explanatory only and are not restrictive. obtained and evaluated. An example of this includes analgesic potentiation. “Analgesic potentiation' is a type of pharmaco BRIEF DESCRIPTION OF THE DRAWINGS logic activity that occurs when greater analgesic effectiveness is measured in patients treated with an analgesic drug com 0007. The accompanying drawings, which are incorpo bined with a non-analgesic ingredient than in patients treated rated in and constitute a part of this specification, illustrate with the analgesic drug alone. There are many reasons for the several aspects described below. potentiation of an analgesic. For example, it would be desir 0008 FIG. 1 shows the reduction in throat Soreness over 6 able to enhance the clinical outcome for the patient (i.e., hours of several analgesics (acetaminophen 500 mg (APAP), analgesic effectiveness). It would also be desirable to reduce ibuprofen 200 mg, celecoxib 200 mg, naproxen sodium 220 the dosage of the analgesic (i.e., "optimal dose') that is mg) and placebo. administered in view of possible side effects exhibited by the 0009 FIG. 2 shows the reduction in throat Soreness over 6 same or higher dose of the analgesic (i.e., "optimal analge hours of ibuprofen 200 mg (Ibu) and several ibuprofen com sia, a reduction of the risk:benefit ratio). It would also be binations (ibuprofen 200 mg+loratadine 20 mg (Ibu+Lorata desirable to provide greater pain relief or faster onset of pain dine), ibuprofen 200 mg--hydroxyzine 50 mg (Ibu--Hydrox relief. It would also be desirable to provide a longer duration, yzine), ibuprofen 200 mg--nizatidine 150 mg (Ibu which results in less frequent dosing and better compliance. Nizatidine). Finally, if the analgesic can improve one or more qualities of 0010 FIG.3 shows the reduction in throat soreness at time pain or one or more bodily functions of the patient or provide points over 6 hours of ibuprofen 200 mg and placebo. definite improvement of the patient, which will be discussed 0011 FIG. 4 shows the percentage of patients who in greater detail below, these would be added benefits. achieved their own Definite Improvement Level on the Throat 0003. The measurement instruments for these overall effects are standard methods for determining general patient Soreness Scale of several analgesics and placebo. response Such as analgesic activity. In the evaluation of anal 0012 FIG. 5 shows the reduction in difficulty swallowing gesic potentiation, for example, clinical investigators by con over 6 hours of ibuprofen combinations and ibuprofen 200 vention utilize these methods to demonstrate, to a statistically ng. significant degree, that a combination of drugs provides 0013 FIG. 6 shows the reduction in difficulty talking over “greater reduction in pain intensity’ and “more pain relief 6 hours of several analgesics and placebo. than the single-ingredient analgesic. However, conventional 0014 FIG. 7 shows the reduction in difficulty talking over methods may not be able to demonstrate that a combination of 6 hours of ibuprofen combinations and ibuprofen 200 mg. the analgesic with another drug provides analgesic effective 0015 FIG. 8 shows the reduction in throat swelling over 6 ness to a greater extent than the analgesic alone. Measuring hours of ibuprofen combinations and ibuprofen 200 mg. these conventional overall endpoints (i.e., "pain' and “relief) may obscure specific clinical benefits that are mean 0016 FIG.9 shows the reduction in throatswelling at time ingful to the patient and analgesic potentiation due to the points over 6 hours of ibuprofen 200 mg and placebo. presence of an additional drug or ingredient used in combi (0017 FIG. 10 shows the reduction in the Quality-of-Pain nation with the analgesic. Index over 6 hours of ibuprofen combinations and ibuprofen 0004 Thus, what are needed are methods for increasing or 200 mg. enhancing the measurement of patient responses. These 0018 FIG. 11 shows the reduction in the Annoying Qual methods could be used to demonstrate what is otherwise ity-of-Pain Scale over 6 hours of several analgesics and pla non-demonstrable using conventional methods. cebo. US 2014/0275188A1 Sep. 18, 2014

DETAILED DESCRIPTION 0033 c. evaluating whether or not there is definite improvement of the adverse symptoms after administra 0019. Before the present compounds, compositions, and/ tion of the drug or drugs to the Subject; and or methods are disclosed and described, it is to be understood 0034 d. comparing the response in step (c) in the subject that the aspects described below are not limited to specific with a response of the Subject who was administered a compounds, synthetic methods, or uses as such may, of comparative agent. course, vary. It is also to be understood that the terminology 0035. In general, the methods described herein are more used herein is for the purpose of describing particular aspects sensitive with respect to detecting and measuring a patients only and is not intended to be limiting. response to one or more drugs. The methods can be used in a 0020. In this specification and in the claims that follow, variety of therapeutic areas exhibiting adverse symptoms reference will be made to a number of terms that shall be including, but not limited to, gastrointestinal (e.g., for defined to have the following meanings: patients with heartburn, abdominal pain, nausea and vomit 0021. It must be noted that, as used in the specification and ing); respiratory (e.g., for patients with asthma, chronic the appended claims, the singular forms “a,” “an and “the obstructive lung disease, cough, nasal congestion); muscu include plural referents unless the context clearly dictates loskeletal (e.g., for patients with osteoarthritis, sprains, rheu otherwise. Thus, for example, reference to “a pharmaceutical matoid arthritis, spinal disorders); dermatological (e.g., for carrier includes mixtures of two or more such carriers, and patients with eczema, hives, psoriasis, Sun sensitivity); psy the like. chiatric (e.g., for patients with depression, anxiety, sleep dis 0022 "Optional or “optionally’ means that the subse orders); CNS (e.g., for patients with tension headache, quently described event or circumstance can or cannot occur, migraine headache, light sensitivity); and allergic disorders and that the description includes instances where the event or (e.g., for patients with seasonal allergic rhinitis, perennial circumstance occurs and instances where it does not. For allergic rhinitis). example, the phrase “optionally substituted lower alkyl 0036. In one aspect, the methods described herein mea means that the lower alkyl group can or cannot be substituted sure a definite improvement after the administration of the and that the description includes both unsubstituted lower drug(s). The phrase “definite improvement is defined herein alkyl and lower alkyl where there is substitution. as the ability of the drug to elicit a response followed by 0023 The term “comparative agent” as used herein is any Subsequent questioning to evaluate whether or not the Sub agent that is used to compare or evaluate the ability of an jects condition has improved. In general, "definite improve antihistamine to potentiate the analgesic properties of an ment can be evaluated by directly asking the subject certain analgesic. For example, the comparative agent can be a pla questions that will prompt the Subject to precisely consider cebo, another drug, or a combination of drugs. Thus, the whether or not the Subject's condition has unequivocally effects of a known analgesic can be evaluated and compared improved such that the response is significantly perceptible to to that of the comparative agent, confirming the pharmaco the Subject and is so reported by the Subject. In one aspect, the logic activity of the analgesic and thus validating the method degree or amount of the response can be measured using a itself. For example, when a patient is administered an anal multipoint Scale, which can vary from little to no improve gesic and an antihistamine, the comparative agent is the ment to certain improvement. “Definite improvement' is administration of just the analgesic to the patient. In this greater than 50% improvement to 100% improvement as example, the effects of the antihistamine on the analgesic can perceived and reported by the patient on this scale. In another be evaluated and compared to that of the analgesic alone, thus aspect, "definite improvement' is at or lower than a response identifying any additional pharmacologic activity provided level perceived by the subject on one or more individual rating by the antihistamine (“analgesic potentiation'). scales. 0024 Described herein are methods for evaluating a sub 0037 For example, patients with asthma may be able to jects response when administered one or more drugs. In one report “definite improvement” because several symptoms aspect, the method includes: have, in Subtle ways, improved, or these patients may be able 0025 a. obtaining a baseline of one or more symptoms in to report less chest tightness, a sensory quality of asthma, the subject; even though, in clinical trials, they may not report “relief of 0026 b. requiring a pre-determined minimal intensity asthma symptoms. Patients with osteoarthritis may report less level of one or more symptoms; joint “stiffness, a sensory quality of arthritic status, even 0027 c. administering one or more drugs to the subject though they may not report “relief of their disease in clinical that will elicit one or more responses perceptible to the studies. Patients with hives may report an ability to move an Subject; effected body part more freely (i.e., function) even though they may not report “relief of their condition in research 0028 d. evaluating one or more responses in the subject trials. For each example, specific “patient-oriented end and comparing them to the baseline in step (a); and points may reveal the actual clinical benefits. Each specific 0029 e. comparing the response in step (d) in the subject endpoint of patient dis-ease (rather than physician-diagnosed with a response of the Subject who was administered a disease) may reveal the actual clinical benefit to the patient. comparative agent. 0038 Examples of definite improvement associated with 0030. In another aspect, a method for evaluating definite pain include, but are not limited to, headache, backache, improvement of a subject afflicted with one or more adverse sinusitis, earache, cough discomfort, sinus pain associated symptoms after the administration of one or more drugs to the with nasal congestion, difficulty breathing, toothache, Subject includes: sprained ankle, muscle strain, sprained or torn ligaments, and 0031 a. administering one or more drugs to the subject; bursitis. 0032) b. requiring a pre-determined minimal intensity 0039. The methods described herein are useful in evaluat level of one or more symptoms; ing if a drug (alone or in combination with other drugs) is US 2014/0275188A1 Sep. 18, 2014 useful in eliciting a desirable response. For example, the effects in order to determine analgesic potentiation, i.e., if response elicited by the patient when administered a drug can sample antihistaminefanalgesic combinations deliver more be compared to the patient’s response when the Subject is pronounced analgesia compared to the respective single-in administered a comparative agent as defined above. gredient analgesics. Measuring conventional endpoints (e.g., 0040. In one aspect, described herein is a method for “pain' and “relief) may obscure the identification of clinical evaluating one or more qualities of pain in a subject afflicted benefits. with pain, comprising: 0041 (a) obtaining a baseline of one or more qualities of 0065. The type of pain can be acute or chronic. The source pain in the Subject; of the pain can vary and includes, but is not limited to, renal 0042 (b) requiring a pre-determined minimal intensity colic, colic, gallstone pain, ulcer pain, sinus pain, migraine level of one or more qualities of pain; headache, cluster ("histamine’) headache, muscle contrac 0.043 (c) administering a composition comprising an tion headache, osteoarthritis, rheumatoid arthritis, gouty analgesic and an antihistamine to the Subject; arthritis, other arthritides, ligamentous sprain, bursitis, soft 0044) (d) evaluating one or more qualities of pain in the tissue injuries (e.g., torn Subpatellar meniscus or ligament), Subject and comparing them to the baseline in step (a); and skeletal muscle (e.g., low back pain, muscle ache, muscular 0045 (e) comparing the response in step (d) to the contusion, muscular strain, muscle spasm, neck spasm/pain, response in the Subject administered just the analgesic. etc.). In other aspects, the Source of pain can be post-operative 0046. In another aspect, described herein is a method for (e.g., following abdominal Surgery, thoracic Surgery, neuro evaluating one or more bodily functions of a subject afflicted Surgery, orthopedic Surgery, podiatric Surgery, anorectal Sur with pain, comprising: gery, urologic Surgery, gynecologic Surgery, episiotomy, oral 0047 (a) obtaining a baseline of one or more bodily func tions of the Subject experiencing pain; Surgery, head and neck Surgery, plastic Surgery, etc.). In other 0048 (b) requiring a pre-determined minimal intensity aspects, the Source of pain can be the result of infection (e.g., level of one or more bodily functions: a Subject experiencing pain as a result of sinusitis, laryngitis, 0049 (c) administering a composition comprising an pharyngitis, otitis