US 20090203722A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0203722 A1 Sherman et al. (43) Pub. Date: Aug. 13, 2009

(54) NOVEL COMPOSITIONS AND METHODS tion of application No. 10/047.367, filed on Jan. 14, FOR ENHANCING POTENCY OR REDUCING 2002, now abandoned, which is a continuation of ADVERSE SIDE EFFECTS OF OPOLD application No. 09/849,721, filed on May 4, 2001, now AGONSTS abandoned, which is a continuation of application No. 09/756,331, filed on Jan. 8, 2001, now abandoned, (75) Inventors: Barry M. Sherman, Hillsborough, which is a continuation of application No. 09/566,071, CA (US); Mary M. Remien, San filed on May 5, 2000, now abandoned, Continuation of Francisco, CA (US); Remi Barbier, application No. PCT/US00/12493, filed on May 5, San Francisco, CA (US); Kathleen 2OOO. Dumas, Cupertino, CA (US); Grant L. Schoenhard, San Carlos, Publication Classification CA (US) (51) Int. Cl. Correspondence Address: A63L/485 (2006.01) BELL, BOYD & LLOYD, LLP A63L/35 (2006.01) P.O. Box 1135 A6IP 25/00 (2006.01) CHICAGO, IL 60690 (US) (52) U.S. Cl...... 514/282; 514/646 (73) Assignee: PAIN THERAPEUTICS, INC., (57) ABSTRACT South San Francisco, CA (US) The invention generally relates to novel compositions and methods with an opioid agonist and an opioid antagonist to (21) Appl. No.: 11/456,079 differentially dose a human Subject so as to either enhance analgesic potency without attenuating an adverse side effect (22) Filed: Jul. 6, 2006 of the agonist, or alternatively maintain the analgesic potency of the agonist while attenuating an adverse side effect of the Related U.S. Application Data agonist. The invention additionally relates to novel opioid (63) Continuation of application No. 10/228,835, filed on compositions and methods for the gender-based dosing of Aug. 26, 2002, now abandoned, which is a continua men and women. Patent Application Publication Aug. 13, 2009 Sheet 1 of 73 US 2009/0203722 A1

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NOVELCOMPOSITIONS AND METHODS than its N-allyl cogener, naloxone, and is active when given FOR ENHANCING POTENCY OR REDUCING orally. For example, 50 mg dosage forms of naltrexone, are ADVERSE SIDE EFFECTS OF OPOLD marketed as ReVia(R) in the United States or Trexan in other AGONSTS countries. Nalmefene (6-methylene-6-desoxy-N-cyclopro pyl-methyl-14-hydroxydihydroxydihydronor-morphine) CROSS-REFERENCE TO RELATED was also developed as a long acting, orally available, potent APPLICATIONS opioid antagonist, and has also been characterized as a pure 0001. This application claims the priority of the following antagonist. These drugs are presently commercially available U.S. Patent Application Nos. 60/202,227 filed May 5, 2000 in certain dosage forms, and are so far as is known, the only (provisional); 60/202,268 filed May 5, 2000 (provisional): opioid antagonists characterized as pure antagonists which 09/756,331 filed Jan. 8, 2001, which is a continuation of Ser. have received governmental approval for administration to No. 09/566,071 filed May 5, 2000; 60/244,482 filed Oct. 30, humans. 2000 (provisional); 60/245,110 filed Nov. 1, 2000 (provi 0006 Opioid agonists, such as morphine, are commonly sional); and 60/246.235 filed Nov. 2, 2000 (provisional); and used by clinicians in the treatment of moderate to severe acute PCT/US00/12493 WO 00/67739 filed May 5, 2000. The and chronic pain. The analgesic activity of these agents con applications cited above are hereby incorporated herein by tributes to their pharmacological effects on a large number of reference in their entirety to provide continuity of disclosure. inhibitory opioid receptors on sensory nerve cells that receive and transmit pain signals in the nervous system; the role of FIELD OF THE INVENTION these receptors is to inhibit the transmission of pain signals into the brain. The precise mechanisms of opioid agonists 0002 The present invention relates to novel compositions Such as morphine are not known, although morphine, for and methods, including gender-based compositions and example, is believed to act preferentially at mu-opiate recep methods, for enhancing potency or reducing adverse side tors on neurons in the central and peripheral nervous system. effects of opioid agonists in humans. The present invention In addition to pain relief, other actions of opioidagonists Such also relates to novel compositions and methods with an opioid as morphine, in human Subjects, include adverse side effects agonist and an opioid antagonist to differentially dose a Such as inhibition of gastrointestinal motility (e.g., leading to human Subject, including men and/or women, so as to either constipation), respiratory depression (especially at high enhance analgesic potency without attenuating an adverse doses), peripheral vasodilation (e.g., leading to orthostatic side effect of the agonist, or alternatively maintain the anal hypotension), dizziness, sedation/drowsiness, nausea, vom gesic potency of the agonist while attenuating an adverse side iting, headache, pruritus, dry mouth, difficulty in urination, effect of the agonist. dependence, mood Swings, and clouded sensorium. 