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WO 2017/066488 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date W O 2017/066488 A l 2 0 April 2017 (20.04.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/485 (2006.01) A61P 25/04 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/5415 (2006.01) A61P 1/08 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US20 16/0569 10 HN, HR, HU, ID, IL, EST, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, 13 October 2016 (13.10.201 6) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (25) Filing Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (26) Publication Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 62/240,965 13 October 2015 (13. 10.2015) US (84) Designated States (unless otherwise indicated, for every 62/300,014 25 February 2016 (25.02.2016) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: CHARLESTON LABORATORIES, INC. TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, [US/US]; 1001 N. US Highway 1, Suite 500, Jupiter, Flor TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, ida 33477 (US). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors: BOSSE, Paul; 18822 Rio Vista Drive, Jupiter, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Florida 33469 (US). AMELING, John; 843 University GW, KM, ML, MR, NE, SN, TD, TG). Blvd., Apt. #202, Jupiter, Florida 33458 (US). SCHACHTEL, Bernard; 109 Quayside Drive, Jupiter, Published: Florida 33477 (US). KOZAREK, William; 3102 NE Ivy — with international search report (Art. 21(3)) Lane, Jensen Beach, Florida 34957 (US). (74) Agent: HARBURGER, David S.; Wilson Sonsini Goodrich & Rosati, 650 Page Mill Road, Palo Alto, Cali fornia 94304 (US). (54) Title: TREATING PAIN USING A COMPOSITION COMPRISING AN OPIOID AND AN ANTIEMETIC (57) Abstract: Provided herein are methods and compositions for ef Percentage of Subjects with Repeat Retching over fective treatment or prevention of pain, which also reduce or eliminate 5 Days adverse effects associated with an opioid analgesic. In addition, provided herein are methods and compositions for treatment or pre vention of pain, and for reducing or preventing retching in a subject. Also provided herein are methods and compositions for treatment or prevention of pain, and for reducing or preventing sleep disturbances. Also provided herein are methods and compositions for treatment or prevention of pain, and for reducing or preventing a sensory or affect ive quality associated with the pain, such as agonizing pain, in a sub - ject. Compositions described herein may include an opioid analgesic and an antiemetic. Compositions described herein may further include a non-opioid analgesic. Figure 33 TREATING PAIN USING A COMPOSITION COMPRISING AN OPIOID AND AN ANTIEMETIC CROSS-REFERENCE [0001] This application claims the benefit of U S Provisional Application No 62/240,965 filed October 13, 2015, and U.S. Provisional Application No. 62/300,014 filed February 25, 2016, each of which are incorporated herein by reference in their entirety. INCORPORATION BY REFERENCE [0002] All publications, patents, and patent applications disclosed herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event of a conflict between a term disclosed herein and a term in an incorporated reference, the term herein controls. BACKGROUND [0003] Available pain medications can have adverse effects, such as nausea, retching, vomiting, constipation, skin rashes, sedation, and sleep disturbance. As a result of such adverse effects, many subjects are unable to tolerate recommended dosages needed for effective pain relief because of adverse effects. Accordingly, there remains a need for effective therapeutics with reduced adverse effects. [0004] In addition, to discern analgesic effects, most clinical investigators measure only evaluative end-points, and not affective or sensory qualities. There exists a need for additional types of measurement to assess therapeutic activity for preventing, reducing or treating various forms of pain. BRIEF SUMMARY [0005] The present disclosure provides methods and compositions for effective pain treatment. [0006] Provided herein are methods fpr providing treatment or reduction of agonizing pain in a subject, comprising: administering to a subject in need thereof a pharmaceutical composition, wherein the pharmaceutical composition comprises: an effective amount of an opioid analgesic to treat agonizing pain; and an effective amount of an antiemetic to reduce or prevent nausea associated the opioid analgesic or to reduce or prevent vomiting associated the opioid analgesic, wherein administration of the pharmaceutical composition provides for a reduction or prevention of agonizing pain in the subject. Further provided herein are methods wherein the agonizing pain is measured by the subject on a Likert-type agonizing pain scale. Further provided herein are methods wherein the method reduces severity of the agonizing pain. Further provided herein are methods wherein the method reduces occurrence of the agonizing pain. Further provided herein are methods wherein administration of the pharmaceutical composition provides for about 60% reduction of agonizing pain over 24 hours. Further provided herein are methods wherein administration of the pharmaceutical composition provides for about 30% reduction in pain intensity over 24 hours. Further provided herein are methods wherein administration of the pharmaceutical composition provides increased agonizing pain relief in the subject compared to administration of the opioid analgesic without the antiemetic. Further provided herein are methods wherein the pharmaceutical composition further comprises an effective amount of a non-opioid analgesic to treat pain. Further provided herein are methods wherein the pharmaceutical composition is a solid oral pharmaceutical composition. Provided herein are methods for providing pain relief and reducing or preventing an affective quality pain in a subject in need thereof, comprising: administering to a subject a pharmaceutical composition, wherein the pharmaceutical composition comprises: an effective amount of an opioid analgesic to treat pain; and an effective amount of an antiemetic to reduce or prevent nausea associated the opioid analgesic or to reduce or prevent vomiting associated the opioid analgesic, wherein administration of the pharmaceutical composition provides for a reduction or prevention of an affective quality in the subject. Further provided herein are methods wherein the affective quality is agonizing pain. Further provided herein are methods wherein the method provides the subject a decrease in pain occurrence. Further provided herein are methods wherein the method provides the subject a decrease in pain severity. Further provided herein are methods wherein the pain severity is reduced by more than 30% following first administration of the pharmaceutical composition. Further provided herein are methods wherein the subject has a reduction of at least 30% in severe pain over about 24 hours or more following administration of the pharmaceutical composition. Further provided herein are methods wherein the subject has a reduction of at least 10% in moderate to severe pain over about 48 hours or more following administration of the pharmaceutical composition. Further provided herein are methods wherein the subject has a reduction of at least 20% in moderate to severe pain over about 24 hours or more following administration of the pharmaceutical composition. Further provided herein are methods wherein the subject has a reduction in moderate to severe pain over about 4 to 6 hours or more following administration of the pharmaceutical composition. Further provided herein are methods wherein the subject has a reduction in moderate to severe pain over about 12 hours or more following administration of the pharmaceutical composition. Further provided herein are methods wherein the subject has a reduction in moderate to severe pain over about 2 or 3 doses following administration of the pharmaceutical composition. Further provided herein are methods wherein the subject has an increase of at least 20% in pain relief over about 12 hours or more following administration of the pharmaceutical composition. Further provided herein are methods wherein the subject has an increase of at least 20% in pain relief over about the first 2 or 3 doses or more following administration of the pharmaceutical composition. Further provided herein are methods wherein the subject has a reduction in affective, sensory, or evaluative qualities of pain over about 6 hours or more following initial administration of the pharmaceutical composition. Further provided herein are methods wherein the subject has a reduction in affective, sensory, or evaluative qualities of pain over two or more doses or about 12 hours, about 24 hours, or more following administration of the pharmaceutical composition. Further provided herein are methods wherein the subject has a reduction of at least 15% in affective, sensory, or evaluative qualities of pain over about 24 hours or more following administration of the pharmaceutical composition. Further provided herein are methods wherein the subject has a reduction of at least 50% in the occurrence of vomiting over about 24 hours or more following administration of the pharmaceutical composition.
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