media, cellulitis, abscess, meningitis, con analgesic and an antihistamine to the Subject; junctivitis, osteoarthritis, osteomyelitis, etc.). In other 0050 (d) evaluating one or more bodily functions in the aspects, the source of pain can be the result of vascular insuf Subject and comparing them to the baseline in step (a); and ficiency (e.g., a Subject experiencing pain as a result of 0051 (e) comparing the response in step (d) to the peripheral vascular disease or coronary artery disease). In response in the Subject administered just the analgesic. other aspects, the source of pain can be the result of a previous 0052. In a further aspect, described herein is a method for treatment (e.g., a subject experiencing pain as a result of evaluating definite improvement of a subject afflicted with receiving chemotherapy or radiation) or the result of cancer pain, comprising: (e.g., primary carcinoma or metastatic bone pain). Each type 0053 (a) obtaining a baseline of one or more symptoms in of pain presents “patient-oriented clinical effects that can be the subject; measured by the methods described herein and/or improved 0054 (b) requiring a pre-determined minimal intensity by the compositions described herein. level of one or more symptoms; 0066. In one aspect, the compositions described herein 0.055 (c) administering a composition comprising an improve one or more qualities of pain in a Subject. The phrase analgesic and an antihistamine to the Subject; “improve the quality of pain' is defined hereinas the ability of 0056 (d) evaluating whether there is definite improve the composition to reduce the Subjects sensation of a particu ment in the Subject of one or more symptoms; and lar quality or qualities of pain. For example, when a subject is 0057 (e) comparing the response in step (d) to the experiencing a Sore throat, the Subject may experience a hot, response in the Subject administered just the analgesic. scratchy, raw, raspy, dry, tight, Swollen, or burning sensation 0058. The methods described herein use rating scales that or consider the sensation annoying or irritating. These are measure changes in the words which patients actually use to examples of qualities of pain associated with a sore throat (as describe their discomfort and whether or not they achieved caused, e.g., by pharyngitis, seasonal allergic rhinitis (“hay definite improvement on each scale, instead of traditional fever), perennial allergic rhinitis). Other examples of quali analgesic methods (i.e., measuring differences in overall pain ties of pain associated with other painful conditions include, intensity or relief). In certain aspects, the methods described but are not limited to, headache, backache, sinusitis, earache, herein for evaluating pain in a patient and the effect of the toothache, sprained ankle, joint pain, arthritis, bursitis, vas combination of an analgesic and antihistamine utilize non cular insufficiency, cancer-related pain, post-operative pain. standard methods: 0067. In other aspects, the compositions described herein 0059) 1... to measure qualities of pain clinically relevant to improve one or more bodily functions of a subject afflicted patients with the pain-producing condition; with pain. The phrase “improve one or more bodily func 0060 2. to measure function(s) clinically relevant to tions” is defined herein as the ability of the composition to patients with the pain-producing condition; improve a bodily function of a subject that is debilitated or 0061 3. to examine the effect of each combination drug weakened as a result of pain experienced by the subject. For upon qualities of pain in this sample pain model; example, when a Subject is experiencing a Sore throat, the 0062 4. to examine the effect of each combination drug on Subject may have trouble Swallowing or difficulty talking, function(s); and where swallowing and talking are the bodily functions. These 0063) 5. to examine if a patient was “definitely improved.” are examples of bodily functions associated with a sore throat 0064. The methods described herein represent a progres (as caused, e.g., by tonsillopharyngitis, oral mucositis). Other sion beyond conventional analgesic measurement instru examples of bodily functions associated with other painful ments and attempt to measure “patient-oriented clinical conditions include, but are not limited to, headache, back US 2014/0275188A1 Sep. 18, 2014 ache, sinusitis, earache, toothache, sprained ankle, joint pain, contain, in varying combinations, an analgesic/antipyretic, an arthritis, bursitis, vascular insufficiency, cancer-related pain, antihistamine, an antitussive, a decongestant, an expectorant, post-operative pain. etc.). Alternatively, the analgesic comprises an opioid includ 0068. In another aspect, the compositions described ing, but not limited to, morphine, codeine, buprenorphine, herein can be shown directly to provide definite improve hydrocodone, oxycodone, fentanyl, tramadol, pentazocine, ment. The phrase “definite improvement' is defined hereinas meperidine, or any combination thereof with or without caf the ability of the composition to reduce the subjects sensa feine or other analgesic adjuvant(s), optionally with other tion of a particular quality(ies) of pain or bodily function(s)at ingredients for non-analgesic indications (e.g., "cough-cold least to his/her own level defining successful treatment. Grad products.” which may contain, in varying combinations, an ing a reduction in pain intensity may be inadequate to detect analgesic/antipyretic, an antihistamine, an antitussive, a improvement in physical status. Rather than infer a change in decongestant, an expectorant, etc.). status by Subtracting one “pain” rating from another, as is 0072 Pharmaceutically acceptable salts of the analgesic commonly performed in clinical trials, Subjects can define can be used herein. For example, Suitable pharmaceutically their own criterion of successful treatment as a direct indica acceptable salts of ibuprofen include ibuprofen lysinate, dexi tor of therapeutic efficacy. For example, one subject with a buprofen lysinate, and Sodium and potassium salts of ibupro “swollen' throat may rate it “10 on a 0-10 scale: for him/her. fen. Other examples of pharmaceutically acceptable salts of reducing this sensation to “6” or below may be the clear ibuprofen include salts with alkaline earth metals, such as measure of whether or not a medication is “working.” For magnesium, aluminum, iron, Zinc, copper, nickel or cobalt, another subject, with a “7” rating of throat swelling, reducing and amino acid salts, particularly the basic amino acid salts this sensation to '3' is inadequate, only a rating of '2' or Such as lysine or arginine. Examples of Suitable forms of below means “definite improvement.” Other examples apply ibuprofen include, but are not limited to racemic and indi to other qualities of pain or bodily functions. Each patients vidual purified forms of (S) ibuprofen and (R)-ibuprofen iso “definite improvement level on a rating scale can be used to mers, including (S)-ibuprofen-(S)-lysine, (S)-ibuprofen-(R)- identify a Successful treatment response, or not. Thus lysine, (R)-ibuprofen-(S)-lysine and (R)-ibuprofen-(R)- response rates of patients treated with a drug can be compared lysine and combinations thereof. to those of patients treated with placebo, identifying thera 0073. A variety of different antihistamines can be used peutic efficacy. herein. In one aspect, the antihistamine comprises a sedating 0069. The evaluation methods described herein provide Hantihistamine, a non-sedating H1-antihistamine, a H-an numerous advantages over existing techniques. First, it is tihistamine, an experimental H- and H-receptor antagonist, possible to detect wide differences (e.g., ranging from 20% to or any combination thereof. Examples of sedating H1-anti over 100%) between some antihistamine/analgesic combina histamines include, but are not limited to, diphenhydramine, tions and the corresponding single-ingredient analgesic. hydroxy Zine, any salt or isomer thereof, or a combination Additionally, the methods are more sensitive with respect to thereof. Useful non-sedating H-antihistamines include, but differentiating the effects of different combinations of anal are not limited to, astemizole, azatadine, azelastine, cetiriz gesic and antihistamine. For example, unlike the requirement ine, ebastine, feXofenidine, ketotifen, lodoxamide, lorata for an entry level-7 for the conventional scale Throat Sore dine, desloratadine, levocabastine, meduitazine, oxatomide, ness Scale (TSS), there are no admission criteria for using the setastine, tazifylline, and terfenadine, any salt or isomer methods described herein, which ranged from 0 to 10 at thereof, or any combination thereof. Examples of H-antihis baseline. Despite this “all-comer study sample, the methods tamines include, but are not limited to, nizatidine, ranitidine, described herein were used by the patients in each treatment famotidine, cimetidine, roXatidine, lafutidine, ebrotidine, group to measure impressive effects and identify clear drug burimamide, metiamide, tiotidine, OXmetidine, pabutidine, VS.-placebo and between-drug differences. Due to greater loXtidine, any salt or isomer thereof, or any combination sensitivity, the methods described herein may require fewer thereof. Examples of H-antihistamines include, but are not patients in a clinical trial than with a conventional rating scale limited to, A-349,821, ABT-239, ciproxifan, clobempropit, or and be capable of discerning clinical effects better. thioperamide, any salt or isomer thereof, or any combination 0070. In one aspect, the composition for improving. (e.g., thereof. Examples of Ha-antihistamines include, but are not providing definite improvement of) at least one quality of limited to, thioperamide, JNJ 7777120, VUF-6002, any salt pain and/or at least one bodily function comprises an analge or isomer thereof, or any combination thereof. sic and a sufficient amount of an antihistamine to enhance the 0074 The amounts of analgesic and antihistamine can analgesic properties of the analgesic. In general, the analgesic vary depending upon the selection of the analgesic and anti and antihistamine are FDA-approved chemical compounds. histamine, the type of pain experienced by the Subject, the 0071. In one aspect, the analgesic comprises a non-opioid. route and means of drug administration, and the frequency of Examples of non-opioids include, but are not limited to, dosing. In one aspect, the analgesic is a single dosage from acetaminophen, aspirin, ibuprofen, naproxen Sodium, 0.1 mg to 1,500 mg and the antihistamine is a single dosage naproxen, indomethacin, flurbiprofen, ketoprofen, lornoxi from 0.1 mg to 1 g. In another aspect, the amount of analgesic cam, meloxicam, piroXicam, oxaprozin, etodolac, ketorolac, is 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg. nabumetone, or other nonselective nonsteroidal anti-inflam 50 mg. 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg,300 mg. matory drugs (NSAIDs), selective COX-2 inhibitors (e.g., 400 mg, 500 mg, 600mg, 700 mg,800 mg,900 mg, 1,000 mg. celecoxib, rofecoxib, Valdecoxib, parecoxib, etoricoxib, 1,100 mg, 1,200 mg, 1,300 mg, 1,400 mg, or 1,500 mg, where CS-502, JTE-522, L-745,337, and NS398), NDMA-inhibi any value can form a lower or upper endpoint of a range. In a tors, or any combination thereof, optionally with other com further aspect, the amount of antihistamine is 0.1 mg, 0.5 mg. ponents such as, for example, caffeine or other analgesic 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg. adjuvant(s), with or without other ingredients for non-anal 300 mg, 350 mg. 400 mg. 450 mg, 500 mg, 600 mg, 700 mg. gesic indications (e.g., "cough-cold products which may 800 mg, 900 mg. or 1,000 mg, where any value can form a US 2014/0275188A1 Sep. 18, 2014 lower or upper endpoint of a range. In another aspect, the 007.9 The compositions of the invention may be formu weight ratio of analgesic to antihistamine is 20:1, 18:1, 16:1. lated so as to provide quick release, Sustained release, or 14:1, 12:1, 10:1, 8:1, 6:1, 4:1, 2:1, or 1:1. delayed release of the analgesic and/or antihistamine after 0075. The analgesic and antihistamine can be formulated administration to the subject. Different pharmaceutic formu into a variety of pharmaceutical compositions. The pharma lations and different processing techniques may be employed ceutical compositions can be prepared using techniques to alter the pharmacokinetic characteristics of the composi known in the art. In one aspect, the composition is prepared tions, including, without limitation, time to maximum con by admixing the analgesic and the antihistamine with a phar centration, maximum concentration, area under the curve, maceutically-acceptable carrier. Alternatively, the analgesic etc. In one aspect, the analgesic and antihistamine can be and antihistamine are formulated Such that the analgesic and formulated with biodegradable polymers such as, for the antihistamine are in separate delivery devices. In this example, polylactide, polyglycolide, or polylactide-co-gly aspect, the analgesic and the antihistamine can be adminis collide, where the analgesic and antihistamine are incorpo tered to the Subject separately and independently (e.g., to rated in a polymeric matrix. By varying the amount and achieve immediate-release or delayed-release responses by molecular weight of the biodegradable polymer, it is possible and to one or both component drugs). In one aspect, the to control the rate of release of the analgesic and the antihis antihistamine can be administered first followed by the tamine. In another aspect, the tablet or pill can be formulated administration of the analgesic. For example, when the anti such that the tablet or pill contains two or more layers of histamine is nizatidine and the analgesic is ibuprofen, the varying disintegration and dissolution rates. In other aspects, nizatidine can be administered first followed by the adminis the compositions can be encapsulated in order to control the tration of ibuprofen. Not wishing to be bound by theory, when rate of release of the analgesic and antihistamine With respect the nizatidine is an immediate-release preparation (e.g., a to any of the oral formulations described above, the analgesic powder), the dissolution and bioavailability of the nizatidine and antihistamine can be formulated into one tablet or pillor, is increased when compared to the slower dissolution and in the alternative, the analgesic and antihistamine can be bioavailability of ibuprofen in a compressed tablet. formulated into separate tablets or capsules. 