0007 Opioid antagonists have been widely used in high BACKGROUND OF THE INVENTION doses for the treatment of overdoses of opioid agonists and to 0003) Opioid agonists, including morphine sulfate (here prevent abuse of opioid agonists such as heroin or morphine after called morphine or MS), have been marketed for many (e.g., 50 mg naltrexone). For these uses, doses must be rela years and are widely used for the relief of moderate to severe tively high in order to be therapeutically effective (i.e., block) acute and chronic pain. The potency of oral morphine is less the analgesic potency and the side effects of the opioid ago than that of parenteral morphine, however, the use of the oral nist, by antagonizing the agonist at opioid receptors on noci product for chronic pain control has increased dramatically in ceptive neurons. the past decade. An opioid agonist, such as morphine, exerts 0008 Crain and Shen (Brain Research 757: 176-190 its primary effects on the central nervous system and organs (1997)) reported that opioid agonists not only activate inhibi containing Smooth muscle, and acts as an agonist interacting tory opioid receptors leading to analgesia but also simulta with Stereospecific and Saturable binding sites or receptors in neously activate a smaller group of excitatory opioid recep the brain, spinal cord, and other tissues. The principal thera tors on sensory nerve cells. These effects on the excitatory peutic actions are analgesia and sedation. oploid receptors were proposed to weaken opioid induced 0004 Opioidantagonists are generally accepted for use in analgesia and under certain conditions actually enhance pain. the treatment of human conditions or ailments for reversing Surprisingly, Crain and Shen (e.g., U.S. Pat. No. 5.512.578 opioid toxicity and overdoses, and in preventing abuse of reissued as RE 36,457) showed that co-administration of opioid agonists, such as heroin or morphine. For these uses, remarkably low-doses of an opioidantagonist, Such as nalox the antagonist Such as naloxone or naltrexone is used in one or naltrexone on the order of ng/kg, when administered to relatively high concentrations in order to effectively block the mice with morphine or similar opioid agonists selectively activity and/or effects of the opioid agonist by antagonizing blocked their effects on excitatory, but not inhibitory, opioid the opioid agonist at opioid receptors on nociceptive neurons. receptors, thus markedly enhancing the analgesic potency of 0005 Naloxone (4.5-epoxy-3, 14-dihydroxy-17-(2- opioid agonists. These Surprising results of Crain and Shen prophenyl)morphinan-6-one) was the first of these com have been described in U.S. Pat. Nos. 5,472,943; 5,512,578 pounds to be synthesized in 1960 and is considered a “pure' reissued as RE 36,457: 5,580,876 and 5,767,125, which are antagonist, i.e., exhibiting virtually no agonist activity. directed to methods for selectively enhancing the analgesic Naloxone became the preferred regime for the treatment of potency of a bimodally-acting opioid agonist and simulta acute opioid toxicity. Since naloxone exhibits a relatively neously attenuating anti-analgesia, hyperalgesia, hyperexcit short duration in the body, it became clear that alonger acting ability, physical dependence and/or tolerance effects associ agent having similarly pure antagonist character would be ated with the administration of the bimodally-acting opioid even more advantageous. Naltrexone (17-(cyclopropylm agonist. These methods comprise administering to a subject ethyl)-4,5-epoxy-3, 14-dihydroxy-morphinan-6-one) was an analgesic or Sub-analgesic amount of a bimodally-acting developed in 1965 and has greater potency and longer action opioidagonistandan amount of an excitatory opioid receptor US 2009/0203722 A1 Aug. 13, 2009 antagonist effective to enhance the analgesic potency of the colleagues in patients with postoperative pain with several bimodally-acting opioid agonist and attenuate the anti-anal kappa opioid agonists, e.g., butorphanol Gear et al., Nature, gesia, hyperalgesia, hyperexcitability, physical dependence 2: 1248-1250 (1996); pentazocine Gear et al., Neuroscience and/or tolerance effects of the bimodally-acting opioid ago Let., 205: 207-209 (1996): nalbuphine Gear et al., Pain 83: nist. Also included in these patents are methods for treating 339-345 (1999); and nalbuphine in combination with nalox pain in a Subject comprising administering to the Subject an one, an opioid antagonist Gear et al., J. Pain 1: 122-127 analgesic or Sub-analgesic amount of a bimodally-acting (2000), but not with the mu opioid agonist morphine Gor opioidagonistandan amount of an excitatory opioid receptor don et al., Neuroscience 69(2): 345-349 (1995). According antagonist effective to enhance the analgesic potency of the to Levine and his colleagues, kappa opioid receptor agonists bimodally-acting opioid agonist and simultaneously attenu are unique in their gender-related effects. Studies in rats and ate anti-analgesia, hyperalgesia, hyperexcitability, physical mice evaluating the role of mu opioid agonists and antago dependence and/or tolerance effects of the bimodally-acting nists show gender-based effects, although the results of these opioid agonist. Also included are methods for treating an studies are contradictory and appear to be dependent upon opiate addict comprising administering to