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. as but not limited to Rp 60180; a thiazine derivative, such as but not limited to R-84760; or a benzodiazepine derivative, BACKGROUND OF THE INVENTION Such as, but not limited to, Tifluadom. In certain doses, the agonist exhibits Sexual dimorphism when administered 0004 Opioids are a group of compounds that have opium alone, i.e., at certain doses induces more analgesia in Women or morphine-like properties. Opioids are primarily used to than men or causes anti-analgesia in men and analgesia in treat pain, but may have other pharmacological effects Women in Studies of groups comprising 15, 20, 30 or more including drowsiness, respiratory depression, and constipa Subjects. In preferred embodiments, the K-opioid receptor tion, as well as abuse potential and tolerance. An opioid agonist is butorphanol or pentazocine, or, most preferably, agonist is a compound that binds to an opioid receptor and nalbuphine. The opioid antagonist is also centrally-acting forms a complex which elicits pharmacological responses and is preferably naloxone, naltrexone, methylmaltrexone or particular to the nature of the receptor. Kappa (K)-opioid nalmefene. The opioid antagonist is preferably a non-Selec receptor agonists are compounds that induce analgesia pre tive opioid antagonist, i.e., a compound that antagonizes at dominantly by acting on kappa-opioid receptors. Examples least K, u, and 6 opioid receptors. The K-opioid agonists and of kappa-opioid agonists are nalbuphine, pentazocine, butor the opioid antagonists of the present invention may be in any phanol, benzomorphan, and benzacetamide, phenothiazine, pharmaceutically acceptable form, including the free base, a thiazine, and benzodiazepine derivatives. Salt, a prodrug, or a mixture thereof. 0005 Opioid antagonists are compounds that pharmaco 0009. In particular embodiments, the invention provides logically block or reverse all (or substantially all) the effects methods of intravenous and mucosal (e.g., nasal and pull of opioid agonists. Non-Selective opioid antagonists are monary administration) administration of an amount of a those antagonists that act at least on K, u, and 8 opioid centrally acting K-opioid receptor agonist and an amount of receptorS. Opioid antagonists are generally used to reverse an opioid antagonist that results in greater analgesia than the effects of opioid agonist overdose and treatment of results from administration of either the agonist or the opioid addiction. Examples of opioid antagonists include antagonist alone. In one preferred embodiment, the inven naloxone, naltrexone, methylmaltrexone and nalmefene. tion provides methods of intravenous administration or 0006 To date, severe pain is treated with opioids, par mucosally administering a centrally acting K-opioid receptor ticularly it opioids, Such as morphine, which have significant agonist with 0.02 mg to 8 mg, 0.02 to 7 mg, 0.02 mg to 6 adverse side effects, including abuse potential. What is mg, 0.02 to 5 mg, 0.02 to 4 mg., 0.02 to 3 mg, 0.02 to 2 mg, needed is an analgesic that is Sufficiently potent to treat 0.02 to 2 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 6 Severe and chronic pain with minimal adverse Side effects. mg, 0.1 mg to 5 mg, 0.1 mg to 4 mg., 0.1 mg to 3 mg, 0.1 The present invention fills Such a need Since the combina mg to 2 mg, 0.1 mg to 1 mg, 0.2 mg to 8 mg, 0.2 mg to 7 tions of K-opioid receptor agonists and opioid antagonists mg, 0.2 mg to 6 mg, 0.2 mg to 4 mg., 0.2 mg to 3 mg, 0.2 have high analgesic potency with reduced adverse side mg to 2 mg, 0.2 mg to 1 mg, 0.4 mg to 8 mg, 0.4 to 7 mg, effects compared to morphine and other ul opioid agonists. 0.4 to 6 mg, 0.4 mg to 5 mg, 0.4 mg to 4 mg., 0.4 mg to 3 US 2004/018091.6 A1 Sep. 16, 2004

mg, 0.4 mg to 2 mg, 0.4 mg to 1 mg, 0.5 mg to 8 mg, 0.5 15% to 30%, 5% to 25%, 10% to 25%, 15% to 25%, 5% to mg to 6 mg, 0.5 mg to 5 mg, 0.5 mg to 4 mg., 0.5 mg to 3 20%, and 5% to 15% of the recommended analgesic dose. mg, 0.5 mg to 3 mg, 0.5 to 2 mg, 0.5 mg to 1 mg, 1 mg to 8 mg, 1 mg to 6 mg, 1 mg to 5 mg, 1 mg to 4 mg, 1 mg to 0013 In certain embodiments of the invention, the 3 mg, 1 mg to 2 mg, 5 mg to 8 mg, 4 mg to 7 mg, 3 mg to method comprises administration of nalbuphine, as the 5 mg, 0.02 mg to 1 mg, preferably 0.1 mg to 0.8 mg, 0.2 mg K-opioid agonist, preferably by intravenous or intramucosal to 0.8 mg, 0.3 mg to 0.8 mg, 0.4 mg to 0.8 mg, 0.5 mg to administration (e.g., by intranasal or pulmonary) adminis 0.8 mg, 0.1 mg to 0.7 mg, 0.2 mg to 0.7 mg, 0.3 mg to 0.7 tration, and more preferably Such administration of nalbu mg, 0.4 mg to 0.7 mg, 0.1 mg to 0.6 mg, 0.2 mg to 0.6 mg, phine hydrochloride salt. The nalbuphine hydrochloride salt 0.3 to 0.6 mg, 0.1 mg to 0.5 mg, 0.15 mg to 0.5 mg, 0.2 mg is preferably administered in amounts 6.25 to 49 times to 0.5 mg, 0.25 mg to 0.5 mg, 0.3 mg to 0.5 mg, 0.35 mg to greater, 6.25 to 40 times greater, 6.25 to 35 times greater, 0.5 mg, 0.1 mg to 0.45 mg, 0.15 mg to 0.45 mg, 0.2 mg to 6.25 to 30 times greater, 6.25 to 20 times greater, 8 to 35 0.45 mg, 0.25 mg to 0.45 mg, 0.1 mg to 0.3 mg, 0.13 mg to times greater, 8 to 30 times greater, 8 to 25 times greater, 10 0.3 mg, 0.2 mg to 0.3 mg, 0.1 mg to 0.25 mg, 0.15 mg to 0.25 to 30 times greater, 10 to 20 times greater, 15 to 25 times mg, 0.1 mg to 0.2 mg, 0.1 mg to 0.15 mg of a hydrochloride greater, 20 to 25 times greater, 10 to 15 times greater, 9 to Salt of the opioid antagonists described herein, and most 15 times greater, 5 to 10 times greater, 30 to 49 times greater, preferably, of naloxone hydrochloride. Typical amounts of 20 to 30 times greater, 15 to 20 times greater, 13 to 15 times such hydrochloride salt are 0.1 mg, 0.15 mg, 0.2 mg, 0.25 greater, 11 to 13 times greater, 9 to 11 times greater, 7 to 9 mg, 0.3 mg, 0.35 mg, 0.4 mg., 0.45 mg, 0.5 mg, 0.55 mg, 0.6 times greater, or 6.25 to 7 times greater than the amount of mg 0.7 mg, 0.75 mg, 0.8 mg, 1 mg, 1.6 mg, 2 mg, 2.4 mg, opioid antagonist hydrochloride Salt, preferably naloxone 3 mg, 4 mg, 5 mg, 6 mg, 7 mg and 8 mg. hydrochloride Salt, administered. 0014 Non-limiting examples of the present invention are 0.010 The invention also comprises administration of the methods comprising administration of 3 mg of nalbuphine amount of opioid antagonist (preferably naloxone) free base, hydrochloride Salt with 0.4 mg naloxone hydrochloride salt a non-hydrochloride Salt, a prodrug, or a mixture thereof that (i.e., 7.5 times greater nalbuphine hydrochloride Salt than the would result in the Same blood concentration of the active naloxone hydrochloride Salt); 1.25 mg nalbuphine hydro naloxone or other opioid antagonist (or in certain embodi chloride salt with 0.1 mg naloxone hydrochloride salt, 2.5 ments, the active metabolite thereof) as would intravenous mg nalbuphine hydrochloride Salt with 0.2 mg naloxone administration of the amount of the hydrochloride salt hydrochloride salt; 5 mg nalbuphine hydrochloride salt with Specified, i.e., contains an equivalent amount (i.e., the same 0.4 mg naloxone hydrochloride Salt, 10 mg nalbuphine number of moles) of the active opioid antagonist, or, in hydrochloride salt with 0.8 mg naloxone hydrochloride salt, certain embodiments, Such as Sustained release formula 20 mg nalbuphine hydrochloride Salt with 1.6 mg naloxone tions, results in release into the blood Stream of an equiva hydrochloride salt, 25 mg nalbuphine hydrochloride salt lent amount, but over a period of 15 minutes, 30 minutes, 1 with 2.0 mg naloxone hydrochloride Salt, and 30 mg nal hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, buphine hydrochloride salt with 2.4 mg naloxone hydro or 24 hours. chloride Salt (i.e., 12.5 times greater, by weight, nalbuphine 0.011 The present invention also encompasses methods hydrochloride salt than the naloxone hydrochloride salt); 5 comprising administration of opioid antagonist (preferably mg nalbuphine hydrochloride Salt with 0.2 mg naloxone naloxone) free base, non-hydrochloride Salt, prodrug, or hydrochloride Salt and 10 mg nalbuphine hydrochloride salt mixture thereof in amounts equivalent to administration of with 0.4 mg naloxone hydrochloride salt (i.e., 25 times the above amounts of the hydrochloride Salt, i.e., an amount greater nalbuphine hydrochloride Salt than the naloxone of naloxone or other opioid antagonist free base, non hydrochloride salt); 4.9 mg nalbuphine hydrochloride salt hydrochloride Salt, prodrug, or mixture thereof that produces with 0.1 mg naloxone hydrochloride salt and 9.8 mg nal the same blood concentration of the opioid antagonist (e.g., buphine hydrochloride salt with 0.2 mg naloxone hydro naloxone) or its active metabolite as the administration of a chloride Salt (i.e., 49 times greater, by weight, nalbuphine particular amount of hydrochloride Salt. For example, hydrochloride salt than naloxone hydrochloride salt). Alter approximately 0.1 mg naloxone hydrochloride Salt is natively, 1 mg to 50 mg, 1 mg to 45 mg, 1 mg to 40 mg, 1 equivalent to approximately 0.09 mg naloxone free base, mg to 35 mg, 1 mg to 30 mg, 1 mg to 25 mg, 1 mg to 20 mg, approximately 0.15 mg naloxone hydrochloride Salt is 1 mg to 15 mg, 1 mg to 10 mg, 1 mg to 9 mg, 1 mg to 8 mg, approximately equivalent to 0.135 mg naloxone free base, 2 mg to 8 mg, 3 mg to 8 mg, 1 mg to 7 mg, 2 mg to 7 mg, approximately 0.2 mg of naloxone hydrochloride Salt is 3 mg to 7 mg, 4 mg to 7 mg, 1 mg to 6 mg, 2 mg to 6 mg, equivalent to approximately 0.18 mg naloxone free base, 3 mg to 6 mg, 1 mg to 5 mg, 2 mg to 5 mg, 1 mg to 4 mg, and approximately 0.25 mg of naloxone hydrochloride Salt 1 mg to 3 mg, 1 mg to 2 mg nalbuphine hydrochloride Salt is equivalent to approximately 0.225 mg naloxone free base. is administered. 0012. In general, the amount of K-opioid agonist to be 0015. In certain preferred embodiments in which nalbu administered with the antagonist is in the range of 5% to phine hydrochloride Salt is administered as the opioid ago 100% of the recommended analgesic dose (e.g., as provided nist, 0.02 mg to 8 mg, preferably, 0.1 mg to 0.8 mg naloxone in the Physician's Desk Reference or other commonly used hydrochloride Salt is administered as the opioid antagonist reference). Preferably, the dose of the K-opioid agonist is 5% hydrochloride salt. Non-limiting examples of the method of to 90%, 10% to 90%, 5% to 85%, 10% to 85%, 15% to 85%, the present invention comprises 1 mg, 1.25 mg, 1.5 mg, 2 20% to 80%, 5% to 75%, 10% to 75%, 15% to 70%, 15.9% mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 to 60%, 5% to 55%, 10% to 55%, 15% to 50%, 5% to 50%, mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 5% to 45%, 5% to 40%, 5% to 35%, 5% to 30%, 10% to mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, or 50 mg of 40%, 10% to 35%, 10% to 30%, 15% to 40%, 15% to 35%, malbuphine hydrochloride salt with 0.1 mg, 0.15 mg, 0.2 mg, US 2004/018091.6 A1 Sep. 16, 2004

0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg., 0.5 mg, 0.6 mg, 0017. The present invention also encompasses methods 0.7 mg, 0.8 mg, 1 mg, 1.6 mg, 2.0 mg, 2.4 mg., 3.0 mg, 4 mg, comprising intravenous or mucosal administration of nal 5 mg, 6 mg, 7 mg, or 8 mg of naloxone hydrochloride Salt. buphine free base, non-hydrochloride Salt, prodrug, or a mixture thereof in amounts equivalent to the Specified 0016 For example, specific embodiments of the inven amounts of nalbuphine hydrochloride salt, provided that 5 tion comprise of intravenous or mucosal (e.g., nasal or mg of nalbuphine free base is not administered with 0.4 mg pulmonary) administration of 0.2 mg of naloxone hydro of naloxone free base intravenously. AS Stated above with chloride salt with 1 mg nalbuphine hydrochloride salt, 0.1 regard to naloxone, an equivalent amount of nalbuphine free mg naloxone hydrochloride Salt with 1.25 mg nalbuphine base, non-hydrochloride Salt, prodrug, or mixture thereof is hydrochloride salt, 0.2 mg of naloxone hydrochloride salt an amount that produces the same blood concentration of with 1.5 mg nalbuphine hydrochloride salt, 0.2 mg of malbuphine or active metabolite of nalbuphine as would naloxone hydrochloride Salt with 2 mg nalbuphine hydro intravenous administration of the Specified amount of nal chloride salt, 0.2 mg of naloxone hydrochloride salt with 2.5 buphine hydrochloride salt or the same amount of nalbu mg nalbuphine hydrochloride Salt, 0.2 mg of naloxone phine released into the blood stream over a period of 15 hydrochloride salt with 3 mg nalbuphine hydrochloride salt, minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 0.2 mg of naloxone hydrochloride Salt with 3.5 mg nalbu hours, 10 hours, 12 hours, or 24 hours. For example, phine hydrochloride salt, 0.2 mg of naloxone hydrochloride approximately 1 mg of nalbuphine hydrochloride Salt salt with 4 mg nalbuphine hydrochloride salt, 0.2 mg of administered intravenously is equivalent to approximately naloxone hydrochloride Salt with 4.5 mg nalbuphine hydro 0.9 mg of nalbuphine free base administered intravenously. chloride salt, 0.2 mg of naloxone hydrochloride salt with 5 0018. In certain embodiments, the method of the inven mg nalbuphine hydrochloride Salt, 0.2 mg of naloxone tion comprises intravenous administration of pentazocine as hydrochloride Salt with 5.5 mg nalbuphine hydrochloride the K-opioid agonist, preferably as pentazocine hydrochlo Salt, 0.2 mg of naloxone hydrochloride Salt with 6 mg ride Salt. In particular, the invention provides methods of nalbuphine hydrochloride Salt, 0.2 mg of naloxone hydro administering intravenously an opioid antagonist hydrochlo chloride salt with 6.5 mg nalbuphine hydrochloride salt, 0.2 ride Salt, preferably naloxone hydrochloride Salt, and 18 to mg of naloxone hydrochloride Salt with 7 mg nalbuphine 120 times greater, 25 to 120 times greater, 18 to 110 times hydrochloride Salt 0.2 mg of naloxone hydrochloride salt greater, 25 to 110 times greater. 18 to 100 times greater, 25 with 7.5 mg nalbuphine hydrochloride salt, 0.2 mg of to 100 times greater, 18 to 95 times greater, 25 to 90 times naloxone hydrochloride salt with 8 mg nalbuphine hydro greater, 30 to 90 times greater, 18 to 85 times greater, 18 to chloride salt, 0.2 mg of naloxone hydrochloride salt with 8.5 80 times greater, 20 to 80 times greater, 20 to 60 times mg nalbuphine hydrochloride Salt, 0.2 mg of naloxone greater, 20 to 50 times greater, 25 to 55 times greater, 35 to hydrochloride salt with 9 mg nalbuphine hydrochloride salt, 80 times greater, 20 to 75 times greater, 25 to 70 times 0.2 mg of naloxone hydrochloride Salt with 9.5 mg nalbu greater, 40 to 100 times greater, 50 to 100 times greater, 55 phine hydrochloride salt, 0.2 mg of naloxone hydrochloride to 95 times greater, 45 to 90 times greater, 40 to 70 times salt with 10 mg nalbuphine hydrochloride salt, 0.4 mg of greater, 18 to 50 times greater, 18 to 40 times greater, or 18 naloxone hydrochloride Salt with 1 mg nalbuphine hydro to 35 times greater, 18 to 30 times greater, by weight, chloride salt, 0.4 mg of naloxone hydrochloride salt with 1.5 pentazocine hydrochloride Salt. Non-limiting examples of mg nalbuphine hydrochloride Salt, 0.4 mg of naloxone the methods of the present invention comprise intravenous hydrochloride Salt with 2.0 mg nalbuphine hydrochloride administration of 10 mg of pentazocine hydrochloride Salt salt, 0.4 mg of naloxone hydrochloride Salt with 2.5 mg with 0.4 mg of naloxone hydrochloride salt (i.e., 25 times nalbuphine hydrochloride Salt, 0.4 mg of naloxone hydro greater, by weight, pentazocine hydrochloride Salt than the chloride salt with 3 mg nalbuphine hydrochloride salt, 0.4 naloxone hydrochloride Salt), 15 mg of pentazocine hydro mg of naloxone hydrochloride Salt with 3.5 mg nalbuphine chloride salt with 0.3 mg naloxone hydrochloride salt (i.e., hydrochloride salt, 0.4 mg of naloxone hydrochloride salt 30 times greater, by weight, pentazocine hydrochloride Salt with 4 mg nalbuphine hydrochloride Salt, 0.4 mg of nalox than the naloxone hydrochloride Salt), and 25 mg of penta one hydrochloride salt with 4.5 mg nalbuphine hydrochlo zocine hydrochloride salt with 0.5 mg naloxone hydrochlo ride salt, 0.4 mg of naloxone hydrochloride salt with 5 mg ride Salt (i.e., 50 times greater pentazocine hydrochloride nalbuphine hydrochloride Salt, 0.4 mg of naloxone hydro salt than naloxone hydrochloride salt). Preferably, the chloride salt with 5.5 mg nalbuphine hydrochloride salt, 0.4 weight of pentazocine hydrochloride Salt administered is 3 mg of naloxone hydrochloride Salt with 6 mg nalbuphine mg to 50 mg, 4 mg to 50 mg, 5 mg to 50 mg, 6 mg to 50 mg, hydrochloride salt, 0.4 mg of naloxone hydrochloride salt 7 mg to 50 mg, 3 mg to 45 mg, 5 mg to 45 mg, 10 mg to 45 with 6.5 mg nalbuphine hydrochloride salt, 0.4 mg of mg, 15 mg to 45 mg, 5 mg to 40 mg, 10 mg to 40 mg, 3 mg naloxone hydrochloride Salt with 7 mg nalbuphine hydro to 35 mg, 4 mg to 35 mg, 5 mg to 35 mg, 10 mg to 35 mg, chloride salt, 0.4 mg of naloxone hydrochloride salt with 7.5 3 mg to 30 mg, 4 mg to 30 mg, 5 mg to 30 mg, 3 mg to 25 mg nalbuphine hydrochloride Salt, 0.4 mg of naloxone mg, 4 mg to 25 mg, 3 mg to 20 mg, 4 mg to 20 mg, 5 mg hydrochloride salt with 8 mg nalbuphine hydrochloride salt, to 25 mg, 10 mg to 25 mg, 15 mg to 30 mg, 15 mg to 25 mg, 0.4 mg of naloxone hydrochloride Salt with 8.5 mg nalbu 10 mg to 20 mg, and 10 mg to 15 mg. phine hydrochloride salt, 0.4 mg of naloxone hydrochloride 0019. In certain embodiments in which pentazocine salt with 9 mg nalbuphine hydrochloride salt, 0.4 mg of hydrochloride Salt is administered, 0.02 mg to 8 mg, pref naloxone hydrochloride Salt with 9.5 mg nalbuphine hydro erably 0.1 mg to 0.8 mg of naloxone hydrochloride is chloride salt, 0.4 mg of naloxone hydrochloride salt with 10 preferably administered as the opioid antagonist hydrochlo mg nalbuphine hydrochloride Salt, and 0.8 mg naloxone ride Salt. Non-limiting examples of the present invention are hydrochloride salt with 10 mg nalbuphine hydrochloride methods comprising administration of 3 mg, 4 mg, 5 mg, 6 Salt. mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, US 2004/018091.6 A1 Sep. 16, 2004

15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, (i.e., the same number of moles) of the active butorphanol, 23 mg, 24 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, and 50 or, in certain embodiments, Such as Sustained release for mg pentazocine hydrochloride Salt with 0.1 mg, 0.15 mg, 0.2 mulations, results in release into the blood Stream of an mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg., 0.8 mg, 1 equivalent amount, but over a period of 15 minutes, 30 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, or 8 mg naloxone minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, hydrochloride salt. 12 hours, or 24 hours. 0020 Additionally, in certain embodiments, the inven 0024. The invention further provides methods of treating, tion comprises administration equivalent amounts of penta ameliorating or managing pain by administering the Zocine free base, non-hydrochloride Salt, prodrug, or mix K-opioid agonist/opioid antagonist combinations of the ture thereof to the Specified amounts of pentazocine invention by modes of administration other than intravenous hydrochloride Salt, i.e., contains the same amount (i.e., same administration and, in certain embodiments, other than oral number of moles) of active pentazocine and/or results in the administration for gastro-intestinal uptake, preferably, by Same blood concentration of pentazocine or active metabo mucosal administration, Such as, but not limited to, Sublin lite of pentazocine as a particular amount of pentazocine gual, intranasal, inhalation (e.g., pulmonary), Suppository hydrochloride Salt, or, in certain embodiments, Such as (e.g., rectal) but also by buccal, intramuscular, Subcutaneous Sustained release formulations, results in release into the or other parenteral administration, or, in certain cases, by blood Stream of an equivalent amount, but over a period of oral, transdermal (e.g., patch), etc. These methods comprise 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 administering, by a method other than intravenous admin hours, 10 hours, 12 hours, or 24 hours. istration, amounts of the K-opioid agonist free base, Salt, prodrug, or mixture thereof and the opioid antagonist free 0021. In other embodiments, the method of the invention base, Salt, prodrug, or mixture thereof that result in the same comprises intravenous administration ofbutorphanol, e.g. as blood concentration of the K-opioid agonist or the active the tartrate Salt, as the K-opioid agonist. The butorphanol metabolite of the K-opioid agonist and opioid antagonist or tartrate Salt form is preferably administered intravenously at active metabolite of opioid antagonist as would result from 0.3 to 10 times greater, 0.3 to 9 times greater, 0.3 to 8 times intravenous administration of the amounts of the K-opioid greater, 0.5 to 10 times greater, 0.3 to 7 times greater, 0.5 to agonist and opioid antagonists discussed above for intrave 7 times greater, 0.3 to 6 times greater. 0.5 to 6 times greater, nous administration. The exact amounts of the K-opioid 0.3 to 5 times greater, 0.5 to 5 times greater, 0.3 to 4 times agonist and opioid antagonist will vary depending on the greater, 0.5 to 4 times greater, 0.3 to 3 times greater, or 0.5 method of administration chosen due to different absorption to 3 times greater, by weight, than the amount of opioid rates and bioavailability of the agonist and antagonist. antagonist hydrochloride Salt, preferably naloxone hydro chloride Salt, administered. Non-limiting examples of the 0025. In certain preferred embodiments of the invention, present invention are methods comprising administration of the method of administration is Sublingual (or other oral 0.3 mg of butorphanol tartrate salt with 0.3 mg of naloxone cavity administration). In embodiments comprising Sublin hydrochloride Salt (i.e., 1 time greater, by weight, of butor gual administration of nalbuphine, the amount of nalbuphine phanol tartrate salt than naloxone hydrochloride salt), 0.5 hydrochloride salt is 1 to 60 times greater, 1 to 50 times mg ofbutorphanol tartrate Salt with 0.2 mg naloxone hydro greater, 1 to 45 times greater, 1 to 40 times greater, 5 to 50 chloride Salt (i.e., 2.5 times greater, by weight, butorphanol times greater, 5 to 40 times greater, 5 to 35 times greater, 10 tartrate Salt than naloxone hydrochloride Salt), and 0.8 mg of to 40 times greater, 15 to 40 times greater, 10 to 30 times butorphanol tartrate salt with 0.4 mg naloxone hydrochlo greater, 15 to 30 times greater, 1 to 30 times greater, 1 to 20 ride Salt (i.e., 2 times greater, by weight butorphanol tartrate times greater, 1 to 15 times greater, or 1 to 9 times greater, Salt than naloxone hydrochloride Salt). Alternatively, the by weight, than the amount of opioid antagonist hydrochlo weight ofbutorphanol tartrate Salt administered is 0.2 mg to ride Salt, preferably naloxone hydrochloride Salt, adminis 2 mg, 0.2 mg to 1.9 mg, 0.2 mg to 1.8 mg, 0.2 mg to 1.7 mg, tered. Non-limiting examples of methods of the present 0.25 mg to 1.9 mg, 0.25 mg to 1.8 mg, 0.25 mg to 1.75 mg, invention comprise Sublingual administration of 8 mg nal 0.25 mg to 1.5 mg, 0.25 mg to 1 mg, or 0.2 mg to 1 mg. buphine hydrochloride salt with 0.4 mg naloxone hydro chloride Salt (i.e., 20 times greater, by weight, nalbuphine 0022. In certain preferred embodiments comprising hydrochloride Salt than the opioid antagonist hydrochloride administration ofbutorphanol tartrate Salt, 0.02 mg to 8 mg, salt), 15 mg nalbuphine hydrochloride salt with 3 mg preferably 0.1 mg to 0.8 mg of naloxone hydrochloride salt naloxone hydrochloride Salt (i.e., 5 times greater, by weight, is administered as the opioid antagonist hydrochloride. nalbuphine hydrochloride Salt than the opioid antagonist Non-limiting examples of the present invention are methods hydrochloride salt), and 30 mg nalbuphine hydrochloride comprising administration of 0.2 mg, 0.3 mg, 0.4 mg., 0.5 Salt with 4 mg naloxone hydrochloride Salt (i.e., 7.5 times mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.1 mg, greater, by weight, nalbuphine hydrochloride Salt than the 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, or opioid antagonist hydrochloride Salt). Alternatively, 5 mg to 2.0 mg of butorphanol tartrate salt with 0.1 mg, 0.15 mg, 0.2 65 mg, 5 mg to 60 mg, 5 mg to 55 mg, 5 mg to 50 mg, 5 mg mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg., 0.45 mg, 0.5 mg, to 40 mg, 5 mg to 35 mg, 6 mg to 55 mg, 6 mg to 50 mg, 0.55 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 1 mg, 2 mg, 3 6 mg to 45 mg, 6 mg to 40 mg, 6 mg to 30 mg, 7 mg to 40 mg, 4 mg, 5 mg, 6 mg, 7 mg, or 8 mg naloxone hydrochlo mg, 7 mg to 35 mg, or 7.5 to 30 mg of nalbuphine ride Salt. hydrochloride Salt is administered Sublingually with an 0023. Additionally, the invention comprises administra amount of naloxone that enhances nalbuphine analgesia. tion of equivalent amounts of butorphanol free base, non 0026. In certain preferred embodiments of the invention tartrate Salt, prodrug, or mixture to the Specified amounts of in which the method comprises Sublingual administration of butorphanol tartrate Salt, i.e., contains an equivalent amount malbuphine hydrochloride salt, naloxone hydrochloride salt US 2004/018091.6 A1 Sep. 16, 2004

is preferably administered Sublingually as the opioid antago to 10 mg, 1 mg to 9 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg nist hydrochloride in amounts preferably 0.1 mg to 10 mg, to 6 mg, 1 mg to 5 mg, 1 mg to 4 mg, 2 mg to 10 mg, 2 mg 0.1 mg to 9 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to to 9 mg, 2 mg to 8 mg, 2 mg to 7 mg, 2 mg to 6 mg, 2 mg 6 mg, 0.2 mg to 10 mg, 0.2 mg to 9 mg, 0.2 mg to 8 mg, 0.2 to 5 mg, 2 mg to 4 mg, 2 mg to 3.8 mg, 2 mg to 3.6 mg, 2 mg to 7 mg, 0.2 mg to 6 mg, 0.2 mg to 5 mg, 0.3 mg to 10 mg to 3.4 mg, 2 mg to 3.4 mg, 2.2 mg to 3.5 mg, 2 mg to mg, 0.3 mg to 9 mg, 0.3 mg to 7 mg, 0.3 mg to 6 mg, 0.3 3.2 mg, 3 mg to 4 mg, or 2 mg to 3 mg. Non-limiting mg to 5 mg, 0.3 mg to 4 mg., 0.4 mg to 4 mg., 0.5 mg to 4 examples of the present invention are methods comprising mg, 0.4 mg to 3.5 mg, 0.5 mg to 3.5 mg, 0.6 mg to 3.5 mg, Sublingual administration of 30 mg, 31 mg, 32 mg, 33 mg, 0.4 mg to 3 mg, 0.5 mg to 3 mg, 0.4 mg to 2.8 mg, 0.6 mg 34 mg., 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, to 2.7 mg, 0.4 mg to 2.5 mg, 0.5 mg to 2.2 mg, 0.4 mg to 42 mg, 43 mg, 44 mg., 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 2 mg, 0.6 mg to 2 mg, 0.4 mg to 1.5 mg, or 0.4 mg to 1 mg. 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg Non-limiting examples of the present invention are methods pentazocine hydrochloride Salt with 2 mg, 2.1 mg, 2.2 mg, comprising administration of 5 mg, 5.5 mg, 6 mg, 6.5 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 g, 3 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg 10 mg, 15 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg., 3.5 mg, 3.6 mg, 3.7 mg, 3.8 20 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg nalbuphine mg, 3.9 mg, or 4.0 mg naloxone hydrochloride Salt. hydrochloride salt with naloxone hydrochloride salt. 0031 AS discussed above, the invention also encom 0027. For example, in specific embodiments of the passes Sublingual administration of amounts of pentazocine present invention, the method comprises Sublingual admin and/or naloxone free base, non-hydrochloride Salt, prodrug, istration of 0.4 mg of naloxone hydrochloride salt with 5 mg or mixtures thereof equivalent to the amounts of pentazocine of nalbuphine hydrochloride salt, 0.4 mg of naloxone hydro hydrochloride salt and naloxone hydrochloride Salt recited chloride salt with 6 mg of nalbuphine hydrochloride salt, 0.4 immediately above. In other embodiments, the invention mg of naloxone hydrochloride salt with 7 mg of nalbuphine provides, for example, controlled or Sustained release for hydrochloride salt, 0.4 mg of naloxone hydrochloride salt mulations that release equivalent amounts of pentazocine with 8 mg of nalbuphine hydrochloride salt, 0.4 mg of and naloxone to the Site of administration (e.g., the oral naloxone hydrochloride salt with 9 mg of nalbuphine hydro cavity) over a period of 15 minutes, 30 minutes, 1 hour, 2 chloride salt, 0.4 mg of naloxone hydrochloride salt with 10 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, or 24 mg of nalbuphine hydrochloride Salt, 0.4 mg of naloxone hours. hydrochloride salt with 15 mg of nalbuphine hydrochloride 0032. In certain embodiments comprising Sublingual salt, 0.4 mg of naloxone hydrochloride Salt with 20 mg of administration ofbutorphanol as the K-opioid agonist, butor nalbuphine hydrochloride Salt, 0.4 mg of naloxone hydro phanol tartrate Salt is administered in amounts 0.1 to 60 chloride salt with 25 mg of nalbuphine hydrochloride salt, times greater, 0.1 to 50 times greater, 0.1 to 45 times greater, and 0.4 mg of naloxone hydrochloride salt with 30 mg of 0.3 to 40 times greater, or 0.5 to 30 greater, 10 to 60 times malbuphine hydrochloride salt. greater, 20-60 times greater, and 10-30 times greater, by weight, than the opioid antagonist hydrochloride Salt, pref 0028. As discussed above, the invention also encom erably naloxone hydrochloride salt, administered. Non-lim passes Sublingual administration of amounts of nalbuphine iting examples of the present invention are methods com and/or naloxone free base, non-hydrochloride Salt, prodrug, prising Sublingual administration of 0.5 mg butorphanol or mixtures thereof equivalent to the amounts of nalbuphine tartrate Salt with 0.25 mg naloxone hydrochloride Salt (i.e., hydrochloride salt and naloxone hydrochloride salt recited 2 times greater, by weight, butorphanol tartrate Salt than the immediately above. In other embodiments, the invention opioid antagonist hydrochloride Salt), 2 mg butorphanol provides, for example, controlled or Sustained release for tartrate salt with 0.2 mg naloxone hydrochloride salt (i.e., 10 mulations that release equivalent amounts of nalbuphine and times greater, by weight, butorphanol tartrate Salt than the naloxone to the site of administration (e.g., the oral cavity) opioid antagonist hydrochloride Salt), and 6 mg butorphanol over a period of 15 minutes, 30 minutes, 1 hour, 2 hours, 4 tartrate salt with 0.3 mg naloxone hydrochloride salt (i.e., 20 hours, 6 hours, 8 hours, 10 hours, 12 hours, or 24 hours. times greater, by weight, butorphanol tartrate Salt than the 0029. In certain embodiments comprising Sublingual opioid antagonist hydrochloride Salt). Alternatively, 0.1 mg administration of pentazocine, the amount of pentazocine to 10 mg, 0.1 mg to 9 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, hydrochloride salt is 7.5 to 50 times greater, 7.5 to 45 times 0.1 mg to 6 mg, 0.2 mg to 9 mg, 0.2 mg to 8 mg, 0.2 mg to greater, 10 to 50 times greater, 10 to 40 times greater, 15 to 7 mg, 0.2 mg to 6 mg, 0.2 mg to 5.5 mg, 0.3 to 6.5 mg, 0.4 50 times greater, 15 to 45 times greater, 7.5 to 30 times mg to 7 mg, or 0.5 mg to 6 mg of butorphanol tartrate Salt greater, 7.5 to 25 times greater, 7.5 to 20 times greater, 10 is administered Sublingually. to 30 times greater, or 7.5 to 15 times greater, by weight, 0033. If the K-opioid agonist is butorphanol tartrate salt, than the amount of opioid antagonist hydrochloride Salt then, preferably, 0.1 to 4 mg., 0.1 mg to 3.5 mg, 0.1 mg to administered. Alternatively, the amount of pentazocine 3 mg, 0.1 to 2.5 mg, 0.1 mg to 2 mg, 0.1 mg to 1 mg, 0.3 hydrochloride Salt administered Sublingually is 30 mg to 100 mg to 0.8 mg, or 0.1 mg to 0.8 mg of naloxone hydrochloride mg, 30 to 90 mg, 40 mg to 100 mg, 30 mg to 85 mg, 40 mg Salt is administered. Non-limiting examples of the present to 85 mg, 30 mg to 70 mg, 40 mg to 70 mg, 30 mg to 60 mg, invention are methods comprising administration of 0.1 mg, 40 mg to 60 mg, 30 mg to 50 mg, 50 mg to 80, or 30 mg to 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 45 mg. 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, or 7 mg butorphanol 0.030. In embodiments of the invention in which penta tartrate Salt with 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg., 0.5 mg, 0.6 Zocine hydrochloride Salt is administered Sublingually, mg, 0.7 mg, or 0.85 mg naloxone hydrochloride Salt. naloxone hydrochloride Salt is the preferred opioid antago 0034. As discussed above, the invention also encom nist hydrochloride Salt and is administered in amounts 1 mg passes Sublingual administration of equivalent amounts of US 2004/018091.6 A1 Sep. 16, 2004 butorphanol and/or naloxone free base, other Salt, prodrug, phan, oxylorphan or cyprenorphine, and (b) an amount of a or mixtures thereof to the amounts of butorphanol tartrate free base, hydrochloride Salt, prodrug, non-hydrochloride Salt and naloxone hydrochloride Salt recited immediately Salt or mixture thereof of a kappa opioid, that results in above. In other embodiments, the invention provides, for greater analgesia than administration of either Said opioid example, controlled or Sustained release formulations that antagonist hydrochloride Salt or said kappa-opioid, wherein release equivalent amounts of butorphanol and naloxone to the kappa-opioid is pentazocine, butorphanol, ketazocine, the Site of administration (e.g., the oral cavity) over a period ethylketazocine, dezocine, bremazocine, a benzacetamide of 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, derivative, a phenothiazine derivative, a thiazine derivative, 8 hours, 10 hours, 12 hours, or 24 hours. or a benzodiazepine derivative, provided that 60 mg of pentazocine free base or an equivalent amount of pentazo 0035) In a preferred form of the invention, the combina cine hydrochloride Salt, non-hydrochloride Salt, prodrug, or tion of the K-opioid agonist, preferably nalbuphine, for mixture thereof, is not administered with 0.4 mg naloxone example as the hydrochloride Salt, and opioid antagonist, free base or equivalent amount of naloxone hydrochloride preferably naloxone, for example as the hydrochloride Salt, Salt, non-hydrochloride Salt, prodrug, or mixture thereof. is administered to the patient or Subject (preferably a human) Here, too the invention also comprises Such compositions. by mucosal administration, particularly by intranasal or pulmonary administration. In Such administration a compo 0039. In yet another embodiment the invention comprises Sition containing the two ingredients Suitable for Such a method of treating pain comprising administering to an administration, is used, as described hereinafter. In Such individual in need of said treatment (a) from about 0.1 to administration, the amounts of the opioid agonist and about 0.8 mg of a hydrochloride salt of naloxone or an antagonist, and the ratio of the one to the other, are as equivalent amount of naloxone free base, prodrug, non described above. Particularly good results are obtained by hydrochloride salt, or mixture thereof; and either (b) from administration of the combination wherein the weight ratio about 1 to about 2.5 mg, or (c) from about 8.5 to about 10.0 of nalbuphine component to naloxone component is from mg, of nalbuphine hydrochloride, or an equivalent amount about 10:1 to about 15:1, most preferably about 12.5:1 and of nalbuphine free base, prodrug, non-hydrochloride Salt or where the amount of nalbuphine (as the hydrochloride salt) mixture thereof. Here, too, the invention further comprises is 5 mg and the amount of naloxone (as the hydrochloride compositions for use in both methods. salt) is about 0.4 mg. 0040. In still another embodiment the invention com 0.036 The two ingredients also may be administered at prises a method of treating pain comprising administering to one-quarter of the appropriate dosage (e.g., 1.25 nalbuphine an individual in need of Said treatment (a) 0.2 mg of a hydrochloride and 0.1 mg naloxone hydrochloride), at one hydrochloride Salt of naloxone or an equivalent amount of half of that dosage (e.g., 2.5 mg nalbuphine hydrochloride naloxone free base, prodrug, non-hydrochloride Salt, or and 0.2 mg naloxone hydrochloride) or at twice (e.g., 10 mg mixture thereof; and (b) 2.5 mg of nalbuphine hydrochlo malbuphine hydrochloride and 0.8 mg naloxone hydrochlo ride, or an equivalent amount of nalbuphine free base, ride) or four times that dosage (e.g., 20 mg nalbuphine prodrug, non-hydrochloride Salt or mixture thereof. The hydrochloride and 1.6 mg naloxone hydrochloride). Such invention also comprises a method of treating pain compris dosage variations may be used, for example Such that ing administering to an individual in need of Said treatment patients of less body mass or less pain would receive higher (a) 0.8 mg of a hydrochloride Salt of naloxone or an doses and patients with greater body mass or more Severe equivalent amount of naloxone free base, prodrug, non pain would receive higher doses. hydrochloride salt, or mixture thereof; and (b) 10 mg of 0037 More specifically, in one embodiment the invention nalbuphine hydrochloride, or an equivalent amount of nal comprises a method of treating pain comprising mucosally buphine free base, prodrug, non-hydrochloride Salt or mix administering to an individual in need of Said treatment (a) ture thereof. Here, too, the invention further comprises 0.02 mg to 8 mg, preferably 0.1 mg to 0.8 mg of a compositions for use in both methods. hydrochloride Salt of an opioid antagonist or an equivalent 0041. The invention also provides pharmaceutical com amount of opioid antagonist free base, prodrug, non-hydro positions, formulations, and dosage units comprising the chloride Salt, or mixture thereof, wherein Said opioid antago K-opioid agonist-opioid antagonist combinations of the nist is naloxone, naltrexone, methylnaltrexone, nalmefene, invention. nalorphine, levalorphan, oxylorphan or cyprenorphine, and (b) an amount of nalbuphine free base, hydrochloride Salt, BRIEF DESCRIPTION OF DRAWINGS prodrug, non-hydrochloride Salt or mixture thereof that results in greater analgesia than administration of either said 0042 FIGS. 1a-d depicts the effects on postoperative opioid antagonist hydrochloride Salt or said nalbuphine pain of administration of 2.5 mg, 5 mg, and 10 mg nalbu alone. The invention further comprises compositions com phine hydrochloride Salt and 0.4 mg naloxone hydrochloride prising Such ingredients in Such amounts. Salt alone and in combination with each other in 264 Subjects who had undergone Surgery for removal of third molar 0.038. In another embodiment, the invention comprises a method of treating pain comprising administering to an (“wisdom”) teeth. individual in need of Said treatment (a) 0.02 mg to 8 mg, 0043 FIGS. 2a-d depicts the effects on postoperative preferably 0.1 mg to 0.8 mg of a hydrochloride salt of an pain of administration of 2.5 mg, 5 mg, and 10 mg nalbu opioid antagonist or an equivalent amount of opioid antago phine hydrochloride Salt and 0.4 mg naloxone hydrochloride nist free base, prodrug, non-hydrochloride Salt, or mixture Salt alone and in combination with each other in 281 patients thereof, wherein Said opioid antagonist is naloxone, naltr who had undergone Surgery for removal of third molar exone, methylmaltrexone, nalmefene, nalorphine, levalor (“wisdom”) teeth. US 2004/018091.6 A1 Sep. 16, 2004