0076. The analgesic and antihistamine can be formulated 0080. The compositions described herein can be adminis in any excipient the Subject can tolerate. Examples of Such tered topically (including ophthalmically, vaginally, rectally, excipients include, but are not limited to, water, Saline, Ring buccally, intranasally). Formulations for topical administra er's Solution, dextrose solution, Hank’s Solution, and other tion can include ointments, lotions, creams, gels, patches, aqueous physiologically balanced salt Solutions. Nonaqueous drops, Suppositories, sprays, liquids and powders. Alterna vehicles, such as fixed oils, vegetable oils such as olive oil and tively, the compositions described herein can be prepared as sesame oil, triglycerides, propylene glycol, polyethylene gly sterile aqueous or non-aqueous solutions, Suspensions, and col, and injectable organic esters such as ethyl oleate can also emulsions. Examples of non-aqueous carriers include water, be used. Other useful formulations include Suspensions con alcoholic/aqueous solutions, emulsions or Suspensions, taining viscosity-enhancing agents, such as sodium car including saline and buffered media. Parenteral vehicles, if boxymethylcellulose, sorbitol, or dextran. needed for collateral use of the disclosed compositions and 0077. The pharmaceutical compositions can include other methods, include Sodium chloride solution, Ringer's dex components that are non-analgesics and non-antihistamines. trose, dextrose and Sodium chloride, lactated Ringers, or For example, the pharmaceutical compositions can contain fixed oils. Intravenous vehicles, if needed for collateral use of minor amounts of additives, such as Substances that enhance the disclosed compositions and methods, include fluid and isotonicity and chemical stability. Examples of buffers nutrient replenishers, electrolyte replenishers (such as those include phosphate buffer, bicarbonate buffer and Tris buffer, based on Ringer's dextrose), and the like. Preservatives and while examples of preservatives include thimerosol, cresols, other additives can also be present Such as, for example, formalin and benzyl alcohol. In one aspect, the compounds antimicrobials, anti-oxidants, chelating agents, and inert described herein are admixed with a non-FDA approved gases and the like. delivery device Such as, for example, Sunscreen or a nutra I0081 Provided below is a representative study for evalu ceutical. In other aspects, the pharmaceutical compositions ating the qualities of pain and bodily functions that are can also include one or more active ingredients such as anti reduced and definite improvement when a Subject is experi microbial agents, antiinflammatory agents, anesthetics, encing pain using the compositions and methods described decongestants, antitussives, expectorants, antipyretics, and herein. Specific methodology and techniques are provided in the like. the Examples. 0078. The pharmaceutical compositions can be adminis Treatment Schedule tered in a number of ways. In one aspect, the compositions can be administered orally as a tablet or pill. The analgesic 0082. According to a computer-generated randomization and antihistamine can beformulated with a variety of suitable code, the following treatments will be assigned under double carriers, excipients, and diluents known in the art. Examples blind conditions: of Such materials include, but are not limited to, lactose, dextrose, Sucrose, Sorbitol, mannitol, starches, gum acacia, 1. Acetaminophen 500 mg calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, I0083. 2. Acetaminophen 500 mg--cetirizine 20 mg cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium Stearate and mineral oil. 3. Celecoxib 200 mg The formulations can additionally include lubricating agents, I0084. 4. Celecoxib 200 mg--cetirizine 20 mg wetting agents, emulsifying and Suspending agents, preserv 5. Naproxen sodium 220 mg ing agents, Sweetening agents or flavoring agents. 6. Naproxen Sodium 220 mg-loratadine 20 mg US 2014/0275188A1 Sep. 18, 2014

7. Ibuprofen 200 mg 0.109 11. Post-treatment evaluations of throat soreness, swollen throat, difficulty swallowing, difficulty talking, 0085 8. Ibuprofen 200 mg--loratadine 20 mg and improvement at 3, 4, 5, and 6 hours. 9. Ibuprofen 200 mg--hydroxyzine 50 mg 0110 12. Post-treatment evaluations of qualities of pain at 10. Ibuprofen 200 mg--nizatidine 150 mg 6 hours. 11. Placebo 0111 13. Follow-up visit within 5 days to determine defi nite improvement levels for each scale, review Diary and Baseline Characteristics evaluate any side effects. Discharge from study, routine care and follow-up per standard clinic protocol. I0086 1. Onset of sore throat in past 5 days 0087 2. Tonsillo-Pharyngitis Assessment (TPA).5 Endpoints 0088. 3. Throat Soreness Scale>7 0089 4. No mouth-breathing or throat discomfort with 0112 1. Primary Endpoint: Difference in difficulty swal coughing lowing over 6 hours 0090. 5. May have symptoms of allergic rhinitis, but no 2. Secondary Endpoints: use of antihistamines on a regular basis 0091 6. No medical contraindications (e.g., relevant drug 0113 a. Difference in Quality-of-Pain Index over 6 hours allergies or diseases) 0114 b. Difference in Throat Function Index over 6 hours 0115 c. Difference in throat soreness over 6 hours Measurement Instruments 0116 d. Difference in throat swelling over 6 hours 0117 e. Difference in relatively severe (baseline-7) quali 0092] 1. Throat Soreness Scale evaluative quality-of ties of pain pain scale 0118 f. Difference in relatively severe sensory qualities of 0093. 2. Swollen Throat Scale sensory quality-of-pain pa1n Scale 0119 g. Difference in most bothersome quality(ies) of 0094) 3. Difficulty Swallowing Scale function scale pain: ** 0095 4. Difficulty Talking Scale function scale I0120 h. Differences in difficulty swallowing at individual 0096 5. Quality-of-Pain Scales* measuring other sen time points sory qualities of pain (hot, Scratchy, raw, raspy, tight, dry, I0121 i. Differences in relatively severe difficulty talking burning), affective qualities of pain (irritating, annoying), 0.122 j. Differences in throat soreness at individual time and another evaluative quality of pain (it hurts) points 0097 6. Definite Improvement Assessment transitional I0123 k. Differences in throat swelling at individual time Scale points 0098 7. Definite Improvement Level nominal scale 0.124 1. Percentage of patients with definite improvement 0.125 m. Total improvement over 6 hours Study Procedures 0.126 n. Improvement at individual time points 0099. 1. Screening, Consent process 0127. In certain aspects, for each treatment group, 0100 2. Brief Medical History, URTISymptoms and Sore improvement and differences from Baseline may be reported Throat History (duration, treatments) as medians and percentage differences. 0101 3. Temperature (oral), pulse, respiratory rate *Throat soreness (an evaluative quality of pain), throat swell 0102 4. Respiratory (lungs and nose) examination and ing (a sensory quality of pain), and the other 10 qualities of TPA throat pain comprise the 0-to-120 point 0103) 5. Urine pregnancy test on all eligible female patients Quality-of-Pain Index. 0104 6. Baseline evaluations (throat soreness, swollen I0128 **Difficulty Swallowing and Difficulty Talking throat, difficulty Swallowing, difficulty talking, qualities of comprise the 0-to-20 point pain) under the supervision of the Study Nurse 0105 7. Qualifying patients are administered the ran Throat Function Index. domly assigned identically-appearing study medications (prepared, packaged, and coded by independent pharma I0129. ***The most bothersome quality of pain has the cist) with a full glass of water highest Baseline score. Qualities that have the same highest 0106 8. Post-treatment evaluations of throat soreness, Baseline score (i.e., ties) may be examined, too. “Most both Swollen throat, difficulty Swallowing, and improvement erSome quality(ies)’ will be analyzed separately and as a under the supervision of the Study Nurse at 15-minute group since these are the most bothersome qualities of pain intervals over 2 hours from the patient’s point of view (in keeping with the guiding 0107 9. Post-treatment evaluations of difficulty talking principle and focus of this research, “patient-oriented clini and qualities of pain under the Supervision of the Study cal effects). Nurse at 1 hour and 2 hours Additional Compositions and Tests 0108 10. After these 2-hour evaluations: routine clinic procedures (e.g., Strep Test, Throat Culture, Mono Test). 0.130) 1. Ibuprofen 200 mg vs. placebo Treatment (e.g., topical/systemic analgesics, antibiotic) I0131 2. Ibuprofen 200 mg--loratadine 20 mg vs. ibuprofen initiated at physician’s discretion (e.g., after Throat Cul 200 mg ture results). After these procedures: discharge from clinic 0.132. 3. Ibuprofen 200 mg+hydroxyzine 50 mg vs. ibu with instructions how to use Home Diary. profen 200 mg US 2014/0275188A1 Sep. 18, 2014

0.133 4. Ibuprofen 200 mg--nizatidine 150 mg vs. ibupro 220 mg with loratadine 20 mg (naproxen/loratadine); or pla fen 200 mg cebo. There were 9 patients randomly assigned to each treat 0134) 5. Acetaminophen 500 mg vs. placebo ment group. 0135 6 Acetaminophen 500 mg+cetirizine 20 mg vs. 0145 Patients remained in the study center for a two-hour acetaminophen 500 mg observed treatment period to assess their responses to study 0.136 7. Celecoxib 200 mg vs. placebo medication during the initial 2-hour post-dose period. They were discharged home for hourly assessments up to 6 hours 0.137 8. Celecoxib 200 mg--cetirizine 20 mg vs. celecoxib post-dose. Patients were allowed alternative analgesic medi 200 mg cation at any time during the study. 0138 9. Naproxen sodium 220 mg vs. placebo 0146 The Throat Soreness Scale (TSS), Swollen Throat 0139 10. Naproxen sodium 220 mg+loratadine 20 mg vs. Scale (SwoTS), Difficulty Swallowing Scale (DSS), Diffi naproxen Sodium 220 mg culty Talking Scale (DTS), and other Quality-of-Pain Scales 0140 11. Each combination vs. placebo at individual time were completed at Baseline (immediately pre-treatment). points Each of these measurement instruments is a 0-10 ordinal 0141 12. Sensitivity appraisals and internal validation of scale (see TEST PROTOCOL below). measurements on the Quality-of Pain Index, the Throat 0.147. After administration of the assigned study medica Function Index, and the Definite Improvement Assessment tion, patients completed (1) the Throat Soreness Scale, (2) the by examining the comparison of ibuprofen 200 mg (the Swollen Throat Scale, (3) the Difficulty Swallowing Scale, positive control) with placebo. External validation of mea and (4) the Improvement Assessment (IA) every 15 minutes Surements by examining the comparison of ibuprofen 200 up to 2 hours. Measurements on the Difficulty Talking Scale mg (the positive control) with placebo and correlating and the Quality-of-Pain Scales were obtained after these four these measurements with those from the Throat Soreness assessments at 60 minutes and at 2 hours after treatment. Scale, a validated Scale. 10148. After these 2" hour assessments, patients were dis charged from the clinic with a Diary for entering responses on EXAMPLES the Throat Soreness Scale, Swollen Throat Scale, Difficulty Swallowing Scale. Difficulty Talking Scale, and Improve 0142. The following examples are put forth so as to pro ment Assessment at 3, 4, 5, and 6 hours. After the 6 hour vide those of ordinary skill in the art with a complete disclo assessments, patients completed the Quality-of-Pain Scales. Sure and description of how the compounds, compositions, 0149 Patients were seen at a Follow-Up Visit (usually the and methods described and claimed herein are made and next day). At this visit they were shown each baseline rating evaluated, and are intended to be purely exemplary and are scale and asked to indicate which level represented “definite not intended to limit the scope of what the inventor regards as improvement to them (Definite Improvement Level), the his invention. Efforts have been made to ensure accuracy with Diary was reviewed for completeness by the Study Nurse, and respect to numbers (e.g., amounts, temperature, etc.) but ongoing evaluation and treatment were provided, if neces some errors and deviations should be accounted for. Unless sary, per standard clinic procedures. indicated otherwise, parts are parts by weight, temperature is 0150. After all coded patient data were verified by double in C. or is at ambient temperature, and pressure is at or near entry, a statistician broke the randomization code and per atmospheric. There are numerous variations and combina formed Statistical analyses and tabulations. tions of reaction conditions, e.g., component concentrations, desired solvents, solvent mixtures, temperatures, pressures Test Protocol and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the 1. Study Procedures described process. Only reasonable and routine experimen tation will be required to optimize Such process conditions. Visit 1: Screening (Pre-Randomization Period) Study Design 0151. Prior to study entry the following screening proce dures will be performed: 0143 A randomized, double-blind, placebo-controlled 0152 Informed Consent single-dose study was performed. In order to be eligible for (O153 Medical History the study, patients were required to have a history of an acute 0154 Physical Examination including Tonsillo-Pharyngi sore throat and physical evidence of pharyngitis. A total of 99 tis Assessment, weight, height patients who met pre-specified inclusion and exclusion crite 0155 Vital Signs (oral temperature, pulse, respiratory ria, including moderate to severe throat pain intensity, as rate), blood pressure measured by a score-7 on the Throat Soreness Scale (TSS), 0156 Previous/Concomitant Medications were admitted to the study. 