the opiate addict an both species and gender (for reviews, see Kest et al., J. Phar amount of an excitatory opioid receptor antagonist either macol. Exper. Therapeutics, 289: 1370-1375 (1999); and alone or in combination with a bimodally-acting opioid ago Kest et al., Anesthesiology, 93: 539-547 (2000)). nist effective to attenuate physical dependence caused by a bimodally-acting opioid agonist and enhance the analgesic SUMMARY OF THE INVENTION potency of a bimodally-acting opioid agonist. Also included 0011. The present invention relates to novel compositions are compositions comprising an analgesic or Sub-analgesic and methods for enhancing potency or reducing adverse side amount of a bimodally-acting opioid agonist and an amount effects of opioid agonists in humans. The present invention is of an excitatory opioid receptor antagonist effective to directed to compositions and methods for the differential enhance the analgesic potency of the bimodally-acting opioid dosing of human Subjects with opioid agonists and low doses agonist and attenuate the anti-analgesia, hyperalgesia, hyper of opioid antagonists to yield either (1) enhancement of anal excitability, physical dependence and/or tolerance effects of gesic potency of the agonist without attenuation (e.g., reduc the bimodally-acting opioid agonist in a subject administered tion) or increase of one or more of the adverse side effects the composition. In all of these studies, the antagonist simul associated with that dose of agonist in humans, or (2) main taneously enhanced potency while attenuating Such adverse tenance of analgesic potency of the agonist with attenuation effects. Two clinical studies on postSurgical hysterectomy (e.g., reduction) of one or more of the adverse side effects patients Joshi, et al., Anesthesiol.90: 1007-1011 (1999); Gan associated with that dose of agonist in humans. The present et al., Anesthesiol. 87: 1075-1081 (1997) demonstrated that invention is based on Surprising results from human clinical cotreatment of women with PCA/IV morphine together with trials that demonstrate that the analgesic potency of opioid a low-dose of the opioid antagonist naloxone (IV) or agonists can be dissociated from the opioid-related adverse nalmefene (IV) enhanced potency of morphine in varying side effects in humans. One novel composition and dosing cumulative doses of morphine over a 24 hour period. Adverse method of the invention utilizes a dose of agonist with a low side effects were attenuated in these studies. Nothing in these dose of antagonist that gives more pain relief in men and/or studies with women suggested or related to any gender-based women but with essentially the same adverse side effect(s) of effect on either opioid-induced analgesia and/or the adverse agonist alone. A second novel composition and dosing effects associated with opioids. method of the invention utilizes a dose of agonist with a low 0009. In a recent review of gender differences in pharma dose of antagonist that gives essentially the same pain relief in cokinetics and pharmacodynamics Beierleet al., Intl.J. Clin. men and/or women as agonist alone, but with attenuated (e.g., Pharmacol. Ther. 37 (11):529-547 (1999), it was pointed out reduced) adverse side effect(s). The maintained potency with that until 1993, women were excluded from clinical phase I attenuated side effect(s) is accomplished without increasing and early phase II trials. Therefore, for most drugs, including or decreasing the cumulative daily dose of agonist. Thus, at analgesics, there is a real paucity of information on sex dif appropriate differential dosing of humans according to the ferences in the pharmacokinetics as well as in the dose-re invention, a low dose of antagonist Surprisingly can enhance sponse relationship or adverse effects of these drugs. The U.S. analgesia with no increase in side effects or Suppress side Food and Drug Administration (FDA) recognized this situa effects with no loss in analgesia. tion and developed new guidelines for drug research in 1993. 0012. The present invention is also directed to novel com Sex-related analgesic responses, including a Summary and positions and methods for gender-based dosing of non-kappa critique of animal and human studies and discrepancies opioid receptor agonists, preferably mu opioid receptor ago between such studies were recently reviewed by Levine and nists such as morphine Sulfate, and/or opioidantagonists Such his colleagues Miaskowski et al., Chapter 11, pages 209 as naltrexone. Such compositions and methods are designed 230, Editor: Fillingim, IASP Press, Seattle, Sex Gender and to achieve appropriate and even optimal analgesia, and are Pain (2000). In another recent review, Miaskowski and useful for treating moderate or severe pain, wherein the pain Levine Pain Forum 8(1): 34-44 (1999), summarize data is either acute or chronic. Appropriate and even optimal anal from human studies on sex-related differences in responses to gesia is only possible when pain relief is enhanced, without opioid analgesics, particularly kappa opioids. enhancing and preferably attenuating, adverse side effects of 0010 Certain gender-based pain responses have been Such agonists or antagonists. reported in both animal and human