0044 FIGS. 3a-b depicts the effects on postoperative are effective for the treatment, management, and ameliora pain of administration of 5 mg nalbuphine hydrochloride Salt tion of pain, including, but not limited to, inflammatory pain, with 0.1 mg, 0.2 mg, and 0.4 mg naloxone hydrochloride Salt neuropathic pain, acute pain, traumatic pain, infection-re in 52 patients who had undergone Surgery for removal of lated pain, postoperative or post-procedural pain, nocicep third molar (“wisdom”) teeth. tive pain, dental pain, migraine, cluster headaches, tension headaches, neuralgia, cancer pain, resistant pain, pain result 004.5 FIGS. 4a–b shows the effects on postoperative pain ing from burns, labor and delivery pain, postpartum pain, of administration of 2.5 mg nalbuphine hydrochloride salt irritable bowel Syndrome, fibromyalgia, pancreatic pain, and 2.5 mg nalbuphine hydrochloride salt with 0.4 mg myocardial infarction pain, temporal-mandibulla disorders, naloxone hydrochloride salt in 67 patients who had under including both pain in the central nervous System as well as gone surgery for removal of third molar (“wisdom”) teeth. pain in the peripheral nervous System, chronic pain, and 0.046 FIGS. 5a-b shows the effects on postoperative pain regional and generalized pain Syndromes, and reduces the of administration of 2.5 mg of nalbuphine hydrochloride likelihood of adverse effects, Such as, but not limited to, alone and in combination with 0.2 mg naloxone hydrochlo drowsiness, intestinal problems, development of physical ride to 65 patients who had undergone oral Surgery for dependence, and tolerance, etc. The terms “alleviating, removal of third molar (“wisdom”) teeth. “Suppressing and “inhibiting” refer to any indicia of Suc ceSS in the treatment or alleviating of pain, including both 0047 FIG. 6 shows visual analog scale (VAS) pain objective and Subjective parameterS Such as abatement, Scores for three patients who received repeated intravenous diminishing of Symptoms, making the pain Symptom or administrations of 5 mg nalbuphine hydrochloride plus 0.4 condition more tolerable to the patient or Subject, decreasing mg naloxone hydrochloride to treat postoperative pain fol the frequency or duration of the pain, or preventing or lowing Le Fort I osteotomy. decreasing the onset of pain expected to occur after an event. 0048 FIG. 7 shows visual analog scale (VAS) pain 0054 The present invention encompasses certain combi Scores for three patients who received repeated intravenous nations of centrally acting (i.e., cross the blood brain barrier) administrations of 5 mg nalbuphine hydrochloride plus 0.4 K-opioid receptor agonists and pure opioid antagonists (pref mg naloxone hydrochloride to treat postoperative pain fol erably, non-Selective opioid antagonists that antagonize at lowing Le Fort I osteotomy. least K, u, and 8 opioid receptors) that produce analgesia, but 0049 FIG. 8 shows visual analog scale (VAS) pain would induce anti-analgesia or produce leSS analgesia when scores for three patients who received repeated intravenous the agonist or the antagonist is administered alone. The administrations of 5 mg nalbuphine hydrochloride plus 0.4 present invention teaches methods and compositions that use mg naloxone hydrochloride to treat postoperative pain fol K-opioid receptor agonists to effectively treat pain with lowing Le Fort I osteotomy. fewer Side effects associated with administration of u recep 0050 FIG. 9 shows visual analog scale (VAS) pain tor opioid agonists, Such as, but not limited to dysphoria and Scores for three patients who received 5 mg nalbuphine potential for addiction or dependency on the u opioid. hydrochloride with 0.4 mg naloxone hydrochloride by intra 0055. Further, in certain embodiments, the present inven venous catheter for treatment of medically refractory tion encompasses certain combinations of K-opioid receptor trigeminal neuropathy. agonists and opioid antagonists that produce enhanced anal gesia in both male and female Subjects whereas administra 0051 FIG. 10 shows the relative change in pain for three tion of the K-opioid agonist alone in human and/or animal patients who received 5 mg nalbuphine hydrochloride with Subjects (preferably human) produces gender dimorphic 0.4 mg naloxone hydrochloride by intravenous catheter for effects, i.e. produces significantly more analgesia in females treatment of medically refractory trigeminal neuropathy. than males or produces analgesia in females and anti 0.052 FIG. 11 shows the effects on postoperative pain of analgesia in males, in groups comprising 10, 15, 20, 25, 30, intranasal administration of 5 mg of nalbuphine hydrochlo or more Subjects. ride alone and in combination with 0.4 mg naloxone hydro chloride to 5 patients who had undergone oral Surgery for Analgesic Compositions removal of third molar (“wisdom”) teeth. This figure 0056. The present invention provides methods for the includes a comparison with intravenous administration of treatment of pain and analgesic pharmaceutical composi the combination of 5 mg nalbuphine hydrochloride and 0.4 tions comprising combinations of centrally-acting-opioid mg naloxone hydrochloride. receptor agonist (preferably, exhibiting gender dimorphism DETAILED DESCRIPTION OF THE at certain doses) and centrally-acting, preferably non-Selec INVENTION tive opioid antagonists that provide greater pain relief than achieved with administration of either the agonist or antago 0.053 According to the present invention, greater anal nist alone (or, in certain embodiments, greater than the gesia is achieved by administration of a centrally acting additive analgesic effects of the agonist and antagonist K-opioid receptor agonist with a centrally acting opioid administered alone). Suitable K-opioid receptor agonists antagonist than administration of either the K-opioid recep include, but are not limited to benzomorphan derivatives, tor agonist or the opioid antagonist alone (and, in certain Such as, but not limited to, nalbuphine, butorphanol, keta embodiments, greater than the additive analgesic effect of Zocine, ethylketazocine, pentazocine, dezocine, and brema the agonist and antagonist when administered alone). AS Zocine; a benzacetamide derivative, Such as, but not limited used herein, "pain' includes all types of pain, including pain to U50,488, U69,593, U62,066 (spiradoline), PD 117302, in both the peripheral and central nervous Systems. The CI-977, DuP 747, ICI 197067, ICI 199441, BRL52537A, or present invention, therefore, provides potent analgesics that BRL 52656A, a phenothiazine derivative, such as but not US 2004/018091.6 A1 Sep. 16, 2004

limited to Rp 60180; a thiazine derivative, such as, but not certain Specific embodiments of the invention provide limited to R-84760; or a benzodiazepine derivative, such as, amounts and/or dosages for a specific form of the K-opioid but not limited to Tifluadom. In preferred embodiments of agonist and/or the opioid antagonist, i.e., the agonist or the the invention, the K-opioid agonist is butorphanol or penta antagonist free base, a pharmaceutically acceptable Salt, Zocine, or, most preferably, nalbuphine. Suitable opioid prodrug, or mixture thereof, the equivalent amount of any antagonists include, but are not limited to nalorphine, form of the agonist or antagonist may be used in this levalorphan, OXylorphan, cyprenorphine, preferably, naltr invention. AS used herein and unless otherwise indicated, the exone, methylmaltrexone and nalnefene, or, most preferably, term “equivalent amount' or “amount equivalent to' is naloxone. defined as the amount of agonist or antagonist free base, Salt, prodrug, or mixture (or any other pharmaceutically accept 0057 The K-opioid receptor agonists and opioid antago able form) thereof that contains the same weight of the nists of this invention may be in any pharmaceutically active ingredient (i.e., the same number of moles of nalox acceptable form, e.g., in the form of the free base compound, one, nalbuphine or other opioid antagonists and K-opioid a pharmaceutically acceptable Salt, a prodrug, or a mixture agonists, etc.), or produces the same blood concentration of thereof. AS used herein and unless otherwise indicated, the the respective agonist or antagonist or active metabolite of term “free base' of the K-opioid agonist or opioid antagonist agonist or antagonist as produced by an amount of the refers to the pure form of the respective agonist or antago agonist or antagonist in Specified form. In certain embodi nist. AS used herein and unless otherwise indicated, the term ments, for example, approximately 1.0 mg of naloxone “pharmaceutically acceptable” means approved by a regu hydrochloride Salt contains approximately 0.9 mg of nalox latory agency of the Federal, State, or other foreign govern one free base and approximately 0.9 mg of naloxone free ment or listed in the U.S. Pharmacopoeia or other generally base produces the same blood concentration of naloxone or recognized pharmacopeias for use in animals, more particu active metabolite of naloxone when administered intrave larly humans. nously as does intravenous administration of approximately 0.058. The term “pharmaceutically acceptable salts' is 1 mg of naloxone hydrochloride Salt, therefore, an equiva meant to include Salts of the active compounds which are lent amount of naloxone free base to 1 mg of naloxone prepared with relatively nontoxic acids or bases, depending hydrochloride salt would be approximately 0.9 mg. on the particular Substituents found on the compounds 0061 The actual equivalent amounts of one form to described herein. By “pharmaceutically acceptable” is another form may depend on how the respective forms are meant that the Salt in question is or can be approved by a administered due to different absorption rates of the agonist regulatory agency of the Federal, State, or other foreign or antagonist based the on method of administration. Unless government or listed in the U.S. Pharmacopoeia or other otherwise indicated, the different forms of the agonist or generally recognized pharmacopeias for use in animals, antagonist are administered by the same method. If the more particularly in humans. When compounds of the different forms of the agonist or antagonist are administered present invention contain relatively acidic functionalities, by different methods, the equivalent amounts of the forms base addition Salts can be obtained by contacting the neutral are amounts that produce the same blood concentration of form of Such compounds with a Sufficient amount of the the respective agonist or antagonist, or active metabolite of desired base, either neat or in a Suitable inert Solvent. the agonist or antagonist. In certain embodiments, an equivalent amount includes an amount of the agonist and/or 0059 Examples of pharmaceutically acceptable base antagonist that is released over a period of time, e.g., 15 addition Salts include Sodium, potassium, calcium, ammo minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 nium, organic amino, or magnesium Salt, or a similar Salt. hours, 10 hours, 12 hours, or 24 hours, into the site of When compounds of the present invention contain relatively delivery, even if the administration does not achieve the basic functionalities, acid addition Salts can be obtained by Same blood concentration of the agonist and/or antagonist. contacting the neutral form of Such compounds with a Sufficient amount of the desired acid, either neat or in a 0062 Methods of determining equivalent amounts of one Suitable inert Solvent. Examples of pharmaceutically accept form to another form, for example, naloxone hydrochloride able acid addition Salts include those derived from inorganic Salt to naloxone free base, are readily known in the art. Any acids like hydrochloric, hydrobromic, nitric, carbonic, method commonly known in the art may be used to measure monohydrogencarbonic, phosphoric, monohydrogenphos the blood concentration of the K-opioid agonist, the opioid phoric, dihydrogenphosphoric, Sulfuric, monohydrogensul antagonist, or active metabolites of the agonist or antagonist. furic, hydriodic, or phosphorous acids and the like, as well For example, methods for measuring the blood concentra as the Salts derived from relatively nontoxic organic acids tion of opioids, Such as nalbuphine, and of opioid antago like acetic, propionic, isobutyric, maleic, malonic, benzoic, nists are well-known in the art (see, e.g., Pao et al., 2000, Succinic, Suberic, fumaric, lactic, mandelic, phthalic, ben "High-performance liquid chromatographic method for the ZeneSulfonic, p-tolylsulfonic, citric, tartaric, methane Simultaneous determination of nalbuphine and its prodrug, Sulfonic, and the like. Also included are Salts of amino acids Sebacoyl dinalbuphine ester, in dog plasma and application Such as arginate and the like, and Salts of organic acids like to pharmacokinetic Studies in dogs,” J. Chromatogr. B glucuronic or galacturonic acids and the like (see, for Biomed. Sci. Appl. 746(2):241-7; Sung et al., 2000, “Deliv example, Berge et al., “Pharmaceutical Salts”, Journal of ery of nalbuphine and its prodrugs acroSS Skin by passive Pharmaceutical Science, 1977, 66, 1-19, the text of which is diffusion and iontophoresis,” J. Control. Release 67(1): 1-8; de Cazanove et al., 1997, “Determination of nalbuphine in hereby incorporated herein, in its entirety). human plasma by high-performance liquid chromatography 0060. The K-opioid agonist and the antagonist of the with electrochemical detection. Application to pharmacoki invention may be in the form of the free base, a Salt, a netic study,” J. Chromatogr. B Biomed. Sci. Appl. 690(1-2): prodrug, or a mixture of two or more of these. Although 203-10; Ho et al., 1996 Apr. 12, “Determination of nalbu US 2004/018091.6 A1 Sep. 16, 2004

phine by high-performance liquid chromatography with col, water, ethanol, and the like. The composition, if desired, ultraViolet detection: application to human and rabbit phar can also contain minor amounts of wetting or emulsifying macokinetic Studies,” J. Chromatogr. B Biomed. Appl. agents, or pH buffering agents. These compositions can take 678(2): 289-96; Nicolle et al., 1995 Jan. 6, “Rapid and the form of Solutions, Suspensions, emulsions, tablets, pills, Sensitive high-performance liquid chromatographic assay capsules, powders, Sustained-release formations and the for nalbuphine in plasma,” J. Chromatogr. B Biomed. Appl. like. Oral formulations can include Standard carrierS Such as 663(1):111-7; Wetzelsberger et al., 1988 December, “Inter pharmaceutical grades of mannitol, lactose, Starch, magne nally standardized method for the determination of nalbu sium Stearate, Sodium Saccharine, cellulose, magnesium phine in human plasma by means of high performance liquid carbonate, etc. Examples of Suitable pharmaceutical carriers chromatography with electrochemical coulometric detec are described in “Remington's Pharmaceutical Sciences” by tion,” Arzneimittelforschung 38(12):1768-71; Dube et al., E. W. Martin. 1988 May 13, “Determination of nalbuphine by high-per formance liquid chromatography with electrochemical 0064. The invention encompasses pharmaceutical com detection: application to clinical Samples from postoperative positions comprising an amount of a K-opioid receptor patients,” J. Chromatogr. 427(1): 113-20; Lo et al., 1987 agonist and opioid antagonist that produces greater analgesia November, “The disposition and bioavailability of intrave than the administration of either the agonist or antagonist nous and oral nalbuphine in healthy volunteers,” J. Clin. alone (or greater than their additive effects) together with a Pharmacol. 27(11): 866-73; incorporated herein by refer Suitable amount of carrier So as to provide the form for ence in their entireties; Ameyibor et al., 1997 Dec. 5, proper administration to the patient. The formulation of the “Resolution and quantitation of pentazocine enantiomers in invention should Suit the mode of administration. The human Serum by reversed-phase high-performance liquid amount of the compositions of the invention which will be chromatography using Sulfated beta-cyclodextrin as chiral effective in treating, managing, or ameliorating pain can be mobile phase additive and Solid-phase extraction,” J. Chro determined by Standard clinical techniques. The precise dose matogr. B. Biomed. Sci. Appl. 703(1-2):273; Suzuki et al., to be employed in the formulation will depend on the route 1997 November, “Pharmacokinetics of pentazocine and its of administration, the intensity of pain the Subject is expe occupancy of opioid receptors in rat brain,” Biol. Pharm. riencing, and the Size and weight of the Subject, the Subject Bull. 20(11): 1193-8; Kelly et al., 1994 September-October, gender and should be decided according to the judgment of “HPLC Separation of pentazocine enantiomers in Serum the practitioner and each patient's circumstances. using an ovomucoid chiral Stationary phase,” Biomed. Chro 0065. In certain preferred embodiments of the invention, matogr. 8(5):255-7; Misztal et al., 1991 June, “Determina the pharmaceutical compositions comprise an amount of a tion of pentazocine in human plasma by high performance K-opioid receptor agonist and an amount of an opioid liquid chromatography.” Pharmazie, 46(6): 464-5; Moeller receptor antagonist, Such that the combination provides et al., 1990 Aug. 24, “High-performance liquid chromato greater analgesia than either agonist or antagonist alone graphic determination of pentazocine in plasma, J. Chro and/or has reduced side effects compared to either agonist or matogr. 530(1):200-5; Kintz et al., 1990 Apr., “Simultaneous antagonist alone. The opioid antagonist is preferably nalox Screening and quantification of Several nonopiate narcotic OC. analgesics and phencyclidine in human plasma using capil lary gas chromatography,” Methods Find Exp. Clin. Phar 0066 More specifically, preferred pharmaceutical com macol. 12(3):193-6; Shibanoki et al., 1987 Oct. 30, “Appli positions of this invention are formulated for intravenous cation of high-performance liquid chromatography with administration or mucosal administration (e.g., nasal or electrochemical detection for monitoring the concentration pulmonary administration) and comprise of naloxone hydro of pentazocine in human blood,” J. Chromatogr. 421(2):425 chloride salt in amounts of 0.02 mg to 8 mg, 0.02 to 7 mg, 9; Anderson et al., 1982 Jan. 8, “High-performance liquid 0.02 mg to 6 mg, 0.02 to 5 mg, 0.02 to 4 mg., 0.02 to 3 mg, chromatographic analysis of pentazocine in blood and 0.02 to 2 mg, 0.02 to 2 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, plasma,” J. Chromatogr. 227(1): 239-43; Clemans et al., 0.1 mg to 6 mg, 0.1 mg to 5 mg, 0.1 mg to 4 mg., 0.1 mg to 1979 May, “Plasma pentazocine radioimmunoassay,” J. 3 mg, 0.1 mg to 2 mg, 0.1 mg to 1 mg, 0.2 mg to 8 mg, 0.2 mg to 7 mg, 0.2 mg to 6 mg, 0.2 mg to 4 mg., 0.2 mg to 3 Pharm. Sci. 68(5): 626-8; and Williams et al., 1974 Jan., mg, 0.2 mg to 2 mg, 0.2 mg to 1 mg, 0.4 mg to 8 mg, 0.4 “Pentazocine radioimmunoassay,” 7(1): 119-43. to 7 mg, 0.4 to 6 mg, 0.4 mg to 5 mg, 0.4 mg to 4 mg., 0.4 0.063 Certain embodiments of the invention may include mg to 3 mg, 0.4 mg to 2 mg, 0.4 mg to 1 mg, 0.5 mg to 8 a pharmaceutically acceptable carrier. The term “carrier' mg, 0.5 mg to 6 mg, 0.5 mg to 5 mg, 0.5 mg to 4 mg., 0.5 refers to a diluent, adjuvant (e.g., Freund's adjuvant (com mg to 3 mg, 0.5 mg to 3 mg, 0.5 to 2 mg, 0.5 mg to 1 mg, plete or incomplete)), excipient, or vehicle with which the 1 mg to 8 mg, 1 mg to 6 mg, 1 mg to 5 mg, 1 mg to 4 mg, therapeutic is administered. Such pharmaceutical carriers 1 mg to 3 mg, 1 mg to 2 mg, 5 mg to 8 mg, 4 mg to 7 mg, can be Sterile liquids, Such as water and oils, including those 3 mg to 5 mg, 0.02 mg to 1 mg, preferably 0.1 mg to 0.8 mg, of petroleum, animal, vegetable, or Synthetic origin, Such as 0.2 mg to 0.8 mg, 0.3 mg to 0.8 mg, 0.4 mg to 0.8 mg, 0.5 peanut oil, Soybean oil, mineral oil, Sesame oil, and the like. mg to 0.8 mg, 0.1 mg to 0.7 mg, 0.2 mg to 0.7 mg, 0.3 mg Water is a preferred carrier when the pharmaceutical com to 0.7 mg, 0.4 mg to 0.7 mg, 0.1 mg to 0.6 mg, 0.2 mg to position is administered intravenously. Saline Solutions and 0.6 mg, 0.3 to 0.6 mg, 0.1 mg to 0.5 mg, 0.15 mg to 0.5 mg, aqueous dextrose and glycerol Solutions can also be 0.2 mg to 0.5 mg, 0.25 mg to 0.5 mg, 0.3 mg to 0.5 mg, 0.35 employed as liquid carriers, particularly for injectable Solu mg to 0.5 mg, 0.1 mg to 0.45 mg, 0.15 mg to 0.45 mg, 0.2 tions. Suitable pharmaceutical excipients include Starch, mg to 0.45 mg, 0.25 mg to 0.45 mg, 0.1 mg to 0.3 mg, 0.13 glucose, lactose, Sucrose, gelatin, malt, rice, flour, chalk, mg to 0.3 mg, 0.2 mg to 0.3 mg, 0.1 mg to 0.25 mg, 0.15 mg Silica, gel, Sodium Stearate, glycerol monoStearate, talc, to 0.25 mg, 0.1 mg to 0.2 mg, 0.1 mg to 0.15 mg. Typical Sodium chloride, dried skim milk, glycerol, propylene, gly amounts of naloxone hydrochloride Salt are 0.1 mg, 0.15 mg, US 2004/018091.6 A1 Sep. 16, 2004

0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg., 0.45 mg, 0.5 mg, tion, less than or at approximately 2 hours after administra 0.55 mg, 0.6 mg 0.7 mg, 0.75 mg, 0.8 mg, 1 mg, 1.6 mg, 2 tion, less than or approximately 3 hours after administration, mg, 2.4 mg., 3 mg, 4 mg, 5 mg, 6 mg, 7 mg and 8 mg less than or approximately 4 hours after administration, leSS naloxone hydrochloride Salt. The pharmaceutical composi than or approximately 5 hours after administration, or leSS tions of the preferred embodiments of the invention may than or approximately 6 hours after administration. Depend alternatively comprise of an equivalent amount of naloxone ing on the Specific non-intravenous mode of administration, free base, non-hydrochloride Salt, prodrug or mixture thereof a composition for non-intravenous administration may com to the recited amounts of naloxone hydrochloride Salt. prise a ratio of the K-opioid agonist to opioid antagonist that 0067. The present invention also provides pharmaceuti is lesser, equal, or greater than the ratio of K-opioid agonist cal compositions formulated for administration by a method to opioid agonist in an equivalent composition for intrave other than intravenous administration. In these preferred nous administration. Also depending on the Specific non embodiments, the pharmaceutical composition comprises an intravenous mode of administration, a composition for amount of naloxone free base, pharmaceutically acceptable administration other than intravenous may comprise lesser, Salt, prodrug, or mixture thereof equivalent (i.e., resulting in equal, or greater amounts of K-opioid agonist and opioid the same blood concentration) as intravenous administration antagonist, by weight, than an equivalent composition for of 0.02 mg to 8 mg, 0.02 to 7 mg, 0.02 mg to 6 mg, 0.02 to intravenous administration. 5 mg, 0.02 to 4 mg., 0.02 to 3 mg, 0.02 to 2 mg, 0.02 to 2 0070. In certain preferred embodiments of the invention, mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 6 mg, 0.1 pharmaceutical compositions formulated for Sublingual mg to 5 mg, 0.1 mg to 4 mg., 0.1 mg to 3 mg, 0.1 mg to 2 administration, the K-opioid receptor agonist is nalbuphine mg, 0.1 mg to 1 mg, 0.2 mg to 8 mg, 0.2 mg to 7 mg, 0.2 hydrochloride Salt and the opioid antagonist is naloxone mg to 6 mg, 0.2 mg to 4 mg., 0.2 mg to 3 mg, 0.2 mg to 2 hydrochloride Salt and the composition comprises 0.1 mg to mg, 0.2 mg to 1 mg, 0.4 mg to 8 mg, 0.4 to 7 mg, 0.4 to 6 10 mg, 0.1 mg to 9 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg, 0.4 mg to 5 mg, 0.4 mg to 4 mg., 0.4 mg to 3 mg, 0.4 mg to 6 mg, 0.2 mg to 10 mg, 0.2 mg to 9 mg, 0.2 mg to 8 mg to 2 mg, 0.4 mg to 1 mg, 0.5 mg to 8 mg, 0.5 mg to 6 mg, 0.2 mg to 7 mg, 0.2 mg to 6 mg, 0.2 mg to 5 mg, 0.3 mg, 0.5 mg to 5 mg, 0.5 mg to 4 mg., 0.5 mg to 3 mg, 0.5 mg to 10 mg, 0.3 mg to 9 mg, 0.3 mg to 7 mg, 0.3 mg to 6 mg to 3 mg, 0.5 to 2 mg, 0.5 mg to 1 mg, 1 mg to 8 mg, 1 mg, 0.3 mg to 5 mg, 0.3 mg to 4 mg., 0.4 mg to 4 mg., 0.5 mg to 6 mg, 1 mg to 5 mg, 1 mg to 4 mg, 1 mg to 3 mg, 1 mg to 4 mg., 0.4 mg to 3.5 mg, 0.5 mg to 3.5 mg, 0.6 mg to mg to 2 mg, 5 mg to 8 mg, 4 mg to 7 mg, 3 mg to 5 mg, 0.02 3.5 mg, 0.4 mg to 3 mg, 0.5 mg to 3 mg, 0.4 mg to 2.8 mg, mg to 1 mg, preferably 0.1 mg to 0.8 mg, 0.2 mg to 0.8 mg, 0.6 mg to 2.7 mg, 0.4 mg to 2.5 mg, 0.5 mg to 2.2 mg, 0.4 0.3 mg to 0.8 mg, 0.4 mg to 0.8 mg, 0.5 mg to 0.8 mg, 0.1 mg to 2 mg, 0.6 mg to 2 mg, 0.4 mg to 1.5 mg, or 0.4 mg mg to 0.7 mg, 0.2 mg to 0.7 mg, 0.3 mg to 0.7 mg, 0.4 mg to 1 mg naloxone hydrochloride Salt or equivalent amounts to 0.7 mg, 0.1 mg to 0.6 mg, 0.2 mg to 0.6 mg, 0.3 to 0.6 mg, of naloxone free base, non-chloride Salt, prodrug, or mixture 0.1 mg to 0.5 mg, 0.15 mg to 0.5 mg, 0.2 mg to 0.5 mg, 0.25 thereof. mg to 0.5 mg, 0.3 mg to 0.5 mg, 0.35 mg to 0.5 mg, 0.1 mg to 0.45 mg, 0.15 mg to 0.45 mg, 0.2 mg to 0.45 mg, 0.25 mg 0071. If the pharmaceutical composition formulated for to 0.45 mg, 0.1 mg to 0.3 mg, 0.13 mg to 0.3 mg, 0.2 mg to Sublingual administration comprises pentazocine hydrochlo 0.3 mg, 0.1 mg to 0.25 mg, 0.15 mg to 0.25 mg, 0.1 mg to ride Salt as the K-Opioid receptor agonist and naloxone 0.2 mg, 0.1 mg to 0.15 mg naloxone hydrochloride Salt. hydrochloride Salt as the opioid antagonist, the amount of naloxone hydrochloride Salt is preferably 1 mg to 10 mg, 1 0068. In certain embodiments, the pharmaceutical com mg to 9 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 6 mg, 1 position of the present invention comprises an amount of mg to 5 mg, 1 mg to 4 mg, 2 mg to 10 mg, 2 mg to 9 mg, nalbuphine free base, pharmaceutically acceptable Salt, pro 2 mg to 8 mg, 2 mg to 7 mg, 2 mg to 6 mg, 2 mg to 5 mg, drug, or mixture thereof equivalent (i.e., resulting in the 2 mg to 4 mg, 2 mg to 3.8 mg, 2 mg to 3.6 mg, 2 mg to 3.4 same blood concentration) as intravenous administration of mg, 2 mg to 3.4 mg, 2.2 mg to 3.5 mg, 2 mg to 3.2 mg, 3 1 mg to 50 mg, 1 mg to 45 mg, 1 mg to 40 mg, 1 mg to 35 mg to 4 mg, or 2 mg to 3 mg or equivalent amounts of mg, 1 mg to 30 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg naloxone free base, non-chloride Salt, prodrug, or mixture to 15 mg, 1 mg to 10 mg, 1 mg to 9 mg, 1 mg to 8 mg, 2 thereof. mg to 8 mg, 3 mg to 8 mg, 1 mg to 7 mg, 2 mg to 7 mg, 3 mg to 7 mg, 4 mg to 7 mg, 1 mg to 6 mg, 2 mg to 6 mg, 3 0072. In other specific embodiments of the present inven mg to 6 mg, 1 mg to 5 mg, 2 mg to 5 mg, 1 mg to 4 mg, 1 tion, pharmaceutical compositions formulated for Sublingual mg to 3 mg, 1 mg to 2 mg nalbuphine hydrochloride Salt. administration in which butorphanol tartrate Salt is the K-opioid receptor agonist and naloxone is the opioid antago 0069. Any method in the art may be used to measure the nist, comprise 0.1 to 4 mg., 0.1 mg to 3.5 mg, 0.1 mg to 3 mg, blood concentration. For example, but not by way of limi 0.1 to 2.5 mg, 0.1 mg to 2 mg, 0.1 mg to 1 mg, 0.3 mg to tation, blood concentration of K-opioid agonists and opioid antagonists may be measured by high-performance liquid 0.8 mg, or 0.1 mg to 0.8 mg of naloxone hydrochloride salt chromatography or any assays described, Supra. Blood con or equivalent amounts of naloxone free base, non-hydro centration of K-opioid agonists and antagonists may be chloride chloride Salt, prodrug, or mixture thereof. measured immediately after administration, less than or at 0073. In general, the amounts of K-opioid agonist in the approximately 10 minutes after administration, less than or pharmaceutical compositions of this invention are in the at approximately 15 minutes after administration, less than range of 5% to 100% of the recommended analgesic dose or at approximately 20 minutes after administration, leSS (e.g., as provided in the Physician's Desk Reference or other than or at approximately 30 minutes after administration, commonly used reference). Preferably, the dose the K-opioid less than or at approximately 45 minutes after administra agonist is 5% to 90%, 10% to 90%, 5% to 85%, 10% to 85%, tion, less than or at approximately 1 hour after administra 15% to 85%, 20% to 80%, 5% to 75%, 10% to 75%, 15% US 2004/018091.6 A1 Sep. 16, 2004