0144. Under double-blind conditions, each patient was Informed Consent randomly assigned one dose of ibuprofen 200 mg (ibupro fen); ibuprofen 200 mg with hydroxyzine 50 mg (ibuprofen/ 0157. Written informed consent must be obtained from hydroxyzine); ibuprofen 200 mg with loratadine 20 mg (ibu each patient prior to the conduct of any study specific proce profen/loratadine); ibuprofen 200 mg with nizatidine 150 mg dures. A copy of his/her signed consent form will be given to (ibuprofen/nizatidine); acetaminophen 500 mg (acetami each patient. nophen); acetaminophen 500 mg with ceterizine 20 mg (ac etaminophen/ceterizine); celecoxib 200 mg (celecoxib); Medical History celecoxib 200 mg with ceterizine 20 mg (celecoxib/ceteriz 0158 Each patient will provide a medical history includ ine); naproxen Sodium 220 mg (naproxen); naproxen Sodium ing date of birth, duration and assessment of pharyngitis, US 2014/0275188A1 Sep. 18, 2014

including other symptoms of upper respiratory tract illness, use while in the unit and will be instructed on their use by the significant past diseases/procedures and current conditions. Study Nurse in order to capture all patient assessments All results will be recorded on the appropriate CRFs. directly from the patient. (0171 The Study Nurse will review all data recorded by the Physical Examination patient. Data from the patient assessments will be transcribed 0159. Each patient will undergo a limited physical exami onto the appropriate Summary Data CRF pages. nation including height in inches, weight in pounds, evalua tion of general appearance, ears, eyes, nose, and lungs, and Study Medication Administration the Tonsillo-Pharyngitis Assessment. All results will be 0172. The Medication Nurse will administer separately recorded. the two (2) study medication capsules assigned to the patient. Each patient will be observed to swallow each capsule with a Vital Signs few swallows of water, so that approximately 240 ml of water 0160 Vital signs will be taken in the sitting position, is consumed. The time of study medication administration including oral temperature, heart rate, respiratory rate and and the patient’s study medication number will be recorded in blood pressure. Screening vital signs should be taken within the source document and on the appropriate CRF. the 60 minutes prior to administration of the dose of study (0173 “Nothing by mouth” except treatment will be medication. This information will be recorded. allowed for two hours while at the site following study drug administration (e.g. no Smoking, food, drink, candy, loZ Laboratory Tests enges, etc.). 0161 There are no laboratory tests other than a Urine Patient Observation Pregnancy Test on eligible female patients. If the patient is a female of childbearing potential, a Urine Pregnancy Test will 0.174 Patients will remain in the research unit for obser be performed, reviewed, and confirmed as negative prior to vation during the two hour observed treatment period post the patient’s enrollment in the study. Results of the pregnancy administration of the dose of study medication. test will be recorded on a Pregnancy Test Log and in the CRF. 0162. Upon completion of the first 2 hours of the study or Adverse Events later, at the Investigator's medical discretion, laboratory tests 0.175 Details of adverse events occurring at Baseline and for patients with pharyngitis (e.g., Abbott Quick 1-step Strep within 2 hours post administration of the first dose of study Test, throat culture, MonoSpot Test, CBC, etc.) may be per medication should be recorded in the source document and on formed according to standard medical procedures. appropriate CRFs. Previous/Concomitant Medications Concomitant Medications 0163 The use of previous medications within the previous 0176) No other medications are permitted during the study 7 days, including current (concomitant) medications, will be (unless the patient requests rescue medication). recorded at Screening on the appropriate CRF. Visit 1: 15 Minutes Up to 2 Hours Post-Dose (Treatment Visit 1: Baseline Period) 0164. During the Baseline portion of the visit, the follow 0177. During the period of 15 minutes up to 2 hours post ing procedures will be performed: administration of the dose of study medication (or just prior to receiving rescue medication), the following procedures will Patient Assessments be performed at 15, 30, 45, 60, 75,90, 105, and 120 minutes: 0.165. Throat Soreness Scale 0.178 Patient Observation (0166 Difficulty Swallowing Scale 0179 Throat Soreness Scale (0167 Swollen Throat Scale 0180. Difficulty Swallowing Scale (0168 Difficulty Talking Scale 0181 Swollen Throat Scale (0169 Quality-of-Pain Scales (10) 0182 Improvement Assessment 0183 Rescue Medication Study Medication Administration 0.184 Adverse Events Patient Observation Patient Observation Adverse Event Monitoring 0185. Patients will remain in the research unit for obser vation during the two hour observed treatment period post Concomitant Medication administration of the dose of study medication.

Patient Assessments Rescue Medication (0170 At the Baseline portion of Visit 1, patients will be 0186 The study site will supply one dose of rescue anal dispensed the patient assessment pages from the CRF (i.e., gesic medication, acetaminophen 650 mg, for each patient. pages containing the rating scales for throat Soreness, diffi 0187. The use of rescue analgesic medication should be culty Swallowing, Swollen throat, difficulty talking, etc.) for delayed for at least two hours following consumption of the US 2014/0275188A1 Sep. 18, 2014 first dose of study medication, if possible. Rescue analgesic first dose of study medication, if possible. Rescue analgesic medication will be permitted at any time, as the needs of the medication will be permitted at any time, as the needs of the patient dictate. patient dictate. 0188 The following details concerning rescue analgesia 0211 The following details concerning rescue analgesia will be collected: date and time taken, drug name and dose will be collected: date and time taken, drug name and dose regimen. Just prior to taking rescue medication, patients will regimen. Just prior to taking rescue medication, patients will provide responses to pain assessments. provide responses to pain assessments. 0189 Patients taking rescue medication will be required to 0212 Patients taking rescue medication will be required to complete all efficacy assessments through 24 hours but these complete all efficacy assessments through 24 hours but these ratings will not be transcribed onto the CRFs and will not be ratings will not be transcribed onto the CRFs and will not be analyzed. analyzed. 0190. Following dispensing or administration of rescue 0213 Following dispensing or administration of rescue medication, acetaminophen 650 mg. the Investigator will pro medication, acetaminophen 650 mg orally, the Investigator vide advice for additional relief medication according to stan will provide advice about additional relief medication dard medical care. Any additional relief medication will be according to standard medical care. Any additional relief Source documented and transcribed accordingly onto the con medication will be source documented and transcribed comitant medication CRF. accordingly onto the concomitant medication CRF. Adverse Events Adverse Events 0191) Details of adverse events occurring up to 2 hours 0214) Details of adverse events occurring at the end of the post administration of the study medication should be two hour observed treatment period or just prior to receiving recorded in the source document and on the appropriate rescue medication or withdrawal due to reasons other than CRFS. rescue medication will be recorded in the source documents and on the appropriate CRFs. Visit 1:1 and 2 Hours Post-Dose (Treatment Period) Concomitant Medications 0.192 After the patient assessments at 1 hour and at 2 hours (or just prior to receiving rescue medication), the following 0215. The use of concomitant medications during or at the procedures will also be performed: end of the two-hour observed treatment period (if the patient (0193 Difficulty Talking Scale has received rescue medication or if the patient has with (0194 Quality-of-Pain Scales (10) drawn due to reasons other than rescue medication) will be recorded on the appropriate CRFs. Visit 1:2 Hours Post-Dose or Withdrawal (Treatment Period) Collect Patient Assessment Pages 0.195 At the end of the in-clinic treatment period (at 2 hours, i.e.), or just prior to receiving rescue medication or 0216. The patient assessment pages of the CRF used dur withdrawal due to reasons other than rescue medication, the ing the patient's 2-hour evaluation in the unit will be collected following procedures will be performed: and reviewed by the Study Nurse while the patient is still at the site. Data from the patient assessments will be transcribed 0196. Vital Sign (oral temperature) onto the appropriate Summary Data CRF pages. 0197) Throat Soreness Scale (0198 Difficulty Swallowing Scale Dispense Diary (0199 Swollen Throat Scale 0217. The patient will be discharged from the unit with a 0200 Improvement Assessment Diary. The Study Nurse will instruct the patient how to use the 0201 Difficulty Talking Scale Diary on an hourly basis, filling out the following procedures (0202 Quality-of-Pain Scales (10) at 3, 4, 5, and 6 hours: 0203 Rescue Medication 0218. Throat Soreness Scale 0204 Adverse Events 0219 Swollen Throat Scale 0205 Concomitant Medication(s) 0220 Difficulty Swallowing Scale 0206 Collect Patient Assessment Pages 0221) Difficulty Talking Scale 0207 Dispense Diary 0222 Improvement Assessment. 0223) The Study Nurse will instruct the patient how to use Vital Sign the Diary by filling out the 10 Quality-of-Pain Scales after the 0208 Oral temperature will be recorded on the appropri other patient assessments are completed at 6 hours. ate CRF at the two-hour post-administration of study medi 0224. The patient will also be instructed to document any cation or within +/-5 minutes of receiving rescue medication use of rescue medication and any adverse events that may or withdrawal due to reasons other than rescue medication. OCCU 0225. The Study Nurse will also instruct the patient about Rescue Medication study conditions through 6 hours: 0226 Alcohol and caffeine-containing beverages may 0209. The study site will supply one dose of rescue anal not be consumed until after the 6-hour patient assess gesic medication, acetaminophen 650 mg, for each patient. mentS. 0210. The use of rescue analgesic medication should be 0227 Patients who use inhaled steroids or B-agonists on delayed for at least two hours following consumption of the an intermittent, as-needed basis and patients who use an US 2014/0275188A1 Sep. 18, 2014