clinical studies for 0013 The present invention is based in part on additional reviews, see Fillingham and Maixner, Pain Forum 4: 209-221 Surprising results from human clinical trials that demonstrate (1995); Unruh, Pain 65: 123-167 (1996): Miaskowski et al. that the analgesic potency and/or the adverse side effects of (2000), supra. Gender-based differences in analgesia and morphine Sulfate, a mu opioid receptor agonist, is gender anti-analgesia have recently been shown by Levine and his specific. Additionally Surprising are gender-specific US 2009/0203722 A1 Aug. 13, 2009 responses to Such agonists, including the discovery of the for example, with non-kappa opioid receptor agonists, pref problem that current methods of treatment with Such agonists erably mu opioid receptoragonists, based on co-treatment of result in hypo-analgesia in men, including anti-analgesia, Such agonists with low doses of opioid receptor antagonists. while similar treatment of women results in analgesia but Specifically provided are compositions and methods of with significant adverse side effects. Compositions and meth enhancing pain relief or attenuating pain intensity in men ods described herein provide for the first time a solution to comprising administering, for example, to a man a hypo problems related to previously undiscovered differences in analgesic dose (including a non-analgesic or anti-analgesic drug effects, including pain intensity differences, pain relief dose) of a mu opioid receptor agonist and a dose of an opioid or adverse side effects, using Such agonists in women and antagonist that in combination enhances pain relief or attenu men, including those effects associated with the management ates pain intensity. Such compositions and methods convert of pain. non-responder human Subjects, (e.g., men) into responders. 0014. The present invention is also directed to novel com Also specifically provided are compositions and methods of positions and methods for gender-based dosing of opioid enhancing pain relief or attenuating pain intensity, for antagonists, such as naltrexone, to avoid hypo-analgesia. This example, in women comprising administering to a woman an is based in part on Surprising results from human clinical trials analgesic dose of a mu opioid receptor agonist and a dose of that the responses to naltrexone, an opioidantagonist, are also opioid antagonist that in combination enhances pain relief or gender-specific. Additionally surprising are results that indi attenuates pain intensity comparable to that of the analgesic cate that such an antagonist can act as a partial opioid agonist dose of agonist alone but with attenuation of one or more on opioid receptors differentially in women and men. adverse side effects of the agonist. Thus, compositions and 0015 The present invention is also directed to novel com methods for providing, enhancing or maintaining pain relief, positions and methods for gender-based dosing of combina as well as for attenuating pain intensity, are specifically pro tions of non-kappa opioid receptor agonists, preferably mu vided as gender-specific compositions and methods for opioid receptor agonists, with opioid antagonists to achieve WOC O. optimal analgesia. This is based in part on Surprising results 0020. The present invention provides compositions and from human clinical trials that there are gender-based differ methods for the differential dosing in women and men of ences in the interactions between Such agonists and antago non-kappa opioid receptor agonists, preferably mu opioid nists. receptor agonists, based on gender-based differences in their 0016. The present invention provides compositions and pharmacodynamic effects, including pain relief or adverse methods for administering to a woman, for example, a dose of side effects, from gender-specific interactions of such ago a non-kappa opioid receptor agonist, preferably a mu opioid nists in women and men. Compositions and methods are receptor agonist, that alone is analgesic in women but hypo provided for administering a non-kappa opioid receptor ago analgesic in men, while attenuating one or more adverse side nist, preferably a mu opioid receptor agonist, at a gender effects of such agonists in women. The present invention also specific compensatory dose based on different pharmacody provides compositions and methods for administering to a namic effects in women and men, wherein such a gender man, for example, a dose of a non-kappa opioid receptor specific compensatory dose provides enhancement of agonist, preferably a mu opioid receptoragonist, that alone is analgesia and/or attenuation of an adverse side effect of the hypo-analgesic in men but analgesic in women, without Sub agonist. stantially enhancing one or more adverse side effects of Such 0021. The present invention provides compositions and agonists in men. methods that include a non-kappa opioid receptor agonist, 0017. The present invention is also directed to novel com preferably a mu opioid receptor agonist, and an opioid positions and methods for ethnic-based dosing of combina antagonist in amounts that are useful for men only, or for tions of opioid receptoragonists, including non-kappa opioid women only, or for both men and women, based