to 70%, 15% to 60%, 5% to 55%, 10% to 55%, 15% to 50%, chloride Salt is the opioid antagonist hydrochloride Salt. 5% to 50%, 5% to 45%, 5% to 40%, 5% to 35%, 5% to 30%, Non-limiting examples of the method of the present inven 10% to 40%, 10% to 35%, 10% to 30%, 15% to 40%, 15% tion comprises 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, to 35%, 15% to 30%, 5% to 25%, 10% to 25%, 15% to 25%, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 5% to 20%, and 5% to 15% of the recommended analgesic 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, dose. However, as mentioned above, the compositions may 25 mg, 30 mg, 40 mg, or 50 mg of nalbuphine hydrochloride contain a fraction or a multiple of the recommended anal Salt with 0.1 mg, 0.15 mg, 0.2 mg, 0.2 mg, 0.25 mg, 0.3 mg, gesic dose. 0.35 mg, 0.4 mg., 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 1 mg, 1.6 0.074. In a specific embodiment of the invention, the mg, 2 mg, 2.4 mg., 3 mg, 4 mg, 5 mg, 6 mg, 7 mg and 8 mg pharmaceutical composition is an intravenous formulation of naloxone hydrochloride salt. or mucosal formulation comprising a K-opioid receptor 0076 For example, specific embodiments of the inven agonist and an opioid antagonist that produces more anal tion comprise of intravenous administration of 0.1 mg gesia and/or reduced Side effects than either the agonist or naloxone hydrochloride salt with 1.25 mg nalbuphine hydro antagonist alone. In preferred embodiments, the pharmaceu chloride salt, 0.2 mg of naloxone hydrochloride salt with 1 tical composition comprises of an amount of an opioid mg nalbuphine hydrochloride Salt, 0.2 mg of naloxone antagonist hydrochloride Salt, preferably naloxone hydro hydrochloride salt with 1.5 mg nalbuphine hydrochloride chloride salt, and 6.25 to 49 times greater, 6.25 to 40 times Salt, 0.2 mg of naloxone hydrochloride Salt with 2 mg greater, 6.25 to 35 times greater, 6.25 to 30 times greater, nalbuphine hydrochloride Salt, 0.2 mg of naloxone hydro 6.25 to 20 times greater, 8 to 35 times greater, 8 to 30 times chloride salt with 2.5 mg nalbuphine hydrochloride salt, 0.2 greater, 8 to 25 times greater, 10 to 30 times greater, 10 to mg of naloxone hydrochloride Salt with 3 mg nalbuphine 20 times greater, 15 to 25 times greater, 20 to 25 times hydrochloride salt, 0.2 mg of naloxone hydrochloride salt greater, 10 to 15 times greater, 9 to 15 times greater, 5 to 10 with 3.5 mg nalbuphine hydrochloride salt, 0.2 mg of times greater, 30 to 49 times greater, 20 to 30 times greater, naloxone hydrochloride Salt with 4 mg nalbuphine hydro 15 to 20 times greater, 13 to 15 times greater, 11 to 13 times chloride salt, 0.2 mg of naloxone hydrochloride Salt with 4.5 greater, 9 to 11 times greater, 7 to 9 times greater, or 6.25 to mg nalbuphine hydrochloride Salt, 0.2 mg of naloxone 7 times greater by weight, nalbuphine hydrochloride Salt hydrochloride salt with 5 mg nalbuphine hydrochloride salt, than the amount of opioid antagonist hydrochloride Salt. 0.2 mg of naloxone hydrochloride Salt with 5.5 mg nalbu Non-limiting examples of intravenous formulations of the phine hydrochloride salt, 0.2 mg of naloxone hydrochloride present invention are 3 mg of nalbuphine hydrochloride Salt salt with 6 mg nalbuphine hydrochloride salt, 0.2 mg of with 0.4 mg naloxone hydrochloride salt (i.e., 7.5 times naloxone hydrochloride Salt with 6.5 mg nalbuphine hydro greater nalbuphine hydrochloride Salt than the opioid chloride salt, 0.2 mg of naloxone hydrochloride salt with 7 antagonist hydrochloride Salt; 1.25 mg nalbuphine hydro mg nalbuphine hydrochloride Salt 0.2 mg of naloxone chloride salt with 0.1 mg naloxone hydrochloride salt, 2.5 hydrochloride salt with 7.5 mg nalbuphine hydrochloride mg nalbuphine hydrochloride Salt with 0.2 mg naloxone Salt, 0.2 mg of naloxone hydrochloride Salt with 8 mg hydrochloride salt, 5 mg nalbuphine hydrochloride salt with nalbuphine hydrochloride Salt, 0.2 mg of naloxone hydro 0.4 mg naloxone hydrochloride Salt, 10 mg nalbuphine chloride salt with 8.5 mg nalbuphine hydrochloride salt, 0.2 hydrochloride Salt with 0.8 mg naloxone hydrochloride salt, mg of naloxone hydrochloride Salt with 9 mg nalbuphine 20 mg nalbuphine hydrochloride Salt with 1.6 mg naloxone hydrochloride salt, 0.2 mg of naloxone hydrochloride salt hydrochloride salt, 25 mg nalbuphine hydrochloride salt with 9.5 mg nalbuphine hydrochloride salt, 0.2 mg of with 2.0 mg naloxone hydrochloride Salt, and 30 mg nal naloxone hydrochloride salt with 10 mg nalbuphine hydro buphine hydrochloride salt with 2.4 mg naloxone hydro chloride salt, 0.4 mg of naloxone hydrochloride salt with 1 chloride Salt (i.e., 12.5 times greater, by weight, nalbuphine mg nalbuphine hydrochloride Salt, 0.4 mg of naloxone hydrochloride salt than the naloxone hydrochloride salt); 5 hydrochloride salt with 1.5 mg nalbuphine hydrochloride mg nalbuphine hydrochloride Salt with 0.2 mg naloxone salt, 0.4 mg of naloxone hydrochloride Salt with 2.0 mg hydrochloride Salt and 10 mg nalbuphine hydrochloride salt nalbuphine hydrochloride Salt, 0.4 mg of naloxone hydro with 0.4 mg naloxone hydrochloride salt (i.e., 25 times chloride salt with 2.5 mg nalbuphine hydrochloride salt, 0.4 greater nalbuphine hydrochloride Salt than the naloxone mg of naloxone hydrochloride Salt with 3 mg nalbuphine hydrochloride salt); 4.9 mg nalbuphine hydrochloride salt hydrochloride salt, 0.4 mg of naloxone hydrochloride salt with 0.1 mg naloxone hydrochloride salt and 9.8 mg nal with 3.5 mg nalbuphine hydrochloride salt, 0.4 mg of buphine hydrochloride salt with 0.2 mg naloxone hydro naloxone hydrochloride Salt with 4 mg nalbuphine hydro chloride Salt (i.e., 49 times greater, by weight, nalbuphine chloride salt, 0.4 mg of naloxone hydrochloride Salt with 4.5 hydrochloride salt than naloxone hydrochloride salt). mg nalbuphine hydrochloride Salt, 0.4 mg of naloxone 0075 Alternatively, preferred embodiments of pharma hydrochloride salt with 5 mg nalbuphine hydrochloride salt, ceutical compositions for intravenous administration com 0.4 mg of naloxone hydrochloride Salt with 5.5 mg nalbu prise 1 mg to 50 mg, 1 mg to 45 mg, 1 mg to 40 mg, 1 mg phine hydrochloride salt, 0.4 mg of naloxone hydrochloride to 35 mg, 1 mg to 30 mg, 1 mg to 25 mg, 1 mg to 20 mg, salt with 6 mg nalbuphine hydrochloride salt, 0.4 mg of 1 mg to 15 mg, 1 mg to 10 mg, 1 mg to 9 mg, 1 mg to 8 mg, naloxone hydrochloride Salt with 6.5 mg nalbuphine hydro 2 mg to 8 mg, 3 mg to 8 mg, 1 mg to 7 mg, 2 mg to 7 mg, chloride salt, 0.4 mg of naloxone hydrochloride salt with 7 3 mg to 7 mg, 4 mg to 7 mg, 1 mg to 6 mg, 2 mg to 6 mg, mg nalbuphine hydrochloride Salt, 0.4 mg of naloxone 3 mg to 6 mg, 1 mg to 5 mg, 2 mg to 5 mg, 1 mg to 4 mg, hydrochloride salt with 7.5 mg nalbuphine hydrochloride 1 mg to 3 mg, 1 mg to 2 mg nalbuphine hydrochloride Salt. Salt, 0.4 mg of naloxone hydrochloride Salt with 8 mg In certain preferred embodiments in which nalbuphine nalbuphine hydrochloride Salt, 0.4 mg of naloxone hydro hydrochloride Salt is the K-opioid agonist, preferably, 0.02 chloride salt with 8.5 mg nalbuphine hydrochloride salt, 0.4 mg to 8 mg, preferably, 0.1 mg to 0.8 mg naloxone hydro mg of naloxone hydrochloride Salt with 9 mg nalbuphine US 2004/018091.6 A1 Sep. 16, 2004 hydrochloride salt, 0.4 mg of naloxone hydrochloride salt 0079. In certain embodiments in which pentazocine with 9.5 mg nalbuphine hydrochloride salt, 0.4 mg of hydrochloride Salt is the K-opioid agonist, the composition naloxone hydrochloride salt with 10 mg nalbuphine hydro comprises 0.02 mg to 8 mg, 0.02 to 7 mg, 0.02 mg to 6 mg, chloride salt, and 0.8 mg naloxone hydrochloride salt with 0.02 to 5 mg, 0.02 to 4 mg., 0.02 to 3 mg, 0.02 to 2 mg, 0.02 10 mg nalbuphine hydrochloride salt. The present invention to 2 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 6 mg, further encompasses pharmaceutical compositions compris 0.1 mg to 5 mg, 0.1 mg to 4 mg., 0.1 mg to 3 mg, 0.1 mg to ing nalbuphine free base, non-hydrochloride Salt, prodrug, 2 mg, 0.1 mg to 1 mg, 0.2 mg to 8 mg, 0.2 mg to 7 mg, 0.2 or mixture thereof in equivalent amounts to nalbuphine mg to 6 mg, 0.2 mg to 4 mg., 0.2 mg to 3 mg, 0.2 mg to 2 hydrochloride Salt intravenously administered, provided that mg, 0.2 mg to 1 mg, 0.4 mg to 8 mg, 0.4 to 7 mg, 0.4 to 6 the composition does not comprise 5 mg of nalbuphine free mg, 0.4 mg to 5 mg, 0.4 mg to 4 mg., 0.4 mg to 3 mg, 0.4 base is not combined with 0.4 mg of naloxone free base mg to 2 mg, 0.4 mg to 1 mg, 0.5 mg to 8 mg, 0.5 mg to 6 when the composition is administered intravenously. In mg, 0.5 mg to 5 mg, 0.5 mg to 4 mg., 0.5 mg to 3 mg, 0.5 other embodiments, the invention provides, for example, mg to 3 mg, 0.5 to 2 mg, 0.5 mg to 1 mg, 1 mg to 8 mg, 1 controlled or Sustained release formulations that release mg to 6 mg, 1 mg to 5 mg, 1 mg to 4 mg, 1 mg to 3 mg, 1 equivalent amounts of nalbuphine and naloxone to the Site of mg to 2 mg, 5 mg to 8 mg, 4 mg to 7 mg, 3 mg to 5 mg, 0.02 administration (e.g., the oral cavity) over a period of 15 mg to 1 mg, preferably 0.1 mg to 0.8 mg, 0.2 mg to 0.8 mg, minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 0.3 mg to 0.8 mg, 0.4 mg to 0.8 mg, 0.5 mg to 0.8 mg, 0.1 hours, 10 hours, 12 hours, or 24 hours. mg to 0.7 mg, 0.2 mg to 0.7 mg, 0.3 mg to 0.7 mg, 0.4 mg to 0.7 mg, 0.1 mg to 0.6 mg, 0.2 mg to 0.6 mg, 0.3 to 0.6 mg, 0077. In another embodiment of the invention, the phar 0.1 mg to 0.5 mg, 0.15 mg to 0.5 mg, 0.2 mg to 0.5 mg, 0.25 maceutical composition for intravenous administration or mg to 0.5 mg, 0.3 mg to 0.5 mg, 0.35 mg to 0.5 mg, 0.1 mg mucosal administration (e.g., nasal or pulmonary adminis to 0.45 mg, 0.15 mg to 0.45 mg, 0.2 mg to 0.45 mg, 0.25 mg tration) comprises pentazocine free base, prodrug, non to 0.45 mg, 0.1 mg to 0.3 mg, 0.13 mg to 0.3 mg, 0.2 mg to hydrochloride salt, most preferably in the hydrochloride salt, 0.3 mg, 0.1 mg to 0.25 mg, 0.15 mg to 0.25 mg, 0.1 mg to or mixture thereof, is administered as the K-opioid receptor 0.2 mg, 0.1 mg to 0.15 mg of naloxone hydrochloride as the agonist with the opioid antagonist, preferably naloxone, to opioid antagonist hydrochloride Salt. Non-limiting examples treat, manage, or ameliorate pain. The amount of pentaZO of the present invention are intravenous formulations com cine hydrochloride Salt in the intravenous formulation is prising 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, preferably 18 to 120 times greater, 25 to 120 times greater, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 18 to 110 times greater, 25 to 110 times greater. 18 to 100 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 30 mg, times greater, 25 to 100 times greater, 18 to 95 times greater, 35 mg, 40 mg, 45 mg, and 50 mg pentazocine hydrochloride 25 to 90 times greater, 30 to 90 times greater, 35 to 90 times Salt with 0.1 mg, 0.15 mg, 0.2 mg, 0.2 mg, 0.25 mg, 0.3 mg, greater, 18 to 85 times greater, 20 to 80 times greater, 20 to 0.35 mg, 0.4 mg., 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg 0.7 mg, 60 times greater, 20 to 50 times greater, 25 to 55 times 0.75 mg, 0.8 mg, 1 mg, 1.6 mg, 2 mg, 2.4 mg., 3 mg, 4 mg, greater, 35 to 80 times greater, 20 to 75 times greater, 25 to 5 mg, 6 mg, 7 mg and 8 mg naloxone hydrochloride Salt. 70 times greater, 40 to 100 times greater, 50 to 100 times 0080. The present invention further encompasses phar greater, 55 to 95 times greater, 45 to 90 times greater, 40 to maceutical compositions comprising pentazocine free base, 70 times greater, 18 to 50 times greater, 18 to 40 times non-hydrochloride Salt, prodrug, or mixture thereof in greater, or 18 to 35 times greater, 18 to 30 times greater, by equivalent amounts to pentazocine hydrochloride Salt intra weight, pentazocine hydrochloride Salt than the opioid venously administered. In other embodiments, the invention antagonist hydrochloride Salt, preferably, naloxone hydro provides, for example, controlled or Sustained release for chloride salt. mulations that release equivalent amounts of pentazocine 0078 Examples of intravenous formulations and mucosal and naloxone to the Site of administration (e.g., the oral formulations of the present invention are, but not limited to, cavity) over a period of 15 minutes, 30 minutes, 1 hour, 2 10 mg of pentazocine hydrochloride Salt with 0.4 mg of hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, or 24 naloxone hydrochloride Salt (i.e., 25 times greater, by hours. weight, pentazocine hydrochloride Salt than naloxone hydro 0081. In another particular embodiment of the invention, chloride Salt), 15 mg of pentazocine hydrochloride Salt with the pharmaceutical composition for intravenous administra 0.3 mg naloxone hydrochloride Salt (i.e., 30 times greater, by tion comprises butorphanol free base, a pharmaceutically weight, pentazocine hydrochloride Salt than naloxone hydro acceptable Salt, a prodrug, or a mixture thereof as the chloride Salt), and 25 mg of pentazocine hydrochloride Salt K-opioid receptor agonist. In preferred embodiments of the with 0.5 mg naloxone hydrochloride salt (i.e., 50 times invention, the pharmaceutical composition for intravenous greater pentazocine hydrochloride Salt than naloxone hydro administration comprises butorphanol tartrate Salt in chloride salt). In preferred embodiments of the invention, amounts 0.3 to 10 times greater, 0.3 to 9 times greater, 0.3 the amounts of pentazocine hydrochloride Salt in the phar to 8 times greater, 0.5 to 10 times greater, 0.3 to 7 times maceutical composition, by weight, are 3 mg to 50 mg, 4 mg greater, 0.5 to 7 times greater, 0.3 to 6 times greater. 0.5 to to 50 mg, 5 mg to 50 mg, 6 mg to 50 mg, 7 mg to 50 mg, 6 times greater, 0.3 to 5 times greater, 0.5 to 5 times greater, 3 mg to 45 mg, 5 mg to 45 mg, 10 mg to 45 mg, 15 mg to 0.3 to 4 times greater, 0.5 to 4 times greater, 0.3 to 3 times 45 mg, 5 mg to 40 mg, 10 mg to 40 mg, 3 mg to 35 mg, 4 greater, or 0.5 to 3 times greater, by weight, than the opioid mg to 35 mg, 5 mg to 35 mg, 10 mg to 35 mg, 3 mg to 30 antagonist hydrochloride Salt, preferably naloxone hydro mg, 4 mg to 30 mg, 5 mg to 30 mg, 3 mg to 25 mg, 4 mg chloride Salt. Examples of intravenous formulations of the to 25 mg, 3 mg to 20 mg, 4 mg to 20 mg, 5 mg to 25 mg, present invention are, but not limited to, 0.3 mg of butor 10 mg to 25 mg, 15 mg to 30 mg, 15 mg to 25 mg, 10 mg phanol tartrate salt with 0.3 mg of naloxone hydrochloride to 20 mg, and 10 mg to 15 mg. Salt (i.e., 1 time greater, by weight, of butorphanol tartrate US 2004/018091.6 A1 Sep. 16, 2004 salt than naloxone hydrochloride salt), 0.5 mg of butorpha oral administration for gastro-intestinal uptake. In certain nol tartrate salt with 0.2 mg naloxone hydrochloride salt embodiments, the pharmaceutical composition comprises an (i.e., 2.5 times greater, by weight, butorphanol tartrate Salt opioid antagonist hydrochloride Salt, preferably naloxone than the naloxone hydrochloride salt), and 0.8 mg of butor hydrochloride salt, and 6.25 to 49 times greater, 6.25 to 40 phanol tartrate Salt with 0.4 mg naloxone hydrochloride Salt times greater, 6.25 to 35 times greater, 6.25 to 30 times (i.e., 2 times greater, by weight butorphanol tartrate Salt than greater, 6.25 to 20 times greater, 8 to 35 times greater, 8 to naloxone hydrochloride Salt). 30 times greater, 8 to 25 times greater, 10 to 30 times greater, 0082 Alternatively, the weight of butorphanol tartrate 10 to 20 times greater, 15 to 25 times greater, 20 to 25 times Salt in the intravenous formulation or mucosal formulation is greater, 10 to 15 times greater, 9 to 15 times greater, 5 to 10 preferably 0.2 mg to 2 mg, 0.2 mg to 1.9 mg, 0.2 mg to 1.8 times greater, 30 to 49 times greater, 20 to 30 times greater, mg, 0.2 mg to 1.7 mg, 0.25 mg to 1.9 mg, 0.25 mg to 1.8 mg, 15 to 20 times greater, 13 to 15 times greater, 11 to 13 times 0.25 mg to 1.75 mg, 0.25 mg to 1.5 mg, 0.25 mg to 1 mg, greater, 9 to 11 times greater, 7 to 9 times greater, or 6.25 to or 0.2 mg to 1 mg. In certain preferred embodiments of the 7 times greater, by weight, nalbuphine hydrochloride Salt present invention, the pharmaceutical composition for intra than the opioid antagonist hydrochloride Salt. venous administration comprises butorphanol tartrate Salt 0085. In specific embodiments in which the pharmaceu and preferably 0.02 mg to 8 mg, 0.02 to 7 mg, 0.02 mg to tical compositions formulated for administration other than 6 mg, 0.02 to 5 mg, 0.02 to 4 mg., 0.02 to 3 mg, 0.02 to 2 intravenous administration, the composition comprises an mg, 0.02 to 2 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg amount of nalbuphine free base, prodrug, Salt, or mixture to 6 mg, 0.1 mg to 5 mg, 0.1 mg to 4 mg., 0.1 mg to 3 mg, thereof equivalent to 1 mg to 50 mg, 1 mg to 45 mg, 1 mg 0.1 mg to 2 mg, 0.1 mg to 1 mg, 0.2 mg to 8 mg, 0.2 mg to to 40 mg, 1 mg to 35 mg, 1 mg to 30 mg, 1 mg to 25 mg, 7 mg, 0.2 mg to 6 mg, 0.2 mg to 4 mg., 0.2 mg to 3 mg, 0.2 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 10 mg, 1 mg to 9 mg to 2 mg, 0.2 mg to 1 mg, 0.4 mg to 8 mg, 0.4 to 7 mg, mg, 1 mg to 8 mg, 2 mg to 8 mg, 3 mg to 8 mg, 1 mg to 7 0.4 to 6 mg, 0.4 mg to 5 mg, 0.4 mg to 4 mg., 0.4 mg to 3 mg, 2 mg to 7 mg, 3 mg to 7 mg, 4 mg to 7 mg, 1 mg to 6 mg, 0.4 mg to 2 mg, 0.4 mg to 1 mg, 0.5 mg to 8 mg, 0.5 mg, 2 mg to 6 mg, 3 mg to 6 mg, 1 mg to 5 mg, 2 mg to 5 mg to 6 mg, 0.5 mg to 5 mg, 0.5 mg to 4 mg., 0.5 mg to 3 mg, 1 mg to 4 mg, 1 mg to 3 mg, 1 mg to 2 mg nalbuphine mg, 0.5 mg to 3 mg, 0.5 to 2 mg, 0.5 mg to 1 mg, 1 mg to hydrochloride Salt administered intravenously. 8 mg, 1 mg to 6 mg, 1 mg to 5 mg, 1 mg to 4 mg, 1 mg to 0086. In certain embodiments of the invention in which 3 mg, 1 mg to 2 mg, 5 mg to 8 mg, 4 mg to 7 mg, 3 mg to the pharmaceutical composition is to be administered Sub 5 mg, 0.02 mg to 1 mg, more preferably 0.1 mg to 0.8 mg, lingually (or other oral cavity administration), the amount of 0.2 mg to 0.8 mg, 0.3 mg to 0.8 mg, 0.4 mg to 0.8 mg, 0.5 malbuphine hydrochloride salt is preferably 1 to 60 times mg to 0.8 mg, 0.1 mg to 0.7 mg, 0.2 mg to 0.7 mg, 0.3 mg greater, 1 to 50 times greater, 1 to 45 times greater, 1 to 40 to 0.7 mg, 0.4 mg to 0.7 mg, 0.1 mg to 0.6 mg, 0.2 mg to times greater, 5 to 50 times greater, 5 to 40 times greater, 5 0.6 mg, 0.3 to 0.6 mg, 0.1 mg to 0.5 mg, 0.15 mg to 0.5 mg, to 35 times greater, 10 to 40 times greater, 15 to 40 times 0.2 mg to 0.5 mg, 0.25 mg to 0.5 mg, 0.3 mg to 0.5 mg, 0.35 greater, 10 to 30 times greater, 15 to 30 times greater, 1 to mg to 0.5 mg, 0.1 mg to 0.45 mg, 0.15 mg to 0.45 mg, 0.2 30 times greater, 1 to 20 times greater, 1 to 15 times greater, mg to 0.45 mg, 0.25 mg to 0.45 mg, 0.1 mg to 0.3 mg, 0.13 or 1 to 9 times greater by weight, than the amount of the mg to 0.3 mg, 0.2 mg to 0.3 mg, 0.1 mg to 0.25 mg, 0.15 mg opioid antagonist hydrochloride Salt, preferably naloxone to 0.25 mg, 0.1 mg to 0.2 mg, 0.1 mg to 0.15 mg naloxone hydrochloride Salt. Non-limiting examples of pharmaceuti hydrochloride Salt as the opioid antagonist hydrochloride. cal compositions for Sublingual administration are 8 mg Non-limiting examples of the present invention are compo malbuphine hydrochloride Salt with 0.4 mg naloxone hydro Sitions comprising 0.2 mg, 0.3 mg, 0.4 mg., 0.5 mg, 0.6 mg, chloride Salt (i.e., 20 times greater, by weight, nalbuphine 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.1 mg, 1.2 mg, 1.3 hydrochloride salt than the naloxone hydrochloride salt), 15 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, or 2.0 mg of mg nalbuphine hydrochloride Salt with 3 mg naloxone butorphanol tartrate salt with 0.1 mg, 0.15 mg, 0.2 mg, 0.25 hydrochloride Salt (i.e., 5 times greater, by weight, nalbu mg, 0.3 mg, 0.35 mg, 0.4 mg., 0.45 mg, 0.5 mg, 0.55 mg, 0.6 phine hydrochloride salt than the naloxone hydrochloride mg, 0.7 mg, 0.75 mg, 0.8 mg, 1 mg, 1.6 mg, 2 mg, 2.4 mg, salt), and 30 mg nalbuphine hydrochloride salt with 4 mg 3 mg, 4 mg, 5 mg, 6 mg, 7 mg and 8 mg naloxone naloxone hydrochloride Salt (i.e., 7.5 times greater, by hydrochloride salt. weight, nalbuphine hydrochloride Salt than the naloxone 0.083. The present invention further encompasses phar hydrochloride salt). maceutical compositions comprising butorphanol free base, 0087 Alternatively, in certain embodiments of the non-tartrate Salt, prodrug, or mixture thereof in equivalent present invention, the pharmaceutical composition for Sub amounts to butorphanol tartrate Salt intravenously adminis lingual administration (or other oral cavity administration) tered. In other embodiments, the invention provides, for comprises 5 mg to 65 mg, 5 mg to 60 mg, 5 mg to 55 mg, example, controlled or Sustained release formulations that 5 mg to 50 mg, 5 mg to 40 mg, 5 mg to 35 mg, 6 mg to SS release equivalent amounts of butorphanol and naloxone to mg, 6 mg to 50 mg, 6 mg to 45 mg, 6 mg to 40 mg, 6 mg the Site of administration (e.g., the oral cavity) over a period to 30 mg, 7 mg to 40 mg, 7 mg to 35 mg, or 7.5 to 30 mg of 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, of nalbuphine hydrochloride salt. In the preferred embodi 8 hours, 10 hours, 12 hours, or 24 hours. ment of the invention in which nalbuphine is the opioid 0084. The present invention also includes pharmaceutical agonist in the composition, naloxone hydrochloride Salt is compositions for the treatment of pain comprising of a the preferred opioid antagonist. More preferably, the phar K-opioid receptor agonist and an opioid antagonist that is to maceutical composition intended for Sublingual administra be administered by a method other than by intravenous tion comprises 0.1 mg to 10 mg, 0.1 mg to 9 mg, 0.1 mg to administration, and in certain embodiments, also other than 8 mg, 0.1 mg to 7 mg, 0.1 mg to 6 mg, 0.2 mg to 10 mg, 0.2 US 2004/018091.6 A1 Sep. 16, 2004

mg to 9 mg, 0.2 mg to 8 mg, 0.2 mg to 7 mg, 0.2 mg to 6 Salt. Alternatively, the pharmaceutical composition com mg, 0.2 mg to 5 mg, 0.3 mg to 10 mg, 0.3 mg to 9 mg, 0.3 prises pentazocine, a prodrug, a pharmaceutically acceptable mg to 7 mg, 0.3 mg to 6 mg, 0.3 mg to 5 mg, 0.3 mg to 4 Salt, or mixture thereof in amounts equivalent to 3 mg to 50 mg, 0.4 mg to 4 mg., 0.5 mg to 4 mg., 0.4 mg to 3.5 mg, 0.5 mg, 4 mg to 50 mg, 5 mg to 50 mg, 6 mg to 50 mg, 7 mg mg to 3.5 mg, 0.6 mg to 3.5 mg, 0.4 mg to 3 mg, 0.5 mg to to 50 mg, 3 mg to 45 mg, 5 mg to 45 mg, 10 mg to 45 mg, 3 mg, 0.4 mg to 2.8 mg, 0.6 mg to 2.7 mg, 0.4 mg to 2.5 mg, 15 mg to 45 mg, 5 mg to 40 mg, 10 mg to 40 mg, 3 mg to 0.5 mg to 2.2 mg, 0.4 mg to 2 mg, 0.6 mg to 2 mg, 0.4 mg 35 mg, 4 mg to 35 mg, 5 mg to 35 mg, 10 mg to 35 mg, 3 to 1.5 mg, or 0.4 mg to 1 mg naloxone hydrochloride Salt. mg to 30 mg, 4 mg to 30 mg, 5 mg to 30 mg, 3 mg to 25 mg, Non-limiting examples of the present invention are methods comprising administration of 5 mg, 5.5 mg, 6 mg, 6.5 mg, 4 mg to 25 mg, 3 mg to 20 mg, 4 mg to 20 mg, 5 mg to 25 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg 10 mg, 15 mg, mg, 10 mg to 25 mg, 15 mg to 30 mg, 15 mg to 25 mg, 10 20 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg nalbuphine mg to 20 mg, and 10 mg to 15 mg pentazocine hydrochloride hydrochloride salt with naloxone hydrochloride salt. For Salt administered intravenously. example, in Specific embodiments of the present invention, 0090. If the method of administration is Sublingual, cer the method comprises Sublingual administration of 0.4 mg tain embodiments of the invention comprise of an opioid of naloxone hydrochloride Salt with 5 mg of nalbuphine antagonist hydrochloride Salt, preferably naloxone hydro hydrochloride salt, 0.4 mg of naloxone hydrochloride salt with 6 mg of nalbuphine hydrochloride salt, 0.4 mg of chloride Salt and 7.5 to 50 times greater, 7.5 to 45 times naloxone hydrochloride salt with 7 mg of nalbuphine hydro greater, 10 to 50 times greater, 10 to 40 times greater, 15 to chloride salt, 0.4 mg of naloxone hydrochloride salt with 8 50 times greater, 15 to 45 times greater, 7.5 to 30 times mg of nalbuphine hydrochloride Salt, 0.4 mg of naloxone greater, 7.5 to 25 times greater, 7.5 to 20 times greater, 10 hydrochloride salt with 9 mg of nalbuphine hydrochloride to 30 times greater, or 7.5 to 15 times greater, by weight, salt, 0.4 mg of naloxone hydrochloride Salt with 10 mg of pentazocine hydrochloride Salt than the amount of opioid nalbuphine hydrochloride Salt, 0.4 mg of naloxone hydro antagonist hydrochloride Salt. Alternatively, in certain chloride salt with 15 mg of nalbuphine hydrochloride salt, embodiments of the invention, the amount of pentazocine 0.4 mg of naloxone hydrochloride Salt with 20 mg of hydrochloride Salt in the Sublingual composition is 30 mg to nalbuphine hydrochloride Salt, 0.4 mg of naloxone hydro 100 mg, 30 to 90 mg, 40 mg to 100 mg, 30 mg to 85 mg, 40 chloride salt with 25 mg of nalbuphine hydrochloride salt, mg to 85 mg, 30 mg to 70 mg, 40 mg to 70 mg, 30 mg to and 0.4 mg of naloxone hydrochloride salt with 30 mg of 60 mg, 40 mg to 60 mg, 30 mg to 50 mg, 50 mg to 80, or malbuphine hydrochloride salt. 30 mg to 45 mg. In preferred embodiments of the invention 0088. The present invention further encompasses phar for Sublingual administration comprising pentazocine maceutical compositions comprising equivalent amounts of hydrochloride Salt as the K-opioid agonist, naloxone hydro nalbuphine free base, non-hydrochloride Salt, prodrug or chloride Salt is the preferred opioid antagonist hydrochloride Salt in amounts of 1 mg to 10 mg, 1 mg to 9 mg, 1 mg to 8 mixture thereof to nalbuphine hydrochloride Salt and equiva mg, 1 mg to 7 mg, 1 mg to 6 mg, 1 mg to 5 mg, 1 mg to 4 lent amounts of the opioid antagonist free base, non-hydro mg, 2 mg to 10 mg, 2 mg to 9 mg, 2 mg to 8 mg, 2 mg to chloride Salt, prodrug, or mixture thereof to the opioid 7 mg, 2 mg to 6 mg, 2 mg to 5 mg, 2 mg to 4 mg, 2 mg to hydrochloride Salt, or that releases the same amount of 3.8 mg, 2 mg to 3.6 mg, 2 mg to 3.4 mg, 2 mg to 3.4 mg, nalbuphine and antagonist into the Site over a period of 15 2.2 mg to 3.5 mg, 2 mg to 3.2 mg, 3 mg to 4 mg, or 2 mg minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 to 3 mg. Non-limiting examples of the present invention are hours, 10 hours, 12 hours, or 24 hours even if the same blood pharmaceutical compositions for Sublingual administration concentration is not achieved, provided that the when the comprising 30 mg, 31 mg, 32 mg, 33 mg, 34 mg., 35 mg, 36 opioid antagonist is naloxone free base, the amount of mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 nalbuphine free base is not 5 mg and the amount of naloxone mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 free base is not 0.4 mg. mg, 85 mg, 90 mg, 95 mg or 100 mg pentazocine hydro 0089. In another preferred embodiment of the present chloride Salt with 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 invention, the pharmaceutical composition for administra mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 g, 3 mg, 3.1 mg, 3.2 mg, tion other than by intravenous administration or oral admin 3.3 mg, 3.4 mg., 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, or istration for gastro-intestinal uptake comprises pentazocine, 4.0 mg naloxone hydrochloride Salt. a prodrug, a pharmaceutically acceptable Salt, or mixture thereof as the opioid agonist and an opioid antagonist in 0091. The present invention further encompasses phar amounts equivalent to intravenous administration of the maceutical compositions comprising equivalent amounts of opioid antagonist hydrochloride salt and 18 to 120 times pentazocine free base, non-hydrochloride Salt, prodrug or greater, 25 to 120 times greater, 18 to 110 times greater, 25 mixture thereof to pentazocine hydrochloride Salt and to 110 times greater. 18 to 100 times greater, 25 to 100 times equivalent amounts of the opioid antagonist free base, greater, 18 to 95 times greater, 25 to 90 times greater, 30 to non-hydrochloride Salt, prodrug, or mixture thereof to the 90 times greater, 35 to 90 times greater, 18 to 85 times opioid hydrochloride Salt, or that releases the Same amount greater, 20 to 80 times greater, 20 to 60 times greater, 20 to of pentazocine and antagonist into the Site over a period of 50 times greater, 25 to 55 times greater, 35 to 80 times 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 greater, 20 to 75 times greater, 25 to 70 times greater, 40 to hours, 10 hours, 12 hours, or 24 hours even if the same blood 100 times greater, 50 to 100 times greater, 55 to 95 times concentration is not achieved, provided that if the pharma greater, 45 to 90 times greater, 40 to 70 times greater, 18 to ceutical composition is for oral administration with gastro 50 times greater, 18 to 40 times greater, 18 to 35 times intestinal uptake, the composition does not comprise 50 mg greater, or 18 to 30 times greater, by weight, pentazocine pentazocine hydrochloride Salt and 0.5 mg naloxone hydro hydrochloride Salt than the opioid antagonist hydrochloride chloride salt. US 2004/018091.6 A1 Sep. 16, 2004