antibiotic on a chronic basis (e.g., for acne) may use 2. Assessments them after the 6-hour study period. 0228 Patients will be allowed food and drink between Tonsillo-Pharyngitis Assessment (TPA) hours 2 and 6 only during the /2-hour after an hourly 0240. The Study Nurse will rate each patient for objective aSSeSSment. findings that confirm the diagnosis of tonsillo-pharyngitis at In other words: Patients must take nothing by mouth during screening. The seven variables below will be rated on semi the /2-hour period prior to each hourly assessment. quantitative scales with values of 0, 1, 2, 3. The values will be added together to make a Tonsillo-Pharyngitis Assessment Visit 2: Follow-Up Visit (TPA) that can range from 0 to 21 points. The patient must 0229. The patient will return to the study site for the Fol have a minimum of 5 points on the 21-point TPA of the low-up Visits5 days post administration of study medication physical examination to qualify for study inclusion: with his/her patient assessment diary. The following proce dures will be performed: O Points 1 Point 2 Points 3 Points 0230 Definite Improvement Level Oral Temperature s98.6F. 98.7-98.9°F. 99.0-99.9°F. s.100.0°F. 0231 Collect Diary Oropharyngeal Normal Slightly Red Red Beefy red 0232 Adverse Events color Pink 0233 Concomitant Medications Size of Tonsils Normal Slightly Moderately Much absent enlarged enlarged enlarged Number of None Few Several Many Definite Improvement Level oropharyngeal exanthems 0234 Patients will be dispensed the patient assessment (vesicles, petechiae, pages from the CRF (i.e., pages containing the Baselinerating or exudates) scales for throat Soreness, difficulty Swallowing, Swollen Largest size of Normal Slightly Moderately Much anterior cervical enlarged enlarged enlarged throat, difficulty talking, etc.) and will be instructed on their lymph nodes use by the Study Nurse in order to capture all patient assess Number of anterior Normal Slightly Moderately Greatly ments directly from the patient. cervical lymph increased increased Increased nodes 0235. The Study Nurse will review all data recorded by the Maximum Not Slightly Moderately Very patient. Data from the patient assessments will be transcribed tenderness of some tender tender tender tender onto the appropriate Summary Data CRF page. anterior cervical lymph nodes Collect Diary 0236. The patient assessment diary will be collected at the Results of the Tonsillo-Pharyngitis Assessment will be Final Visit. The Study Nurse will review the patient assess recorded on the appropriate CRF. ment diary while the patient is still at the site. Data from the patient assessments will be transcribed onto the appropriate Throat Soreness Scale (TSS) Summary Data CRF pages. 0241 The patient will be asked to evaluate his/her throat Soreness using a 0-to-10 ordinal scale at Baselineas well as at Adverse Events 15, 30, 45, 60, 75, 90, 105 and 120 min and then hourly through 6 hours. The patient will be requested to swallow and 0237. The patient assessment diary will be collected and instructed: reviewed and the patient will be queried about all adverse events experienced during the period between discharge from “Circle the number that shows how sore your throat is now the unit and the Follow-up Visit. All adverse events will be when you Swallow: recorded in the Source documents and on the appropriate CRFS. Very Sore 1 O Concomitant Medications 0238. The patient will be queried about all medication taken during the period between discharge from the unit and the Follow-up Visit. Information about any concomitant medications will be transcribed onto the appropriate CRFs. Patient Withdrawal 0239. A completed patient is one who completes all of the Not Sore 2-hour patient assessments. If for any reason a patient is withdrawn before completing the study or before Visit 2, the Data from this scale will be transcribed onto the appropriate reason for withdrawal must be entered on the End of Study Summary Data CRFs. Form and all appropriate CRFs must be completed. All final assessments should be performed as described for Visit 2 Difficulty Swallowing Scale, Swollen Throat Scale, (Follow-up Visit). Patients who terminate study participation Difficulty Talking Scale before Visit 2 due to an adverse event will be reported as 0242. The patient will be asked to evaluate his/her diffi withdrawing due to an “adverse event.” culty Swallowing (dysphagia), how Swollen the throat feels, US 2014/0275188A1 Sep. 18, 2014

and his/her difficulty speaking using separate 0-to-10 ordinal 0254 Data from the Definite Improvement Level for each scales at Baseline and at 15, 30, 45, 60, 75,90, 105, and 120 scale will be transcribed on the appropriate Summary Data minutes and at 3, 4, 5, and 6 hours post dose. The patient will CRF. be instructed to swallow and instructed: “Circle the number that best describes how your throat feels 3. Adverse Event OW.99 Definition of an Adverse Event 0255. An adverse event is any untoward medical occur NOT VERY rence in a clinical investigation patient administered a prod O 1 2 3 4 5 6 7 8 9 10 uct or medical device; the event need not necessarily have a causal relationship with the treatment or usage. Examples of adverse events include but are not limited to: Data from these scales will be transcribed onto the appropri 0256 Abnormal test findings; ate Summary Data CRFs. 0257 Clinically significant symptoms and signs: 0258 Changes in physical examination findings; Quality-of-Pain Scales for the Throat (0259 Hypersensitivity: 0243 The patient will be asked to evaluate 7 other sensory 0260 Progression/worsening of underlying disease. qualities of pain (hot, scratchy, raw, raspy, tight, dry, burning), Additionally, they may include the signs or symptoms result 2 affective qualities of pain (irritating, annoying), and another ing from: evaluative quality of pain (it hurts) using separate 0-to-10 0261 Drug overdose; ordinal scales at Baseline and at 1 hour, 2 hours, and 6 hours 0262 Drug withdrawal: post dose. The patient will be instructed to swallow and 0263 Drug abuse: instructed: 0264 Drug misuse: “For each word, circle the number that best describes how 0265 Drug interactions: your throat feels now.” 0266 Drug dependency; 0267 Extravasation: 0268 Exposure in utero. NOT VERY

O 1 2 3 4. 5 6 7 8 9 10 Abnormal Test Findings 0269. The criteria for determining whether an abnormal objective test finding should be reported as an adverse event Data from these scales will be transcribed onto the appropri are as follows: ate Summary Data CRFs. 0270 Test result is associated with accompanying Improvement Assessment symptoms, and/or 0271 Test result requires additional diagnostic testing 0244. The patient will grade the improvement of his/her or medical/surgical intervention, and/or throat at 15, 30, 45, 60, 75,90, 105, and 120 minutes, and at 0272 Test result leads to a change in study dosing or 3, 4, 5, and 6 hours post dose using a 5-category transitional discontinuation from the study, significant additional scale. The patient will be instructed: concomitant drug treatment, or other therapy, and/or “Considering how your throat felt before you took the study 0273 Test result is considered to be an adverse event by medicine, circle the response that best describes how your the Investigator or sponsor. throat is now.” 0274 Merely repeating an abnormal test, in the absence of 0245 Grading any of the above conditions, does not constitute an adverse 0246 no improvement event. Any abnormal test result that is determined to be an 0247 some improvement error does not require reporting as an adverse event. 0248 50% improvement 0249 definite improvement Serious Adverse Events (0250 100% improvement 0275 A serious adverse event or serious adverse drug Data from this scale will be transcribed onto the appropriate reaction is any untoward medical occurrence at any dose that: Summary Data CRFs. 0276 Results in death: 0277 Is life-threatening (immediate risk of death); Definite Improvement Level (DIL) 0278 Requires inpatient hospitalization; 0251. After the patient is shown his/her completed Base 0279 Results in persistent or significant disability/inca line Throat Soreness Scale, the Study Nurse will point to the pacity; number which the patient marked at Baseline and instruct the 0280 Results in congenital anomaly/birth defect. patient: 0252 “Starting at this level with your sore throat, at and 4. Data Display and Analysis/Statistical Methods below which number means definite improvement to you?” 0253) Next, the Study Nurse will separately show the 4.1. Populations of Analysis patient his/her Baseline Difficulty Swallowing Scale, Swol Safety Population: len Throat Scale. Difficulty Talking Scale, and each of the 10 Quality-of-Pain Scales, with the same instructions for each 0281 A patient will be included in the Safety Population if scale. the patient was randomized and Swallowed the full dose of US 2014/0275188A1 Sep. 18, 2014 study medication. The Safety Population will be used for the Alternate methods of display and analysis may be used when safety analysis. Patients in this population will be assigned to appropriate (including Sub-analyses based on cogent clinical the treatment group corresponding to the treatment they features Such as relatively high baseline throat Soreness, dif received during the study. ficulty Swallowing, Swollen throat). Efficacy Population: Analysis/Display of Secondary Endpoints 0282 Patients who are randomized to treatment, have received the full dose of study medication and have com Secondary Endpoint Variables: pleted all post-treatment assessments for a particular efficacy 0290 a. Difference in Quality-of-Pain Index* over 6 hours variable will form the efficacy population for that variable. b. Difference in Throat Function Index over 6 hours The efficacy population will be used for analysis of primary c. Difference in difficulty swallowing over 6 hours and secondary endpoints. d. Difference in throat swelling over 6 hours Demographics and Baseline Characteristics: e. Difference in relatively severe (baseline-7) qualities of pain over 6 hours 0283 Demographic and Baseline characteristics will be f. Difference in relatively severe sensory qualities of pain over Summarized using descriptive statistics, including the num 6 hours ber of patients in each treatment group, mean, standard devia g. Difference in the most severe quality(ies) of pain over tion, median and range for continuous variables; frequency 6 hours and percent for categorical variables; etc. h. Difference in relatively severe difficulty swallowing at 6 Sample Size Determination hours i. Difference in relatively severe difficulty talking at 6 hours 0284. The sample size (9 patients per treatment group) is j. Differences in difficulty swallowing at individual time considered sufficient for proof-of-concept research. Statisti points cal analyses will be performed when feasible, but it is not k. Differences in throat soreness at individual time points anticipated that there will be sizable treatment differences for 1. Differences in throat swelling at individual time points statistical comparisons between treatment groups. m. Percentage of patients with definite improvement over 6 4.3. Randomization hours n. Total improvement over 6 hours 0285 Patients who qualify will be assigned at the site in o. Improvement at individual time points the order in which they are enrolled in the study. They will 0291 For each treatment group, results for improvement receive their allocated treatment according to a computer and differences from baseline will be reported and displayed generated randomization schedule prepared prior to the start for individual patients and as medians, percentage differ of the study. ences, etc. Alternate methods of display and analysis will be Efficacy Analysis examined, including Sub-analyses based on cogent clinical features (such as relatively high baseline difficulty swallow 0286 Efficacy data that can be analyzed will be analyzed ing, throat Soreness, Swollen throat) and based on the phar using the Efficacy Population. All comparisons will be one macologic time-effect curves of the drugs being tested (i.e., sided at an alpha level of 0.05 and all point estimates will be onset time within the first 2 hours after drug administration). accompanied by 95% confidence intervals. *Throat soreness (an evaluative quality of pain), throat swell ing (a sensory quality of pain), and the other 10 qualities of Analysis/Display of Primary Endpoints throat pain comprise the 120-point Quality-of-Pain Index. **Difficulty Swallowing and Difficulty Talking comprise the Primary Endpoint Variable: 20-point Throat Function Index. 0287. Difference in throat soreness over 6 hours ***The most severe quality of pain has the highest baseline 0288 The primary endpoint variable is the Summed Dif score. Qualities that have the same highest baseline score ference in Throat Soreness at 6 hours, which is based on the (ties) may also be examined. The “most severe qualities' will Throat Soreness Scale. The patient will be asked to evaluate be analyzed separately and as a group since these kinds of his/her throat Soreness, using a 0-to-10 ordinal scale at base discomfort represent the most bothersome from the patients line and at 15, 30, 45, 60, 75,90, 105 minutes and 2, 3, 4, 5, point of view—in keeping with the guiding principle and and 6 hours. At each time point post-dose, a difference is focus of this research, “patient-oriented clinical effects. calculated between the throat Soreness at that time and the patient’s baseline throat soreness. The time-weighted 4.4.3. Comparisons of Interest Summed Difference in Throat Soreness at each time point is calculated as the sum of the differences from baseline until 0292 1. Ibuprofen 200 mg+hydroxyzine 50 mg vs. ibu that time point. profen 200 mg (analgesic potentiation by hydroxyzin) 0289. The Summed Difference in Throat Soreness at 6 0293 2. Ibuprofen 200 mg--loratadine 20 mg vs. ibuprofen hours will be displayed and analyzed by comparing treatment 200 mg (analgesic potentiation by loratadine) groups (e.g., ibuprofen 200 mg with hydroxy Zine 50 mg to 0294 3. Acetaminophen 500 mg--ceterizine 20 mg vs. ibuprofen 200 mg) using a general linear model with treat acetaminophen 500 mg (analgesic potentiation by ceteriz ment and baseline Throat Soreness as fixed effects. The dif ine) ference and 95% confidence interval for the difference of 0295 4. Celecoxib 200 mg+ceterizine 20 mg vs. celecoxib treatment effects will be calculated using least squares means. 200 mg (analgesic potentiation by ceterizine) US 2014/0275188A1 Sep. 18, 2014 13