on the receptor agonists, and preferably mu opioid receptor ago differences described herein. nists, with opioid antagonists to achieve optimal analgesia. This is based in part on Surprising results from human clinical BRIEF DESCRIPTION OF THE FIGURES trials that there are ethnic-based differences in the interac tions between such agonists and antagonists. (0022 FIG. 1 shows the total pain relief (TOTPAR) results 0018. The present invention provides compositions and at 4 hours (see also Table 4) in the five study groups in methods for administering to a Hispanic man, for example, a Example 1: placebo; morphine; morphine and low dose (0.01 dose of opioid receptor agonist, preferably a non-kappa mg) naltrexone (NTX); morphine and mid dose (0.1 mg) opioid receptoragonist, most preferably a mu opioid receptor NTX; and morphine and high dose (1.0 mg) NTX. agonist, that alone is analgesic in Hispanic men but hypo 0023 FIG. 2 shows the sum of pain intensity differences analgesic in non-Hispanic men, while attenuating one or (SPID) results at 4 hours (see also Table 5) in the five study more adverse side effects of Such agonists in Hispanic men. groups in Example 1: placebo; morphine; morphine and low The present invention also provides compositions and meth dose (0.01 mg) naltrexone (NTX); morphine and mid dose ods for administering to a Black man, for example, a dose of (0.1 mg) NTX; and morphine and high dose (1.0 mg) NTX. a opioid receptor agonist, preferably a non-kappa opioid 0024 FIG. 3 shows the time to onset of meaningful pain receptor agonist, most preferably a mu opioid receptor ago relief results (see also Table 6) in the five study groups in nist, that alone is hypo-analgesic in Black men but analgesic Example 1: placebo; morphine; morphine and low dose (0.01 in women and/or Hispanic men, without Substantially mg) naltrexone (NTX); morphine and mid dose (0.1 mg) enhancing one or more adverse side effects of such agonists in NTX; and morphine and high dose (1.0 mg) NTX. Black men. 0025 FIGS. 4 and 5 show the time to remedication (rescue 0019. The present invention thus provides compositions medication) up to 8 and 24 hours, respectively (see also Table and methods for the differential dosing in women and men, 7) in the five study groups in Example 1: placebo; morphine; US 2009/0203722 A1 Aug. 13, 2009

morphine and low dose (0.01 mg) naltrexone (NTX); mor 0035 FIG. 16 shows the time to onset of meaningful pain phine and mid dose (0.1 mg) NTX; and morphine and high relief results (see also Table 32A) for subjects in the six study dose (1.0 mg) NTX. groups as described in Example 3: placebo; morphine (60 0026 FIG. 6 shows the pain reliefresults (see also Table 9) mg); naltrexone (0.01 mg); morphine and low-dose (0.001 for 4 hours in the five study groups in Example 1: placebo mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) represented as Small diamonds (Q); morphine represented as maltrexone; morphine and high-dose (0.1 mg) NTX. squares (D); morphine and low dose (0.01 mg) NTX repre 0036 FIG. 17 shows the time to onset of analgesia results sented as large circles (O); morphine and mid dose (0.1 mg) (see also Table 32B) for subjects in the six study groups as NTX represented as triangles (A); and morphine and high described in Example 3: placebo; morphine (60 mg); naltr dose (1.0 mg) NTX represented as larger diamonds (()). exone (0.01 mg); morphine and low-dose (0.001 mg) naltr 0027 FIG. 7 shows the pain intensity difference (PID) exone (NTX); morphine and mid-dose (0.01 mg) naltrexone: results (see also Table 10) for 4 hours in the five study groups morphine and high-dose (0.1 mg) NTX. in Example 1: placebo; morphine; morphine and low dose 0037 FIG. 18 shows the time to remedication (rescue (0.01 mg) naltrexone (NTX); morphine and mid dose (0.1 medication) up to 8 hours (see also Table 33) for subjects in mg) NTX; and morphine and high dose (1.0 mg) NTX. the six study groups as described in Example 3: placebo. 0028 FIG. 8 shows a summary of adverse side effects of morphine (60 mg); naltrexone (0.01 mg); morphine and low nausea, vomiting, dizziness, headache, Somnolence (seda dose (0.001 mg) naltrexone (NTX); morphine and mid-dose tion) or pruritus in the five study groups in Example 1: pla (0.01 mg) naltrexone; morphine and high-dose (0.1 mg) cebo; morphine; morphine and low dose (0.01 mg) naltrexone NTX. (NTX); morphine and mid dose (0.1 mg) NTX; and morphine 0038 FIG. 19 shows the time to remedication (rescue and high dose (1.0 mg) NTX. medication) up to 8 and 24 hours, (see also Table 33) for 0029 FIGS. 9B and 9C show the summary of pain inten Subjects in the six study groups as described in Example 3: sity difference (SPID) results at 4 hours (SPID-4) (see also placebo; morphine (60 mg); naltrexone (0.01 mg); morphine Tables 18A and 18B) for women and men, respectively, in the and low-dose (0.001 mg) naltrexone (NTX); morphine and five study groups as described in Example 2: placebo; mor mid-dose (0.01 mg) naltrexone; morphine and high-dose (0.1 phine (60 mg); morphine and low-dose (0.01 mg) naltrexone mg) NTX. (NTX); morphine and mid-dose (0.1 mg)NTX; morphine and 0039 FIG. 20 shows the pain relief (PR) results (see also Table 35) for subjects in the six study groups as