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(12) Patent Application Publication (10) Pub. No.: US 2004/0180916A1 Levine (43) Pub US 20040180916A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0180916A1 Levine (43) Pub. Date: Sep. 16, 2004 (54) TREATMENT OF PAIN WITH Publication Classification COMBINATIONS OF NALBUPHINE AND OTHER KAPPA-OPOLD RECEPTOR (51) Int. Cl. ................................................ A61K 31/485 AGONSTS AND OPOLD RECEPTOR (52) U.S. Cl. .............................................................. 514/282 ANTAGONSTS (75) Inventor: Jon D. Levine, San Francisco, CA (US) (57) ABSTRACT Correspondence Address: TOWNSEND AND TOWNSEND AND CREW, LLP Methods and compositions for treating, managing or ame TWO EMBARCADERO CENTER liorating pain in a Subject (preferably, a mammal, and more EIGHTH FLOOR preferably, a human) comprising administration of a cen SAN FRANCISCO, CA 94111-3834 (US) trally acting (i.e., crosses the blood brain barrier) agonist of (73) Assignee: The Regents of the University of Cali a K-opioid receptor and a centrally acting opioid antagonist fornia, Oakland, CA Such that the analgesia achieved by this administration is greater than with administration of either the K-opioid (21) Appl. No.: 10/734,308 receptor agonist or the opioid antagonist alone. Preferably the K-opioid receptor is nalbuphine or a Salt or prodrug of (22) Filed: Dec. 12, 2003 nalbuphine and the opioid antagonist is naloxone or a Salt or Related U.S. Application Data prodrug of naloxone. Preferred methods of administration include mucosal (e.g. intranasal or pulmonary) and intrave (60) Provisional application No. 60/433,217, filed on Dec. nous. Other K-opioid receptors include pentazocine and 13, 2002. butorphanol. Patent Application Publication Sep. 16, 2004 Sheet 1 of 11 US 2004/0180916 A1 FIGURE 1. Males 1 Females Combined - a p a5 - Nalbuphine 2.5 mg Nalbuphine 5 mg Nalbuphine 10 mg -3 -3 -3 a -2 -2 -2 - -1 -1 -1 st(S 0 --- O O 1 d 2 2 2 3 3 3 3 4 4 4 -10 30 70 110 150 -10 30 70 110 150 -10 30 70 110 150 10 50 90 130 170 10 50 90 130 170 10 50 90 's 170 Time After Drug (min) PATIENTS RECEIVING 2.5MG 5 MG 10 MG -O-NALBUPHINE ALONE 31 33 30 -v- +NALOXONE 0.4 MG 30 30 26 -- NALOXONE 0.4 MGALONE 28 28 28 d valuupnine 4.0, 0, i u IIIy T valuMUI it V." Illy Males / Females Combined -N -4 E 9 -3 g -2 as -1 S -O-2.5MG (30 PATIENTS) 0 -v- 5MG (30 PATIENTS) 1 -- 10 MG (26 PATIENTS) 9, 2 3 C O 4 -10 1O 30 50 70 1000 to Time After Drug (min) Patent Application Publication Sep. 16, 2004 Sheet 2 of 11 US 2004/0180916A1 FIGURE 2 Males/femaleS COmbined a Nalbuphine 2.5 mg b Nalbuphine 5 mg C Nalbuphine 10 mg -4 -4 -4 5-3 -3 -3 5 -2 -2 -2 e 0 -1 -1 -1 0 O a O 1 1 1 5, 2 2 2 3 3 3 4. 4. 4. 288 R323 s 28, 2828 e 88s 828 &S Time after drug (min) 2.5 mg 5mg 10 mg -- naibuphine alone 26 33 30 -v- + naloxone 0.4 mg 27 30 25 -- naloxone 0.4 mg alone 28 28 28 d Nalbuphine 2.5, 5, 10 mg+naloxone 0.4 mg -4 O -O- 2.5 mg (27) -v- 5 mg (30) -- 10 mg (25) Patent Application Publication Sep. 16, 2004 Sheet 3 of 11 US 2004/018091.6 A1 FIGURE 3 NaIDupnine b mg t naIOXOne U.1, U.Z. & U.4 mg 3. Men b Women -o- 0.4 mg (14) -v- 0.2 mg (1) -o- 0.4 mg (n=16) -v- 0.2 mg (n=7) -- 0.1 mg (n=14) Cd Co o O C o O C C Co d d C. Cd d d Cd cd d d v vs N or v- N. w v- d to in o was N. y war ves vs was v. v. Time after drug (min) Patent Application Publication Sep. 16, 2004 Sheet 4 of 11 US 2004/0180916A1 FIGURE 4 Women b Men 2 -6 - nalbuphine (2.5 rpg). 3. -o- + naloxone (0.4rrig) Cd C C C Cd d to cd O Co v - co to N od v up a Time after drug (min) Patent Application Publication Sep. 16, 2004 Sheet 5 of 11 US 2004/0180916A1 FIGURES Nalbuphine 2.5 mg alone and + naloxone 0.2 mg (males co-varied for baseline pain) a Women b Men -O- alone (n=19) -o- alone (n=16) -v- 0.2 mg (n=15) -v- 0.2 mg (n=13) a da N CO & O. O. O. O. O. g g s s g g s Time after drug (min) Patent Application Publication Sep. 16, 2004 Sheet 6 of 11 US 2004/0180916A1 FIGURE 6 UU 90 80 Time of Drug Administration 70 (hrs in GCRC) E 9 60 -1- 1 9 -2- 2.5 9 50 -3- 5 5 -4- 7 C/D 40 -5- 11.5 CC -6- 14.5 D -7- 32 30 10 O Pain NauSea Pre- and 60 Minutes Post-drug Administration Patent Application Publication Sep. 16, 2004 Sheet 7 of 11 US 2004/018091.6 A1 FIGURE 7 Time of Drug Administration an (hrs in GCRC) 5 -1- 17.5 CD -2- 23.5 s -3- 33.5 O O?) 2 D Pain NauSea Pre- and 60 Minutes Post-drug Administration Patent Application Publication Sep. 16, 2004 Sheet 8 of 11 US 2004/0180916A1 FIGURE 8 100 90 Time of Drug Administration 80 (hrs in GCRC) 70 -1-2.5 E. -2- 3.5 9 60 -3- 4.5 9 -4- 16 SR 50 -5- 19 COO -6-21 -7 - 23.5 40 -8- 30 D -9- 32.5 30 -10-35 -11-38 20 -12- 41 10 4,9,10,11 O Pain NauSea Pre- and 60 Minutes Post-drug Administration Patent Application Publication Sep. 16, 2004 Sheet 9 of 11 US 2004/0180916A1 FIGURE 9 8.