0296 5. Naproxen sodium 220 mg+loratadine 20 mg vs. Sons (between each active drug and placebo, between each naproxen Sodium 220 mg (analgesic potentiation by lora antihistaminefanalgesic and placebo, between each antihista tadine) minefanalgesic and the corresponding single analgesic) were 0297 6. Ibuprofen 200 mg+nizatadine 150 mg vs. ibupro performed using the Wilcoxon Rank Sum Test. Definite fen 200 mg (analgesic potentiation by nizatidine) Improvement Level comparisons were performed using Fish 0298 7. Ibuprofen 200 mg vs. placebo (efficacy of ibupro er's Exact Test. Correlations between each new rating scale fen 200 mg, assay sensitivity, validation of rating scales) and the TSS were performed using Spearman Rank Correla 0299 8. Naproxen sodium 220 mg vs. placebo (efficacy of tion. naproxen Sodium 220 mg, assay sensitivity, validation of rating scales) Efficacy Variables 0300 9. Acetaminophen 500 mg vs. placebo (efficacy of 0311. To identify the efficacy of each antihistamine/anal acetaminophen 500 mg, assay sensitivity, validation of gesic combination compared to a single-ingredient analgesic rating scales) and to validate and determine the sensitivity of each new 0301 10. Celecoxib 200 mg vs. placebo (efficacy of cele measurement instrument, results over the 6-hour observation coxib 200 mg, assay sensitivity, validation of rating scales) period are presented separately for the standard measurement 0302) 11. Each combination vs. placebo at individual time instrument, the Throat Soreness Scale, and for each new points (onset of action, peak effect, duration of action) method. 0303) 12. Same antihistamine when combined with differ ent analgesics (differential effects of same dose of antihis A. Throat Soreness Scale (TSS) tamine with different analgesics) 0304 13. Comparisons of single-ingredient analgesics 0312. As seen in FIG. 1, all “positive control drugs” (i.e., the standard drugs ibuprofen, acetaminophen, celecoxib, (relative onset, peak, duration and overall analgesia) naproxen) were differentiated from placebo. Acetaminophen 0305 14. Comparisons of the pooled combination treat and celecoxib demonstrated significantly greater reduction in ment arms to each single analgesic. throat soreness compared to placebo over 6 hours (both p-0. 05), with a trend (p=0.10) for ibuprofen compared to placebo. 4.4.4. Other Endpoints All antihistaminefanalgesic combinations also differed from 0306 Sensitivity appraisals and internal validation of placebo. measurements on the 12 quality-of-pain rating scales, the 2 0313 As seen in FIG. 2, the comparison of ibuprofen/ throat function scales, and the improvement assessment by loratadine to ibuprofen revealed an 11% difference in the examining the comparison of ibuprofen 200 mg, the positive median total reduction of TSS over 6 hours. The comparison control, with placebo (and confirming assay sensitivity by of ibuprofen/hydroxyzine to ibuprofen revealed a 22% differ examining the comparisons of each active drug naproxen ence in TSS reduction over 6 hours. The comparison of ibu sodium 220 mg, acetaminophen 500 mg, celecoxib 200 profen/nizatidine to ibuprofen revealed a 73% difference in mg with placebo). TSS reduction over 6 hours (p=0.05). 0307 External validation of measurements on the quality 0314. There was no evidence of enhanced overall analge of-pain rating scales, the throat function scales, and the sic effect on the TSS for the comparison of acetaminophen/ improvement assessment by examining the comparison of ceterizine to acetaminophen alone, for the comparison of ibuprofen 200 mg with placebo on these scales and correlat celecoxib/ceterizine to celecoxib alone, or for the comparison ing these measurements with those from the throat Soreness of naproxen/loratadine to naproxen alone. scale, a validated scale (the “Lasagna Pain Scale'). Confir 0315 All active single- and combination-ingredient drugs matory assessments will also be conducted by examining the also demonstrated greater analgesic efficacy compared with comparisons of each other active drug naproxen Sodium placebo in terms of throat soreness difference at individual 220 mg, acetaminophen 500 mg, celecoxib 200 mg with time points, showing pharmacodynamic curves typical of placebo and correlating these measurements with those from analgesic drugs. Acetaminophen separated from placebo the throat Soreness scale. from 15 minutes through 6 hours; ibuprofen separated from placebo from 30 minutes through 6 hours (FIG. 3), as did Results of Study naproxen and celecoxib. There were no apparent differences 0308. A total of 99 patients were enrolled in the study. between any of the single-ingredient analgesics. Nine patients were randomly assigned to each of the 11 treat 0316 TSS scores showed differences from placebo for ment groups. All patients had physical evidence of tonsillo ibuprofen/loratadine beginning at 15 minutes; for ibuprofen/ pharyngitis and moderately severe sore throat at baseline nizatidine and for celecoxib/ceterizine beginning at 30 min (median TSS-7). Baseline demographic and clinical charac utes; and for ibuprofen/hydroxy Zine beginning at 45 minutes. teristics were similar across all treatment groups. 0317. In summary, evidence of analgesic potentiation was 0309 Among the 99 patients studied, 8 (8%) had docu detected on the TSS in three comparisons: mented infection with Group A, beta-hemolytic Streptococ 0318 1. ibuprofen/hydroxyzine vs. ibuprofen, identifying cus (“Strep throat’) and 4 (4%) had documented infectious analgesic potentiation by hydroxyZine; mono-nucleosis (“Mono) and received appropriate antibi 0319 2. ibuprofen/loratadine vs. ibuprofen, identifying otic treatment at study conclusion. analgesic potentiation by loratadine when combined with 0310 Analyses were performed on all 99 patients (“intent ibuprofen; and to-treat analyses'). There were 14 patients who used addi 0320 3. ibuprofen/nizatidine vs. ibuprofen, identifying tional analgesic treatment during the 6-hour observation analgesic potentiation by nizatidine. period; for each Subsequent evaluation for these patients, the 0321. The most pronounced effects were noted when ibu “last observation (was) carried forward.” Statistical compari profen was combined with the H-antagonist, nizatidine, US 2014/0275188A1 Sep. 18, 2014 greater than ibuprofen alone (perhaps because of the faster 0330 Analyses of total improvement over 6 hours identi bioavailability of nizatidine powder delivered from a capsule, fied 27% difference between ibuprofen/loratadine and ibu compared to the bioavailability of ibuprofen delivered from a profen, 18% difference between ibuprofen/hydroxyzine and coated compressed tablet). ibuprofen, and 36% difference between ibuprofen/nizatidine 0322 Ceterizine showed some enhancement of the onset and ibuprofen. of analgesic action by celecoxib, Suggesting that an 0331. There was no evidence of enhanced overall analge adequately sized onset-of-action study might discern this sic effect on the IA for comparisons of acetaminophen/ceter contribution to pharmacodynamic activity. Overall, however, izine to acetaminophen alone, of celecoxib/ceterizine to cele there was no evidence on the TSS of analgesic potentiation by coxib alone, or of naproxen/loratadine to naproxen alone. ceterizine when combined with acetaminophen or celecoxib. 0332 All active single- and combination-ingredient drugs And, while loratadine does augment ibuprofen's analgesia as also demonstrated greater improvement than placebo at indi measured on the TSS, at this stage in our research it appears vidual time points, showing pharmacodynamic curves typical that loratadine provides no detectable analgesic potentiation of analgesic drugs. The IA curves for acetaminophen and when combined with naproxen Sodium (Suggesting that the ibuprofen separated from placebo from 30 minutes through 6 naproxen Sodium salt, unlike ibuprofen, may interfere with hours; celecoxib and naproxen from 45 minutes through 6 loratadine activity). hours. There were no apparent differences between any of the single-ingredient analgesics. B. Improvement Assessment (IA) 0333 IA scores showed differences from placebo for acetaminophen/ceterizine and ibuprofen/nizatidine begin 0323 Measurements on the Improvement Assessment ning at 30 minutes; for ibuprofen/loratadine, ibuprofen/hy (IA) revealed differences between the active control drugs droxyzine, and celecoxib/ceterizine beginning at 45 minutes; (ibuprofen, acetaminophen, celecoxib, naproxen) and pla and for naproxen/loratadine beginning at 60 minutes. cebo over 6 hours as well as between each antihistamine? 0334. In sum, evidence of analgesic potentiation was analgesic and placebo. detected on the IA in the comparisons of ibuprofen/loratadine 0324. In fact,979 patients who received acetaminophen or vs. ibuprofen, of ibuprofen/hydroxyzine vs. ibuprofen, and, ibuprofenachieved at least some improvement within 1 hour, in particular, of ibuprofen/nizatidine vs. ibuprofen. as did 779 patients who received celecoxib or naproxen, com pared with 4/9 patients who received placebo. Similarly, 9/9 C. Definite Improvement Level (DIL) patients who received ibuprofen/nizatidine, 8/9 patients who received acetaminophen/ceterizine or ibuprofen/hydrox 0335. According to the criterion of achieving the Definite yzine, 779 patients who received ibuprofen/loratadine, and Improvement Level particular for each rating scale, use of the DIL revealed differences between the active control drugs 6/9 patients who received naproxen/loratadine achieved at (ibuprofen, acetaminophen, celecoxib, naproxen) and pla least some improvement within 1 hour. cebo. 0325 Interms of onset of action, 8/9 patients who received 0336. As shown in a representative use of the DIL, for TSS acetaminophen achieved at least some improvement within scores (FIG. 4), 11.1% (1/9) of patients who received placebo 30 minutes, as did 6/9 patients who received ibuprofen, 4/9 achieved their own Definite Improvement Level on the TSS, patients who received naproxen, and 3/9 patients who compared to 44.4% of the patients who received acetami received celecoxib, compared with 1/9 of patients who nophen or ibuprofen, 77.7% of patients who received cele received placebo. coxib (p<0.01), 22.2% of patients who received naproxen. 0326. There was similar direct evidence of onset by the 0337 Similar differentiation of active drugs from placebo antihistaminefanalgesic combinations detected on the IA: 6/9 was detected on the DIL for other rating scales. For example: patients who received ibuprofen/nizatidine, 579 patients who (1) 11.1% (1/9) of patients who received placebo achieved received acetaminophen/ceterizine, 479 patients who their own Definite Improvement Level on the Difficulty Swal received ibuprofen/loratadine or celecoxib/ceterizine, and lowing Scale, compared to 55.6% of patients who received 3/9 patients who received ibuprofen/hydroxyzine or acetaminophen, 44.4% of patients who received ibuprofen, naproxen/loratadine achieved at least Some improvement 66.7% of patients who received celecoxib (p=0.05), 33.3% of over the first 30 minutes, compared with 1/9 of patients who patients who received naproxen; received placebo. (2) 22.2% (2/9) of patients who received placebo achieved 0327. Although no differences between combination and their own Definite Improvement Level on the Swollen Throat single-ingredient analgesics were detected, this method of Scale, compared to 66.7% of patients who received acetami examining the IA over the initial 30 minutes after drug admin nophen, 44.4% of patients who received ibuprofen, 77.8% of istration was very sensitive to the identification of onset of the patients who received celecoxib (p=0.06), 44.4% of drug action. patients who received naproxen; 0328. Over the 6-hour treatment period, 779 patients who (3) 11.1% (1/9) of patients who received placebo achieved received acetaminophen and 8/9 patients who received cele their own Definite Improvement Level on the “It hurts' Qual coxib achieved at least 50% improvement, as did 4/9 patients ity-of-Pain Scale, compared to 55.6% of patients who who received ibuprofen or naproxen, compared with 2/9 received acetaminophen or celecoxib, 33.3% of patients who patients who received placebo. received ibuprofen or naproxen; 0329. Similarly, 8/9 patients who received ibuprofen/niza (4) 22.2% (2/9) of patients who received placebo achieved tidine, 779 patients who received ibuprofen/hydroxyzine, 5/9 their own Definite Improvement Level on the 'Annoying patients who received ibuprofen/loratadine or celecoxib/cet Quality-of-Pain Scale, compared to 66.7% of patients who erizine, and 4/9 patients who received naproxen/loratadine received acetaminophen, 33.3% of the patients who received achieved at least 50% improvement over 6 hours, compared ibuprofen or naproxen, 55.6% of the patients who received with 2/9 patients who received placebo. celecoxib. US 2014/0275188A1 Sep. 18, 2014