described in high-dose (1.0 mg) NTX. Example 3: placebo; morphine (60 mg); naltrexone (0.01 0030 FIGS. 10A and 10B show the time to onset of mean mg); morphine and low-dose (0.001 mg) naltrexone (NTX): ingful pain relief results (see also Tables 19A and 19B) in the morphine and mid-dose (0.01 mg) naltrexone; morphine and five study groups as described in Example 2: placebo; mor high-dose (0.1 mg) NTX. phine; morphine and low-dose (0.01 mg) naltrexone (NTX): 0040 FIG. 21 shows the pain intensity differences (PID) morphine and mid-dose (0.1 mg) NTX; and morphine and results (see also Table 36) for subjects in the six study groups high-dose (1.0 mg) NTX, for women and men, respectively. as described in Example 3: placebo, morphine (60 mg); nal 0031 FIGS. 11A and 12A for women, and 11B and 12B trexone (0.01 mg); morphine and low-dose (0.001 mg) naltr for men, show the time to remedication (rescue medication) exone (NTX); morphine and mid-dose (0.01 mg) naltrexone: up to 8 and 24 hours, respectively (see also Tables 20A and morphine and high-dose (0.1 mg) NTX. 20B) in the five study groups as described in Example 2: 0041 FIG. 22 shows the summary of adverse side effects placebo; morphine; morphine and low-dose (0.01 mg) naltr (see also Tables 39A and 39B) of nausea, vomiting, dizziness, exone (NTX); morphine and mid-dose (0.1 mg) NTX; and headache, Somnolence (sedation) or pruritus for Subjects in morphine and high-dose (1.0 mg) NTX, for women and men, the six study groups as described in Example 3: placebo. respectively. morphine (60 mg); naltrexone (0.01 mg); morphine and low 0032 FIGS. 13A for women, and 13B for men, show the dose (0.001 mg) naltrexone (NTX); morphine and mid-dose pain relief results (see also Tables 22A and 22B) in the five (0.01 mg) naltrexone; morphine and high-dose (0.1 mg) study groups as described in Example 2: placebo; morphine; NTX. morphine and low-dose (0.01 mg) naltrexone (NTX); mor 0042 FIGS. 23A, 23B and 23C show the summary of pain phine and mid-dose (0.1 mg) NTX; and morphine and high intensity difference (SPID) results at 4 hours (SPID-4) (see dose (1.0 mg) NTX, for women and men, respectively. also Tables 44A and 4.4B) for the total study population, 0033 FIGS. 14A for women and 14B for men show the followed by women and men, respectively, in the six study pain intensity difference (PID) results (see also Tables 23A groups as described in Example 4: placebo, morphine (60 and 23B) in the five study groups as described in Example 2: mg); naltrexone (0.01 mg); morphine and low-dose (0.001 placebo; morphine; morphine and low-dose (0.01 mg) naltr mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) exone (NTX); morphine and mid-dose (0.1 mg) NTX; and NTX; morphine and high-dose (0.1 mg) NTX. morphine and high-dose (1.0 mg) NTX, for women and men, 0043 FIGS. 24A and 24B show the time to onset of mean respectively. ingful pain relief results (see also Tables 45A and 45B) in the 0034 FIGS. 15A for women (see also Tables 26A and six study groups as described in Example 4: placebo; mor 26B) and 15B for men (see also Tables 26C and 26D) show a phine (60 mg); naltrexone (0.01 mg); morphine and low-dose Summary of adverse side effects of nausea, vomiting, dizzi (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 ness, headache, Somnolence (sedation) or pruritus in the five mg) NTX; morphine and high-dose (0.1 mg) NTX for men study groups as described in Example 2: placebo; morphine and women respectively. (60 mg); morphine and low-dose (0.01 mg) naltrexone 0044 FIGS. 25A and 26A for women, and 25B and 26B (NTX); morphine and mid-dose (0.1 mg)NTX; morphine and for men, show the time to remedication (rescue medication) high-dose (1.0 mg) NTX. up to 8 and 24 hours, respectively (see also Tables 46A and US 2009/0203722 A1 Aug. 13, 2009

46B) in the six study groups as described in Example 4: 0054 FIG. 36 shows the pain intensity differences (PID) placebo; morphine; naltrexone (0.01 mg); morphine and low results (see also Table 62) for subjects in the six study groups dose (0.001 mg) naltrexone (NTX); morphine and mid-dose as described in Example 5: placebo (A); HC/APAP (B): (0.01 mg) NTX; and morphine and high-dose (0.1 mg) NTX, HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and for women and men, respectively. 0.1 mg NTX (D); HC/APAP and 0.01 mg NTX (E): 004.5 FIGS. 27A for women, and 27B for men, show the HC/APAP and 0.001 mg NTX (F). pain relief results (see also Tables 48A and 48B) in the six 0055 FIG. 37 shows the summary of adverse side effects study groups as described in Example 4: placebo; morphine; (see also Table 65) of nausea, vomiting, dizziness, headache, maltrexone (0.01 mg); morphine and low-dose (0.001 mg) Somnolence (sedation) or pruritus for Subjects in the six study maltrexone (NTX); morphine and mid-dose (0.01 mg) NTX; groups as described in Example 5: placebo: HC/APAP: and morphine and high-dose (0.1 mg) NTX, for women and HC/APAP and 1.0 mg naltrexone (NTX); HC/APAP and 0.1 men, respectively. mg NTX: HC/APAP and 0.01 mg NTX: HC/APAP and 0.001 0046 FIGS. 28A for women and 28B for men show the mg NTX. pain intensity difference (PID) results (see also Tables 49A 0056 FIGS. 38B and 38C show the summary of pain and 49B) in the six study groups as