0092. In certain preferred embodiments, the pharmaceu of butorphanol and antagonist into the Site over a period of tical composition for administration other than intravenous 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 administration comprises butorphanol, a prodrug, a pharma hours, 10 hours, 12 hours, or 24 hours even if the same blood ceutically acceptable Salt, or mixture thereof as the K-opioid concentration is not achieved. receptor agonist and an opioid antagonist, pharmaceutically 0095. In a preferred form of the invention, the combina acceptable Salt, prodrug, or mixture thereof in amount tion of the K-opioid agonist, preferably nalbuphine, for equivalent to the opioid antagonist hydrochloride Salt and example as the hydrochloride Salt, and opioid antagonist, 0.3 to 10 times greater, 0.3 to 9 times greater, 0.3 to 8 times preferably naloxone, for example as the hydrochloride Salt, greater, 0.5 to 10 times greater, 0.3 to 7 times greater, 0.5 to is administered to the patient or Subject (preferably a human) 7 times greater, 0.3 to 6 times greater. 0.5 to 6 times greater, by mucosal administration, particularly by intranasal or 0.3 to 5 times greater, 0.5 to 5 times greater, 0.3 to 4 times pulmonary administration. In Such administration a compo greater, 0.5 to 4 times greater, 0.3 to 3 times greater, or 0.5 Sition containing the two ingredients Suitable for Such to 3 times greater, by weight, butorphanol tartrate Salt than administration, is used, as described hereinafter. In Such the opioid antagonist hydrochloride Salt, preferably nalox administration, the amounts of the opioid agonist and one hydrochloride Salt, administered intravenously. Alterna antagonist, and the ratio of the one to the other, are as tively, the amount of butorphanol, a prodrug, a pharmaceu described above. Particularly good results are generally tically acceptable Salt, or mixture thereof in the composition obtained by administration of the combination wherein the is equivalent to 0.2 mg to 2 mg, 0.2 mg to 1.9 mg, 0.2 mg weight ratio of nalbuphine component to naloxone compo to 1.8 mg, 0.2 mg to 1.7 mg, 0.25 mg to 1.9 mg, 0.25 mg to nent is from about 10:1 to about 15:1, most preferably about 1.8 mg, 0.25 mg to 1.75 mg, 0.25 mg to 1.5 mg, 0.25 mg to 12.5:1 and where the amount of nalbuphine (as the hydro 1 mg, or 0.2 mg to 1 mg butorphanol tartrate Salt adminis chloride Salt) is 5 mg and the amount of naloxone (as the tered intravenously. hydrochloride salt) is about 0.4 mg. Similarly, the two may 0093. If the pharmaceutical composition is intended to be be administered at one-quarter of that dosage (e.g., 1.25 mg administered Sublingually, the amount of butorphanol tar nalbuphine hydrochloride and 0.1 mg naloxone hydrochlo trate salt is preferably 0.1 to 60 times greater, 0.1 to 50 times ride), at one-half the dosage (e.g., 2.5 mg nalbuphine hydro greater, 0.1 to 45 times greater, 0.3 to 40 times greater, or 0.5 chloride and 0.2 mg naloxone hydrochloride) at twice (e.g., to 30 greater, 10 to 60 times greater, 20 to 50 times greater, 10 mg nalbuphine hydrochloride and 0.8 mg naloxone or 10 to 30 times greater, by weight, than the amount of hydrochloride) or at four times that dosage (e.g., 20 mg opioid antagonist hydrochloride Salt, preferably naloxone hydrochloride and 1.6 mg naloxone hydrochloride). Such hydrochloride Salt. Non-limiting examples of pharmaceuti dosage variations may be used, for example, for patients cal compositions for Sublingual administration are 0.5 mg with lesser body mass or less pain the dose may be lower and butorphanol tartrate salt with 0.25 mg naloxone hydrochlo for patients with greater body mass or more Severe pain the ride Salt (i.e., 2 times greater, by weight, butorphanol tartrate dose may be larger. Salt than naloxone hydrochloride Salt), 2 mg butorphanol tartrate salt with 0.2 mg naloxone hydrochloride salt (i.e., 10 Administration and Formulations times greater, by weight, butorphanol tartrate Salt than naloxone hydrochloride Salt), and 6 mg butorphanol tartrate 0096 Methods of administering K-opioid receptor ago salt with 0.3 mg naloxone hydrochloride salt (i.e., 20 times nist and opioid antagonists are well known in the art. greater, by weight, butorphanol tartrate Salt naloxone hydro Methods of administration include, but are not limited to, chloride Salt). Alternatively, the pharmaceutical composition parenteral administration (e.g., intradermal, intramuscular, for Sublingual administration comprises 0.1 mg to 10 mg, intra peritoneal, intravenous, and Subcutaneous) and 0.1 mg to 9 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to mucosal (e.g., intranasal, oral, and rectal routes). In pre 6 mg, 0.2 mg to 9 mg, 0.2 mg to 8 mg, 0.2 mg to 7 mg, 0.2 ferred embodiments of the present invention, the K-opioid mg to 6 mg, 0.2 mg to 5.5 mg, 0.3 to 6.5 mg, 0.4 mg to 7 receptor agonist and opioid antagonist and pharmaceutical mg, or 0.5 mg to 6 mg of butorphanol tartrate Salt as the compositions thereof are administered intravenously or K-opioid agonist. (most preferably) mucosally, including, but not limited to 0094. If the K-opioid agonist in the pharmaceutical com nasal, Sublingual (or other oral cavity administration), pull positions for Sublingual administration is butorphanol tar monary (i.e., inhaled into the lungs, Such as by an inhaler or trate Salt, then, preferably, the opioid antagonist is naloxone nebulizer), and rectal administration. The K-opioid receptor hydrochloride Salt in amounts of 0.1 to 4 mg., 0.1 mg to 3.5 agonist and opioid antagonist and pharmaceutical composi mg, 0.1 mg to 3 mg, 0.1 to 2.5 mg, 0.1 mg to 2 mg, 0.1 mg tions thereof may be administered alone or together with to 1 mg, 0.3 mg to 0.8 mg, or 0.1 mg to 0.8 mg. Non-limiting other biologically active agents, e.g., as described in this examples of the present invention are methods comprising Section. Administration can be Systemic or local. administration of 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 0097. The K-opioid agonist and opioid antagonist of the mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 invention may be administered by different methods, mg, or 7 mg butorphanol tartrate Salt with 0.1 mg, 0.2 mg, although, preferably, the agonist and antagonist are admin 0.3 mg, 0.4 mg., 0.5 mg, 0.6 mg, 0.7 mg, or 0.85 mg istered by the same method, and most preferably, by mucosal naloxone hydrochloride salt. The present invention further administration, by intravenous administration, or Sublingual encompasses pharmaceutical compositions comprising administration (or other oral cavity administration not for equivalent amounts of butorphanol free base, non-tartrate Significant gastro-intestinal uptake). For example, the opioid Salt, prodrug or mixture thereof to butorphanol tartrate Salt agonist and opioid antagonist may be administered intrave and equivalent amounts of the opioid antagonist free base, nously or mucosally together, or the opioid agonist admin non-hydrochloride Salt, prodrug, or mixture thereof to the istered intramuscularly and the opioid antagonist adminis opioid hydrochloride Salt, or that releases the Same amount tered intravenously. Other routes of administration include US 2004/018091.6 A1 Sep. 16, 2004

intramuscular, Subcutaneous and intrathecal injection. For Sterile water for injection or Saline can be provided So that parenteral administration (intravenous, intramuscular, Sub the ingredients may be mixed prior to administration. In cutaneous, or intrathecal injection), the opioid agonist and Specific embodiments, the dosage form for intravenous antagonist of the invention are preferably in a Sterile aque administration comprises 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.5 ous Solution that may also contain other dissolved Sub mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 stances Such as, but not limited to, preservatives, Stabilizers, mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 and pH adjusting agents. mg, 20 mg, 25 mg, 30 mg, 40 mg, or 50 mg of nalbuphine 0098. The K-opioid receptor agonist and opioid antago hydrochloride Salt with 0.1 mg, 0.15 mg, 0.2 mg, 0.2 mg, nist are preferably administered Simultaneously, but can be 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg., 0.5 mg, 0.6 mg, 0.7 mg, administered Sequentially in any order. Sequential adminis 0.8 mg, 1 mg, 1.6 mg, 2 mg, 2.4 mg., 3 mg, 4 mg, 5 mg, 6 tration is carried out within a time period Such that the opioid mg, 7 mg and 8 mg of naloxone hydrochloride Salt. antagonist modulates the effects (i.e., analgesia and/or 0103) If the compositions of the invention are to be adverse side effects) of the K-opioid agonist. Preferably, the administered orally, preferably Sublingually, and, in certain opioid agonist and antagonist are administered within 10 to embodiments, not for gastro-intestinal uptake, the compo 12 hours, 6 to 8 hours, 3 to 6 hours, 3 hours, 2 hours, 1 hour, Sitions can be formulated orally in the form of, e.g., tablets, 15 to 45 minutes, or 10 to 15 minutes, and most preferably, capsules, cachets, gelcaps, Solutions, Suspensions and the Substantially at the same time. The compositions can also be like. Tablets or capsules can be prepared by conventional formulated for and administered according to patient con means with pharmaceutically acceptable excipients Such as trolled analgesia methods known in the art. binding agents (e.g., pregelatinzed maize Starch, polyvi nylpyrrolidone or hydroxypropyl methylcellulose); fillers 0099. The invention encompasses pharmaceutical com (e.g., lactose, microcrystalline cellulose or calcium hydro positions comprising an amount of a K-Opioid receptor gen phosphate), lubricants (e.g., magnesium Stearate, talc or agonist and opioid antagonist that produces greater analgesia Silica); disintegrants (e.g., potato Starch or Sodium starch than the administration of either the agonist or antagonist glycolate); or wetting agents (e.g., Sodium lauryl Sulfate). alone, together with a Suitable amount of carrier So as to The tablets may be coated by methods well-known in the art. provide the form for proper administration to the patient. Liquid preparations for oral administration may take the The formulation of the invention should suit the mode of form of, for example, Solutions, Syrups or Suspensions, or administration. The amount of the compositions of the they may be presented as a dry product for constitution with invention which will be effective in treating, managing, or water or other Suitable vehicle before use. Such liquid ameliorating pain can be determined by Standard clinical preparations may be prepared by conventional means with techniques. The precise dose to be employed in the formu pharmaceutically acceptable additives Such as Suspending lation will depend on the route of administration, the inten agents (e.g., Sorbitol Syrup, cellulose derivatives or hydro sity of pain the Subject is experiencing, gender of the Subject, genated edible fats); emulsifying agents (e.g., lecithin or and the Size and weight of the Subject, and should be decided acacia); non-aqueous vehicles (e.g., almond oil, oily esters, according to the judgment of the practitioner and each ethyl alcohol or fractionated vegetable oils); and preserva patient's circumstances. tives (e.g., methyl or propyl-p-hydroxybenzoates or Sorbic 0100. The pharmaceutical compositions of the invention acid). The preparations may also contain buffer salts, fla are formulated to be compatible with their intended route of Voring, coloring and Sweetening agents as appropriate. administration. Examples of routes of administration Preparations for oral administration may be suitably formu include, but are not limited to, parenteral, e.g., intravenous, lated for slow release, controlled release or Sustained release intradermal, Subcutaneous, and mucosal, e.g., nasal, Sublin of a prophylactic or therapeutic agent(s). gual, pulmonary, or rectal. In a Specific embodiment, the composition is formulated in accordance with routine pro 0104. The compositions of the invention may also be cedures as a pharmaceutical composition adapted for formulated for parenteral administration by injection, e.g., mucosal, intravenous or Sublingual administration to human by bolus injection or continuous infusion. Formulations for beings. injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added pre 0101. In one preferred embodiment, a pharmaceutical Servative. The compositions may take Such forms as Sus composition is formulated in accordance with routine pro pensions, Solutions or emulsions in oily or aqueous vehicles, cedures for intravenous administration to human beings. and may contain formulatory agents Such as Suspending, Typically, compositions for intravenous administration are Stabilizing and/or dispersing agents. Alternatively, the active Solutions in Sterile isotonic aqueous buffer. Where necessary, ingredient may be in powder form for constitution with a the composition may also include a Solubilizing agent and a Suitable vehicle, e.g., Sterile pyrogen-free water, before use. local anesthetic Such as lidocaine to ease pain at the Site of 0105 The present invention also includes pharmaceutical the injection. compositions for the treatment of pain comprising of a 0102 Generally, the ingredients of compositions of the K-opioid receptor agonist and an opioid antagonist that is to invention are Supplied either Separately or mixed together in be administered by a method other than intravenous admin unit dosage form, for example, as a dry lyophilized powder istration. The composition, Shape, and type of dosage forms or water free concentrate in a hermetically Sealed container of the invention will vary depending on their use and method Such as an ampoule or Sachette indicating the quantity of of administration. The differences of the Specific dosage active agent. Where the composition is to be administered by forms encompassed by this invention are readily apparent to infusion, it can be dispensed with an infusion bottle con those skilled in the art. See, e.g., Remington ’s Pharmaceu taining Sterile pharmaceutical grade water or Saline. Where tical Sciences, 18" ed., Mack Publishing, Easton, Pa. the composition is administered by injection, an ampoule of (1990). US 2004/018091.6 A1 Sep. 16, 2004

0106 If the compositions of the invention are to be 0110. A preferred method of administration of the com administered mucosally through the nasal cavity, the com positions of this invention is mucosal administration, par positions can be formulated in an aeroSol form, Spray, mist ticularly intranasal administration or administration by inha or in the form of drops. In particular, the compositions of the lation (pulmonary administration). Pulmonary drug delivery present invention can be conveniently delivered in the form can be achieved by Several different approaches, including of an aeroSol Spray presentation from pressurized packs or a liquid nebulizers, aeroSol-based metered dose inhalers nebulizer, with the use of a Suitable propellant, e.g., dichlo (MDIs), and dry powder dispersion devices. Compositions rodifluoromethane, trichlorofluoromethane, dichlorotet for use in administrations of this type are typically dry rafluoroethane, carbon dioxide or other Suitable gas. In the powders or aerosols. For administration of aerosols, which case of a pressurized aerosol the dosage unit may be is the preferred method of administration of this invention, determined by providing a valve to deliver a metered the compositions are delivered by inhalers, Some types of amount. Capsules and cartridges of, e.g., gelatin for use in which are described below. an inhaler or insufflator may be formulated containing a 0111 Dry powders contain, in addition to the active powder mix of the compound and a Suitable powder base ingredient, a carrier, an absorption enhancer, and optionally Such as lactose or Starch. other ingredients. The carrier is, for example, a mono-, di or polysaccharide, a Sugar alcohol or another polyol. Suit 0107 The compositions of the invention may also be able carriers include lactose, glucose, raffinose, meleZitose, formulated in rectal compositions Such as Suppositories or lactitol, maltitol, trehalose, Sucrose, mannitol, and Starch. retention enemas, e.g., containing conventional Suppository Lactose is particularly preferred, especially in the form of its bases Such as cocoa butter or other glycerides. monohydrate. Also included are absorption enhancerS Such 0108. The compositions of the invention may also be as polypeptides, Surfactants, alkyl glycosides, amine Salts of formulated for transdermal administration. For transdermal fatty acids or phospholipids. The ingredients of the formu administration, the active compounds are formulated into lation typically must be in a finely divided form, i.e. their ointments, Salves, gels, or creams as generally known in the volume median diameter should generally be from about 30 art. Pharmaceutical compositions adapted for transdermal to about 200 microns, as measured by a laser diffraction administration can be provided as discrete patches intended instrument or a coulter counter. The desired particle size to remain in intimate contact with the epidermis for a may be produced using methods known in the art, e.g. prolonged period of time. If the compositions of the inven milling, micronization or direct precipitation. tion are to be administered topically, the compositions can 0112 The intranasal route of administration provides be formulated in the form of, e.g., an ointment, cream, numerous advantages over intravenous and intramuscular transdermal patch, lotion, gel, Spray, aeroSol, Solution, emul injections. For instance, one advantage of intranasal admin Sion, or other form well-known to one of skill in the art. For istration is convenience. An injectable System requires Ster nonsprayable topical dosage forms, Viscous to Semi-Solid or ilization of the hypodermic Syringe and in the institutional Solid forms comprising a carrier or one or more excipients Setting, leads to concerns among medical perSonnel about compatible with topical application and having a dynamic the risk of contracting disease by being accidentally Stuck by Viscosity preferably greater than water are typically a contaminated needle. Strict requirements for the Safe employed. Suitable formulations include, without limitation, disposal of the used needle and Syringe must also be Solutions, Suspensions, emulsions, creams, ointments, pow imposed in the institutional Setting. In contrast, intranasal ders, liniments, Salves, and the like, which are, if desired, Sterilized or mixed with auxiliary agents (e.g., preservatives, administration requires little time on the part of the patient Stabilizers, wetting agents, buffers, or salts) for influencing and the attending medical perSonnel, and is far less burden various properties, Such as, for example, osmotic pressure. Some on the institution than injectables. Other Suitable topical dosage forms include Sprayable aero 0113 A Second important advantage of intranasal admin Sol preparations wherein the active ingredient, preferably in istration over IM and IV is patient acceptance of the drug combination with a Solid or liquid inert carrier, is packaged delivery System. Intranasal administration is perceived as in a mixture with a pressurized volatile (e.g., a gaseous noninvasive, is not accompanied by pain, has no significant propellant, Such as Freon), or in a Squeeze bottle. Moistur after-effects and produces the gratification of prompt relief izers or humectants can also be added to pharmaceutical in the patient exhibiting the Symptom. This is of particular compositions and dosage forms if desired. Examples of Such advantage when the patient is a child. Another important additional ingredients are well-known in the art. consideration is that the patient may be able to Self-admin ister the prescribed dosage(s) of nasal spray. 0109. In addition to the formulations described previ ously, the compositions of the invention may also be for 0114 For intranasal administration the compositions of mulated as a depot preparation. Such long acting formula this invention may be formulated as liquids or as Solids. tions may be administered by implantation (for example Such compositions may contain one or more adjuvants, Subcutaneously or intramuscularly) or by intramuscular agents for enhancing absorption of the active ingredients by injection. Thus, for example, the compositions may be permeation across the nasal membrane, and (for liquid formulated with suitable polymeric or hydrophobic materi compositions) an aqueous diluent, for instance water. Alter als (for example as an emulsion in an acceptable oil) or ion natively, the diluent may comprise an aqueous buffer Such as eXchange resins, or as sparingly Soluble derivatives, for phosphate buffer. The composition may further optionally example, as a sparingly Soluble Salt. Compositions of the include one or more polyhydric alcohols and one or more present invention may also be prepared in unit dosage forms preservative agents Such as, for example, gentamicin, baci or in concentrated forms that may be diluted before admin tracin (0.005%), or cresol. The compositions may be admin istration. istered to the nasal cavity in the form of a spray by using an US 2004/018091.6 A1 Sep. 16, 2004