- : Q: --v-- Case 1: Male e --O-- Case 2: Female 5. 6- -O- Case 3: Female 9 O D O 2> . ? O 20 40 60 80 100 120 140 160 180 Post Injection (min) Patent Application Publication Sep. 16, 2004 Sheet 10 of 11 US 2004/0180916A1 FIGURE 10 Nerve injury Study (Nalbuphine 5 mg + Naloxone 04 mg) -10 10 30 50 70 90 110 130 150 170 Post Drug (min) Patent Application Publication Sep. 16, 2004 Sheet 11 of 11 US 2004/018091.6 A1 FIGURE 11 intra-nasal nalbuphine-naloxone combination -O- intra-nasal nalb 5 nbd0.4 (2) -v- i.v. nalb 5 nix 0.4 (14) -O- intra-nasal nalb 5 nix 0 (0) E 9. 9. C d is . S. 3. O)CC > . 3. -O- Intra-nasal nalb 5 nix 0.4 (2) -v- i.v. nalb 5 nix 0.4 (16) O -O- intra-nasal nalb 5 nib. O (1) O intra-nasal nalb 5 nib 0.4 (4) v. iv. naib 5 nix 0.4 (32) O Intra-nasal nalb 5 nib 0 (1) -10 10 30 50 7O 90 1 1 0 130 1501.70 US 2004/018091.6 A1 Sep. 16, 2004 TREATMENT OF PAIN WITH COMBINATIONS OF BRIEF SUMMARY OF INVENTION NALBUPHINE AND OTHER KAPPA-OPOD 0007. The present invention provides methods of treat RECEPTORAGONSTS AND OPOLD RECEPTOR ing, managing or ameliorating pain (including, e.g., inflam ANTAGONSTS matory pain, neuropathic pain, acute pain, chronic pain, CROSS-REFERENCES TO RELATED generalized pain Syndromes, post-operative and post-proce APPLICATIONS dural pain, etc.) in a Subject (preferably, a mammal, and more preferably, a human) comprising administration of a 0001. This application claims the benefit of the priority of centrally acting (i.e., crosses the blood brain barrier) agonist U.S. provisional application 60/433,217 filed Dec. 13, 2002, of a K-opioid receptor and a centrally acting opioid antago which is incorporated herein in its entirety. nist Such that the analgesia achieved by this administration is greater than with administration of either the K-opioid STATEMENT AS TO RIGHTS TO INVENTIONS receptor agonist or the opioid antagonist alone (in certain MADE UNDER FEDERALLY SPONSORED circumstances, analgesia is achieved by administration of RESEARCH OR DEVELOPMENT the combination whereas administration of the agonist or 0002 The invention was made with government support antagonist alone results in anti-analgesia or leSS analgesia under Grant Number NR 03923 of the National Institutes of than administration of the combination). Health. The government has certain rights in this invention. 0008. The invention further provides pharmaceutical compositions comprising combinations of a centrally acting FIELD OF INVENTION K-opioid agonist and an opioid antagonist that provide pain 0003. The present invention provides methods for treat relief greater than the pain relief achieved with either the ing, managing, and ameliorating pain, Such as pain, includ agonist or antagonist alone (and, preferably, greater than the ing inflammatory pain, neuropathic pain, acute and chronic additive analgesic effects of the agonist and antagonist on pain, and regional and generalized pain Syndromes while their own). The centrally acting K-opioid agonist may be a avoiding adverse side effects Such as abuse potential. In benzomorphan derivative, Such as, but not limited to, butor particular, the present invention provides methods of treat phanol, ketazocine, ethylketazocine, pentazocine, dezocine, ing, managing, and ameliorating pain by administration of a and bremazocine; a benzacetamide derivative, Such as, but generally low dose of a kappa opioid agonist with an opioid not limited to U50,488, U69,593, U62,066 (spiradoline), PD antagonist. The present invention also provides pharmaceu 117302, CI-977, DuP 747, ICI 197067, ICI 199441, BRL tical compositions, pharmaceutical kits, and combination 52537A, or BRL 52656A, a phenothiazine derivative, such therapies for treating, managing, and ameliorating pain.
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