described in Example 4: intensity difference (SPID) results at 4 hours (SPID-4) (see placebo; morphine (60 mg); naltrexone (0.01 mg); morphine also Tables 69A and 69B) for women and men, respectively, and low-dose (0.001 mg) naltrexone (NTX); morphine and in the six study groups as described in Example 6: placebo. mid-dose (0.01 mg) NTX; and morphine and high-dose (0.1 HC (5 mg)/APAP (500 mg); HC/APAP and 0.001 mg naltr mg) NTX, for women and men, respectively. exone (NTX); HC/APAP and 0.01 mg NTX; HC/APAP and 0047 FIGS. 29A for women (see also Tables 52A and 0.1 mg NTX: HC/APAP and 1.0 mg NTX. 52B) and 29B for men (see also Tables 52C and 52D) show a 0057 FIGS. 39A and 39B show the time to remedication Summary of adverse side effects of nausea, vomiting, dizzi (rescue medication) up to 8 hours, for women and men, ness, headache, Somnolence (sedation) or pruritus in the six respectively (see also Tables 72A and 72B) in the six study study groups described in Example 4: placebo, morphine (60 groups as described in Example 6: placebo (A); HC/APAP mg); naltrexone (0.01 mg); morphine and low-dose (0.001 (B): HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) and 0.1 mg NTX (D): HC/APAP and 0.01 mg NTX (E): NTX; morphine and high-dose (0.1 mg) NTX. HC/APAP and 0.001 mg NTX (F) 0048 FIG. 30 shows the total pain relief (TOTPAR) 0058 FIGS. 40A for women and 40B for men show a results (see also Table 56) for subjects in the six study groups summary of adverse side effects (see also Tables 77A and as described in Example 5: placebo (A); HC/APAP (B): 77B) of nausea, vomiting, dizziness, headache, Somnolence HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and (sedation) or pruritus in the six study groups described in 0.1 mg NTX (D): HC/APAP and 0.01 mg NTX (E): Example 6: placebo: HC (5 mg)/APAP (500 mg); HC/APAP HC/APAP and 0.001 mg NTX (F). and 0.001 mg naltrexone (NTX); HC/APAP and 0.01 mg 0049 FIG.31 shows the summary of pain intensity differ NTX; HC/APAP and 0.1 mg NTX; HC/APAP and 1.0 mg ence (SPID) results at 4 hours (SPID-4), at 6 hours (SPID-6), NTX. and at 8 hours (SPID-8) (see also Table 57) for subjects in the 0059 FIG. 41 shows the total pain relief (TOTPAR) six study groups as described in Example 5: placebo (A): results (see also Table 81) for subjects in the seven study HC/APAP (B): HC/APAP and 1.0 mg naltrexone (NTX) (C); groups as described in Example 7: placebo; morphine (30 HC/APAP and 0.1 mg NTX (D): HC/APAP and 0.01 mg NTX mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 (E); HC/APAP and 0.001 mg NTX (F). mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 0050 FIG. 32 shows the time to onset of meaningful pain mg); morphine (90 mg) and NTX (0.1 mg). relief results (see also Table 58A) for subjects in the six study 0060 FIG. 42 shows the summary of pain intensity differ groups as described in Example 5: placebo (A); HC/APAP ence (SPID) results at 4 hours (SPID-4) (see also Table 82) for (B): HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP Subjects in the seven study groups as described in Example 7: and 0.1 mg NTX (D): HC/APAP and 0.01 mg NTX (E): placebo; morphine (30 mg); morphine (30 mg) and NTX (0.1 HC/APAP and 0.001 mg NTX (F). mg); morphine (60 mg); morphine (60 mg) and NTX (0.1 0051 FIG.33 shows the time to onset to analgesia results mg); morphine (90 mg); morphine (90 mg) and NTX (0.1 (see also Table 58B) for subjects in the six study groups as mg). described in Example 5: placebo (A); HC/APAP (B): 0061 FIG. 43 shows the probability to onset of analgesia HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and (see also Table 43) for Subjects in the seven study groups as 0.1 mg NTX (D): HC/APAP and 0.01 mg NTX (E): described in Example 7: placebo: morphine (30 mg); mor HC/APAP and 0.001 mg NTX (F). phine (30 mg) and NTX (0.1 mg); morphine (60 mg); mor 0052 FIG. 34 shows the time to remedication (rescue phine (60 mg) and NTX (0.1 mg); morphine (90 mg); mor medication) up to 8 hours (see also Table 59) for subjects in phine (90 mg) and NTX (0.1 mg). the six study groups as described in Example 5: placebo (A): 0062 FIG. 44 shows the probability to remedication (res HC/APAP (B): HC/APAP and 1.0 mg naltrexone (NTX) (C); cue medication) over time up to 24 hours (see also Table 84) HC/APAP and 0.1 mg NTX (D): HC/APAP and 0.01 mg NTX for Subjects in the seven study groups as described in (E); HC/APAP and 0.001 mg NTX (F). Example 7: placebo; morphine (30 mg); morphine (30 mg) 0053 FIG. 35 shows the pain relief (PR) results (see also and NTX (0.1 mg); morphine (60 mg); morphine (60 mg) and Table 61) for subjects in the six study groups as described in NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and Example 5: placebo (A); HC/APAP (B): HC/APAP and 1.0 NTX (0.1 mg). mg naltrexone (NTX) (C); HC/APAP and 0.1 mg NTX (D): 0063 FIG. 45 shows the pain relief (PR) results (see also HC/APAP and 0.01 mg NTX (E); HC/APAP and 0.001 mg Table 86) for subjects in the seven study groups as described NTX (F). in Example 7: placebo; morphine (30 mg); morphine (30 mg) US 2009/0203722 A1 Aug. 13, 2009 and NTX (0.1 mg); morphine (60 mg); morphine (60 mg) and potency) of the opioid agonists while attenuating (e.g., reduc NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and