atomizer, nebulizer, Sprayer, dropper or other device which and then the antagonist or the agonist, respectively is insures contact of the Solution with the nasal mucous mem released 10 to 12 hours, 6 to 8 hours, 3 to 6 hours, 3 hours, brane. The device may be a simple one Such as a simple 2 hours, 1 hour, 15 to 45 minutes, or 10 to 15 minutes after nasal Sprayer that may be used by the patient, or may be a the first release, or according to the practitioner's judgment. more elaborate instrument for more accurate dispensing of In Such a controlled or Sustained release formulation, the the compositions, that may be used in a physicians office or amount of the K-opioid agonist and opioid antagonist deliv a medical facility. ered over time may be equivalent to an amount delivered at 0115 Nasal powder compositions can be made by mixing one time by a different type of formulation for the same the active agent and the excipient, both possessing the mode of administration. desired particle size. Firstly, a Solution of the active agent and the cyclodextrin excipients made, followed by precipi Methods of Treatment tation, filtration and pulverization. It is also possible to remove the solvent by freeze drying, followed by pulveri 0118. The invention provides methods of treating, man Zation of the powder in the desired particle size by using aging, or ameliorating pain by administration of a K-opioid conventional techniques, known from the pharmaceutical receptor agonist with an opioid antagonist Such that the literature. The final Step is size classification for instance by analgesia achieved by administration is greater than with Sieving, to get particles that are preferably between 30 and administration of either the K-opioid receptor agonist or the 200 microns in diameter. Powders can be administered using opioid antagonist alone (or, in certain embodiments, is a nasal insufflator, or they may be placed in a capsule Set in greater than the additive analgesic effect of the agonist and an inhalation or insufflation device. A needle is penetrated antagonist administered alone). The Subject is preferably a through the capsule to make pores at the top and the bottom mammal, Such as a non-primate (e.g., cows, pigs, horses, of the capsule and air is Sent to blow out the powder cats, dogs, rats, etc.) or a primate (e.g., monkey, Such as a particles. Powder formulation can also be administered in a cynomolgous monkey, and human). In a preferred embodi jet-spray of an inert gas or Suspended in liquid organic fluids. ment, the Subject is a human. The Subject can be male, female, adult, adolescent, or infant. The Specific embodi 0116. In a specific embodiment, the pharmaceutical com ments, the present invention encompasses methods and position can be delivered in a controlled or Sustained release compositions for the treatment of pain in children, adoles System. In one embodiment, a pump may be used to achieve cents, and the elderly. In Specific embodiments, the dose of a controlled or Sustained release (see Langer, Science, opioid agonist and antagonist administered in accordance 249:1527-1533 (1990); Sefton, 1987, CRC Crit. Ref. with the present invention is reduced based on the weight of Biomed. Eng. 14:10; Buschwald et al., 1980, Surgery the Subject receiving treatment. In another preferred 88:507; Saudek et al., 1989 N. Engl. J. Med. 321:574). In embodiment, the Subject is not or preferably, has not been, another embodiment, polymeric materials can be used to addicted to opioids, particularly it opioids, Such as, but not achieve controlled or Sustained release of the K-opioid limited to, morphine, codeine, or methadone, or K-opioids, receptor agonist and/or opioid antagonist (see e.g., Medical Such as, but not limited to pentazocine. Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. 1974); Controlled Drug Bio 0119 Methods for assaying for pain are well known in availability, Drug Product Design and Performance, Smolen the art. Certain methods for assaying for pain include the use and Ball (eds.), Wiley, New York (1984); Ranger and of a visual analog scale (VAS). This is a Subjective mea Peppas, 1983, J. Macromol. Sci. Rev. Macrol. Chem. 23:61; Surement of pain, in which perSons participating in the Study See also Levy et al., 1985 Science 228:190; During et al., are requested to indicate a level of pain at a certain time on 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neuro a 10-cm line. The patient makes an indication on the line at surg. 71:105; U.S. Pat. No. 5,679,377; U.S. Pat. No. 5,916, a value from 0 to 10 indicating the level of pain felt at that 597, U.S. Pat. No. 5,912,015; U.S. Pat. No. 5,989,463; U.S. time (where 0 indicates no pain and 10 indicates the worst Pat. No. 5,128,326; PCT Publication No. WO99/12154; and pain imaginable to the patient). Patients rated pain on the PCT Publication No. WO99/20253). Examples of polymers VAS at 20 minute intervals, both before and after adminis used in Sustained release formulations include, but are not tration of the active agents according to this invention. limited to, poly(2-hydroxy ethyl methacrylate), poly(methyl Tabulations were then made indicating increase or decrease methacrylate), poly(acrylic acid), poly(ethylene-co-Vinyl in the pain level with time, with a negative value indicating acetate), poly(methacrylic acid), polyglycolides (PLG), a decrease in pain experienced by the patient and a positive polyanhydrides, poly(N-vinyl pyrrolidone), poly(Vinyl alco value, an increase in Such pain. hol), polyacrylamide, poly(ethylene glycol), polyactides 0120 In accordance to this invention, the combination of (PLA), poly(lactideco-glycolides)(PLGA), and polyorthoe K-opioid receptor agonists and opioid antagonists can be Sters. In a preferred embodiment, the polymer used in a used to treat or prevent acute or chronic and regional or Sustained release formulation is inert, free of leachable generalized pain. For example, the combinations can be used impurities, stable on Storage, Sterile, and biodegradable. In for, but are not limited to, treating or preventing inflamma yet another embodiment, a controlled or Sustained release tory pain, neuropathic pain, acute chronic pain, cancer pain, System can be placed in proximity to the therapeutic target, labor pain, myocardial infarction pain, pancreatic pain, colic thus requiring only a fraction of the Systematic dose (see, pain, headache pain, pain associated with intensive care, e.g., Goodson, in Medical Applications of Controlled pain associated with thalamic Syndrome, and regional pain Release, supra, vol. 2, pp. 115-138 (1984)). Syndromes, e.g., refleX Sympathetic dystrophy, Sympathetic 0117. In a specific embodiment, the pharmaceutical com maintained pain Syndrome and casalgia, and generalized position is formulated for differential release so that either pain Syndromes, e.g., fibromyalgia, irritable bowel Syn the K-opioid agonist or the opioid antagonist is released first drome, temperal-mandibulla disorders, Syndrome X, and US 2004/018091.6 A1 Sep. 16, 2004 migraine headaches. The present invention is particularly to 6 mg, 0.02 to 5 mg, 0.02 to 4 mg., 0.02 to 3 mg, 0.02 to useful in treating, managing, or ameliorating post-operative 2 mg, 0.02 to 2 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg pain. to 6 mg, 0.1 mg to 5 mg, 0.1 mg to 4 mg., 0.1 mg to 3 mg, 0.1 mg to 2 mg, 0.1 mg to 1 mg, 0.2 mg to 8 mg, 0.2 mg to 0121 Certain embodiments of the invention provide 7 mg, 0.2 mg to 6 mg, 0.2 mg to 4 mg., 0.2 mg to 3 mg, 0.2 methods treating and lessening pain in Subjects experiencing mg to 2 mg, 0.2 mg to 1 mg, 0.4 mg to 8 mg, 0.4 to 7 mg, inflammatory pain. The inflammatory pain may be acute or 0.4 to 6 mg, 0.4 mg to 5 mg, 0.4 mg to 4 mg., 0.4 mg to 3 chronic and can be due to any condition characterized by mg, 0.4 mg to 2 mg, 0.4 mg to 1 mg, 0.5 mg to 8 mg, 0.5 inflammation, including, but not limited to, Sunburn, rheu mg to 6 mg, 0.5 mg to 5 mg, 0.5 mg to 4 mg., 0.5 mg to 3 matoid arthritis, Osteoarthritis, colitis, carditis, dermatitis, mg, 0.5 mg to 3 mg, 0.5 to 2 mg, 0.5 mg to 1 mg, 1 mg to myositis, neuritis, and collagen vascular diseases. The 8 mg, 1 mg to 6 mg, 1 mg to 5 mg, 1 mg to 4 mg, 1 mg to method of the present invention comprising administration 3 mg, 1 mg to 2 mg, 5 mg to 8 mg, 4 mg to 7 mg, 3 mg to of the combination of K-opioid receptor agonists and opioid 5 mg, 0.02 mg to 1 mg, preferably 0.1 mg to 0.8 mg, 0.2 mg antagonists in amounts taught by this invention reduces both to 0.8 mg, 0.3 mg to 0.8 mg, 0.4 mg to 0.8 mg, 0.5 mg to the acute pain and chronic hyperalgesia that the Subject 0.8 mg, 0.1 mg to 0.7 mg, 0.2 mg to 0.7 mg, 0.3 mg to 0.7 Suffers. mg, 0.4 mg to 0.7 mg, 0.1 mg to 0.6 mg, 0.2 mg to 0.6 mg, 0122) In another embodiment, the invention provides 0.3 to 0.6 mg, 0.1 mg to 0.5 mg, 0.15 mg to 0.5 mg, 0.2 mg methods for treating neuropathic pain in a Subject. Such to 0.5 mg, 0.25 mg to 0.5 mg, 0.3 mg to 0.5 mg, 0.35 mg to Subjects can have neuropathy classified as a radiculopathy, 0.5 mg, 0.1 mg to 0.45 mg, 0.15 mg to 0.45 mg, 0.2 mg to mononeuropathy, mononeuropathy multiplex, polyneuropa 0.45 mg, 0.25 mg to 0.45 mg, 0.1 mg to 0.3 mg, 0.13 mg to thy, or pleXopathy. Diseases in these classes can be caused 0.3 mg, 0.2 mg to 0.3 mg, 0.1 mg to 0.25 mg, 0.15 mg to 0.25 by a variety of nerve-damaging conditions or procedures, mg, 0.1 mg to 0.2 mg, 0.1 mg to 0.15 mg naloxone including, but not limited to, trauma, Stroke, demyelinating hydrochloride Salt. Typical amounts of naloxone hydrochlo diseases, absceSS, Surgery, amputation, inflammatory dis ride salt are 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 eases of the nerves, causalgia, diabetes, collagen Vascular mg, 0.4 mg., 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg 0.7 mg, 0.75 diseases, trigeminal neuralgia, rheumatoid arthritis, toxins, mg, 0.8 mg, 1 mg, 1.6 mg, 2 mg, 2.4 mg., 3 mg, 4 mg, 5 mg, chronic alcoholism, complex regional pain Syndrome type I, 6 mg, 7 mg and 8 mg naloxone hydrochloride Salt. complex regional pain Syndrome type II, AIDS and other 0.125 The invention also encompasses administration of Viral infections, including herpes, cancer (which can cause naloxone free base, non-hydrochloride Salt, prodrug, or direct or remote (e.g., paraneoplastic) nerve damage), anti mixture thereof in equivalent amounts to intravenous admin Viral therapies (e.g., AIDS or hepatitis therapies (Such as istration of naloxone hydrochloride Salt. nucleoside analogs and protease inhibitors)), and cancer treatment (e.g., Vinca, alkaloids, taxanes, cyclophospha 0.126 In general, the amount of K-opioid agonist to be mide, and melphalan). Nerve damage causing hyperalgesia administered with the antagonist is in the range of 5% to can be in peripheral or CNS nerves or both. 100% of the recommended analgesic dose (e.g., as provided in the Physician's Desk Reference or other commonly used 0123 The invention encompasses methods of treating, reference). Preferably, the dose the K-opioid agonist is 5% to managing, or ameliorating pain by administration of an 90%, 10% to 90%, 5% to 85%, 10% to 85%, 15% to 85%, amount of a K-opioid receptor agonists and an opioid 20% to 80%, 5% to 75%, 10% to 75%, 15% to 70%, 15% antagonist to produce greater analgesia than administration to 60%, 5% to 55%, 10% to 55%, 15% to 50%, 5% to 50%, of either the agonist or antagonist alone. The precise dosage 5% to 45%, 5% to 40%, 5% to 35%, 5% to 30%, 10% to of the K-opioid agonist and opioid antagonist will depend on 40%, 10% to 35%, 10% to 30%, 15% to 40%, 15% to 35%, the route of administration, the intensity of pain of the Subject is experiencing, and the size and weight of the 15% to 30%, 5% to 25%, 10% to 25%, 15% to 25%, 5% to Subject, and should be decided according to the judgment of 20%, and 5% to 15% of the recommended analgesic dose. the practitioner and each patient's circumstances. The However, as mentioned above, the amount administered K-opioid agonist and opioid antagonist can be administered may be a fraction or a multiple of the recommended dosage. to Subjects in dosages Suitable for continuous administra 0127. The precise dosages of the K-opioid agonist and tion, administration once daily, administration twice daily, opioid antagonist will depend on the size and weight of the administration three times a day, administration four times a Subject, the route of administration, and the intensity of pain day, administration six times a daily, administration every the Subject is experiencing, and should be decided according other day, and in other dosage regimens that the practitioner to the judgment of the practitioner and each patient's cir determines to be appropriate. The dosages can also be cumstances. For example, children and adolescents may be Self-administered by the patient as patient controlled anal administered Smaller amounts of the K-opioid agonist and gesic therapy. opioid antagonist compositions of the present invention than an adult and an obese adult may be administered larger 0.124. In particular embodiments, the invention provides dosages of the K-opioid agonist and opioid antagonist com for methods of treating, managing, or ameliorating pain by position than those dosages administered to a non-obese intravenous administration of an amount of a K-opioid receptor agonist and an amount of an opioid antagonist that adult according to the methods of the present invention. results in greater analgesia than that which results from 0128. In a specific embodiment of the invention, the administration of either the agonist or the antagonist alone. opioid agonist is nalbuphine free base, prodrug, or mixture The invention encompasses methods of intravenous admin thereof, but most preferably nalbuphine hydrochloride salt is istration or mucosal administration (e.g., nasal or pulmonary administered. In specific embodiments, the amount of nal administration) of 0.02 mg to 8 mg, 0.02 to 7 mg, 0.02 mg buphine salt administered intravenously is 6.25 to 49 times US 2004/018091.6 A1 Sep. 16, 2004 greater, 6.25 to 40 times greater, 6.25 to 35 times greater, 0.3 to 0.6 mg, 0.1 mg to 0.5 mg, 0.15 mg to 0.5 mg, 0.2 mg 6.25 to 30 times greater, 6.25 to 20 times greater, 8 to 35 to 0.5 mg, 0.25 mg to 0.5 mg, 0.3 mg to 0.5 mg, 0.35 mg to times greater, 8 to 30 times greater, 8 to 25 times greater, 10 0.5 mg, 0.1 mg to 0.45 mg, 0.15 mg to 0.45 mg, 0.2 mg to to 30 times greater, 10 to 20 times greater, 15 to 25 times 0.45 mg, 0.25 mg to 0.45 mg, 0.1 mg to 0.3 mg, 0.13 mg to greater, 20 to 25 times greater, 10 to 15 times greater, 9 to 0.3 mg, 0.2 mg to 0.3 mg, 0.1 mg to 0.25 mg, 0.15 mg to 0.25 15 times greater, 5 to 10 times greater, 30 to 49 times greater, mg, 0.1 mg to 0.2 mg, 0.1 mg to 0.15 mg naloxone 20 to 30 times greater, 15 to 20 times greater, 13 to 15 times hydrochloride Salt is administered as the opioid antagonist greater, 11 to 13 times greater, 9 to 11 times greater, 7 to 9 hydrochloride salt. Non-limiting examples of the method of times greater, or 6.25 to 7 times greater, by weight, than the the present invention comprise intravenous administration opioid antagonist hydrochloride Salt, preferably naloxone of 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 hydrochloride Salt. In a specific embodiments, the opioid mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 antagonist hydrochloride Salt is preferably naloxone hydro mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, mg, 25 mg, 30 mg, chloride Salt. AS non-limiting examples, the method of the 40 mg, 50 mg, to 60 mg of nalbuphine hydrochloride salt present invention comprises administration of 3 mg of with 0.1 mg, 0.15 mg, 0.2 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 malbuphine hydrochloride Salt with 0.4 mg naloxone hydro mg, 0.4 mg., 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 1 mg, 1.6 mg, chloride Salt (i.e., 7.5 times greater nalbuphine hydrochlo 2 mg, 2.4 mg., 3 mg, 4 mg, 5 mg, 6 mg, 7 mg and 8 mg of ride Salt than the opioid antagonist hydrochloride Salt); 1.25 naloxone hydrochloride Salt. mg nalbuphine hydrochloride Salt with 0.1 mg naloxone hydrochloride salt, 2.5 mg nalbuphine hydrochloride salt 0.130 For example, specific embodiments of the inven with 0.2 mg naloxone hydrochloride Salt, 5 mg nalbuphine tion comprise intravenous administration of 0.1 mg nalox hydrochloride Salt with 0.4 mg naloxone hydrochloride salt, one hydrochloride salt with 1.25 mg nalbuphine hydrochlo 10 mg nalbuphine hydrochloride Salt with 0.8 mg naloxone ride Salt, 0.2 mg of naloxone hydrochloride Salt with 1 mg hydrochloride salt, 20 mg nalbuphine hydrochloride salt nalbuphine hydrochloride Salt, 0.2 mg of naloxone hydro with 1.6 mg naloxone hydrochloride Salt, 25 mg nalbuphine chloride salt with 1.5 mg nalbuphine hydrochloride salt, 0.2 hydrochloride Salt with 2.0 mg naloxone hydrochloride salt, mg of naloxone hydrochloride Salt with 2 mg nalbuphine and 30 mg nalbuphine hydrochloride salt with 2.4 mg hydrochloride salt, 0.2 mg of naloxone hydrochloride salt naloxone hydrochloride Salt (i.e., 12.5 times greater, by with 2.5 mg nalbuphine hydrochloride salt, 0.2 mg of weight, nalbuphine hydrochloride Salt than naloxone hydro naloxone hydrochloride Salt with 3 mg nalbuphine hydro chloride salt); 5 mg nalbuphine hydrochloride salt with 0.2 chloride salt, 0.2 mg of naloxone hydrochloride Salt with 3.5 mg naloxone hydrochloride Salt and 10 mg nalbuphine mg nalbuphine hydrochloride salt, 0.2 mg of naloxone hydrochloride Salt with 0.4 mg naloxone hydrochloride salt hydrochloride salt with 4 mg nalbuphine hydrochloride salt, (i.e., 25 times greater nalbuphine hydrochloride Salt than the 0.2 mg of naloxone hydrochloride Salt with 4.5 mg nalbu naloxone hydrochloride salt); 4.9 mg nalbuphine hydrochlo phine hydrochloride salt, 0.2 mg of naloxone hydrochloride ride salt with 0.1 mg naloxone hydrochloride Salt and 9.8 mg salt with 5 mg nalbuphine hydrochloride salt, 0.2 mg of malbuphine hydrochloride Salt with 0.2 mg naloxone hydro naloxone hydrochloride Salt with 5.5 mg nalbuphine hydro chloride salt, 0.2 mg of naloxone hydrochloride salt with 6 chloride Salt (i.e., 49 times greater, by weight, nalbuphine mg nalbuphine hydrochloride Salt, 0.2 mg of naloxone hydrochloride salt than naloxone hydrochloride salt). hydrochloride salt with 6.5 mg nalbuphine hydrochloride 0129. In a specific embodiment, the weight of nalbuphine salt, 0.2 mg of naloxone hydrochloride salt with 7 mg hydrochloride Salt administered intravenously or mucosally malbuphine hydrochloride Salt 0.2 mg of naloxone hydro is 1 mg to 50 mg, 1 mg to 45 mg, 1 mg to 40 mg, 1 mg to chloride salt with 7.5 mg nalbuphine hydrochloride salt, 0.2 35 mg, 1 mg to 30 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg mg of naloxone hydrochloride Salt with 8 mg nalbuphine to 15 mg, 1 mg to 10 mg, 1 mg to 9 mg, 1 mg to 8 mg, 2 hydrochloride salt, 0.2 mg of naloxone hydrochloride salt mg to 8 mg, 3 mg to 8 mg, 1 mg to 7 mg, 2 mg to 7 mg, 3 with 8.5 mg nalbuphine hydrochloride salt, 0.2 mg of mg to 7 mg, 4 mg to 7 mg, 1 mg to 6 mg, 2 mg to 6 mg, 3 naloxone hydrochloride Salt with 9 mg nalbuphine hydro mg to 6 mg, 1 mg to 5 mg, 2 mg to 5 mg, 1 mg to 4 mg, 1 chloride salt, 0.2 mg of naloxone hydrochloride Salt with 9.5 mg to 3 mg, 1 mg to 2 mg. In certain preferred embodiments mg nalbuphine hydrochloride Salt, 0.2 mg of naloxone in which nalbuphine hydrochloride salt is administered as hydrochloride Salt with 10 mg nalbuphine hydrochloride the opioid agonist, 0.02 mg to 8 mg, 0.02 to 7 mg, 0.02 mg Salt, 0.4 mg of naloxone hydrochloride Salt with 1 mg to 6 mg, 0.02 to 5 mg, 0.02 to 4 mg., 0.02 to 3 mg, 0.02 to nalbuphine hydrochloride Salt, 0.4 mg of naloxone hydro 2 mg, 0.02 to 2 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg chloride salt with 1.5 mg nalbuphine hydrochloride salt, 0.4 to 6 mg, 0.1 mg to 5 mg, 0.1 mg to 4 mg., 0.1 mg to 3 mg, mg of naloxone hydrochloride Salt with 2.0 mg nalbuphine 0.1 mg to 2 mg, 0.1 mg to 1 mg, 0.2 mg to 8 mg, 0.2 mg to hydrochloride salt, 0.4 mg of naloxone hydrochloride salt 7 mg, 0.2 mg to 6 mg, 0.2 mg to 4 mg., 0.2 mg to 3 mg, 0.2 with 2.5 mg nalbuphine hydrochloride salt, 0.4 mg of mg to 2 mg, 0.2 mg to 1 mg, 0.4 mg to 8 mg, 0.4 to 7 mg, naloxone hydrochloride Salt with 3 mg nalbuphine hydro 0.4 to 6 mg, 0.4 mg to 5 mg, 0.4 mg to 4 mg., 0.4 mg to 3 chloride salt, 0.4 mg of naloxone hydrochloride Salt with 3.5 mg, 0.4 mg to 2 mg, 0.4 mg to 1 mg, 0.5 mg to 8 mg, 0.5 mg nalbuphine hydrochloride Salt, 0.4 mg of naloxone mg to 6 mg, 0.5 mg to 5 mg, 0.5 mg to 4 mg., 0.5 mg to 3 hydrochloride salt with 4 mg nalbuphine hydrochloride salt, mg, 0.5 mg to 3 mg, 0.5 to 2 mg, 0.5 mg to 1 mg, 1 mg to 0.4 mg of naloxone hydrochloride Salt with 4.5 mg nalbu 8 mg, 1 mg to 6 mg, 1 mg to 5 mg, 1 mg to 4 mg, 1 mg to phine hydrochloride salt, 0.4 mg of naloxone hydrochloride 3 mg, 1 mg to 2 mg, 5 mg to 8 mg, 4 mg to 7 mg, 3 mg to salt with 5 mg nalbuphine hydrochloride salt, 0.4 mg of 5 mg, 0.02 mg to 1 mg, preferably 0.1 mg to 0.8 mg, 0.2 mg naloxone hydrochloride Salt with 5.5 mg nalbuphine hydro to 0.8 mg, 0.3 mg to 0.8 mg, 0.4 mg to 0.8 mg, 0.5 mg to chloride salt, 0.4 mg of naloxone hydrochloride salt with 6 0.8 mg, 0.1 mg to 0.7 mg, 0.2 mg to 0.7 mg, 0.3 mg to 0.7 mg nalbuphine hydrochloride Salt, 0.4 mg of naloxone mg, 0.4 mg to 0.7 mg, 0.1 mg to 0.6 mg, 0.2 mg to 0.6 mg, hydrochloride salt with 6.5 mg nalbuphine hydrochloride US 2004/018091.6 A1 Sep. 16, 2004 salt, 0.4 mg of naloxone hydrochloride salt with 7 mg 6 mg to 50 mg, 7 mg to 50 mg, 3 mg to 45 mg, 5 mg to 45 nalbuphine hydrochloride Salt, 0.4 mg of naloxone hydro mg, 10 mg to 45 mg, 15 mg to 45 mg, 5 mg to 40 mg, 10 chloride salt with 7.5 mg nalbuphine hydrochloride salt, 0.4 mg to 40 mg, 3 mg to 35 mg, 4 mg to 35 mg, 5 mg to 35 mg, mg of naloxone hydrochloride Salt with 8 mg nalbuphine 10 mg to 35 mg, 3 mg to 30 mg, 4 mg to 30 mg, 5 mg to 30 hydrochloride salt, 0.4 mg of naloxone hydrochloride salt mg, 3 mg to 25 mg, 4 mg to 25 mg, 3 mg to 20 mg, 4 mg with 8.5 mg nalbuphine hydrochloride salt, 0.4 mg of to 20 mg, 5 mg to 25 mg, 10 mg to 25 mg, 15 mg to 30 mg, naloxone hydrochloride Salt with 9 mg nalbuphine hydro 15 mg to 25 mg, 10 mg to 20 mg, and 10 mg to 15 mg. chloride salt, 0.4 mg of naloxone hydrochloride salt with 9.5 0.134. In certain embodiments in which pentazocine mg nalbuphine hydrochloride Salt, 0.4 mg of naloxone hydrochloride Salt is administered intravenously, naloxone hydrochloride salt with 10 mg nalbuphine hydrochloride hydrochloride is preferably administered as the opioid salt, and 0.8 mg of naloxone hydrochloride salt with 10 mg antagonist hydrochloride Salt in amounts of 0.02 mg to 8 mg, malbuphine hydrochloride salt. The present invention also 0.02 to 7 mg, 0.02 mg to 6 mg, 0.02 to 5 mg, 0.02 to 4 mg, encompasses methods comprising intravenous administra 0.02 to 3 mg, 0.02 to 2 mg, 0.02 to 2 mg, 0.1 mg to 8 mg, tion of nalbuphine free base, non-hydrochloride Salt, pro 0.1 mg to 7 mg, 0.1 mg to 6 mg, 0.1 mg to 5 mg, 0.1 mg to drug, or mixture thereof in an amount equivalent to nalbu 4 mg., 0.1 mg to 3 mg, 0.1 mg to 2 mg, 0.1 mg to 1 mg, 0.2 phine hydrochloride Salt and/or administration of the opioid mg to 8 mg, 0.2 mg to 7 mg, 0.2 mg to 6 mg, 0.2 mg to 4 antagonist free base, non-hydrochloride Salt, prodrug, or mg, 0.2 mg to 3 mg, 0.2 mg to 2 mg, 0.2 mg to 1 mg, 0.4 mixture thereof in an equivalent amount to the opioid mg to 8 mg, 0.4 to 7 mg, 0.4 to 6 mg, 0.4 mg to 5 mg, 0.4 antagonist hydrochloride Salt, provided that 5 mg nalbu mg to 4 mg., 0.4 mg to 3 mg, 0.4 mg to 2 mg, 0.4 mg to 1 phine free base is not administered with 0.4 mg naloxone mg, 0.5 mg to 8 mg, 0.5 mg to 6 mg, 0.5 mg to 5 mg, 0.5 free base. mg to 4 mg., 0.5 mg to 3 mg, 0.5 mg to 3 mg, 0.5 to 2 mg, 0131 The present invention also encompass methods 0.5 mg to 1 mg, 1 mg to 8 mg, 1 mg to 6 mg, 1 mg to 5 mg, comprising administration of pentazocine free base, non 1 mg to 4 mg, 1 mg to 3 mg, 1 mg to 2 mg, 5 mg to 8 mg, hydrochloride Salt, prodrug, or mixture thereof in an equiva 4 mg to 7 mg, 3 mg to 5 mg, 0.02 mg to 1 mg, preferably lent amount to pentazocine hydrochloride Salt and/or admin 0.1 mg to 0.8 mg, 0.2 mg to 0.8 mg, 0.3 mg to 0.8 mg, 0.4 istration of the opioid antagonist free base, non mg to 0.8 mg, 0.5 mg to 0.8 mg, 0.1 mg to 0.7 mg, 0.2 mg hydrochloride Salt, prodrug, or mixture thereof in an to 0.7 mg, 0.3 mg to 0.7 mg, 0.4 mg to 0.7 mg, 0.1 mg to equivalent amount to the opioid antagonist hydrochloride 0.6 mg, 0.2 mg to 0.6 mg, 0.3 to 0.6 mg, 0.1 mg to 0.5 mg, Salt. 0.15 mg to 0.5 mg, 0.2 mg to 0.5 mg, 0.25 mg to 0.5 mg, 0.3 mg to 0.5 mg, 0.35 mg to 0.5 mg, 0.1 mg to 0.45 mg, 0.15 0.132. In another embodiment of the invention, pentazo mg to 0.45 mg, 0.2 mg to 0.45 mg, 0.25 mg to 0.45 mg, 0.1 cine free base, prodrug, non-hydrochloride Salt, most pref mg to 0.3 mg, 0.13 mg to 0.3 mg, 0.2 mg to 0.3 mg, 0.1 mg erably in the hydrochloride salt, or mixture thereof is admin to 0.25 mg, 0.15 mg to 0.25 mg, 0.1 mg to 0.2 mg, 0.1 mg istered intravenously as the K-opioid receptor agonist with to 0.15 mg. Non-limiting examples of the present invention the opioid antagonist to treat, manage, or ameliorate pain. In are methods comprising administration of 3 mg, 4 mg, 5 mg, certain embodiments, the method of the invention comprises 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 administration of an opioid antagonist hydrochloride Salt, mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 particularly naloxone hydrochloride salt, and 18 to 120 mg, 23 mg, 24 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, and times greater, 25 to 120 times greater, 18 to 110 times 50 mg pentazocine hydrochloride Salt with 0.1 mg, 0.15 mg, greater, 25 to 110 times greater. 18 to 100 times greater, 25 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg., 0.45 mg, 0.5 mg, to 100 times greater, 18 to 95 times greater, 25 to 90 times 0.55 mg, 0.6 mg 0.7 mg, 0.75 mg, 0.8 mg, 1 mg, 1.6 mg, 2 greater, 30 to 90 times greater, 35 to 90 times greater, 18 to mg, 2.4 mg., 3 mg, 4 mg, 5 mg, 6 mg, 7 mg and 8 mg 85 times greater, 20 to 80 times greater, 20 to 60 times naloxone hydrochloride Salt. greater, 20 to 50 times greater, 25 to 55 times greater, 35 to 80 times greater, 20 to 75 times greater, 25 to 70 times 0135) In another particular embodiment of the invention, greater, 40 to 100 times greater, 50 to 100 times greater, 55 butorphanol free base, a pharmaceutically acceptable Salt, a to 95 times greater, 45 to 90 times greater, 40 to 70 times prodrug, or a mixture thereof is administered with an opioid greater, 18 to 50 times greater, 18 to 40 times greater, 18 to antagonist to achieve greater analgesia than that produced by 35 times greater, or 18 to 30 times greater, by weight, administration of the butorphanol or the antagonist alone. pentazocine hydrochloride Salt. Non-limiting examples of The butorphanol tartrate salt form is preferably administered the methods of the present invention comprise of intrave at 0.3 to 10 times greater, 0.3 to 9 times greater, 0.3 to 8 nous administration of 10 mg of pentazocine hydrochloride times greater, 0.5 to 10 times greater, 0.3 to 7 times greater, salt with 0.4 mg of naloxone hydrochloride salt (i.e., 25 0.5 to 7 times greater, 0.3 to 6 times greater. 0.5 to 6 times times greater, by weight, pentazocine hydrochloride Salt greater, 0.3 to 5 times greater, 0.5 to 5 times greater, 0.3 to 4 times greater, 0.5 to 4 times greater, 0.3 to 3 times greater, than naloxone hydrochloride Salt), 15 mg of pentazocine or 0.5 to 3 times greater, by weight, than the amount of hydrochloride Salt with 0.3 mg naloxone hydrochloride salt opioid antagonist hydrochloride Salt administered. Non (i.e., 30 times greater, by weight, pentazocine hydrochloride limiting examples of the present invention are methods Salt than naloxone hydrochloride Salt), and 25 mg of pen comprising administration of 0.3 mg ofbutorphanol tartrate tazocine hydrochloride salt with 0.5 mg naloxone hydro salt with 0.3 mg of naloxone hydrochloride salt (i.e., 1 time chloride Salt (i.e., 50 times greater pentazocine hydrochlo greater, by weight, ofbutorphanol tartrate Salt than naloxone ride Salt than naloxone hydrochloride Salt). hydrochloride salt), 0.5 mg of butorphanol tartrate salt with 0133. In specific embodiments of the invention, the 0.2 mg naloxone hydrochloride Salt (i.e., 2.5 times greater, weight of pentazocine hydrochloride Salt administered intra by weight, butorphanol tartrate Salt than naloxone hydro venously is 3 mg to 50 mg, 4 mg to 50 mg, 5 mg to 50 mg, chloride salt), and 0.8 mg of butorphanol tartrate salt with US 2004/018091.6 A1 Sep. 16, 2004 22