0338. With distinct differentiations of active drugs and E. Difficulty Talking Scale (DTS) antihistaminefanalgesic combinations from placebo, the 0350 All four positive control drugs demonstrated greater Definite Improvement Level system was thus validated as a reduction in difficulty talking compared with placebo over 6 measurement instrument. Using the DIL measure, differ hours (FIG. 6). The differences between acetaminophen com ences were clearly seen between antihistaminefanalgesic pared to placebo and between celecoxib compared to placebo combinations and placebo on different rating scales. How were significant on the DTS (both p-0.05). This differentia ever, the DIL did not differentiate antihistamine/analgesic tion of known active analgesic drugs from placebo serves as a combinations from single analgesics perhaps because, as a source of internal validation of the DTS, which correlated nominal scale (i.e., definite improvement, no definite with ratings on the TSS (r=0.54, p<0.0001). improvement), the DIL identifies the presence (or absence) of 0351 All antihistamine/analgesic combinations also dif drug activity, not differences between degrees of response. fered from placebo on the DTS. D. Difficulty Swallowing Scale (DSS) 0352. The comparison of ibuprofen/loratadine to ibupro fen revealed 80% difference in the total reduction of DTS 0339 Acetaminophen, ibuprofen, and celecoxib demon over 6 hours (FIG. 7). The comparison of ibuprofen/hydrox strated greater reduction in difficulty Swallowing compared yzine to ibuprofen revealed 40% difference in DTS reduction with placebo over 6 hours. There was a significant difference over 6 hours. The comparison of ibuprofen/nizatidine to ibu between acetaminophen and placebo on the DSS (p=0.01). profen revealed 120% difference in DTS reduction over 6 This differentiation of known active analgesic drugs from hours. placebo serves as a source of internal validation of the DSS. 0353. There was no evidence of enhanced overall analge Indeed, ratings on the DSS correlated with ratings on the TSS sic effect on the DTS for the comparison of acetaminophen/ (r=0.80, p<0.0001). ceterizine to acetaminophen, the comparison of celecoxib/ 0340 Ibuprofen/loratadine, ibuprofen/hydroxyzine, ibu ceterizine to celecoxib, or the comparison of naproxen/ profen/nizatidine, and celecoxib/ceterizine also differed from loratadine to naproxen. placebo on this measurement. 0354 All single- and combination-ingredient drugs also 0341. As seen in FIG. 5, the comparison of ibuprofen/ demonstrated greater analgesic efficacy compared with pla loratadine to ibuprofen revealed an 18% difference in the total cebo in terms of a difference in difficulty talking at individual reduction of DSS over 6 hours. The comparison of ibuprofen/ time points, showing pharmacodynamic curves typical of hydroxyzine to ibuprofen revealed a 55% difference in DSS analgesic drugs. reduction over 6 hours. The comparison of ibuprofen/nizati 0355 Because patients were admitted to the study regard dine to ibuprofen revealed a 78% difference in DSS reduction less of the severity of their pre-treatment DTS (which ranged over 6 hours. from 0 to 10, i.e., not -7, as required for the TSS), these 0342. There was no evidence of enhanced overall analge findings represent underestimates of treatment effects mea sic effect on the DSS for the comparisons of acetaminophen/ sured on the DTS. Nevertheless, the extremely low placebo ceterizine to acetaminophen, of celecoxib/ceterizine to cele response when patients used the DTS is noteworthy. coxib, or of naproxen/loratadine to naproxen. 0343 All single- and combination-ingredient drugs also 0356. In sum, evidence of analgesic potentiation was demonstrated greater analgesic efficacy compared with pla detected on the functional DTS in four comparisons: cebo in terms of a difference in difficulty swallowing at indi 0357 1. ibuprofen/hydroxyzine vs. ibuprofen, identifying vidual time points, showing pharmacodynamic curves typical analgesic potentiation by hydroxyZine; of analgesic drugs. 0358 2. ibuprofen/loratadine vs. ibuprofen, identifying 0344. It should be noted that, because patients were admit analgesic potentiation by loratadine when combined with ted to the study regardless of the severity of their pre-treat ibuprofen; and ment difficulty swallowing, which ranged from 0 to 10 (i.e., 0359. 3. ibuprofen/nizatidine vs. ibuprofen, identifying all patients baseline DSS scores were not a7, as required for analgesic potentiation by nizatidine. the TSS), these findings represent underestimates of treat 0360. There was no evidence of analgesic potentiation by ment effects detected on the Difficulty Swallowing Scale. ceterizine when combined with acetaminophen or celecoxib. 0345. In sum, evidence of analgesic potentiation was As on other scales, while loratadine does augment ibupro detected on the functional DSS in three comparisons: fen's analgesia as measured on the DTS, it appears that lora 0346 1. ibuprofen/hydroxyzine vs. ibuprofen, identifying tadine provides no detectable analgesic potentiation when analgesic potentiation by hydroxyzine; combined with naproxen Sodium. 0347 2, ibuprofen/loratadine vs. ibuprofen, identifying analgesic potentiation by loratadine when combined with F. Throat Function Index (TFI) ibuprofen; and 0361 Acetaminophen and celecoxib demonstrated sig 0348 3. ibuprofen/nizatidine vs. ibuprofen, identifying nificantly greater reduction in the TFI (a summary index of analgesic potentiation by nizatidine. the two throat functions, Swallowing and talking) compared 0349 The most pronounced effects were noted when ibu with placebo over 6 hours (both ps0.01). This clear differen profen was combined with nizatidine, greater than ibuprofen tiation of known active analgesic drugs from placebo serves alone. There was no evidence of analgesic potentiation by as a source of internal validation of the TFI. Ratings on the ceterizine when combined with acetaminophen or celecoxib. TFI correlated with ratings on the TSS (r—0.76, p<0.0001). Finally, while loratadine does augment ibuprofen's analgesia 0362. With the exception of the comparison of acetami as measured on the DSS, it appears that loratadine provides nophen/ceterizine to placebo, all antihistaminefanalgesic no detectable analgesic potentiation when combined with combinations differed from placebo on the TFI, too. naproxen Sodium (perhaps because the naproxen Sodium salt 0363 The comparison of ibuprofen/loratadine to ibupro interferes with loratadine activity). fen and of ibuprofen/hydroxyzine to ibuprofen revealed US 2014/0275188A1 Sep. 18, 2014

100% differences in the total reduction of TFI over 6 hours. 0375. In sum, evidence of analgesic potentiation was The comparison of ibuprofen/nizatidine to ibuprofen detected on the SwoTS in three comparisons: revealed 142% difference in TFI reduction over 6 hours. 0376 1. ibuprofen/hydroxyzine vs. ibuprofen, identifying There was no evidence of enhanced overall analgesic effect analgesic potentiation by hydroxyZine; on the TFI for the comparisons of acetaminophen/ceterizine or celecoxib/ceterizine to the single analgesic or the compari 0377 2. ibuprofen/loratadine vs. ibuprofen, identifying Son of naproxen/loratadine to naproxen. analgesic potentiation by loratadine when combined with 0364 All single- and combination-ingredient drugs also ibuprofen; and demonstrated greater analgesic efficacy compared with pla 0378. 3. ibuprofen/nizatidine vs. ibuprofen, identifying cebo in terms of a difference in throat function at individual analgesic potentiation by nizatidine. time points, showing pharmacodynamic curves typical of 0379 There was no evidence of analgesic potentiation by analgesic drugs. ceterizine when combined with acetaminophen or celecoxib 0365 However, because patients were admitted to the or by loratadine when combined with naproxen Sodium. study regardless of the severity of their pre-treatment TFI (which ranged from 4 to 20), these findings represent under G. Quality of Pain Index (QPI) estimates of treatment effects measured on the TFI. 0366. In sum, evidence of analgesic potentiation was 0380. There was greater reduction in the QPI (a summary detected on the TFI in three comparisons: index of 12 sensory, affective, and evaluative qualities of 0367. 1. ibuprofen/hydroxyzine vs. ibuprofen, identifying throat pain) by single analgesics compared with placebo over analgesic potentiation by hydroxyzine; 6 hours. Acetaminophen and celecoxib were significantly 0368 2. ibuprofen/loratadine vs. ibuprofen, identifying differentiated from placebo on the QPI (both ps0.05). This analgesic potentiation by loratadine when combined with differentiation of known active analgesic drugs from placebo ibuprofen; and serves as a source of internal validation of the QPI. All anti 0369. 3. ibuprofen/nizatidine vs. ibuprofen, identifying histaminefanalgesic combinations differed from placebo, too, analgesic potentiation by nizatidine. further validating the QPI. Ratings on the QPI correlated with 0370. There was no evidence of analgesic potentiation by TSS ratings (r=0.82, p<0.0001). ceterizine when combined with acetaminophen or celecoxib 0381. The comparison of ibuprofen/loratadine to ibupro or when loratadine was combined with naproxen Sodium. fen revealed 250% difference in the reduction of qualities of throat pain over 6 hours (FIG. 10). The comparison of ibu G. Swollen Throat Scale (SwoTS) profen/hydroxyzine to ibuprofen revealed 130% difference in the reduction of qualities of throat pain over 6 hours. The 0371 All four positive control drugs demonstrated greater comparison of ibuprofen/nizatidine to ibuprofen revealed reduction in throat swelling compared with placebo over 6 3.10% difference in the reduction of qualities of throat pain hours. Acetaminophen and celecoxib were shown to be sig over 6 hours (p=0.10). There was no evidence of enhanced nificantly differentiated from placebo on this scale (both ps0. overall analgesic effect on the QPI for the comparisons of 05). This differentiation of known active analgesic drugs acetaminophen/ceterizine, celecoxib/ceterizine, or naproxen/ from placebo serves as a source of internal validation of the loratadine to each single analgesic. SwoTS. Ratings on the SwoTS correlated with ratings on the 0382 Because patients were admitted to the study regard TSS (r=0.74, p<0.0001). less of the pre-treatment the severity of each of the 12 quali 0372 With the exception of the comparison of naproxen/ ties of throat pain (which ranged from 0 to 10, i.e., not-7, as loratadine to placebo, all antihistaminefanalgesic combina required for the TSS at baseline), these findings represent tions differed from placebo. As seen in FIG.8, the comparison of ibuprofen/loratadine to ibuprofen revealed 56% difference underestimates of treatment effects measured on the QPI. in the reduction of throat swelling over 6 hours, the compari 0383 Though we have not examined the responses on son of ibuprofen/hydroxyzine to ibuprofen a 36% difference, every quality-of-pain scale, we did notice responses on one and the comparison of ibuprofen/nizatidine to ibuprofen a scale that highlight the theme of this application (i.e., the 90% difference in the reduction of throat swelling over 6 sensitivity and utility of patient-oriented Scales): patients hours. ratings on the annoying quality-of-pain scale (FIG. 11) iden 0373 There was no evidence of enhanced overall analge tified clear differences between active drugs and placebo, thus sic effect on the SwoTS for the comparisons of acetami validating the scale itself. nophen/ceterizine, celecoxibfceterizine, or naproxen/lorata 0384. In sum, evidence of analgesic potentiation was dine to each single analgesic. With the exception of naproxen/ detected on the QPI in three comparisons: loratadine, all single- and combination-ingredient drugs also 0385 1. ibuprofen/loratadine vs. ibuprofen, identifying demonstrated greater reduction in throat Swelling compared analgesic potentiation by loratadine when combined with to placebo at individual time points with pharmacodynamic ibuprofen; curves typical of analgesic drugs, as shown for ibuprofen 0386 2. ibuprofen/hydroxyzine vs. ibuprofen, identifying compared with placebo in FIG. 9. analgesic potentiation by hydroxyZine; and 0374 Because patients were admitted to the study regard less of the severity of their pre-treatment SwoTS (which 0387 3. ibuprofen/nizatidine vs. ibuprofen, identifying ranged from 0 to 10, i.e., not -7, as required for the TSS at analgesic potentiation by nizatidine. baseline), these findings represent underestimates of treat 0388. As on other scales, there was no evidence of anal ment effects measured on the SwoTS. Given this range of low gesic potentiation by ceterizine when combined with baseline values, it is noteworthy that analgesic activity was acetaminophen or celecoxib or by loratadine when combined detected on the SwoTS even at early time points. with naproxen Sodium. US 2014/0275188A1 Sep. 18, 2014