0.4 mg naloxone hydrochloride Salt (i.e., 2 times greater, by comprises administration by a method, other than intrave weight butorphanol tartrate Salt than naloxone hydrochloride nous administration (and in certain embodiments, also other salt). than oral administration for gastro-intestinal uptake) an 0136. In specific embodiments, the method of the inven opioid antagonist free base, Salt, prodrug, or mixture thereof tion comprises intravenous administration of butorphanol and an nalbuphine free base, Salt, prodrug, or mixture tartrate Salt as the K-opioid agonist. In more specific embodi thereof in equivalent amounts to intravenous administration ments, the weight of butorphanol tartrate Salt administered of the opioid antagonist hydrochloride salt and 6.25 to 49 intravenously is 0.2 mg to 2 mg, 0.2 mg to 1.9 mg, 0.2 mg times greater, 6.25 to 40 times greater, 6.25 to 35 times to 1.8 mg, 0.2 mg to 1.7 mg, 0.25 mg to 1.9 mg, 0.25 mg to greater, 6.25 to 30 times greater, 6.25 to 20 times greater, 8 1.8 mg, 0.25 mg to 1.75 mg, 0.25 mg to 1.5 mg, 0.25 mg to to 35 times greater, 8 to 30 times greater, 8 to 25 times 1 mg, or 0.2 mg to 1 mg. In certain preferred embodiments greater, 10 to 30 times greater, 10 to 20 times greater, 15 to comprising intravenous administration of butorphanol tar 25 times greater, 20 to 25 times greater, 10 to 15 times trate Salt, 0.02 mg to 8 mg, 0.02 to 7 mg, 0.02 mg to 6 mg, greater, 9 to 15 times greater, 5 to 10 times greater, 30 to 49 0.02 to 5 mg, 0.02 to 4 mg., 0.02 to 3 mg, 0.02 to 2 mg, 0.02 times greater, 20 to 30 times greater, 15 to 20 times greater, to 2 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 6 mg, 13 to 15 times greater, 11 to 13 times greater, 9 to 11 times 0.1 mg to 5 mg, 0.1 mg to 4 mg., 0.1 mg to 3 mg, 0.1 mg to greater, 7 to 9 times greater, or 6.25 to 7 times greater, by 2 mg, 0.1 mg to 1 mg, 0.2 mg to 8 mg, 0.2 mg to 7 mg, 0.2 weight, nalbuphine hydrochloride Salt. mg to 6 mg, 0.2 mg to 4 mg., 0.2 mg to 3 mg, 0.2 mg to 2 0.139. Alternatively, nalbuphine free base, salt, prodrug, mg, 0.2 mg to 1 mg, 0.4 mg to 8 mg, 0.4 to 7 mg, 0.4 to 6 or mixture thereof is administered by a method other than mg, 0.4 mg to 5 mg, 0.4 mg to 4 mg., 0.4 mg to 3 mg, 0.4 intravenously in amounts equivalent to 0.02 mg to 8 mg, mg to 2 mg, 0.4 mg to 1 mg, 0.5 mg to 8 mg, 0.5 mg to 6 0.02 to 7 mg, 0.02 mg to 6 mg, 0.02 to 5 mg, 0.02 to 4 mg, mg, 0.5 mg to 5 mg, 0.5 mg to 4 mg., 0.5 mg to 3 mg, 0.5 0.02 to 3 mg, 0.02 to 2 mg, 0.02 to 2 mg, 0.1 mg to 8 mg, mg to 3 mg, 0.5 to 2 mg, 0.5 mg to 1 mg, 1 mg to 8 mg, 1 0.1 mg to 7 mg, 0.1 mg to 6 mg, 0.1 mg to 5 mg, 0.1 mg to mg to 6 mg, 1 mg to 5 mg, 1 mg to 4 mg, 1 mg to 3 mg, 1 4 mg., 0.1 mg to 3 mg, 0.1 mg to 2 mg, 0.1 mg to 1 mg, 0.2 mg to 2 mg, 5 mg to 8 mg, 4 mg to 7 mg, 3 mg to 5 mg, 0.02 mg to 8 mg, 0.2 mg to 7 mg, 0.2 mg to 6 mg, 0.2 mg to 4 mg to 1 mg, preferably 0.1 mg to 0.8 mg, 0.2 mg to 0.8 mg, mg, 0.2 mg to 3 mg, 0.2 mg to 2 mg, 0.2 mg to 1 mg, 0.4 0.3 mg to 0.8 mg, 0.4 mg to 0.8 mg, 0.5 mg to 0.8 mg, 0.1 mg to 8 mg, 0.4 to 7 mg, 0.4 to 6 mg, 0.4 mg to 5 mg, 0.4 mg to 0.7 mg, 0.2 mg to 0.7 mg, 0.3 mg to 0.7 mg, 0.4 mg mg to 4 mg., 0.4 mg to 3 mg, 0.4 mg to 2 mg, 0.4 mg to 1 to 0.7 mg, 0.1 mg to 0.6 mg, 0.2 mg to 0.6 mg, 0.3 to 0.6 mg, mg, 0.5 mg to 8 mg, 0.5 mg to 6 mg, 0.5 mg to 5 mg, 0.5 0.1 mg to 0.5 mg, 0.15 mg to 0.5 mg, 0.2 mg to 0.5 mg, 0.25 mg to 4 mg., 0.5 mg to 3 mg, 0.5 mg to 3 mg, 0.5 to 2 mg, mg to 0.5 mg, 0.3 mg to 0.5 mg, 0.35 mg to 0.5 mg, 0.1 mg 0.5 mg to 1 mg, 1 mg to 8 mg, 1 mg to 6 mg, 1 mg to 5 mg, to 0.45 mg, 0.15 mg to 0.45 mg, 0.2 mg to 0.45 mg, 0.25 mg 1 mg to 4 mg, 1 mg to 3 mg, 1 mg to 2 mg, 5 mg to 8 mg, to 0.45 mg, 0.1 mg to 0.3 mg, 0.13 mg to 0.3 mg, 0.2 mg to 4 mg to 7 mg, 3 mg to 5 mg, 0.02 mg to 1 mg, preferably 0.3 mg, 0.1 mg to 0.25 mg, 0.15 mg to 0.25 mg, 0.1 mg to 0.1 mg to 0.8 mg, 0.2 mg to 0.8 mg, 0.3 mg to 0.8 mg, 0.4 0.2 mg, 0.1 mg to 0.15 mg naloxone hydrochloride Salt is mg to 0.8 mg, 0.5 mg to 0.8 mg, 0.1 mg to 0.7 mg, 0.2 mg administered as the opioid antagonist hydrochloride. Non to 0.7 mg, 0.3 mg to 0.7 mg, 0.4 mg to 0.7 mg, 0.1 mg to limiting examples of the present invention are methods 0.6 mg, 0.2 mg to 0.6 mg, 0.3 to 0.6 mg, 0.1 mg to 0.5 mg, comprising intravenous administration of 0.2 mg, 0.3 mg, 0.15 mg to 0.5 mg, 0.2 mg to 0.5 mg, 0.25 mg to 0.5 mg, 0.3 0.4 mg., 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg to 0.5 mg, 0.35 mg to 0.5 mg, 0.1 mg to 0.45 mg, 0.15 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, mg to 0.45 mg, 0.2 mg to 0.45 mg, 0.25 mg to 0.45 mg, 0.1 1.8 mg, or 2.0 mg of butorphanol tartrate Salt with 0.1 mg, mg to 0.3 mg, 0.13 mg to 0.3 mg, 0.2 mg to 0.3 mg, 0.1 mg 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg., 0.45 to 0.25 mg, 0.15 mg to 0.25 mg, 0.1 mg to 0.2 mg, 0.1 mg mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 1 to 0.15 mg nalbuphine hydrochloride Salt or equivalent mg, 1.6 mg, 2 mg, 2.4 mg., 3 mg, 4 mg, 5 mg, 6 mg, 7 mg amount of free base, non-hydrochloride Salt, prodrug, or and 8 mg naloxone hydrochloride salt. The preferred mixture thereof intravenously administered. embodiments of the present invention also encompass meth 0140. An amount of a K-opioid agonist and an opioid ods comprising administration of butorphanol free base, antagonist administered by a method other than intravenous non-tartrate Salt, prodrug, or mixture thereof in an equivalent administration and an amount of a K-opioid opioid agonist amount to butorphanol tartrate Salt and/or administration of and an opioid antagonist administered intravenously are the opioid antagonist free base, non-hydrochloride Salt, equivalent amounts if both amounts produce approximately prodrug, or mixture thereof in an equivalent amount to the the same blood concentration of K-opioid agonist and opioid opioid antagonist hydrochloride Salt. antagonist after administration. Any method in the art may be used to measure the blood concentration. For example, 0.137 The present invention also encompasses methods but not by way of limitation, blood concentration of K-opioid of treating pain comprising administration by a method other agonists and opioid antagonists may be measured by high than intravenous (and, in certain embodiments, also other performance liquid chromatography. Blood concentration of than oral administration for gastro-intestinal uptake) an K-opioid agonists and antagonists may be measured imme amount of a K-opioid receptor antagonist and an amount of diately after administration, less than or at approximately 10 an opioid agonist that results in greater analgesia than the minutes after administration, leSS than or at approximately administration of the opioid agonist or antagonist alone. The 15 minutes after administration, less than or at approxi formulation of the specific embodiment of the invention mately 20 minutes after administration, less than or at should Suit the particular mode of administration. approximately 30 minutes after administration, less than or 0.138. In certain embodiments of the present invention, at approximately 45 minutes after administration, less than the method of treating, managing, and ameliorating pain or at approximately 1 hour after administration, less than or US 2004/018091.6 A1 Sep. 16, 2004 23 at approximately 2 hours after administration, less than or istration of 0.4 mg of naloxone hydrochloride salt with 5 mg approximately 3 hours after administration, less than or of nalbuphine hydrochloride salt, 0.4 mg of naloxone hydro approximately 4 hours after administration, less than or chloride Salt with 6 mg of nalbuphine hydrochloride salt, 0.4 approximately 5 hours after administration, or less than or mg of naloxone hydrochloride salt with 7 mg of nalbuphine approximately 6 hours after administration. hydrochloride salt, 0.4 mg of naloxone hydrochloride salt with 8 mg of nalbuphine hydrochloride salt, 0.4 mg of 0.141. Depending on the specific non-intravenous mode naloxone hydrochloride salt with 9 mg of nalbuphine hydro of administration, a dose for non-intravenous administration chloride salt, 0.4 mg of naloxone hydrochloride salt with 10 may comprise a ratio of K-opioid agonist to opioid antago mg of nalbuphine hydrochloride Salt, 0.4 mg of naloxone nist that is lesser, equal, or greater than the ratio of K-opioid hydrochloride Salt with 15 mg of nalbuphine hydrochloride agonist to opioid agonist in an equivalent dose for intrave salt, 0.4 mg of naloxone hydrochloride Salt with 20 mg of nous administration. Also depending on the Specific non nalbuphine hydrochloride Salt, 0.4 mg of naloxone hydro intravenous mode of administration, a dose for non-intrave chloride salt with 25 mg of nalbuphine hydrochloride salt, nous administration may comprise great amounts of and 0.4 mg of naloxone hydrochloride salt with 30 mg of K-opioid agonist and opioid antagonist, by weight, than an malbuphine hydrochloride salt. equivalent dose for intravenous administration. 0145 The present invention further encompasses meth 0142. In certain embodiments of the invention, the ods comprising administration of equivalent amounts of method comprises Sublingual administration (or other oral nalbuphine free base, non-hydrochloride Salt, prodrug or cavity administration), the opioid antagonist hydrochloride mixture thereof to nalbuphine hydrochloride Salt and equiva salt is administered with 1 to 60 times greater, 1 to 50 times lent amounts of the opioid antagonist free base, non-hydro greater, 1 to 45 times greater, 1 to 40 times greater, 5 to 50 chloride Salt, prodrug, or mixture thereof to the opioid times greater, 5 to 40 times greater, 5 to 35 times greater, 10 hydrochloride salt. to 40 times greater, 15 to 40 times greater, 10 to 30 times greater, 15 to 30 times greater, 1 to 30 times greater, 1 to 20 0146 The present invention also encompasses methods times greater, 1 to 15 times greater, or 1 to 9 times greater comprising administration, other than intravenous adminis nalbuphine hydrochloride Salt is administered Sublingually. tration (and, in certain embodiments, other than oral admin Non-limiting examples of methods of the present invention istration for gastro-intestinal uptake), pentazocine, a pro comprise Sublingual administration of 8 mg nalbuphine drug, a pharmaceutically acceptable Salt, or mixture thereof hydrochloride Salt with 0.4 mg naloxone hydrochloride Salt with an opioid antagonist, prodrug, a pharmaceutically (i.e., 20 times greater, by weight, nalbuphine hydrochloride acceptable Salt, or mixture thereof in amounts equivalent to Salt than naloxone hydrochloride Salt), 15 mg nalbuphine intravenous administration of an opioid antagonist hydro hydrochloride salt with 3 mg naloxone hydrochloride salt chloride salt, preferably naloxone hydrochloride salt, and 18 (i.e., 5 times greater, by weight, nalbuphine hydrochloride to 120 times greater, 25 to 120 times greater, 18 to 110 times Salt than naloxone hydrochloride Salt), and 30 mg nalbu greater, 25 to 110 times greater. 18 to 100 times greater, 25 phine hydrochloride salt with 4 mg naloxone hydrochloride to 100 times greater, 18 to 95 times greater, 25 to 90 times Salt (i.e., 7.5 times greater, by weight, nalbuphine hydro greater, 30 to 90 times greater, 35 to 90 times greater, 18 to chloride Salt than naloxone hydrochloride Salt). Alterna 80 times greater, 20 to 80 times greater, 20 to 60 times tively, 5 mg to 65 mg, 5 mg to 60 mg, 5 mg to 55 mg, 5 mg greater, 20 to 50 times greater, 25 to 55 times greater, 35 to to 50 mg, 5 mg to 40 mg, 5 mg to 35 mg, 6 mg to 55 mg, 80 times greater, 20 to 75 times greater, 25 to 70 times 6 mg to 50 mg, 6 mg to 45 mg, 6 mg to 40 mg, 6 mg to 30 greater, 40 to 100 times greater, 50 to 100 times greater, 55 mg, 7 mg to 40 mg, 7 mg to 35 mg, or 7.5 to 30 mg of to 95 times greater, 45 to 90 times greater, 40 to 70 times nalbuphine hydrochloride Salt is administered Sublingually. greater, 18 to 50 times greater, 18 to 40 times greater, 18 to 35 times greater, or 18 to 30 times greater, by weight, 0143. In certain preferred embodiments of the invention pentazocine hydrochloride Salt than the opioid antagonist in which the method comprises Sublingual administration of hydrochloride salt, preferably naloxone hydrochloride salt. malbuphine hydrochloride salt, naloxone hydrochloride salt Alternatively, the amount of pentazocine, a prodrug, a is preferably administered Sublingually as the opioid antago pharmaceutically acceptable Salt, or mixture thereof admin nist hydrochloride in amounts preferably 0.1 mg to 10 mg, istered is an amount equivalent to intravenous administra 0.1 mg to 9 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to tion of 3 mg to 50 mg, 4 mg to 50 mg, 5 mg to 50 mg, 6 mg 6 mg, 0.2 mg to 10 mg, 0.2 mg to 9 mg, 0.2 mg to 8 mg, 0.2 to 50 mg, 7 mg to 50 mg, 3 mg to 45 mg, 5 mg to 45 mg, mg to 7 mg, 0.2 mg to 6 mg, 0.2 mg to 5 mg, 0.3 mg to 10 10 mg to 45 mg, 15 mg to 45 mg, 5 mg to 40 mg, 10 mg to mg, 0.3 mg to 9 mg, 0.3 mg to 7 mg, 0.3 mg to 6 mg, 0.3 40 mg, 3 mg to 35 mg, 4 mg to 35 mg, 5 mg to 35 mg, 10 mg to 5 mg, 0.3 mg to 4 mg., 0.4 mg to 4 mg., 0.5 mg to 4 mg to 35 mg, 3 mg to 30 mg, 4 mg to 30 mg, 5 mg to 30 mg, mg, 0.4 mg to 3.5 mg, 0.5 mg to 3.5 mg, 0.6 mg to 3.5 mg, 3 mg to 25 mg, 4 mg to 25 mg, 3 mg to 20 mg, 4 mg to 20 0.4 mg to 3 mg, 0.5 mg to 3 mg, 0.4 mg to 2.8 mg, 0.6 mg mg, 5 mg to 25 mg, 10 mg to 25 mg, 15 mg to 30 mg, 15 to 2.7 mg, 0.4 mg to 2.5 mg, 0.5 mg to 2.2 mg, 0.4 mg to mg to 25 mg, 10 mg to 20 mg, and 10 mg to 15 mg 2 mg, 0.6 mg to 2 mg, 0.4 mg to 1.5 mg, or 0.4 mg to 1 mg. pentazocine hydrochloride Salt. Non-limiting examples of the present invention are methods comprising administration of 5 mg, 5.5 mg, 6 mg, 6.5 mg, 0147 In certain embodiments comprising Sublingual 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg 10 mg, 15 mg, administration (or other oral cavity administration) of pen 20 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg nalbuphine tazocine, the amount of pentazocine hydrochloride Salt 7.5 hydrochloride salt with naloxone hydrochloride salt. to 50 times greater, 7.5 to 45 times greater, 10 to 50 times greater, 10 to 40 times greater, 15 to 50 times greater, 15 to 014.4 For example, in specific embodiments of the 45 times greater, 7.5 to 30 times greater, 7.5 to 25 times present invention, the method comprises Sublingual admin greater, 7.5 to 20 times greater, 10 to 30 times greater, or 7.5 US 2004/018091.6 A1 Sep. 16, 2004 24 to 15 times greater, by weight, than the amount of opioid mg, or 0.2 mg to 1 mg of butorphanol tartrate Salt admin antagonist hydrochloride Salt administered. istered intravenously. In certain embodiments comprising Sublingual administration (or other oral cavity administra 0148 Alternatively, the amount of pentazocine hydro tion) of butorphanol as the K-opioid agonist, butorphanol chloride salt administered sublingually (or by other oral tartrate salt is administered in amounts 0.1 to 60 times cavity administration) is 30 mg to 100 mg, 30 to 90 mg, 40 greater, 0.1 to 50 times greater, 0.1 to 45 times greater, 0.3 mg to 100 mg, 30 mg to 85 mg, 40 mg to 85 mg, 30 mg to to 40 times greater, or 0.5 to 30 greater, 10 to 60 times 70 mg, 40 mg to 70 mg, 30 mg to 60 mg, 40 mg to 60 mg, greater, 20 to 50 times greater, or 10 to 30 times greater by 30 mg to 50 mg, 50 mg to 80, or 30 mg to 45 mg. In weight, than the opioid antagonist hydrochloride Salt, pref embodiments of the invention in which pentazocine hydro erably naloxone hydrochloride salt, administered. Non-lim chloride Salt is administered Sublingually (or by other oral iting examples of the present invention are methods com cavity administration), naloxone hydrochloride Salt is the prising Sublingual administration of 0.5 mg butorphanol preferred opioid antagonist hydrochloride Salt and is admin tartrate Salt with 0.25 mg naloxone hydrochloride Salt (i.e., istered in amounts 1 mg to 10 mg, 1 mg to 9 mg, 1 mg to 2 times greater, by weight, butorphanol tartrate Salt than 8 mg, 1 mg to 7 mg, 1 mg to 6 mg, 1 mg to 5 mg, 1 mg to naloxone hydrochloride Salt), 2 mg butorphanol tartrate Salt 4 mg, 2 mg to 10 mg, 2 mg to 9 mg, 2 mg to 8 mg, 2 mg with 0.2 mg naloxone hydrochloride salt (i.e., 10 times to 7 mg, 2 mg to 6 mg, 2 mg to 5 mg, 2 mg to 4 mg, 2 mg greater, by weight, butorphanol tartrate Salt than naloxone to 3.8 mg, 2 mg to 3.6 mg, 2 mg to 3.4 mg, 2 mg to 3.4 mg, hydrochloride Salt), and 6 mg butorphanol tartrate Salt with 2.2 mg to 3.5 mg, 2 mg to 3.2 mg, 3 mg to 4 mg, or 2 mg 0.3 mg naloxone hydrochloride Salt (i.e., 20 times greater, by to 3 mg. Non-limiting examples of the present invention are weight, butorphanol tartrate Salt than naloxone hydrochlo methods comprising Sublingual administration of 30 mg, 31 ride Salt). Alternatively, 0.1 mg to 10 mg, 0.1 mg to 9 mg, mg, 32 mg, 33 mg, 34 mg., 35 mg, 36 mg, 37 mg, 38 mg, 39 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 6 mg, 0.2 mg to mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg., 45 mg, 50 mg, 55 9 mg, 0.2 mg to 8 mg, 0.2 mg to 7 mg, 0.2 mg to 6 mg, 0.2 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg to 5.5 mg, 0.3 to 6.5 mg, 0.4 mg to 7 mg, or 0.5 mg to mg or 100 mg pentazocine hydrochloride Salt with 2 mg, 2.1 6 mg of butorphanol tartrate Salt is administered Sublin mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, gually. 2.9 g, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg., 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, or 4.0 mg naloxone hydrochloride 0152) If the K-opioid agonist is butorphanol tartrate salt, Salt. then, preferably, 0.1 to 4 mg., 0.1 mg to 3.5 mg, 0.1 mg to 3 mg, 0.1 to 2.5 mg, 0.1 mg to 2 mg, 0.1 mg to 1 mg, 0.3 014.9 The present invention further encompasses meth mg to 0.8 mg, or 0.1 mg to 0.8 mg of naloxone hydrochloride ods comprising administration of equivalent amounts of Salt is administered. Non-limiting examples of the present pentazocine free base, non-hydrochloride Salt, prodrug or invention are methods comprising administration of 0.1 mg, mixture thereof to pentazocine hydrochloride Salt and 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, equivalent amounts of the opioid antagonist free base, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, or 7 mg butorphanol non-hydrochloride Salt, prodrug, or mixture thereof to the tartrate Salt with 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg., 0.5 mg, 0.6 opioid hydrochloride salt, provided that if the method of mg, 0.7 mg, or 0.85 mg naloxone hydrochloride Salt. administration is oral for gastro-intestinal uptake, 50 mg pentazocine hydrochloride is not administered with 0.5 mg 0153. The present invention further encompasses phar naloxone hydrochloride. maceutical compositions comprising equivalent amounts of butorphanol free base, non-tartrate Salt, prodrug or mixture 0150. In certain preferred embodiments, butorphanol, a thereof to butorphanol tartrate Salt and equivalent amounts prodrug, a pharmaceutically acceptable Salt, or mixture of the opioid antagonist free base, non-hydrochloride Salt, thereof is administered, by a method other than intravenous prodrug, or mixture thereof to the opioid hydrochloride Salt. administration (and, in certain embodiments, other than oral administration for gastro-intestinal uptake), with an opioid Combinational Therapies antagonist, pharmaceutically acceptable Salt, prodrug, or mixture thereof in amounts equivalent to intravenous admin 0154) In certain embodiments of the present invention, istration the opioid antagonist hydrochloride Salt, preferably the composition of the invention can be used in combination naloxone hydrochloride salt, and 0.3 to 10 times greater, 0.3 therapy with at least one other therapeutic agent. The to 9 times greater, 0.3 to 8 times greater, 0.5 to 10 times compound of the invention and the therapeutic agent can act greater, 0.3 to 7 times greater, 0.5 to 7 times greater, 0.3 to additively or, more preferably, Synergistically. In a preferred 6 times greater. 0.5 to 6 times greater, 0.3 to 5 times greater, embodiment, a composition of the invention is administered 0.5 to 5 times greater, 0.3 to 4 times greater, 0.5 to 4 times concurrently with the administration of another therapeutic greater, 0.3 to 3 times greater, or 0.5 to 3 times greater, by agent, which can be part of the same composition as or in a weight, of butorphanol tartrate Salt than the opioid antago different composition from that comprising the combination nist hydrochloride salt. of 6 opioid receptor agonist and opioid antagonist of the invention. In another embodiment, a combination of the 0151. Alternatively, the amount of butorphanol, a pro invention is administered prior or Subsequent to administra drug, a pharmaceutically acceptable Salt, or mixture thereof tion of another therapeutic agent. In one embodiment of is administered by a method other than intravenous admin combination therapy that involves treatment of chronic pain, istration (and, in certain embodiments, other than oral the combination therapy involves alternating between administration for gastro-intestinal uptake) in amounts administering a composition comprising a composition of equivalent to 0.2 mg to 2 mg, 0.2 mg to 1.9 mg, 0.2 mg to the invention and a composition comprising another thera 1.8 mg, 0.2 mg to 1.7 mg, 0.25 mg to 1.9 mg, 0.25 mg to 1.8 peutic agent, e.g., to minimize the toxicity associated with a mg, 0.25 mg to 1.75 mg, 0.25 mg to 1.5 mg, 0.25 mg to 1 particular drug. The duration of administration of the com US 2004/018091.6 A1 Sep. 16, 2004 25 position of the invention or therapeutic agent can be, e.g., indeloxazine hydrochloride, nefopam, nomifensine, oxitrip one month, three months, Six months, a year, or for more tan, oxypertine, paroxetine, Sertraline, thiaZeSim, traZodone, extended periods. In certain embodiments, when a com benmoxine, iproclozide, iproniazid, isocarboxazid, niala pound of the invention is administered concurrently with mide, octamoxin, phenelZine, cotinine, rolicyprine, rollip another therapeutic agent that potentially produces adverse ram, maprotiline, metralindole, mianserin, mirtazepine, adi Side effects including, but not limited to, toxicity, the thera nazolam, amitriptyline, amitriptylinoxide, amoxapine, peutic agent can advantageously be administered at a dose butriptyline, clomipramine, demexiptiline, desipramine, that falls below the threshold at which the adverse side is dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imi elicited. pramine, imipramine N-oxide, iprindole, lofepramine, meli tracen, metapramine, nortriptyline, noxiptilin, opipramol, O155 In certain embodiments, the compositions of the pizotyline, propizepine, protriptyline, quinupramine, tianep present invention can be combined in dosage forms with non-opioid analgesics, e.g., non-Steroidal anti-inflammatory tine, trimipramine, adrafinil, benactyzine, bupropion, buta agents, including aspirin, ibuprofen, diclofenac, naproxen, cetin, dioxadrol, dulloxetine, etoperidone, febarbamate, benoxaporfen, flurbiprofen, fenoprofen, flubufen, ketopro femoxetine, fenpentadiol, fluoxetine, fluvoxamine, hemato fen, indoprofen, piroprofen, carporfen, oxaprozin, pramo porphyrin, hypericin, levophacetoperane, medifoxamine, profen, muroprofen, trioxaprofen, Suprofen, aminoprofen, milnacipran, minaprine, moclobemide, nefazodone, oxaflo tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, Zane, piberaline, prolintane, pyriSuccideanol, ritanserin, roX Sulindac, tolmetin, Zomepirac, tiopinac, Zidometacin, acem indole, rubidium chloride, Sulpiride, tandoSpirone, thozali etacin, fentiaza, clinndanac, OXpinac, mefenamic acid, none, tofenacin, toloxatone, tranylcypromine, L-tryptophan, meclofenamic acid, flufenamic acid, niflumic acid, tolfe Venlafaxine, Viloxazine, and Zimeldine. namic acid, diflurisal, fluefenisal, piroXicam, Sudoxicam, or 0158. In certain embodiments of the present invention, isocxicam, or pharmaceutically acceptable Salts, prodrugs, the composition of the invention can be combined with or mixtures thereof. Other Suitable non-opioid analgesic antiepileptic drugs, e.g., phenyloin (DILANTINTM), which which may be included in dosage forms of the present is usually the drug of choice for the treatment of epilepsy, invention include the following, non-limiting chemical phenobarbital, primidone (MYSOLINETM), carbamazepine classes of analgesics, antipyretic, nonsteroidal anti-inflam (TEGRETOLTM) for complex partial tonic-clonic seizures, matory drugs (NSAIDs) (e.g., aspirin, ibuprofen, celecoxib and ethoSuximide (ZARONTINTM) and clonazepam (CELEBREXTM), diclofenac (VOLTARENTM), etodolac (KLONOPINTM) for absence seizures. (LODINETM), fenoprofen (NALFONTM), indomethacin (INDOCINTM), ketoralac (TORADOLTM), oxaprozin (DAY Pharmaceutical Kits PROTM), sulindac (CLINORILTM), tolmentin (TOLEC TINTM), rofecoxib (VIOXXTM), naproxen (ALEVETM, 0159. The present invention also encompasses pharma NAPROSYNTM), ketoprofen (ACTRONTM), and nabume ceutical kits for the practice of the methods of this invention. tone (RELAFENTM)); steroidal anti-inflammatory drugs The kits include one or more K-opioid receptor agonists and include, but are not limited to, glucocorticoids, dexametha one or more opioid receptor antagonists in dosages and sone (DECADRONTM), cortisone, hydrocortisone, pred amounts used in the methods and compositions of the nisone (DELTASONTM), prednisolone, triamcinolone, azu invention. The K-opioid receptor agonists and the opioid lfindine, and eicosanoids, Such as prostaglandins, antagonists may be provided in the free base, pharmaceuti thromboxanes, and leukortrienes; Salicylic acid derivatives, cally acceptable Salt, prodrug, or mixture thereof in dosages including aspirin, Sodium Salicylate, choline magnesium and amounts used in the methods and compositions of the trisalicylate, Salsalate, diflunisal, Salicylsalicylic acid, Sul invention. The kit may also comprise of additional active fasalazine, and olSalazin; para-aminophenol derivatives and inactive ingredients. The kit may further comprise of including acetaminophen and phenacetin; indole and indene devises that are used to administer the compounds of the acetic acids, including indomethacin, Sulindac, and etodolac, invention. Examples of Such devices include, but are not heteroaryl acetic acids, including tolmetin, diclorfenac, and limited to, Syringes, drip bags, patches, and inhalers. In Some ketorolac, anthranilic acids (e.g., fenamates), including embodiments the kits may comprise nasal Spray bottles or mefanamic acid, and meclofenamic acid; enolic acids, inhalers, or the like, which may either be charged with including oxicams (e.g., prioxicam or tenoxicam), and pyra compositions to be dispensed or which may be accompanied Zolidinediones (e.g., phenylbutazone or oxyphentharta by Said compositions in a separate package or container. Zone); and alkanones, including nabumetone. 0160 In certain embodiments, the kits additionally 0156. In certain embodiments, the compounds of the include instructional materials teaching the methods of present invention can be formulated in a pharmaceutical treating, managing, or ameliorating pain of the present dosage form in combination with antimigraine agents. Anti invention. The instructional material may comprise of writ migraine agents include, but are not limited to, alpiropride, ten or printed materials or in any medium capable of Storing dihydroergotamine, dolasetron, ergocornine, ergocorninine, Such instructions and communicating them to the end user. ergocryptine, ergot, ergotamine, flumedroXone acetate, fona Such media include, but are not limited to electronic Storage Zine, lisuride, lomerizine, methySergide oxetorone, pizoty media (e.g., magnetic discs, tapes, cartridges, chips), optical line, and mixtures thereof. media (e.g., CD ROM), and the like. Such media may O157. In certain embodiments, the compounds of the include addresses to internet Sites that provide Such instruc present invention can be formulated in a pharmaceutical tional materials. dosage form in combination with antidepressants. Suitable 0.161 The following examples are set forth to assist in antidepressants include, but are not limited to, binedaline, understanding the invention and should not be construed as caroXaZone, citalopram, dimethazan, fencamine, indalpine, Specifically limiting the invention described and claimed US 2004/018091.6 A1 Sep. 16, 2004 26 herein. Such variations, including the Substitutions of all hydrochloride Salt, i.e. a ratio of 1:12.5 opioid antagonist to equivalents now known or later developed, which would be agonist produced more analgesia than the other two combi within the purview of those skilled in the art, and changes in nations. The combination of 10 mg nalbuphine hydrochlo formulations or minor changes in methods or experimental ride Salt with 0.4 mg naloxone hydrochloride Salt produced designs, are to be considered to fall within the Scope of the more analgesia than the combination of 2.5 mg nalbuphine invention incorporated herein. hydrochloride Salt with 0.4 mg naloxone hydrochloride salt for the first 90 minutes after administration and similar EXAMPLES analgesia thereafter. 0.165 FIGS. 2a-d shows the comparative analgesic Example 1 effects of administration of 2.5, 5, and 10 mg of nalbuphine 0162. In this clinical trial, patients underwent standard hydrochloride salt with 0.4 mg of naloxone hydrochloride ized Surgery by the same oral Surgeon for removal of third salt in test subjects different than those in FIGS. 1a-d. As molar (“wisdom”) teeth, including at least one bony shown in FIG. 2a, the combination of 2.5 mg nalbuphine impacted mandibular third molar. Prior to Surgery patients Salt with 0.4 mg naloxone Salt, i.e., a ratio of 1:6.25 opioid received intravenous diazepam, nitrous oxide, and a local antagonist to agonist, produced more analgesia than admin anesthetic (mepivacaine without vasoconstrictor to obtain a istration of nalbuphine hydrochloride salt alone 70 minutes nerve block of short duration). After Surgery, each patient after administration and produced more analgesia than was randomly assigned to receive, in an open injection, administration of 0.4 mg naloxone hydrochloride Salt alone double-blinded fashion, through an intravenous line, an for the first 110 minutes after administration. FIG. 2b injection of either naloxone hydrochloride Salt or a mixture illustrates that administration of 5 mg nalbuphine hydro of naloxone hydrochloride salt and nalbuphine hydrochlo chloride Salt with 0.4 mg naloxone hydrochloride Salt, i.e., ride salt (Abbott Laboratories, Abbott Park, Ill.). a ratio of 1:12.5 opioid antagonist to agonist, produces more analgesia than administration of either nalbuphine hydro 0163 Criteria for administration of the test drug were an chloride salt or naloxone hydrochloride salt alone. FIG. 2c elapse of a period of at least 80 minutes after the onset of the shows that the combination of 10 mg nalbuphine hydrochlo local anesthetic and a pain rating that was greater than one ride Salt with 0.4 mg naloxone hydrochloride Salt, i.e., a ratio quarter (2.5 cm) of the maximum possible visual analog of 1:25 opioid antagonist to agonist, has similar analgesic Scale (VAS) rating (10 cm). Baseline pain intensity was effect as administration of 10 mg nalbuphine hydrochloride defined as the last VAS pain rating before administration of Salt alone for the first 70 minutes after administration and the test drug or drugs. VAS pain ratings were recorded at 20 produces more analgesia than administration of 0.4 mg minute intervals beginning ten minutes after administration naloxone hydrochloride Salt alone for 90 minutes after of the test drug, was three hours. For each patient, the administration. FIG.2d compares the analgesia produced by magnitude of the analgesic response was defined as the the combinations of nalbuphine hydrochloride salt and difference between the pain rating at each time point fol naloxone hydrochloride salt in FIGS. 2a-c. As shown in lowing test drug administration and the baseline VAS pain FIG. 2d, the combination of 5 mg nalbuphine hydrochloride rating. Salt with 0.4 mg naloxone hydrochloride Salt, i.e. a ratio of 0164 FIGS. 1a-d show comparative effects of adminis 1:12.5 opioid antagonist to agonist produced more analgesia tration of 2.5, 5 and 10 mg nalbuphine hydrochloride salt in than the other two combinations. The combination of 10 mg combination with 0.4 mg of naloxone hydrochloride Salt on malbuphine hydrochloride Salt with 0.4 mg naloxone hydro postoperative pain. FIG. 1a illustrates that the combination chloride Salt produced more analgesia than the combination of 2.5 mg nalbuphine hydrochloride salt with 0.4 mg nalox of 2.5 mg nalbuphine hydrochloride salt with 0.4 mg nalox one hydrochloride Salt, i.e., a ratio of 1:6.52 naloxone to one hydrochloride salt for the first 90 minutes after admin nalbuphine produced more analgesia than the administration istration and Similar analgesia thereafter. of 2.5 mg nalbuphine alone at 70 minutes after administra 0166 FIGS. 3a and b show the analgesic effects of tion and produced more analgesia than administration of 0.4 administration of 5 mg nalbuphine hydrochloride Salt with mg naloxone hydrochloride salt for the first 90 minutes after 0.1 mg, 0.2 mg, and 0.4 mg naloxone hydrochloride Salt on administration. FIG. 1b shows that the combination of 5 mg postoperative pain. FIG. 3a shows that in women, the of nalbuphine hydrochloride salt with 0.4 mg naloxone combinations of 5 mg nalbuphine hydrochloride Salt with hydrochloride Salt, i.e., a ratio of 1:12.5 opioid antagonist to 0.4 mg naloxone hydrochloride Salt, i.e., a ratio of 1:12.5 agonist, produced more analgesia than administration of opioid antagonist to agonist, and 5 mg of nalbuphine hydro either nalbuphine hydrochloride Salt or naloxone hydrochlo chloride Salt with 0.2 mg naloxone hydrochloride Salt, i.e., ride salt alone. FIG. 1c shows that administration of 10 mg a ratio of 1:25 opioid antagonist to agonist, produced similar of nalbuphine hydrochloride salt with 0.4 mg of naloxone amounts of analgesia, and in comparison to data presented hydrochloride Salt, i.e., a ratio of 1:25 opioid antagonist to in FIGS. 1b and 2b, more analgesia than administration of agonist, produced analgesia Similar to administration of 10 5 mg nalbuphine hydrochloride Salt alone. FIG. 3b shows mg nalbuphine hydrochloride salt alone for the first 70 inconclusive data for comparison of the analgesic effects of minutes after administration and produced more analgesia 5 mg nalbuphine hydrochloride salt with either 0.4 mg and than administration of 0.4 mg naloxone hydrochloride Salt 0.2 mg naloxone hydrochloride Salt Since only one Subject alone during the first 90 minutes after administration. FIG. was administered the combination of 5 mg nalbuphine 2D compares the data presented in FIGS. 2A-C for the hydrochloride salt with 0.2 mg naloxone hydrochloride salt. analgesic effects of the administration of 2.5, 5, and 10 mg of nalbuphine hydrochloride salt with 0.4 mg of naloxone Example 2 hydrochloride Salt on post operative pain. The combination 0167. In this clinical trial 67 patients underwent standard of 5 mg nalbuphine hydrochloride salt with 0.4 mg naloxone ized Surgery by the same oral Surgeon for removal of third US 2004/018091.6 A1 Sep. 16, 2004 27 molar teeth, including at least one bony impacted mandibu (mepivacaine without vasoconstrictor to obtain a nerve lar third molar. Prior to Surgery, patients received intrave block of short duration). After Surgery, each patient was nous diazepam, nitrous oxide, and a local anesthetic (mepi randomly assigned to receive an injection of 2.5 mg of vacaine without vasoconstrictor to obtain a nerve block of nalbuphine hydrochloride salt (Abbott Laboratories, Abbott Short duration). After Surgery, each patient was randomly Park, Ill.) either alone or combined with 0.2 mg naloxone assigned to receive an injection of nalbuphine hydrochloride hydrochloride Salt in an open injection, double-blinded salt (Abbott Laboratories, Abbott Park, Ill.) 2.5 mg either fashion, through an intravenous line. alone or combined with naloxone hydrochloride salt (0.4 0172 Criteria for administration of the test drug were an mg) in an open injection, double-blinded fashion, through an elapse of a period of at least 80 minutes after the onset of the intravenous line. local anesthetic and a pain rating that was greater than 30% 0168 Criteria for administration of the test drug were an (3 cm) of the maximum possible visual analog Scale (VAS) elapse of a period of at least 80 minutes after the onset of the rating (10 cm). Baseline pain intensity was defined as the local anesthetic and a pain rating that was greater than one last VAS pain rating before administration of the test drug. quarter (2.5 cm) of the maximum possible visual analog VAS pain ratings were recorded at 20 minute intervals Scale (VAS) rating (10 cm). Baseline pain intensity was beginning ten minutes after administration of the test drug. defined as the last VAS pain rating before administration of The duration of the experiment, measured from the time of the test drug. VAS pain ratings were recorded at 20 minute administration of the test drug, was two hours and fifty intervals beginning ten minutes after administration of the minutes. For each patient, the magnitude of the analgesic (or test drug. The duration of the experiment was two hours and anti-analgesic) response was defined as the difference fifty minutes, measured from the time of administration of between the pain rating at each time point following test the test drug. For each patient, the magnitude of the anal drug administration and the baseline VAS pain rating. gesic (or anti-analgesic) response was defined as the differ 0173 FIGS. 5a and b show that the naloxone (hydro ence between the pain rating at each time point following chloride salt) to nalbuphine (hydrochloride salt) ratio of test drug administration and the baseline VAS pain rating. 1:12.5 (i.e. 0.2 mg to 2.5 mg) significantly enhanced the 0169 FIG. 4a depicts that in women, nalbuphine hydro analgesic effect of nalbuphine (hydrochloride Salt) (2.5 mg) chloride Salt (2.5 mg) induced brief analgesia and this effect in both women and men. This enhancement was manifested was antagonized by naloxone hydrochloride Salt (0.4 g). as a significant prolongation of the initial analgesic effect of Kappa-like opioids have been shown to act as agonists at administration of nalbuphine alone observed in both Sexes. Ö-receptors, which produce dysphoria and can antagonize ...t-receptor mediated antinociception in mice, and as com Example 4 petitive antagonists at ul-receptors. Since, in the present 0.174. This example describes the treatment of postopera Study, only mild analgesia was observed in the nalbuphine tive pain following Le Fort I osteotomy using intravenous group and this effect was abolished by the addition of administration of a combination of nalbuphine and nalox naloxone, the lower (2.5 mg) dose of nalbuphine hydrochlo one. In 11 all three patients, repeated administration pro ride Salt in women is apparently insufficient to produce duced marked analgesia. While a Single administration of anti-analgesia. FIG. 4b depicts that in men, nalbuphine malbuphine hydrochloride Salt (5 mg) plus naloxone hydro hydrochloride salt (2.5 mg), either alone or combined with chloride Salt (0.4 mg) produces powerful and long-lasting naloxone hydrochloride Salt (0.4 mg), failed to produce analgesia in both males and females (Example 1, above), Significant analgesia indicating that this lower dose of nal this analgesic could have even greater clinical impact if the buphine is not Sufficient to induce either analgesia or anti efficacy were Sustained dining repeated administration. In a analgesia. Our observation that women receiving nalbuphine preliminary Study in three patients who underwent a Le Fort alone (above) experienced, mild analgesia at the early time I Osteotomy Surgical procedure, 5 mg nalbuphine hydrochlo points in the Study, but that men did not, is consistent with ride Salt plus 0.4 mg naloxone hydrochloride Salt were our previous findings that 6-like opioids are more efficacious administered when requested by the patient. The VAS pain in producing analgesia in women than in men. Scores just prior to administration of the drug combination 0170 The present results suggest that nalbuphine: 1) acts and 60 minutes afterwards are recorded in FIGS. 6, 7, and in males and females to produce both analgesic and anti 8. The same data for the major Side-effect, nausea, for these analgesic effects, 2) the analgesic effect is greater in females three patients, are also presented. The left end of the line and the anti-analgesic effect is greater in males, and 3) the represents the Visual analog Scale (pain and nausea) rating analgesic effect occurs at a lower dose than the anti-anal immediately before drug administration; the right Side rep gesic effect. Since naloxone reverses the Side effects of resents the Visual analog Scale rating 60 minutes after opioids, it is possible that optimal dosing of the partial administration. AS can be seen, most of the lines descend to the right, indicating that nausea as well as pain decreased agonist K-opioid nalbuphine and opioid antagonist naloxone following multiple administrations. Thus, three patients had may allow the presence of a marked enhancement and repeated effective analgesia following most drug adminis prolongation of analgesia with minimal Side effects. trations over a 48-hour period, with, if anything a decrease in nausea associated with each administration. This Study Example 3 further Suggests that early tolerance to the nalbuphine plus 0171 In this clinical trial, 65 patients underwent stan naloxone combination does not occur. dardized Surgery by the same oral Surgeon for removal of third molar teeth, including at least one bony impacted Example 5 mandibular third molar. Prior to Surgery, patients received 0.175. This example describes the treatment of medically intravenous diazepam, nitrous oxide, and a local anesthetic refractory trigeminal neuropathy in three patients using US 2004/018091.6 A1 Sep. 16, 2004 28 intravenous administration of a combination of nalbuphine 0181 All publications, patents, and patent applications and naloxone. Painful peripheral neuropathies are frequent cited herein are hereby incorporated by reference in their complications of chemical and mechanical injuries and entirety for all purposes. metabolic disorders, and are relatively refractory to narcotic analgesics. It has been documented that inferior alveolar What is claimed is: nerve block can cause painful peripheral neuropathy. In this 1. A method of treating pain comprising intravenously example, medically refractory painful trigeminal neuropathy administering to an individual in need of Said treatment (a) 0.1 mg to 0.8 mg of naloxone hydrochloride Salt or an in three patients was treated with intravenous administration equivalent amount of naloxone free base, prodrug, non of a combination of nalbuphine hydrochloride salt (5 mg) hydrochloride salt, or mixture thereof and (b) an amount of and naloxone hydrochloride Salt (0.4 mg). In all patients this nalbuphine free base, hydrochloride Salt, prodrug, non combination produced marked analgesia (FIGS. 9 and 10). hydrochloride Salt or mixture thereof that results in greater These findings Suggest a novel form of medical management analgesia than administration of either said naloxone hydro for chronic neuropathic pain. This is extremely important chloride Salt or Said nalbuphine alone, provided that 5 mg Since neuropathic pain is poorly managed by available nalbuphine free base or an equivalent amount of nalbuphine therapies. hydrochloride Salt, non-hydrochloride Salt, prodrug, or mix 0176). In all three patients this combination produced ture thereof, is not intravenously administered with 0.4 mg marked analgesia. This result is believed to represent the naloxone free base or equivalent amount of naloxone hydro first showing of effective treatment of neuropathic pain with chloride Salt, non-hydrochloride Salt, prodrug, or mixture a kappa-opioid. thereof. 2. The method of claim 1 wherein the amount of nalbu 0177. The study involved three patients with painful phine hydrochloride salt administered is 6.25 to 49 times peripheral neuropathy involving the mandibular division of greater, by weight, than the amount of naloxone hydrochlo the trigeminal nerve. One was a 42-year-old man, the Second ride Salt, or an equivalent amount of nalbuphine free base, a 40 year-old woman, and the third a 25-year-old woman. prodrug, non-chloride Salt, or mixture thereof is adminis Each patient discontinued all medications that had been tered. prescribed to treat pain 2 weeks prior to the test date. They 3. The method of claim 1 wherein the amount of nalbu had reported that those medications had had little effect. phine hydrochloride salt administered is 10 to 30 times 0.178 The test ingredients were administered via an intra greater, by weight, than the amount of naloxone hydrochlo venous catheter. Pain intensity was measured using a 10 cm ride salt, or an equivalent amount of nalbuphine free base, VAS with the words “no pain” at the extreme left and the prodrug, non-chloride Salt, or mixture thereof is adminis words “worst pain imaginable” at the extreme right. FIG. 9 tered. shows the level of pain (on the VAS scale) experienced by 4. The method of claim 1 wherein the amount of nalbu each of the three patients individually at times up to about phine hydrochloride salt administered is 9 to 15 times 180 minutes after injection. FIG. 10 is a composite for all greater, by weight, than the amount of naloxone hydrochlo three patients, showing the relative change in pain in the ride Salt, or an equivalent amount of nalbuphine free base, Same approximate time period. Extremely marked analgesia prodrug, non-chloride Salt, or mixture thereof is adminis was achieved for at least a 2.5-hour period. tered. 5. The method of claim 1 wherein 1 mg to 10 mg of Example 6 nalbuphine hydrochloride Salt is administered, or an equiva lent amount of nalbuphine free base, prodrug, non-chloride 0179 Five patients that had bony impacted mandibular Salt, or mixture thereof is administered, provided that 5 mg third molar (wisdom) teeth removed under local anesthetic nalbuphine free base is not administered with 0.4 mg nalox block, were studied. Following dissipation of the nerve one free base. block patients developed moderate-to-Severe pain. When 6. The method of claim 1 wherein 1 mg to 6 mg of their pain level was 230 on a 10 cm Visual analog Scale, they nalbuphine hydrochloride Salt is administered, or an equiva patient received either nalbuphine hydrochloride Salt (5 mg) lent amount of nalbuphine free base, prodrug, non-chloride plus naloxone hydrochloride Salt (0.4 mg) or just the same Salt, or mixture thereof is administered, provided that 5 mg dose of nalbuphine hydrochloride Salt (5 mg), by nasal spray nalbuphine free base is not administered with 0.4 mg nalox (Pfeiffer nasal spray units were used). The nasal spray one free base. contained, in addition to the two hydrochloride Salts, citrate, 7. The method of any of the claims 1 to 6 wherein 0.1 mg citric acid, HCl and water. Pain ratings were obtained every to 0.4 mg naloxone hydrochloride Salt or an equivalent 20 minutes, the nasal Spray administration being half-way amount of naloxone free base, prodrug, non-chloride Salt, or between two pain ratings. FIG. 11 shows the response to the mixture thereof is administered. nasal Spray as change in pain, decrease in pain indicates 8. The method of any of the claims 1 to 6 wherein 0.4 mg analgesia. Also included, for comparison, is the response for to 0.8 mg naloxone hydrochloride Salt or an equivalent 32 patients who underwent the same Surgical procedure, to amount of naloxone free base, prodrug, non-chloride Salt, or intravenous administration of nalbuphine hydrochloride Salt mixture thereof is administered. (5 mg) plus naloxone hydrochloride Salt (0.4 mg). 9. A method of treating pain comprising administering 0180. It is understood that the examples and embodi intravenously to an individual in need of Said treatment (a) ments described herein are for illustrative purposes only and 0.1 mg to 0.8 mg of naloxone hydrochloride Salt or an that various modifications or changes in light thereof will be equivalent amount of naloxone free base, prodrug, non Suggested to perSons Skilled in the art and are to be included hydrochloride salt, or mixture thereof and (b) an amount of within the Spirit and purview of this application and Scope of pentazocine free base, hydrochloride Salt, prodrug, non the appended claims. hydrochloride Salt or mixture thereof that results in greater US 2004/018091.6 A1 Sep. 16, 2004 29 analgesia than administration of either Said naloxone hydro that results in greater analgesia than administration of either chloride Salt or Said pentazocine hydrochloride Salt alone, Said naloxone hydrochloride Salt or Said nalbuphine alone. provided that 60 mg of pentazocine free base or an equiva 20. The method of claim 19 wherein the nalbuphine free lent amount of pentazocine hydrochloride Salt, non-hydro base, Salt, prodrug, or mixture thereof, and naloxone are chloride Salt, prodrug, or mixture thereof, is not adminis administered in amounts equivalent to intravenous admin tered with 0.4 mg naloxone free base or equivalent amount istration of 6.25 to 30 times greater in weight of nalbuphine of naloxone hydrochloride Salt, non-hydrochloride Salt, pro hydrochloride salt than naloxone hydrochloride salt. drug, or mixture thereof. 21. The method of claim 19 wherein the nalbuphine free 10. The method of claim 9 wherein pentazocine hydro base, Salt, prodrug, or mixture thereof, and naloxone are chloride Salt is administered in an amount 18 to 120 times administered in amounts equivalent to intravenous admin greater, by weight, than the amount of naloxone hydrochlo istration of 10 to 20 times greater in weight of nalbuphine ride Salt, or an equivalent amount of pentazocine free base, hydrochloride salt than naloxone hydrochloride salt. prodrug, non-hydrochloride Salt, or mixture thereof is 22. The method of claim 19 wherein the nalbuphine free administered. base, Salt, prodrug, or mixture thereof, is administered in an 11. The method of claim 9 wherein pentazocine hydro amount equivalent to intravenous administration of 1 mg to chloride Salt is administered in an amount 18 to 50 times 10 mg of nalbuphine hydrochloride salt. greater, by weight, than the amount of naloxone hydrochlo 23. The method of claim 19 wherein the nalbuphine free ride Salt, or an equivalent amount of pentazocine free base, base, Salt, prodrug, or mixture thereof, is administered in an prodrug, non-hydrochloride Salt, or mixture thereof is amount equivalent to intravenous administration of 2 mg to administered. 8 mg of nalbuphine hydrochloride salt. 12. The method of claim 9 wherein 3 mg to 50 mg 24. The method of claim 19 wherein the nalbuphine free pentazocine hydrochloride Salt or an equivalent amount of base, Salt, prodrug, or mixture thereof, is administered in an pentazocine free base, prodrug, hydrochloride Salt, or mix amount equivalent to intravenous administration of 1 mg to ture thereof is administered. 4 mg of nalbuphine hydrochloride Salt. 13. The method of claim 9 wherein 3 mg to 30 mg 25. The method of claim 19 wherein the method of pentazocine hydrochloride Salt or an equivalent amount of administration is mucosal. pentazocine free base, prodrug, hydrochloride Salt, or mix 26. The method of claim 25 wherein administration is ture thereof is administered. nasal. 14. A method of treating pain comprising administering 27. The method of claim 26 wherein the nasal adminis intravenously to an individual in need of Said treatment (a) tration is in the form of a nasal Spray or nose drops. 0.1 mg to 0.8 mg of naloxone hydrochloride Salt or an 28. The method of claim 19 wherein administration is equivalent amount of naloxone free base, prodrug, non Sublingual. hydrochloride salt, or mixture thereof and (b) an amount of 29. The method of claim 28 wherein 1 to 60 times greater, butorphanol free base, prodrug, pharmaceutically acceptable by weight, nalbuphine hydrochloride Salt is administered Salt or mixture thereof that results in greater analgesia than than naloxone hydrochloride Salt, or equivalent amounts administration of either said nalbuphine hydrochloride salt thereof, respectively, of nalbuphine free base, non-hydro or Said butorphanol alone. chloride Salt, prodrug, or mixture thereof and naloxone free 15. The method of claim 14 wherein 0.3 to 10 times base, non-hydrochloride Salt, prodrug, and mixture thereof. greater, by weight, butorphanol tartrate Salt than naloxone 30. The method of claim 28 wherein 1 to 30 times greater, hydrochloride Salt is administered, or equivalent amount of by weight, nalbuphine hydrochloride Salt is administered butorphanol free base, non-tartrate Salt, prodrug, or mixture than naloxone hydrochloride Salt, or equivalent amounts thereof and/or naloxone free base, non-hydrochloride Salt, thereof, respectively, of nalbuphine free base, non-hydro prodrug, or mixture thereof is administered. chloride Salt, prodrug, or mixture thereof and naloxone free 16. The method of claim 14 wherein 0.5 to 4 times greater, base, non-hydrochloride Salt, prodrug, and mixture thereof. by weight, butorphanol tartrate Salt than naloxone hydro 31. The method of claim 28 wherein 5 mg to 65 mg chloride Salt is administered, or equivalent amount ofbutor nalbuphine hydrochloride Salt or an equivalent amount of phanol free base, non-tartrate Salt, prodrug, or mixture nalbuphine free base, non-hydrochloride Salt, prodrug, or thereof and/or naloxone free base, non-hydrochloride Salt, mixture thereof is administered. prodrug, or mixture thereof is administered. 32. The method of claim 28 wherein 7.5 mg to 30 mg 17. The method of claim 14 wherein 0.2 mg to 2 mg nalbuphine hydrochloride Salt or an equivalent amount of butorphanol tartrate Salt or an equivalent amount of butor nalbuphine free base, non-hydrochloride Salt, prodrug, or phanol free base, non-tartrate Salt, prodrug, or mixture mixture thereof is administered. thereof is administered. 33. The method of claim 28 wherein 0.4 mg to 4 mg 18. The method of claim 14 wherein 0.2 mg to 1 mg naloxone hydrochloride Salt or an equivalent amount of butorphanol tartrate Salt or an equivalent amount of butor naloxone free base, non-hydrochloride Salt, prodrug, or phanol free base, non-tartrate Salt, prodrug, or mixture mixture thereof is administered. thereof is administered. 34. The method of claim 28 wherein 0.4 mg to 2 mg 19. A method of treating pain comprising administering, naloxone hydrochloride Salt or an equivalent amount of by a method other than intravenous administration, to an naloxone free base, non-hydrochloride Salt, prodrug, or individual in need of said treatment (a) 0.1 mg to 0.8 mg of mixture thereof is administered. naloxone hydrochloride Salt or an equivalent amount of 35. A method of treating pain comprising administering, naloxone free base, prodrug, non-hydrochloride Salt, or by a method other than intravenous administration, to an mixture thereof and (b) an amount of nalbuphine free base, individual in need of said treatment (a) 0.1 mg to 0.8 mg of prodrug, pharmaceutically acceptable Salt or mixture thereof naloxone hydrochloride Salt or an equivalent amount of US 2004/018091.6 A1 Sep. 16, 2004 30 naloxone free base, prodrug, non-hydrochloride Salt, or that results in greater analgesia than administration of either mixture thereof and (b) an amount of pentazocine free base, said nalbuphine hydrochloride salt or said butorphanol hydrochloride Salt, prodrug, non-hydrochloride Salt or mix alone. ture thereof that results in greater analgesia than adminis 48. The method of claim 47 wherein the butorphanol free tration of either Said naloxone hydrochloride Salt or said base, Salt, prodrug, or mixture thereof is administered in an pentazocine hydrochloride Salt alone, provided that 50 mg of amount equivalent to intravenous administration of nalox pentazocine free base or an equivalent amount of pentaZO one hydrochloride salt and 0.3 to 10 times greater, by cine hydrochloride Salt, non-hydrochloride Salt, prodrug, or weight, butorphanol tartrate Salt. mixture thereof, is not administered orally for gastro-intes 49. The method of claim 47 wherein naloxone and butor tinal uptake with 0.5 mg naloxone free base or equivalent phanol free base, Salt, prodrug, or mixture thereof is admin amount of naloxone hydrochloride Salt, non-hydrochloride istered in an amount equivalent to intravenous administra Salt, prodrug, or mixture thereof. tion of naloxone hydrochloride salt and 0.5 to 4 times 36. The method of claim 35 wherein the pentazocine free greater, by weight, butorphanol tartrate Salt than naloxone base, Salt, prodrug, or mixture thereof, is administered in an hydrochloride salt. amount equivalent to intravenous administration of nalox 50. The method of claim 47 wherein butorphanol free one hydrochloride salt and 18 to 120 times greater, by base, Salt, prodrug, or mixture thereof is administered in an weight, of pentazocine hydrochloride Salt. amount equivalent to intravenous administration of 0.2 mg to 2 mg butorphanol tartrate Salt. 37. The method of claim 35 wherein the pentazocine free 51. The method of claim 47 wherein butorphanol free base, Salt, prodrug, or mixture thereof, is administered in an base, Salt, prodrug, or mixture thereof is administered in an amount equivalent to intravenous administration of 10 mg to amount equivalent to intravenous administration of 0.2 mg 50 mg of pentazocine hydrochloride Salt. to 1 mg butorphanol tartrate Salt. 38. The method of claim 35 wherein the pentazocine free 52. The method of claim 47 wherein the method of base, Salt, prodrug, or mixture thereof, is administered in an administration is mucosal. amount equivalent to intravenous administration of 15 mg to 53. The method of claim 52 wherein administration is 30 mg of pentazocine hydrochloride Salt. nasal. 39. The method of claim 35 wherein administration is 54. The method of claim 53 wherein administration is nasal. nasal in the form of a nasal Spray or nose drops. 40. The method of claim 39 wherein administration is 55. The method of claim 47 wherein administration is nasal in the form of a nasal Spray or nose drops. Sublingual. 41. The method of claim 35 wherein administration is 56. The method of claim 55 wherein 0.1 to 60 times Sublingual. greater, by weight, butorphanol tartrate Salt is administered 42. The method of claim 41 wherein 7.5 to 50 times than naloxone hydrochloride Salt, or equivalent amounts greater, by weight, pentazocine hydrochloride Salt is admin thereof, respectively, of butorphanol and/or naloxone free istered than naloxone hydrochloride Salt, or equivalent base, other Salt, prodrug, or mixture thereof is administered. amounts thereof, respectively, of pentazocine or naloxone 57. The method of claim 55 wherein 10-30 times greater, free base, non-hydrochloride Salt, prodrug, or mixture by weight, butorphanol tartrate Salt is administered than thereof. naloxone hydrochloride Salt, or equivalent amounts thereof, 43. The method of claim 41 wherein 10 to 30 times respectively, ofbutorphanol and/or naloxone free base, other greater, by weight, pentazocine hydrochloride Salt is admin Salt, prodrug, or mixture thereof is administered. istered than naloxone hydrochloride Salt, or equivalent 58. The method of claim 55 wherein 0.1 mg to 7 mg amounts thereof, respectively, of pentazocine or naloxone butorphanol tartrate Salt or an equivalent amount of butor free base, non-hydrochloride Salt, prodrug, or mixture phanol free base, other Salt, prodrug, or mixture thereof is thereof. administered. 59. The method of claim 55 wherein 0.5 mg to 6 mg 44. The method of claim 41 wherein 30 mg to 100 mg butorphanol tartrate Salt or an equivalent amount of butor pentazocine hydrochloride Salt or equivalent amount of phanol free base, other Salt, prodrug, or mixture thereof is pentazocine free base, non-hydrochloride Salt, prodrug or administered. mixture thereof is administered. 60. The method of claim 55 wherein 0.1 to 1 mg naloxone 45. The method of claim 41 wherein 30 mg to 60 mg hydrochloride Salt or an equivalent amount of naloxone free pentazocine hydrochloride Salt or equivalent amount of base, other Salt, prodrug, or mixture thereof is administered. pentazocine free base, non-hydrochloride Salt, prodrug or 61. A method of treating pain comprising administering mixture thereof is administered. intravenously to an individual in need of Said treatment (a) 46. The method of claim 41 wherein 2 mg to 4 mg 0.1 mg to 0.8 mg of the naloxone hydrochloride Salt or an naloxone hydrochloride Salt or equivalent amount of nalox equivalent amount of naloxone free base, prodrug, non one free base, non-hydrochloride Salt, prodrug or mixture hydrochloride salt, or mixture thereof and (b) an amount of thereof is administered. a K opioid agonist Selected from a group consisting of 47. A method of treating pain comprising administering, benzomorphan, benzacetamide, phenothiazine, thiazine, and by a method other than intravenous administration, to an a benzodiazepine, or a pharmaceutically acceptable Salt, individual in need of said treatment (a) 0.1 mg to 0.8 mg of prodrug, derivative, or mixture thereof, that results in greater naloxone hydrochloride Salt or an equivalent amount of analgesia than administration of either said naloxone hydro naloxone free base, prodrug, non-hydrochloride Salt, or chloride Salt or said Kopioid agonist alone. mixture thereof and (b) an amount of butorphanol free base, 62. The method of claim 61 wherein the kappa opioid prodrug, pharmaceutically acceptable Salt or mixture thereof agonist is Selected from the group consisting of benzomor US 2004/018091.6 A1 Sep. 16, 2004 phan, benzacetamide, phenothiazine, thiazine, and a benzo intravenous administration, provided that the composition diazepine, or a pharmaceutically acceptable Salt, prodrug, does not comprise 5 mg nalbuphine free base with 0.4 mg derivative, or mixture thereof. naloxone free base. 63. The method of claim 62 wherein the benzomorphan 74. The composition of claim 73 wherein the amount of derivative is Selected from the group consisting of ketaZO malbuphine hydrochloride salt is 6.25 to 49 times greater, by cine, ethylketazocine, dezocine, bremazocine, and Tiflua weight, than the amount of naloxone hydrochloride Salt, or dom, or pharmaceutically acceptable Salt, prodrug, or mix an equivalent amount of nalbuphine free base, prodrug, ture thereof. non-chloride Salt, or mixture thereof. 64. The method of claim 62 wherein the benzacetamide 75. The composition of claim 73 wherein the amount of derivative is selected from the group consisting of U50,488, malbuphine hydrochloride Salt is 8 to 30 times greater, by U69,593, U62,606 (spiradoline), PD 117302, CI-977, DuP weight, than the amount of naloxone hydrochloride Salt, or 747, ICI 197067, ICI 199441, BRL 52537A, and BRL an equivalent amount of nalbuphine free base, prodrug, 52656A, or a pharmaceutically acceptable Salt, prodrug, or non-chloride Salt, or mixture thereof. mixture thereof. 76. The composition of claim 73 wherein the amount of 65. The method of claim 62 wherein the kappa opioid malbuphine hydrochloride salt is 10 to 20 times greater, by agonist is the phenothiazine derivative, Rp.60180, or a weight, than the amount of naloxone hydrochloride Salt, or pharmaceutically acceptable Salt, prodrug, or mixture an equivalent amount of nalbuphine free base, prodrug, thereof. non-chloride Salt, or mixture thereof. 66. The method of claim 62 wherein the kappa receptor 77. The composition of claim 73 wherein the amount of agonist is the thiazine derivative, R084760, or a pharma nalbuphine hydrochloride Salt is 1 mg to 10 mg or an ceutically acceptable Salt, prodrug, or mixture thereof. equivalent amount of nalbuphine free base, prodrug, non 67. A method of treating pain comprising administering to chloride Salt, or mixture thereof. an individual in need of said treatment by a method other than intravenous administration (a) 0.1 mg to 0.8 mg of the 78. The composition of claim 73 wherein the amount of naloxone hydrochloride Salt or an equivalent amount of nalbuphine hydrochloride Salt is 3 mg to 8 mg or an naloxone free base, prodrug, non-hydrochloride Salt, or equivalent amount of nalbuphine free base, prodrug, non mixture thereof and (b) an amount of a K opioid agonist chloride Salt, or mixture thereof. Selected from a group consisting of benzomorphan, benza 79. The composition of claim 73 wherein the amount of cetamide, phenothiazine, thiazine, and a benzodiazepine, or nalbuphine hydrochloride Salt is 1 mg to 6 mg or an a pharmaceutically acceptable Salt, prodrug, derivative, or equivalent amount of nalbuphine free base, prodrug, non mixture thereof, that results in greater analgesia than admin chloride Salt, or mixture thereof. istration of either said naloxone hydrochloride Salt or Said K 80. The composition of claim 73 comprising 0.5 mg to 0.8 opioid agonist alone. mg naloxone hydrochloride Salt or an equivalent amount of 68. The method of claim 67 wherein the kappa opioid naloxone free base, prodrug, non-chloride Salt, or mixture agonist is Selected from the group consisting of benzomor thereof. phan, benzacetamide, phenothiazine, thiazine, and a benzo 81. The composition of claim 73 comprising 0.1 mg to 0.5 diazepine, or a pharmaceutically acceptable Salt, prodrug, mg naloxone hydrochloride Salt or an equivalent amount of derivative, or mixture thereof. naloxone free base, prodrug, non-chloride Salt, or mixture 69. The method of claim 68 wherein the benzomorphan thereof is administered, provided that the composition does derivative is Selected from the group consisting of ketaZO not comprise 5 mg nalbuphine free base with 0.4 mg cine, ethylketazocine, dezocine, bremazocine, and Tiflua naloxone free base. dom, or pharmaceutically acceptable Salt, prodrug, or mix 82. A pharmaceutical composition comprising (a) 0.1 mg ture thereof. to 0.8 mg of naloxone hydrochloride Salt or an equivalent 70. The method of claim 68 wherein the benzacetamide amount of naloxone freebase, prodrug, non-hydrochloride derivative is selected from the group consisting of U50,488, Salt, or mixture thereof; (b) an amount of pentazocine free U69,593, U62,606 (spiradoline), PD 117302, CI-977, DuP base, Salt, prodrug, or mixture thereof that results in greater 747, ICI 197067, ICI 199441, BRL 52537A, and BRL analgesia than administration of Said pentazocine or Said 52656A, or a pharmaceutically acceptable Salt, prodrug, or naloxone hydrochloride Salt alone; and (c) a pharmaceuti mixture thereof. cally acceptable carrier, Said pharmaceutical composition 71. The method of claim 68 wherein the kappa opioid being formulated for intravenous administration, provided agonist is the phenothiazine derivative, Rp.60180, or a that the composition does not comprise 60 mg of pentazo pharmaceutically acceptable Salt, prodrug, or mixture cine with 0.4 mg naloxone. thereof. 83. The composition of claim 82 comprising pentazocine 72. The method of claim 68 wherein the kappa receptor hydrochloride salt is administered in an amount 18 to 120 agonist is the thiazine derivative, R084760, or a pharma times greater, by weight, than the amount of naloxone ceutically acceptable Salt, prodrug, or mixture thereof. hydrochloride Salt or an equivalent amount of pentazocine 73. A pharmaceutical composition comprising (a) 0.1 mg free base, prodrug, non-hydrochloride Salt, or mixture to 0.8 mg of naloxone hydrochloride Salt or an equivalent thereof, provided that the composition does not comprise 60 amount of naloxone freebase, prodrug, non-hydrochloride mg of pentazocine with 0.4 mg naloxone. Salt, or mixture thereof; (b) an amount of nalbuphine free 84. The composition of claim 82 comprising pentazocine base, Salt, prodrug, or mixture thereof that results in greater hydrochloride salt is administered in an amount 18 to 50 analgesia than administration of Said nalbuphine or said times greater, by weight, than the amount of naloxone naloxone alone; and (c) a pharmaceutically acceptable car hydrochloride Salt or an equivalent amount of pentazocine rier, Said pharmaceutical composition being formulated for free base, prodrug, non-hydrochloride Salt, or mixture US 2004/018091.6 A1 Sep. 16, 2004 32 thereof, provided that the composition does not comprise 60 ketazocine, ethylketazocine, dezocine, bremazocine, and mg of pentazocine with 0.4 mg naloxone. Tifluadom, or pharmaceutically acceptable Salt, prodrug, or 85. The composition of claim 82 comprising 3 mg to 50 mixture thereof. mg pentazocine hydrochloride Salt or an equivalent amount 96. The composition of claim 93 wherein the benzaceta of pentazocine free base, prodrug, hydrochloride Salt, or mide derivative is Selected from the group consisting of mixture thereof. U50,488, U69,593, U62,606 (spiradoline), PD 117302, CI-977, DuP 747, ICI 197067, ICI 199441, BRL52537A, 86. The composition of claim 82 comprising 3 mg to 30 and BRL 52656A, or a pharmaceutically acceptable salt, mg pentazocine hydrochloride Salt or an equivalent amount prodrug, or mixture thereof. of pentazocine free base, prodrug, hydrochloride Salt, or 97. The composition of claim 93 wherein the kappa opioid mixture thereof. agonist is the phenothiazine derivative, Rp.60180, or a 87. The composition of claim 82 comprising 10 mg to 20 pharmaceutically acceptable Salt, prodrug, or mixture mg pentazocine hydrochloride Salt or an equivalent amount thereof. of pentazocine free base, prodrug, hydrochloride Salt, or 98. The composition of claim 93 wherein the kappa mixture thereof. receptor agonist is the thiazine derivative, R084760, or a 88. A pharmaceutical composition comprising (a) 0.1 mg pharmaceutically acceptable Salt, prodrug, or mixture to 0.8 mg of naloxone hydrochloride Salt or an equivalent thereof. amount of naloxone freebase, prodrug, non-hydrochloride 99. The composition of claim 93 wherein the kappa opioid Salt, or mixture thereof; (b) an amount of butorphanol free agonist is nalbuphine or a hydrochloride Salt, non-hydro base, Salt, prodrug, or mixture thereof that results in greater chloride Salt, prodrug, or mixture thereof. analgesia than administration of Said butorphanol or said 100. A pharmaceutical composition comprising (a) 0.1 mg naloxone alone; and (c) a pharmaceutically acceptable car to 0.8 mg of an naloxone hydrochloride Salt or an equivalent rier, Said pharmaceutical composition being formulated for amount of naloxone freebase, prodrug, non-hydrochloride intravenous administration. Salt, or mixture thereof; (b) an amount of nalbuphine free 89. The composition of claim 88 comprising 0.3 to 10 base, Salt, prodrug, or mixture thereof that results in greater times greater, by weight, butorphanol tartrate Salt than analgesia than administration of the Said nalbuphine or Said naloxone hydrochloride Salt, or equivalent amounts of, naloxone alone; and (c) a pharmaceutically acceptable car respectively, butorphanol free base, non-tartrate Salt, pro rier, Said pharmaceutical composition being formulated for drug, or mixture thereof and naloxone free base, non administration other than intravenous administration. hydrochloride Salt, prodrug, or mixture thereof. 101. The composition claim 100 comprising nalbuphine 90. The composition of claim 88 comprising 0.3 to 6 times free base, Salt, prodrug, or mixture thereof, in an amount greater, by weight, butorphanol tartrate Salt than naloxone equivalent to intravenous administration of the naloxone hydrochloride Salt, or equivalent amounts of, respectively, hydrochloride salt and 6.25 to 30 times greater in weight of butorphanol free base, non-tartrate Salt, prodrug, or mixture malbuphine hydrochloride salt than the naloxone hydrochlo thereof and naloxone free base, non-hydrochloride Salt, ride Salt. prodrug, or mixture thereof. 102. The composition claim 100 comprising nalbuphine 91. The composition of claim 88 comprising 0.2 mg to 2 free base, Salt, prodrug, or mixture thereof, in an amount mg butorphanol tartrate Salt or an equivalent amount of equivalent to intravenous administration of the naloxone butorphanol free base, non-tartrate Salt, prodrug, or mixture hydrochloride salt and 10 to 20 times greater in weight of thereof. malbuphine hydrochloride salt than the naloxone hydrochlo 92. The composition of claim 88 comprising 0.2 mg to 1.2 ride Salt. mg butorphanol tartrate Salt or an equivalent amount of 103. The composition claim 100 comprising nalbuphine butorphanol free base, non-tartrate Salt, prodrug, or mixture free base, Salt, prodrug, or mixture thereof, in an amount thereof. equivalent to intravenous administration of 1 mg to 10 mg 93. A pharmaceutical composition comprising (a) 0.1 mg of nalbuphine hydrochloride salt. to 0.8 mg of naloxone hydrochloride Salt or an equivalent 104. The composition claim 100 comprising nalbuphine amount of naloxone freebase, prodrug, non-hydrochloride free base, Salt, prodrug, or mixture thereof, in an amount Salt, or mixture thereof; (b) an amount of a K opioid agonist equivalent to intravenous administration of 1 mg to 6 mg of Selected from the group consisting of benzomorphan, ben malbuphine hydrochloride salt. Zacetamide, phenothiazine, thiazine, and a benzodiazepine, 105. The composition of any of the claims 100 to 104 or a pharmaceutically acceptable Salt, prodrug, derivative, or wherein the composition is formulated for mucosal admin mixture thereof, that results in greater analgesia than admin istration. istration of Said K-opioid agonist or Said naloxone alone; and 106. The composition of claim 105 wherein the compo (c) a pharmaceutically acceptable carrier, said pharmaceu Sition is formulated for nasal administration. tical composition being formulated for intravenous admin 107. The composition of claim 105 wherein the compo istration. sition is formulated for nasal administration in the form of 94. The composition of claim 93 wherein the kappa opioid a nasal Spray or nose drops. agonist is Selected from the group consisting of benzomor 108. The composition of claims 100 wherein the compo phan, benzacetamide, phenothiazine, thiazine, and a benzo Sition is formulated for Sublingual administration. diazepine, or a pharmaceutically acceptable Salt, prodrug, 109. The composition of claim 108 comprising 1 to 60 derivative, or mixture thereof. times greater, by weight, nalbuphine hydrochloride Salt than 95. The composition of claim 93 wherein the benzodiaz naloxone hydrochloride Salt, or equivalent amounts thereof, epine derivative is Selected from the group consisting of respectively, of nalbuphine free base, non-hydrochloride US 2004/018091.6 A1 Sep. 16, 2004 33

Salt, prodrug, or mixture thereof and naloxone free base, 124. The composition of claim 122 comprising 10 to 30 non-hydrochloride Salt, prodrug, and mixture thereof. times greater, by weight, pentazocine hydrochloride Salt 110. The composition of claim 108 comprising 1 to 30 than naloxone hydrochloride Salt, or equivalent amounts times greater, by weight, nalbuphine hydrochloride Salt is thereof, respectively, of pentazocine or naloxone free base, administered than naloxone hydrochloride Salt, or equivalent non-hydrochloride Salt, prodrug, or mixture thereof. amounts thereof, respectively, of nalbuphine free base, non 125. The composition of claim 122 comprising 30 mg to hydrochloride Salt, prodrug, or mixture thereof and naloxone 100 mg pentazocine hydrochloride Salt or equivalent amount free base, non-hydrochloride Salt, prodrug, and mixture of pentazocine free base, non-hydrochloride Salt, prodrug or thereof. mixture thereof. 111. The composition of claim 108 comprising 5 mg to 65 126. The composition of claim 122 comprising 30 mg to mg nalbuphine hydrochloride Salt or an equivalent amount 60 mg pentazocine hydrochloride Salt or equivalent amount of nalbuphine free base, non-hydrochloride Salt, prodrug, or of pentazocine free base, non-hydrochloride Salt, prodrug or mixture thereof. mixture thereof. 112. The composition of claim 108 comprising 7.5 mg to 127. The composition of claim 122 comprising 2 mg to 4 30 mg nalbuphine hydrochloride Salt or an equivalent mg naloxone hydrochloride Salt or equivalent amount of amount of nalbuphine free base, non-hydrochloride Salt, naloxone free base, non-hydrochloride Salt, prodrug or mix prodrug, or mixture thereof. ture thereof. 113. The composition of any claims 108 to 112 compris 128. A pharmaceutical composition comprising (a) 0.1 mg ing 0.4 mg to 4 mg naloxone hydrochloride Salt or an to 0.8 mg naloxone hydrochloride Salt or an equivalent equivalent amount of naloxone free base, non-hydrochloride amount of naloxone freebase, prodrug, non-hydrochloride Salt, prodrug, or mixture thereof. Salt, or mixture thereof; (b) an amount of butorphanol free 114. The composition of any claims 108 to 112 compris base, Salt, prodrug, or mixture thereof that results in greater ing 0.4 mg to 2.5 mg naloxone hydrochloride Salt or an analgesia than administration of Said butorphanol or Said equivalent amount of naloxone free base, non-hydrochloride naloxone alone; and (c) a pharmaceutically acceptable car Salt, prodrug, or mixture thereof. rier, Said pharmaceutical composition being formulated for 115. A pharmaceutical composition comprising (a) 0.1 mg administration other than intravenous administration. to 0.8 mg of naloxone hydrochloride Salt or an equivalent 129. The composition of claim 128 comprising butorpha amount of naloxone freebase, prodrug, non-hydrochloride nol free base, Salt, prodrug, or mixture thereof in an amount Salt, or mixture thereof; (b) an amount of pentazocine free equivalent to intravenous administration of naloxone hydro base, Salt, prodrug, or mixture thereof that results in greater chloride salt and 0.3 to 10 times greater, by weight, butor analgesia than administration of Said pentazocine or said phanol tartrate Salt. naloxone alone; and (c) a pharmaceutically acceptable car rier, Said pharmaceutical composition being formulated for 130. The composition of claim 128 comprising butorpha administration other than intravenous administration, pro nol free base, Salt, prodrug, or mixture thereof in an amount Vided that the composition formulated for oral administra equivalent to intravenous administration of naloxone hydro tion does not comprise 50 mg pentazocine hydrochloride Salt chloride Salt and 0.3 to 6 times greater, by weight, butor with 0.5 mg naloxone hydrochloride salt. phanol tartrate Salt. 116. The composition of claim 115 comprising an amount 131. The composition of claim 128 comprising butorpha of pentazocine free base, Salt, prodrug, or mixture thereof, nol free base, Salt, prodrug, or mixture thereof in an amount equivalent to intravenous administration of the opioid equivalent to intravenous administration of 0.2 mg to 2 mg antagonist hydrochloride Salt and 18 to 120 times greater, by butorphanol tartrate Salt. weight, of pentazocine hydrochloride Salt. 132. The composition of claim 128 comprising butorpha 117. The composition of claim 115 comprising an amount nol free base, Salt, prodrug, or mixture thereof in an amount of pentazocine free base, Salt, prodrug, or mixture thereof, equivalent to intravenous administration of 0.2 mg to 1 mg equivalent to intravenous administration of 10 mg to 50 mg butorphanol tartrate Salt. of pentazocine hydrochloride Salt. 133. The compositions of claim 128 wherein the compo 118. The composition of claim 115 comprising an amount Sition is formulated for mucosal administration. of pentazocine free base, Salt, prodrug, or mixture thereof, 134. The composition of claim 133 wherein the compo equivalent to intravenous administration of 15 mg to 30 mg Sition is formulated for nasal administration. of pentazocine hydrochloride Salt. 135. The composition of claim 134 wherein the compo 119. The composition of claim 115 wherein the compo Sition is formulated for nasal administration the form of a Sition is formulated for mucosal administration. nasal Spray or nose drops. 120. The composition of claim 119 wherein the compo 136. The composition of claim 128 wherein the compo Sition is formulated for nasal administration. Sition is formulated for Sublingual administration. 121. The composition of claim 120 wherein the compo 137. The composition of claim 136 comprising 0.1 to 60 sition is formulated for nasal administration in the form of times greater, by weight, butorphanol tartrate Salt than a nasal Spray or nose drops. naloxone hydrochloride Salt, or equivalent amounts thereof, 122. The composition of claim 115 wherein the compo respectively, ofbutorphanol and/or naloxone free base, other Sition is formulated for Sublingual administration. Salt, prodrug, or mixture thereof. 123. The composition of claim 122 comprising 7.5 to 50 138. The composition of claim 136 comprising 10-30 times greater, by weight, pentazocine hydrochloride Salt times greater, by weight, butorphanol tartrate Salt is admin than naloxone hydrochloride Salt, or equivalent amounts istered than naloxone hydrochloride Salt, or equivalent thereof, respectively, of pentazocine or naloxone free base, amounts thereof, respectively, of butorphanol and/or nalox non-hydrochloride Salt, prodrug, or mixture thereof. one free base, other Salt, prodrug, or mixture thereof. US 2004/018091.6 A1 Sep. 16, 2004 34

139. The composition of claim 138 comprising 0.1 mg to 150. The composition of claim 149 wherein the benzo 7 mg butorphanol tartrate Salt or an equivalent amount of diazepine derivative is Selected from the group consisting of butorphanol free base, other Salt, prodrug, or mixture ketazocine, ethylketazocine, dezocine, bremazocine, and thereof. Tifluadom, or pharmaceutically acceptable Salt, prodrug, or 140. The composition of claim 138 comprising 0.5 mg to mixture thereof. 6 mg butorphanol tartrate Salt or an equivalent amount of 151. The composition of claim 149 wherein the benzac butorphanol free base, other Salt, prodrug, or mixture etamide derivative is Selected from the group consisting of thereof. U50,488, U69,593, U62,606 (spiradoline), PD 117302, 141. A pharmaceutical composition comprising (a) 0.1 mg CI-977, DuP 747, ICI 197067, ICI 199441, BRL52537A, to 0.8 mg of naloxone hydrochloride Salt or an equivalent and BRL 52656A, or a pharmaceutically acceptable salt, amount of naloxone freebase, prodrug, non-hydrochloride prodrug, or mixture thereof. Salt, or mixture thereof; (b) an amount of a K opioid agonist 152. The composition of claim 149 wherein the kappa Selected from the group consisting of benzomorphan, ben opioid agonist is the phenothiazine derivative, Rp.60180, or Zacetamide, phenothiazine, thiazine, and a benzodiazepine, a pharmaceutically acceptable Salt, prodrug, or mixture or a pharmaceutically acceptable Salt, prodrug, derivative, or thereof. mixture thereof, that results in greater analgesia than admin 153. The composition of claim 149 wherein the kappa istration of Said K opioid agonist or Said naloxone alone; and receptor agonist is the thiazine derivative, R084760, or a (c) a pharmaceutically acceptable carrier, said pharmaceu pharmaceutically acceptable Salt, prodrug, or mixture tical composition being formulated for intravenous admin thereof. istration. 154. A method of treating pain comprising mucosally 142. The method of claim 141 wherein the kappa opioid administering to an individual in need of Said treatment (a) agonist is Selected from the group consisting of benzomor 0.1 mg to 0.8 mg of a hydrochloride salt of an opioid phan, benzacetamide, phenothiazine, thiazine, and a benzo antagonist or an equivalent amount of opioid antagonist free diazepine, or a pharmaceutically acceptable Salt, prodrug, base, prodrug, non-hydrochloride Salt, or mixture thereof, derivative, or mixture thereof. wherein Said opioid antagonist is naloxone, naltrexone, 143. The composition of claim 142 wherein the benzo methylmaltrexone, nalmefene, nalorphine, levalorphan, oxy diazepine derivative is Selected from the group consisting of lorphan or cyprenorphine, and (b) an amount of nalbuphine ketazocine, ethylketazocine, dezocine, bremazocine, and free base, hydrochloride Salt, prodrug, non-hydrochloride Tifluadom, or pharmaceutically acceptable Salt, prodrug, or Salt or mixture thereof that results in greater analgesia than mixture thereof. administration of either Said opioid antagonist hydrochloride 144. The composition of claim 142 wherein the benzac Salt or said nalbuphine alone. etamide derivative is Selected from the group consisting of 155. A method according to claim 154 wherein the opioid U50,488, U69,593, U62,606 (spiradoline), PD 117302, antagonist is a Salt of naloxone, naltrexone, methylnaltrex CI-977, DuP 747, ICI 197067, ICI 199441, BRL52537A, one, nalmefene, nalorphine, levalorphan, oxylorphan, or and BRL 52656A, or a pharmaceutically acceptable salt, cyprenorphine. prodrug, or mixture thereof. 156. A method according to claim 154 wherein the opioid 145. The composition of claim 142 wherein the kappa antagonist is naloxone or a Salt or prodrug of naloxone. opioid agonist is the phenothiazine derivative, Rp.60180, or 157. A method according to claim 154 wherein an opioid a pharmaceutically acceptable Salt, prodrug, or mixture antagonist hydrochloride Salt is administered and the amount thereof. of nalbuphine hydrochloride Salt administered is 6.25 to 49 146. The composition of claim 142 wherein the kappa times greater, by weight, than the amount of opioid antago receptor agonist is the thiazine derivative, R084760, or a nist hydrochloride Salt, or an equivalent amount of nalbu pharmaceutically acceptable Salt, prodrug, or mixture phine free base, prodrug, non-chloride Salt, or mixture thereof. thereof, is administered. 147. The composition of claim 142 wherein the kappa 158. A method according to claim 154 wherein an opioid opioid agonist is nalbuphine or a hydrochloride Salt, non antagonist hydrochloride Salt is administered and the amount hydrochloride Salt, prodrug, or mixture thereof. of nalbuphine hydrochloride salt administered is 10 to 15 148. A pharmaceutical composition comprising (a) 0.1 mg times greater, by weight, than the amount of naloxone to 0.8 mg of naloxone hydrochloride Salt or an equivalent hydrochloride Salt, or an equivalent amount of nalbuphine amount of naloxone freebase, prodrug, non-hydrochloride free base, prodrug, non-chloride Salt, or mixture thereof, is Salt, or mixture thereof; (b) an amount of a Kopioid agonist administered. Selected from the group consisting of benzomorphan, ben 159. A method according to claim 154 wherein an opioid Zacetamide, phenothiazine, thiazine, and a benzodiazepine, antagonist hydrochloride Salt is administered and the amount or a pharmaceutically acceptable Salt, prodrug, derivative, or of nalbuphine hydrochloride salt administered is 12.5 times mixture thereof, that results in greater analgesia than admin greater, by weight, than the amount of naloxone hydrochlo istration of Said K opioid agonist or Said naloxone alone; and ride Salt, or an equivalent amount of nalbuphine free base, (c) a pharmaceutically acceptable carrier, said pharmaceu prodrug, non-chloride Salt, or mixture thereof, is adminis tical composition being formulated for administration by a tered. method other than intravenous administration. 160. A method according to claim 154 wherein 2 mg to 10 149. The method of claim 148 wherein the kappa opioid mg of nalbuphine hydrochloride Salt is administered, or an agonist is Selected from the group consisting of benzomor equivalent amount of nalbuphine free base, prodrug, non phan, benzacetamide, phenothiazine, thiazine, and a benzo chloride Salt, or mixture thereof, is administered. diazepine, or a pharmaceutically acceptable Salt, prodrug, 161. A method according to claim 154 wherein 0.1 mg to derivative, or mixture thereof. 0.8 mg of naloxone hydrochloride Salt is administered, or an US 2004/018091.6 A1 Sep. 16, 2004 35 equivalent amount of naloxone free base, prodrug, non 175. A method according to any of claim 168 wherein the chloride Salt, or mixture thereof, is administered. ingredients are administered mucosally. 162. A method according to claim 154 wherein 2 mg to 5 176. A method according to claim 168 wherein the mg of nalbuphine hydrochloride Salt is administered, or an ingredients are administered intranasally. equivalent amount of nalbuphine free base, prodrug, non 177. A method according to claim 168 wherein the chloride Salt, or mixture thereof, is administered. ingredients are administered by pulmonary administration. 163. A method according to claim 154 wherein 0.4 mg of 178. A method of treating pain comprising administering naloxone hydrochloride and 5 mg of nalbuphine hydrochlo to an individual in need of said treatment (a) from 0.1 to 0.8 ride are administered. mg of a hydrochloride Salt of naloxone or an equivalent 164. A method according to claim 154 wherein 0.2 mg of amount of naloxone free base, prodrug, non-hydrochloride naloxone hydrochloride and 2.5 mg of nalbuphine hydro salt, or mixture thereof; and (b) from 1 to 2.5 mg of chloride are administered. nalbuphine hydrochloride, or an equivalent amount of nal 165. A method according to claim 154 wherein 0.8 mg of buphine free base, prodrug, non-hydrochloride Salt or mix naloxone hydrochloride and 10 mg of nalbuphine hydro ture thereof. chloride are administered. 179. A method of treating pain comprising administering 166. A method according to claim 154 wherein the to an individual in need of said treatment (a) from 0.1 to 0.8 ingredients are administered intranasally. mg of a hydrochloride Salt of naloxone or an equivalent 167. A method according to claim 154 wherein the amount of naloxone free base, prodrug, non-hydrochloride ingredients are administered by pulmonary administration. salt, or mixture thereof; and (b) from 8.5 to 10 mg of 168. A method of treating pain comprising administering nalbuphine hydrochloride, or an equivalent amount of nal to an individual in need of said treatment (a) 0.1 mg to 0.8 buphine free base, prodrug, non-hydrochloride Salt or mix mg of a hydrochloride Salt of an opioid antagonist or an ture thereof. equivalent amount of opioid antagonist free base, prodrug, 180. A method of treating pain comprising administering non-hydrochloride Salt, or mixture thereof, wherein Said to an individual in need of Said treatment (a) 0.1 mg of a opioid antagonist is naloxone, naltrexone, methylnaltrexone, hydrochloride Salt of naloxone or an equivalent amount of nalmefene, nalorphine, leValorphan, oxylorphan or naloxone free base, prodrug, non-hydrochloride Salt, or cyprenorphine, and (b) an amount of a free base, hydrochlo mixture thereof; and (b) 1.25 mg of nalbuphine hydrochlo ride Salt, prodrug, non-hydrochloride Salt or mixture thereof ride, or an equivalent amount of nalbuphine free base, of a kappa-opioid, that results in greater analgesia than prodrug, non-hydrochloride Salt or mixture thereof. administration of either Said opioid antagonist hydrochloride 181. A method of treating pain comprising administering Salt or said kappa-opioid, wherein the kappa-opioid is pen to an individual in need of Said treatment (a) 0.2 mg of a tazocine, butorphanol, ketazocine, ethylketazocine, deZo hydrochloride Salt of naloxone or an equivalent amount of cine, bremazocine, a benzacetamide derivative, a phenothi naloxone free base, prodrug, non-hydrochloride Salt, or azine derivative, a thiazine derivative, or a benzodiazepine mixture thereof; and (b) 2.5 mg of nalbuphine hydrochlo derivative, provided that 60 mg of pentazocine free base or ride, or an equivalent amount of nalbuphine free base, an equivalent amount of pentazocine hydrochloride Salt, prodrug, non-hydrochloride Salt or mixture thereof. non-hydrochloride Salt, prodrug, or mixture thereof, is not 182. A method of treating pain comprising administering administered with 0.4 mg naloxone free base or equivalent to an individual in need of Said treatment (a) 0.8 mg of a amount of naloxone hydrochloride Salt, non-hydrochloride hydrochloride Salt of naloxone or an equivalent amount of Salt, prodrug, or mixture thereof. naloxone free base, prodrug, non-hydrochloride Salt, or 169. A method according to claim 168 wherein the mixture thereof; and (b) 10 mg of nalbuphine hydrochloride, kappa-opioid is pentazocine and the opioid antagonist is or an equivalent amount of nalbuphine free base, prodrug, naloxone. non-hydrochloride Salt or mixture thereof. 170. A method according to claim 169 wherein pentazo 183. A method according to claim 178 wherein the cine hydrochloride salt is administered in an amount 18 to 30 ingredients are administered intravenously. times greater, by weight, than the amount of naloxone hydrochloride Salt, or an equivalent amount of pentazocine 184. A method according to claim 178 wherein the free base, prodrug, non-hydrochloride Salt, or mixture ingredients are administered mucosally. thereof is administered. 185. A method according to claim 178 wherein the 171. A method according to claim 168 wherein the ingredients are administered intranasally. kappa-opioid is butorphanol and the opioid antagonist is 186. A method according to claim 178 wherein the naloxone. ingredients are administered by pulmonary administration. 172. A method according to claim 175 wherein 0.3 to 10 187. A method according to claim 154 wherein the pain is times greater, by weight, butorphanol tartrate Salt than neuropathic pain. naloxone hydrochloride Salt is administered, or equivalent 188. A method according to claim 154 wherein the pain is amount of butorphanol free base, non-tartrate Salt, prodrug, inflammatory pain. or mixture thereof and/or naloxone free base, non-hydro 189. A method according to claim 154 wherein the pain is chloride Salt, prodrug, or mixture thereof is administered. acute pain. 173. A method according to claim 168 wherein 0.1 to 0.8 190. A method according to claim 154 wherein the pain is mg naloxone hydrochloride Salt or an equivalent amount of traumatic pain. naloxone free base, non-hydrochloride Salt, prodrug, or 191. A method according to claim 154 wherein the pain is mixture thereof is administered post-procedural pain. 174. A method according to claim 168 wherein the 192. A method according to claim 154 wherein the pain is ingredients are administered intravenously. infection-related pain. US 2004/018091.6 A1 Sep. 16, 2004 36