H. Most Bothersome Qualities of Pain (MBQs) ments (e.g., Difficulty Swallowing Scale. Difficulty Talking Scale, Throat Function Index, Swollen Throat Scale, Quali 0389 Analyses based on the qualities of pain that were ties of Pain Index) described herein indicated that hydrox most bothersome to the patient (i.e., the highestrated sensory, yZine, loratadine, and nizatidine enhance the analgesic prop affective, or evaluative quality of throat pain for each patient erties of ibuprofen. Wide differences (ranging from 20% to at baseline) have not been performed. over 100%) were detected between ibuprofen/loratadine and ibuprofen, between ibuprofen/hydroxyzine and ibuprofen, J. Types of Throat Pain (Heat, Dryness, Soreness, Emotional, and between ibuprofen/nizatadine and ibuprofen, evidence Function, Size) that was replicated consistently. 0390 Examination of the patients ratings on each scale 0397. It is noteworthy, too, that the effects of the H-an delineated six specific types of throat pain: tagonist (hydroxyzine) and of the H-antagonist (nizatidine) appeared to provide not only greater analgesia but indications of a more prolonged duration of effect. Heat: hot, burning “Hot throat Dryness: dry, raw, Scratchy, tight, raspy “Dry throat 0398. The most striking (and surprising) effect was noted Soreness: Sore, hurts “Sore throat in the comparison of ibuprofen with nizatidine to ibuprofen Emotional: annoying, irritating Annoying throat” alone, a large difference that is attributable perhaps to the Function: difficulty Swallowing, difficulty “Can't Swallow?talk faster bioavailability of nizatidine powder in a capsule, com talking pared to the slower bioavailability of ibuprofen in a coated Size: Swollen “Swollen throat and compressed tablet. (Thus, one possible administration schedule involves the pre-administration of an antihistamine 0391. It was observed that patients reported some clusters to assure analgesic potentiation.) The wide differentiation of of symptoms as more severe than others: for some patients ibuprofen 200 mg/nizatadine 150 mg from ibuprofen 200 mg “heat was a predominant symptom complex, for others Suggests, too, that this combination may confer the same or "Soreness, etc. Analyses have not been performed comparing greater extent of analgesia as a 400-mg dose of ibuprofen treatment responses among patients within each specific clus (thus avoiding potential side effects associated with high ter (e.g., patients with a “dry throat” or a “swollen throat’). dosages of NSAIDs), an example of “optimal analgesia' in the antihistaminefanalgesic combination. K. Safety and Tolerability 0399. This study also had some negative findings. For 0392 There were no serious adverse events or discontinu example, there was no evidence that ceterizine potentiates ations due to an adverse event. analgesia when combined with acetaminophen or celecoxib. There was the Suggestion, however, that ceterizine may has ten the onset of action of celecoxib: an adequately sized CONCLUSIONS onset-of-action study might discern this feature of analgesic 0393 As measured on the primary rating scale (TSS), the potentiation by ceterizine and other antihistamines.) positive control drugs acetaminophen, ibuprofen, celecoxib, Although loratadine does augment ibuprofen's analgesia and naproxen Sodium were clearly distinguished from pla (which was repeatedly detected on different measurement cebo. Each antihistaminefanalgesic combination was also instruments), it appears that loratadine does not provide anal distinguished from placebo on the TSS. These findings pro gesic potentiation when combined with naproxen Sodium, vide internal validation of the study and its results: if known Suggesting a pharmaceutical incompatibility or pharmaco analgesics cannot be distinguished from placebo on a vali logic interaction (i.e., the naproxen Sodium salt, unlike ibu dated measurement instrument, the study model itself is defi profen, may interfere with loratadine activity). cient. 0400. These findings are informative. Both the standard 0394. Using this standard scale, differences were detected and the new methods were capable of distinguishing the between ibuprofen/loratadine and ibuprofen, between ibu single-ingredient analgesics from placebo as well as the anti profen/hydroxyzine and ibuprofen, and between ibuprofen/ histaminefanalgesic combinations from placebo (i.e., they are nizatadine and ibuprofen. sensitive measurement instruments). However, these meth 0395. The sensitivity of the new methods, moreover, was ods did not identify analgesic potentiation for every combi remarkable. Unlike the conventional requirement for a de nation. They discriminated additional analgesia only when it minimis entry level (in this case, a 7 on the TSS), there were existed (i.e., only some antihistaminefanalgesic combina no admission criteria for the new scales used herein, which tions were shown to “work better than the single analgesic). ranged from 0 to 10 at baseline. Despite this “all-comer Altogether, these findings add credibility to the positive find study sample, the new scales used herein were used by the ings of the study. patients in each treatment group to measure impressive treat 04.01 Throughout this application, various publications ment effects between active drugs and placebo. Thoughtested are referenced. The disclosures of these publications in their in a small sample size (when statistically significant differ entireties are hereby incorporated by reference into this appli ences are less likely), some differences between single-ingre cation in order to more fully describe the compounds, com dient analgesics and placebo were statistically significant, in positions and methods described herein. fact. This clinical experiment repeatedly confirmed the ability 0402 Various modifications and variations can be made to of these new methods to measure pain status and detect the compounds, compositions and methods described herein. changes after treatment and validated them as assays of anal Other aspects of the compounds, compositions and methods gesic activity. described herein will be apparent from consideration of the 0396 The new scales used herein also identified differ specification and practice of the compounds, compositions ences between antihistaminefanalgesic combinations and the and methods disclosed herein. It is intended that the specifi respective single analgesics Several new measurement instru cation and examples be considered as exemplary. US 2014/0275188A1 Sep. 18, 2014

What is claimed: 11. The method of claim 8, wherein said analgesic poten 1. A method for enhancing an analgesic response in a tiating compound defined in (ii) is 50 mg of nizatidine or the human desiring treatment for reducing acute pain which com pharmaceutically acceptable salt or isomer thereof per single prises orally administering to said human having acute pain a dose composition. single dose composition comprising (i) an analgesic effective 12. The method of claim 8, wherein said analgesic poten amount of a compound selected from the group consisting of tiating compound defined in (ii) is 100 mg to 200 mg nizati naproxen and the pharmaceutically acceptable salt thereof at dine or the pharmaceutically acceptable salt or isomerthereof a dosage from 100 mg to 900 mg per single dose composition, per single dose composition. and (ii) an analgesic potentiating amount of a compound 13. The method of claim 8, wherein said analgesic poten selected from the group consisting of nizatidine and the phar tiating compound defined in (ii) is 150 mg ofnizatidine or the maceutically effective salt or isomer thereofat a dosage from pharmaceutically acceptable salt or isomer thereof per single 10 mg to 200 mg per single dose composition, dose composition. wherein said single dose composition comprises an admix 14. The method of claim 1, wherein said analgesic com ture of (i) and (ii), wherein the single dose composition pound defined in (i) is naproxen Sodium. does not have an enteric coating so that (i) and (ii) are 15. The method of claim 14, wherein said naproxen sodium released concomitantly after administration to said is 220 mg per single dose composition. human, 16. The method of claim 15, wherein said analgesic poten wherein said naproxen or the pharmaceutically acceptable tiating compound defined in (ii) is 50 mg to 100 mgnizatidine salt thereof and said nizatidine or the pharmaceutically or the pharmaceutically acceptable salt or isomer thereof per acceptable salt or isomer thereof provides an enhanced single dose composition. analgesic response in said human compared to the 17. The method of claim 15, wherein said analgesic poten administration to said human of the same dosage tiating compound defined in (ii) is 10 mg to 50 mg nizatidine strength of said naproxen or the pharmaceutically or the pharmaceutically acceptable salt or isomer thereof per acceptable salt thereof in the absence of said nizatidine single dose composition. or the pharmaceutically acceptable salt or isomer 18. The method of claim 15, wherein said analgesic poten thereof. tiating compound defined in (ii) is 50 mg of nizatidine or the 2. The method of claim 1, wherein said analgesic com pharmaceutically acceptable salt or isomer thereof per single pound defined in (i) is 100 mg to 300 mg naproxen or the dose composition. pharmaceutically acceptable salt thereof per single dose com 19. The method of claim 15, wherein said analgesic poten position. tiating compound defined in (ii) is 100 mg to 200 mg nizati 3. The method of claim 2, wherein said analgesic potenti dine or the pharmaceutically acceptable salt or isomerthereof ating compound defined in (ii) is 50 mg to 100 mg nizatidine per single dose composition. or the pharmaceutically acceptable salt or isomer thereof per 20. The method of claim 15, wherein said analgesic poten single dose composition. tiating compound defined in (ii) is 150 mg ofnizatidine or the 4. The method of claim 2, wherein said analgesic potenti pharmaceutically acceptable salt or isomer thereof per single ating compound defined in (ii) is 10 mg to 50 mgnizatidine or dose composition. the pharmaceutically acceptable salt or isomer thereof per 21. The method of claim 14, wherein said naproxen sodium single dose composition. is 200 mg to 600 mg per single dose composition. 5. The method of claim 2, wherein said analgesic potenti 22. The method of claim 21, wherein said analgesic poten ating compound defined in (ii) is 50 mg of nizatidine or the tiating compound defined in (ii) is 50 mg to 100 mgnizatidine pharmaceutically acceptable salt or isomer thereof per single or the pharmaceutically acceptable salt or isomer thereof per dose composition. single dose composition. 6. The method of claim 2, wherein said analgesic potenti 23. The method of claim 21, wherein said analgesic poten ating compound defined in (ii) is 100 mg to 200 mgnizatidine tiating compound defined in (ii) is 10 mg to 50 mg nizatidine or the pharmaceutically acceptable salt or isomer thereof per or the pharmaceutically acceptable salt or isomer thereof per single dose composition. single dose composition. 7. The method of claim 2, wherein said analgesic potenti 24. The method of claim 21, wherein said analgesic poten ating compound defined in (ii) is 150 mg of nizatidine or the tiating compound defined in (ii) is 50 mg of nizatidine or the pharmaceutically acceptable salt or isomer thereof per single pharmaceutically acceptable salt or isomer thereof single dose composition. dose composition. 8. The method of claim 1, wherein said analgesic com 25. The method of claim 21, wherein said analgesic poten pound defined in (i) is 200 mg to 600 mg naproxen or the tiating compound defined in (ii) is 100 mg to 200 mg nizati pharmaceutically acceptable salt thereofper single dose com dine or the pharmaceutically acceptable salt or isomerthereof position. per single dose composition. 9. The method of claim 8, wherein said analgesic potenti 26. The method of claim 21, wherein said analgesic poten ating compound defined in (ii) is 50 mg to 100 mg nizatidine tiating compound defined in (ii) is 150 mg ofnizatidine or the or the pharmaceutically acceptable salt or isomer thereof per pharmaceutically acceptable salt or isomer thereof per single single dose composition. dose composition. 10. The method of claim 8, wherein said analgesic poten 27. The method of claim 1, wherein said analgesic com tiating compound defined in (ii) is 10 mg to 50 mg nizatidine pound defined in (i) is naproxen. or the pharmaceutically acceptable salt or isomer thereof per 28. The method of claim 27, wherein said naproxen sodium single dose composition. is 200 mg per single dose composition. US 2014/0275188A1 Sep. 18, 2014

29. The method of claim 27, wherein said analgesic poten 35. The method of claim 1, wherein said naproxen or the tiating compound defined in (ii) is 50 mg to 100 mgnizatidine pharmaceutically acceptable salt thereof and said nizatidine or the pharmaceutically acceptable salt or isomer thereof per or the pharmaceutically acceptable salt or isomer thereof, single dose composition. provide a faster onset of pain reduction in said human com 30. The method of claim 27, wherein said analgesic poten pared to the administration to said human of the same dosage tiating compound defined in (ii) is 10 mg to 50 mg nizatidine strength of said naproxen or the pharmaceutically acceptable or the pharmaceutically acceptable salt or isomer thereof per salt thereof in the absence of said nizatidine or the pharma single dose composition. ceutically acceptable salt or isomer thereof. 31. The method of claim 27, wherein said analgesic poten tiating compound defined in (ii) is 50 mg of nizatidine or the 36. The method of claim 1, wherein said administration of pharmaceutically acceptable salt or isomer thereof single said naproxen or the pharmaceutically acceptable salt thereof dose composition. and said nizatidine or the pharmaceutically acceptable salt or 32. The method of claim 27, wherein said analgesic poten isomer thereof, provides pain relief of longer duration than tiating compound defined in (ii) is 100 mg to 200 mg nizati the administration of said naproxen or the pharmaceutically dine or the pharmaceutically acceptable salt or isomerthereof acceptable salt thereof in the absence of said nizatidine or the per single dose composition. pharmaceutically acceptable salt or isomer thereof. 33. The method of claim 27, wherein said analgesic poten 37. The method of claim 1, wherein the human is an adult tiating compound defined in (ii) is 150 mg ofnizatidine or the human. pharmaceutically acceptable salt or isomer thereof per single dose composition. 38. The method of claim 1, wherein the acute pain is 34. The method of claim 1, wherein the analgesic com selected from the group consisting of Sore throat, earache, pound defined in (i) and nizatidine or the pharmaceutically toothache, muscular aches, backache, headache, sprained acceptable salt or isomer thereofare incorporated into a poly ankle, sinus pain, and joint pain. meric matrix. k k k k k