193. A pharmaceutical composition comprising (a) 0.1 mg 205. A composition according to claim 193 comprising to 0.8 mg of a hydrochloride Salt of an opioid antagonist or 0.2 mg of naloxone hydrochloride and 2.5 mg of nalbuphine an equivalent amount of opioid antagonist free base, pro hydrochloride. drug, non-hydrochloride Salt, or mixture thereof, wherein 206. A composition according to claim 193 comprising Said opioid antagonist is naloxone, naltrexone, methylmaltr 0.8 mg of naloxone hydrochloride and 10 mg of nalbuphine exone, nalmefene, nalorphine, leValorphan, oxylorphan or hydrochloride. cyprenorphine; (b) an amount of nalbuphine free base, 207. A composition according to claim 193 formulated for nalbuphine Salt, nalbuphine prodrug, or mixture thereof that intranasal administration. results in greater analgesia than administration of the nal 208. A composition according to claim 193 formulated for buphine ingredient or the opioid antagonist ingredient alone; pulmonary administration. and (c) a pharmaceutically acceptable carrier, said pharma 209. A composition for treating pain comprising (a) 0.1 ceutical composition being formulated for mucosal admin mg to 0.8 mg of a hydrochloride Salt of an opioid antagonist istration. or an equivalent amount of opioid antagonist free base, 194. A composition according to claim 193 wherein the prodrug, non-hydrochloride Salt, or mixture thereof, wherein opioid antagonist is a Salt of naloxone, naltrexone, meth Said opioid antagonist is naloxone, naltrexone, methylmaltr ylnaltrexone, nalmefene, nalorphine, leValorphan, oxylor exone, nalmefene, nalorphine, leValorphan, oxylorphan or phan, or cyprenorphine. cyprenorphine; (b) an amount of a free base, hydrochloride 195. A composition according to claim 193 wherein the Salt, prodrug, non-hydrochloride Salt or mixture thereof of a opioid antagonist is naloxone or a Salt or prodrug of nalox kappa opioid, that results in greater analgesia than admin Oc. istration of either Said opioid antagonist hydrochloride Salt 196. A composition according to claim 193 comprising or Said kappa-opioid, wherein the kappa-opioid is pentazo malbuphine hydrochloride, the amount of nalbuphine hydro cine, butorphanol, ketazocine, ethylketazocine, dezocine, chloride Salt being 6.25 to 49 times greater, by weight, than bremazocine, a benzacetamide derivative, a phenothiazine the amount of opioid antagonist hydrochloride Salt, or an derivative, a thiazine derivative, or a benzodiazepine deriva equivalent amount of nalbuphine free base, prodrug, non tive; and (c) a pharmaceutically acceptable carrier; provided hydrochloride salt, or mixture thereof. that the composition does not comprise 60 mg of pentazo 197. A composition according to claim 193 comprising cine free base or an equivalent amount of pentazocine malbuphine hydrochloride, the amount of nalbuphine hydro hydrochloride Salt, non-hydrochloride Salt, prodrug, or mix chloride Salt being 10 to 15 times greater, by weight, than the ture thereof and 0.4 mg naloxone free base or equivalent amount of naloxone hydrochloride Salt, or an equivalent amount of naloxone hydrochloride Salt, non-hydrochloride amount of nalbuphine free base, prodrug, non-hydrochloride Salt, prodrug, or mixture thereof. Salt, or mixture thereof. 210. A composition according to claim 209 wherein the 198. A composition according to claim 193 comprising kappa-opioid is pentazocine and the opioid antagonist is malbuphine hydrochloride, the amount of nalbuphine hydro naloxone. chloride Salt being 12.5 times greater, by weight, than the 211. A composition according to claim 210 comprising amount of naloxone hydrochloride Salt, or an equivalent pentazocine hydrochloride salt in an amount 18 to 30 times amount of nalbuphine free base, prodrug, non-hydrochloride greater, by weight, than the amount of naloxone hydrochlo Salt, or mixture thereof. ride Salt, or an equivalent amount of pentazocine free base, 199. A composition according to claim 193 comprising prodrug, non-hydrochloride Salt, or mixture thereof. 1.25 mg to 10 mg of nalbuphine hydrochloride Salt, or an 212. A composition according to claim 209 wherein the equivalent amount of nalbuphine free base, prodrug, non kappa-opioid is butorphanol and the opioid antagonist is hydrochloride salt, or mixture thereof. naloxone. 200. A composition according to claim 193 comprising 213. A composition according to claim 212 comprising 0.1 mg to 0.8 mg of naloxone hydrochloride Salt or an 0.3 to 10 times greater, by weight, butorphanol tartrate Salt equivalent amount of naloxone free base, prodrug, non than naloxone hydrochloride Salt, or equivalent amount of hydrochloride salt, or mixture thereof. butorphanol free base, non-tartrate Salt, prodrug, or mixture 201. A composition according to claim 193 comprising 1 thereof and/or naloxone free base, non-hydrochloride Salt, mg to 2.5 mg of nalbuphine hydrochloride Salt, or an prodrug, or mixture thereof. equivalent amount of nalbuphine free base, prodrug, non 214. A composition according to claim 212 comprising chloride Salt, or mixture thereof and 0.1 to 0.8 naloxone 0.1 to 0.8 mg naloxone hydrochloride Salt or an equivalent hydrochloride Salt or an equivalent amount of naloxone free amount of naloxone free base, non-hydrochloride Salt, pro base, prodrug, non-hydrochloride Salt or mixture thereof. drug, or mixture thereof. 202. A composition according to claim 193 comprising 215. A composition according to claim 209 formulated for 8.5 mg to 10 mg of nalbuphine hydrochloride salt, or an intravenous administration. equivalent amount of nalbuphine free base, prodrug, non 216. A composition according to claim 209 formulated for chloride Salt, or mixture thereof and 0.1 to 0.8 naloxone mucosal administration. hydrochloride Salt or an equivalent amount of naloxone free 217. A composition according to claim 209 formulated for base, prodrug, non-hydrochloride Salt or mixture thereof. intranasal administration. 203. A composition according to claim 193 comprising 218. A composition according to claim 209 formulated for 0.4 mg of naloxone hydrochloride and 5 mg of nalbuphine pulmonary administration. hydrochloride. 219. A composition for treating pain comprising (a) 0.1 to 204. A composition according to claim 193 comprising 0.8 mg of a hydrochloride Salt of naloxone or an equivalent 0.125 mg of naloxone hydrochloride and 2.5 mg of nalbu amount of naloxone free base, prodrug, non-hydrochloride phine hydrochloride. salt, or mixture thereof; (b) 1-2.5 mg of nalbuphine hydro US 2004/018091.6 A1 Sep. 16, 2004 37 chloride, or an equivalent amount of nalbuphine free base, antagonist hydrochloride free base, prodrug, Salt, or mixture prodrug, non-hydrochloride Salt or mixture thereof, and (c) thereof are administered in amounts equivalent to intrave a pharmaceutically acceptable carrier. nous administration of 6.25 to 25 times greater in weight of 220. A composition for treating pain comprising (a) 0.1 to nalbuphine hydrochloride Salt than opioid antagonist hydro 0.8 mg of a hydrochloride Salt of naloxone or an equivalent chloride salt. amount of naloxone free base, prodrug, non-hydrochloride 233. The method of claim 230 wherein the nalbuphine salt, or mixture thereof; (b) 8.5 to 10 mg of nalbuphine free base, Salt, prodrug, or mixture thereof, and opioid hydrochloride, or an equivalent amount of nalbuphine free antagonist hydrochloride free base, prodrug, Salt, or mixture base, prodrug, non-hydrochloride Salt or mixture thereof; thereof are administered in amounts equivalent to intrave and (c) a pharmaceutically acceptable carrier. nous administration of 6.25 to 20 times greater in weight of 221. A composition for treating pain comprising (a) 0.1 nalbuphine hydrochloride Salt than opioid antagonist hydro mg of a hydrochloride Salt of naloxone or an equivalent chloride salt. amount of naloxone free base, prodrug, non-hydrochloride 234. The method of claim 230 wherein the nalbuphine salt, or mixture thereof; (b) 1.25 mg of nalbuphine hydro free base, Salt, prodrug, or mixture thereof, and opioid chloride, or an equivalent amount of nalbuphine free base, antagonist hydrochloride free base, prodrug, Salt, or mixture prodrug, non-hydrochloride Salt or mixture thereof, and (c) thereof are administered in amounts equivalent to intrave a pharmaceutically acceptable carrier. nous administration of 10 to 20 times greater in weight of 222. A composition for treating pain comprising (a) 0.2 nalbuphine hydrochloride Salt than opioid antagonist hydro mg of a hydrochloride Salt of naloxone or an equivalent chloride salt. amount of naloxone free base, prodrug, non-hydrochloride 235. The method of claim 230 wherein the nalbuphine salt, or mixture thereof; (b) 2.5 mg of nalbuphine hydro free base, Salt, prodrug, or mixture thereof, and opioid chloride, or an equivalent amount of nalbuphine free base, antagonist hydrochloride free base, prodrug, Salt, or mixture prodrug, non-hydrochloride Salt or mixture thereof, and (c) thereof are administered in amounts equivalent to intrave a pharmaceutically acceptable carrier. nous administration of 5 to 10 times greater in weight of 223. A composition for treating pain comprising (a) 0.8 nalbuphine hydrochloride Salt than opioid antagonist hydro mg of a hydrochloride Salt of naloxone or an equivalent chloride salt. amount of naloxone free base, prodrug, non-hydrochloride 236. The method of claim 230 wherein the nalbuphine salt, or mixture thereof; (b) 10 mg of nalbuphine hydrochlo free base, Salt, prodrug, or mixture thereof, is administered ride, or an equivalent amount of nalbuphine free base, in an amount equivalent to intravenous administration of 1 prodrug, non-hydrochloride Salt or mixture thereof, and (c) mg to 30 mg of nalbuphine hydrochloride salt. a pharmaceutically acceptable carrier. 237. The method of claim 230 wherein the nalbuphine 224. A composition according to claim 193 formulated for free base, Salt, prodrug, or mixture thereof, is administered treatment of neuropathic pain. in an amount equivalent to intravenous administration of 1 225. A composition according to claim 193 formulated for mg to 20 mg of nalbuphine hydrochloride Salt. treatment of inflammatory pain. 238. The method of claim 230 wherein the nalbuphine 226. A composition according to claim 193 formulated for free base, Salt, prodrug, or mixture thereof, is administered treatment of acute pain. in an amount equivalent to intravenous administration of 1 227. A composition according to claim 193 formulated for mg to 10 mg of nalbuphine hydrochloride Salt. treatment of traumatic pain. 239. The method of claim 230 wherein the nalbuphine 228. A composition according to claim 193 formulated for free base, Salt, prodrug, or mixture thereof, is administered treatment of post-procedural pain. in an amount equivalent to intravenous administration of 1 229. A composition according to claim 193 formulated for mg to 6 mg of nalbuphine hydrochloride Salt. treatment of infection-related pain. 240. The method of claim 230 wherein the nalbuphine 230. A method of treating pain comprising mucosally free base, Salt, prodrug, or mixture thereof, is administered administering to an individual in need of Said treatment (a) in an amount equivalent to intravenous administration of 1 an amount of an opioid antagonist free base, prodrug, Salt, mg to 5 mg of nalbuphine hydrochloride Salt. or mixture thereof equivalent to intravenous administration 241. The method of any of claims 230-240 wherein the of 0.1 mg to 0.8 mg of a hydrochloride salt of an opioid opioid antagonist is naloxone. antagonist, wherein Said opioid antagonist is naloxone, 242. The method of claim 241 wherein the amount of naltrexone, methyltrexone, nalmefene, nalorphine, levalor naloxone free base, Salt, or prodrug is equivalent to intra phan, oxylorphan or cyprenorphine, and (b) an amount of venous administration of 0.1 mg naloxone hydrochloride nalbuphine free base, hydrochloride Salt, prodrug or mixture Salt and the amount of nalbuphine free base, Salt, or prodrug thereof that results in greater analgesia than administration is equivalent to intravenous administration of 1.25 mg of either Said opioid antagonist free base, prodrug, Salt, or malbuphine hydrochloride salt. mixture thereof or Said nalbuphine alone. 243. The method of claim 241 wherein the amount of 231. The method of claim 230 wherein the nalbuphine naloxone free base, Salt, or prodrug is equivalent to intra free base, Salt, prodrug, or mixture thereof, and opioid venous administration of 0.2 mg naloxone hydrochloride antagonist hydrochloride free base, prodrug, Salt, or mixture Salt and the amount of nalbuphine free base, Salt, or prodrug thereof are administered in amounts equivalent to intrave is equivalent to intravenous administration of 2.5 mg nal nous administration of 6.25 to 30 times greater in weight of buphine hydrochloride Salt are administered. nalbuphine hydrochloride Salt than the opioid antagonist 244. The method of claim 241 wherein the amount of hydrochloride salt. naloxone free base, Salt, or prodrug is equivalent to intra 232. The method of claim 230 wherein the nalbuphine venous administration of 0.4 mg naloxone hydrochloride free base, Salt, prodrug, or mixture thereof, and opioid Salt and the amount of nalbuphine free base, Salt, or prodrug US 2004/018091.6 A1 Sep. 16, 2004 38 is equivalent to intravenous administration of 5 mg nalbu hydrochloride Salt and Said Second amount is equivalent to phine hydrochloride Salt are administered. intravenous administration of 10 mg nalbuphine hydrochlo 245. The method of claim 241 wherein the amount of ride Salt. naloxone free base, Salt, or prodrug is equivalent to intra 258. The method of claim 253 wherein said first amount venous administration of 0.8 mg naloxone hydrochloride is an amount of naloxone free base, Salt, or prodrug equiva Salt and the amount of nalbuphine free base, Salt, or prodrug lent to intravenous administration of 1.6 mg naloxone is equivalent to intravenous administration of 10 mg nalbu hydrochloride Salt and Said Second amount is equivalent to phine hydrochloride Salt are administered. intravenous administration of 20 mg nalbuphine hydrochlo 246. The method of claim 230 wherein the method of ride Salt. mucosal administration is intranasally. 259. The method of claim 253 wherein said first amount is an amount of naloxone free base, Salt, or prodrug equiva 247. The method of claim 230 wherein the method of lent to intravenous administration of 2.0 mg naloxone mucosal administration is pulmonary. hydrochloride Salt and Said Second amount is equivalent to 248. A method of treating pain comprising mucosally intravenous administration of 30 mg nalbuphine hydrochlo administering to an individual in need of Said treatment (a) ride Salt. a first amount of an opioid antagonist as a free base, prodrug, Salt, or mixture thereof, wherein Said opioid antagonist is 260. The method of claim 253 wherein the method of naloxone, naltrexone, methyltrexone, nalmefene, nalor mucosal administration is intranasally. phine, levalorphan, oxylorphan or cyprenorphine, and (b) a 261. The method of claim 253 wherein the method of Second amount of nalbuphine as a free base, Salt, prodrug or mucosal administration is pulmonary. mixture, wherein Said first amount and Said Second amount 262. A method of treating pain comprising administering are equivalent to intravenous administration of a weight to an individual in need of Said treatment (a) a first amount ratio of 1 to 12.5 of Said opioid antagonist free base and of an opioid antagonist as a free base, prodrug, Salt, or nalbuphine free base and wherein Said administration results mixture thereof, wherein Said opioid antagonist is naloxone, in greater analgesia than administration of either said opioid naltrexone, methyltrexone, nalmefene, nalorphine, levalor antagonist or Said nalbuphine alone. phan, oxylorphan or cyprenorphine, and (b) a second amount of nalbuphine as a free base, Salt, prodrug or 249. The method of claim 248 wherein said second mixture, wherein Said first amount and Said Second amount amount is equivalent to intravenous administration of 1 mg are equivalent to intravenous administration of a weight to 30 mg of nalbuphine hydrochloride salt. ratio of said opioid antagonist free base and said nalbuphine 250. The method of claim 248 wherein said second free base that is 1:6.25 to 1:49 and wherein said adminis amount is equivalent to intravenous administration of 1 mg tration results in greater analgesia than administration of to 20 mg of nalbuphine hydrochloride salt. either said opioid antagonist or Said nalbuphine alone, 251. The method of claim 248 wherein said second provided that 5 mg nalbuphine free base or an equivalent amount is equivalent to intravenous administration of 1 mg amount of nalbuphine hydrochloride salt, non-hydrochloride to 10 mg of nalbuphine hydrochloride salt. Salt, prodrug, or mixture thereof, is not intravenously admin 252. The method of claim 248 wherein said second istered with 0.4 mg naloxone free base or equivalent amount amount is equivalent to intravenous administration of 1 mg of naloxone hydrochloride Salt, non-hydrochloride Salt, pro to 5 mg of nalbuphine hydrochloride salt. drug, or mixture thereof. 253. The method of claim 248 wherein the opioid antago 263. A method of treating pain comprising administering nist is naloxone hydrochloride Salt or an equivalent amount to an individual in need of Said treatment (a) a first amount of free base, non-hydrochloride Salt, prodrug, or mixture of an opioid antagonist as a free base, prodrug, Salt, or thereof. mixture thereof, wherein Said opioid antagonist is naloxone, 254. The method of claim 253 wherein said first amount naltrexone, methyltrexone, nalmefene, nalorphine, levalor is an amount of naloxone free base, Salt, or prodrug equiva phan, oxylorphan or cyprenorphine, and (b) a second lent to intravenous administration of 0.1 mg naloxone amount of nalbuphine as a free base, Salt, prodrug or hydrochloride Salt and Said Second amount is equivalent to mixture, wherein Said first amount and Said Second amount intravenous administration of 1.25 mg nalbuphine hydro are equivalent to intravenous administration of a weight chloride salt. ratio of Said opioid antagonist free base and Said nalbuphine free base that is 1:6.25 to 1:7 and wherein said administra 255. The method of claim 253 wherein said first amount tion results in greater analgesia than administration of either is an amount of naloxone free base, Salt, or prodrug equiva Said opioid antagonist or Said nalbuphine alone. lent to intravenous administration of 0.2 mg naloxone 264. A method of treating pain comprising administering hydrochloride Salt and Said Second amount is equivalent to to an individual in need of Said treatment (a) a first amount intravenous administration of 2.5 mg nalbuphine hydrochlo of an opioid antagonist as a free base, prodrug, Salt, or ride Salt. mixture thereof, wherein Said opioid antagonist is naloxone, 256. The method of claim 253 wherein said first amount naltrexone, methyltrexone, nalmefene, nalorphine, levalor is an amount of naloxone free base, Salt, or prodrug equiva phan, oxylorphan or cyprenorphine, and (b) a second lent to intravenous administration of 0.4 mg naloxone amount of nalbuphine as a free base, Salt, prodrug or hydrochloride Salt and Said Second amount is equivalent to mixture, wherein Said first amount and Said Second amount intravenous administration of 5 mg nalbuphine hydrochlo are equivalent to intravenous administration of a weight ride Salt. ratio of Said opioid antagonist free base and Said nalbuphine 257. The method of claim 253 wherein said first amount free base that is 1:7 to 1:9 and wherein said administration is an amount of naloxone free base, Salt, or prodrug equiva results in greater analgesia than administration of either said lent to intravenous administration of 0.8 mg naloxone opioid antagonist or Said nalbuphine alone. US 2004/018091.6 A1 Sep. 16, 2004 39

265. A method of treating pain comprising administering amount of nalbuphine as a free base, Salt, prodrug or to an individual in need of Said treatment (a) a first amount mixture, wherein Said first amount and Said Second amount of an opioid antagonist as a free base, prodrug, Salt, or are equivalent to intravenous administration of a weight mixture thereof, wherein Said opioid antagonist is naloxone, ratio of Said opioid antagonist free base and Said nalbuphine naltrexone, methyltrexone, nalmefene, nalorphine, levalor free base that is 1:20 to 1:30 and wherein said administration phan, oxylorphan or cyprenorphine, and (b) a second results in greater analgesia than administration of either said amount of nalbuphine as a free base, Salt, prodrug or opioid antagonist or Said nalbuphine alone. mixture, wherein Said first amount and Said Second amount 270. A method of treating pain comprising administering are equivalent to intravenous administration of a weight to an individual in need of Said treatment (a) a first amount ratio of Said opioid antagonist free base and Said nalbuphine of an opioid antagonist as a free base, prodrug, Salt, or free base that is 1:9 to 1:11 and wherein said administration mixture thereof, wherein Said opioid antagonist is naloxone, results in greater analgesia than administration of either said naltrexone, methyltrexone, nalmefene, nalorphine, levalor opioid antagonist or Said nalbuphine alone. phan, oxylorphan or cyprenorphine, and (b) a second 266. A method of treating pain comprising administering amount of nalbuphine as a free base, Salt, prodrug or to an individual in need of Said treatment (a) a first amount mixture, wherein Said first amount and Said Second amount of an opioid antagonist as a free base, prodrug, Salt, or are equivalent to intravenous administration of a weight mixture thereof, wherein Said opioid antagonist is naloxone, ratio of Said opioid antagonist free base and Said nalbuphine naltrexone, methyltrexone, nalmefene, nalorphine, levalor free base that is 1:30 to 1:49 and wherein said administration phan, oxylorphan or cyprenorphine, and (b) a second results in greater analgesia than administration of either said amount of nalbuphine as a free base, Salt, prodrug or opioid antagonist or Said nalbuphine alone. mixture, wherein Said first amount and Said Second amount 271. The method of claim 262, wherein the second are equivalent to intravenous administration of a weight amount of nalbuphine hydrochloride Salt is 1 mg to 5 mg, or ratio of Said opioid antagonist free base and Said nalbuphine an equivalent amount of nalbuphine free base, prodrug, free base that is 1:11 to 1:13 and wherein said administration non-hydrochloride Salt, or a mixture of one or more thereof. results in greater analgesia than administration of either said 272. The method of claim 262, wherein the second opioid antagonist or said nalbuphine alone, provided that 5 amount of nalbuphine hydrochloride Salt is 1 mg to 10 mg, mg nalbuphine free base or an equivalent amount of nalbu or an equivalent amount of nalbuphine free base, prodrug, phine hydrochloride Salt, non-hydrochloride Salt, prodrug, or non-hydrochloride Salt, or a mixture of one or more thereof. mixture thereof, is not intravenously administered with 0.4 273. The method of claim 262, wherein the second mg naloxone free base or equivalent amount of naloxone amount of nalbuphine hydrochloride Salt is 1 mg to 20 mg, hydrochloride Salt, non-hydrochloride Salt, prodrug, or mix or an equivalent amount of nalbuphine free base, prodrug, ture thereof. non-hydrochloride Salt, or a mixture of one or more thereof. 267. A method of treating pain comprising administering 274. The method of claim 262, wherein the second to an individual in need of Said treatment (a) a first amount amount of nalbuphine hydrochloride Salt is 1 mg to 30 mg, of an opioid antagonist as a free base, prodrug, Salt, or or an equivalent amount of nalbuphine free base, prodrug, mixture thereof, wherein Said opioid antagonist is naloxone, non-hydrochloride Salt, or a mixture of one or more thereof. naltrexone, methyltrexone, nalmefene, nalorphine, levalor 275. The method of claim 262, wherein the method of phan, oxylorphan or cyprenorphine, and (b) a second administration is intranasal. amount of nalbuphine as a free base, Salt, prodrug or 276. The method of claim 262, wherein the method of mixture, wherein Said first amount and Said Second amount administration is intravenous. are equivalent to intravenous administration of a weight 277. The method of claim 262, wherein the method of ratio of Said opioid antagonist free base and Said nalbuphine administration is pulmonary. free base that is 1:13 to 1:15 and wherein said administration 278. The method of claim 262, wherein the method of results in greater analgesia than administration of either said administration is transdermal. opioid antagonist or Said nalbuphine alone. 279. The method of claim 262, wherein the method of 268. A method of treating pain comprising administering administration is mucosal. to an individual in need of Said treatment (a) a first amount 280. A method of treating pain comprising mucosally of an opioid antagonist as a free base, prodrug, Salt, or administering to an individual in need of Said treatment (a) mixture thereof, wherein Said opioid antagonist is naloxone, 0.02 mg to 8 mg of a hydrochloride Salt of an opioid naltrexone, methyltrexone, nalmefene, nalorphine, levalor antagonist or an equivalent amount of opioid antagonist free phan, oxylorphan or cyprenorphine, and (b) a second base, prodrug, non-hydrochloride Salt, or mixture thereof, amount of nalbuphine as a free base, Salt, prodrug or wherein Said opioid antagonist is naloxone, naltrexone, mixture, wherein Said first amount and Said Second amount methylmaltrexone, nalmefene, nalorphine, levalorphan, oxy are equivalent to intravenous administration of a weight lorphan or cyprenorphine, and (b) an amount of nalbuphine ratio of Said opioid antagonist free base and Said nalbuphine free base, hydrochloride Salt, prodrug, non-hydrochloride free base that is 1:15 to 1:20 and wherein said administration Salt or mixture thereof that results in greater analgesia than results in greater analgesia than administration of either said administration of either Said opioid antagonist hydrochloride opioid antagonist or Said nalbuphine alone. Salt or said nalbuphine alone. 269. A method of treating pain comprising administering 281. A pharmaceutical composition comprising (a) 0.02 to an individual in need of Said treatment (a) a first amount mg to 8 mg of a hydrochloride Salt of an opioid antagonist of an opioid antagonist as a free base, prodrug, Salt, or or an equivalent amount of opioid antagonist free base, mixture thereof, wherein Said opioid antagonist is naloxone, prodrug, non-hydrochloride Salt, or mixture thereof, wherein naltrexone, methyltrexone, nalmefene, nalorphine, levalor Said opioid antagonist is naloxone, naltrexone, methylmaltr phan, oxylorphan or cyprenorphine, and (b) a second exone, nalmefene, nalorphine, leValorphan, oxylorphan or US 2004/018091.6 A1 Sep. 16, 2004 40 cyprenorphine; (b) an amount of nalbuphine free base, exone, methylmaltrexone, nalmefene, nalorphine, levalor nalbuphine Salt, nalbuphine prodrug, or mixture thereof that phan, oxylorphan or cyprenorphine, (b) an amount of nal results in greater analgesia than administration of the nal buphine free base, hydrochloride Salt, prodrug, non buphine ingredient or the opioid antagonist ingredient alone; hydrochloride Salt or mixture thereof that results in greater and (c) a pharmaceutically acceptable carrier, said pharma analgesia than administration of either Said opioid antagonist ceutical composition being formulated for mucosal admin hydrochloride Salt or said nalbuphine alone; and (c) a istration. pharmaceutically acceptable carrier; provided that Said com 282. A method of treating pain comprising mucosally position formulated for intravenous administration does not administering to an individual in need of Said treatment (a) comprise 5 mg nalbuphine free base with 0.4 mg naloxone an amount of an opioid antagonist free base, prodrug, Salt, free base. or mixture thereof equivalent to intravenous administration 286. A composition for treating pain comprising (a) 0.02 of 0.02 mg to 8 mg of a hydrochloride salt of an opioid mg to 8 mg of a hydrochloride Salt of an opioid antagonist antagonist, wherein Said opioid antagonist is naloxone, or an equivalent amount of opioid antagonist free base, naltrexone, methyltrexone, nalmefene, nalorphine, levalor prodrug, non-hydrochloride Salt, or mixture thereof, wherein phan, oxylorphan or cyprenorphine, and (b) an amount of Said opioid antagonist is naloxone, naltrexone, methylmaltr nalbuphine free base, hydrochloride Salt, prodrug or mixture exone, nalmefene, nalorphine, leValorphan, oxylorphan or thereof that results in greater analgesia than administration cyprenorphine; (b) an amount of a free base, hydrochloride of either Said opioid antagonist free base, prodrug, Salt, or Salt, prodrug, non-hydrochloride Salt or mixture thereof of a mixture thereof or Said nalbuphine alone. kappa opioid, that results in greater analgesia than admin 283. A method of treating pain comprising administering istration of either Said opioid antagonist hydrochloride Salt to an individual in need of said treatment (a) from 0.02 to 8 or Said kappa-opioid, wherein the kappa-opioid is pentazo mg of a hydrochloride Salt of naloxone or an equivalent cine, butorphanol, ketazocine, ethylketazocine, dezocine, amount of naloxone free base, prodrug, non-hydrochloride bremazocine, a benzacetamide derivative, a phenothiazine salt, or mixture thereof; and (b) from 1 to 2.5 mg of derivative, a thiazine derivative, or a benzodiazepine deriva nalbuphine hydrochloride, or an equivalent amount of nal tive; and (c) a pharmaceutically acceptable carrier; provided buphine free base, prodrug, non-hydrochloride Salt or mix that Said composition formulated for intravenous adminis ture thereof. tration does not comprise 60 mg of pentazocine free base or 284. A method of treating pain comprising administering an equivalent amount of pentazocine hydrochloride Salt, to an individual in need of said treatment (a) from 0.02 to 8 non-hydrochloride Salt, prodrug, or mixture thereof and 0.4 mg of a hydrochloride Salt of naloxone or an equivalent mg naloxone free base or equivalent amount of naloxone amount of naloxone free base, prodrug, non-hydrochloride hydrochloride Salt, non-hydrochloride Salt, prodrug, or mix salt, or mixture thereof; and (b) from 8.5 to 30 mg of ture thereof and provided that Said composition formulated nalbuphine hydrochloride, or an equivalent amount of nal for oral administration does not comprise 50 mg of penta buphine free base, prodrug, non-hydrochloride Salt or mix Zocine free base or an equivalent amount of pentazocine ture thereof. hydrochloride Salt, non-hydrochloride Salt, prodrug, or mix 285. A pharmaceutical composition for treating pain com ture thereof and 0.5 mg naloxone free base or equivalent prising (a) 0.02 mg to 8 mg of a hydrochloride Salt of an amount of naloxone hydrochloride Salt, non-hydrochloride opioid antagonist or an equivalent amount of opioid antago Salt, prodrug, or mixture thereof. nist free base, prodrug, non-hydrochloride Salt, or mixture thereof, wherein Said opioid antagonist is naloxone, naltr k k k k k