ing, blocking, inhibiting or preventing) the adverse side NTX (0.1 mg). effects in humans associated with that dose of agonist. For 0064 FIG. 46 shows the pain intensity differences (PD) compositions and methods of the invention that enhance anal results (see also Table 87) for subjects in the seven study gesic potency of the opioid agonist, it is advantageous that groups as described in Example 7: placebo; morphine (30 adverse side effects are maintained or not increased with that mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 enhanced (e.g., increased) potency. For compositions and mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 methods of the invention that attenuate (e.g., reduce, block or mg); morphine (90 mg) and NTX (0.1 mg). prevent) the adverse side effects of the opioid agonist, it is 0065 FIG. 47 shows the global evaluations of pain relief advantageous that the analgesic potency is maintained with (see also Table 89) for subjects in the seven study groups as out increasing or decreasing the cumulative daily dose of described in Example 7: placebo: morphine (30 mg); mor agonist. phine (30 mg) and NTX (0.1 mg); morphine (60 mg); mor 0073. The present invention is also directed to novel com phine (60 mg) and NTX (0.1 mg); morphine (90 mg); mor positions of and methods using non-kappa opioid receptor phine (90 mg) and NTX (0.1 mg). agonists, preferably mu opioid receptor agonists, and opioid 0066 FIG. 48 shows the summary of adverse side effects antagonists for gender-based dosing of the agonist and/or the (see also Table 90) of nausea, vomiting, dizziness, headache, antagonist in men and women. Such novel combinations of Sommolence (sedation) or pruritus for Subjects in the seven Such agonists and antagonists are unexpectedly efficacious in study groups as described in Example 7: placebo; morphine enhancing (e.g., increasing) the analgesic potency of the ago (30 mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 nists without enhancing the side effects of the agonists in mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 men, and in maintaining the analgesic potency of the agonist mg); morphine (90 mg) and NTX (0.1 mg). while attenuating (e.g., reducing, blocking, inhibiting or pre 0067 FIG. 49 shows the day-one mean pain intensity dif venting) the adverse side effects of the agonist in women. ference (PD) results (see also Table 91) for the three intrath 0074 The present invention is based on several surprising ecal morphine study groups as described in Example 8: pla results from human clinical trials, including that (i) the anal cebo, NTX (0.001 mg), and NTX (0.01 mg). gesic potency and/or the adverse side effects of morphine 0068 FIG. 50 shows the mean pain intensity difference Sulfate, a non-kappa (mu) opioid receptor agonist is gender (PID) results (see also Table 92) for days two through seven specific; (ii) the effects of naltrexone, an opioid antagonist, results for the three intrathecal morphine study groups as are gender-specific, and it appears to act as a partial opioid described in Example 8: placebo, NTX (0.001 mg), and NTX agonist on opioid receptors in women and men, but its partial (0.01 mg). agonist effects are gender-specific; and (iii) interactions 0069 FIG. 51 shows the day-one pain intensity difference between such a non-kappa (mu) opioid receptor agonist and (PID) results morphine study groups as described in Example an opioid antagonist are gender-specific. Additionally Sur 8: Tables 93A and 93B for days two through eight results for prising from these clinical trials is that the analgesic activity, the three intrathecal placebo, NTX (0.001 mg), and NTX including analgesic potency, of Such non-kappa (mu) opioid (0.01 mg). receptoragonists can be dissociated from their adverse effects 0070 FIGS. 52A and 52B show the mean hourly pain in humans based upon gender. Thus, for the first time, the intensity difference (PID) results for women and men, respec present invention provides compositions and methods for the tively, in the five study groups as described in Example 9: differential dosing of non-kappa opioid receptor agonists, placebo (A); tramadol and placebo (B); tramadol and 1.0 mg preferably mu opioid receptoragonists, and/or opioidantago maltrexone (NTX) (C); tramadol and 0.1 mg NTX (D); tra nists in men and women. Compositions and methods accord madol and 0.01 mg NTX (E). ing to the invention include those that yield, for example, either (1) analgesia in men using a hypo-analgesic dose (in DETAILED DESCRIPTION cluding a non-analgesic or anti-analgesic dose) of a non 0071. The present invention is directed to novel composi kappa opioid receptoragonist, preferably a mu opioid recep tions and methods with opioid agonists and opioid antago tor agonist, and a dose of opioid receptor antagonist that in nists. Novel combinations of Such agonists and antagonists combination provides or enhances analgesia, thus converting were unexpectedly efficacious in enhancing the analgesic non-responder human Subjects (e.g. men) into responder, or potency of the agonist without attenuating (e.g., reducing, (2) analgesia in women using an analgesic dose of a non blocking, inhibiting or preventing) the side effects of the kappa opioid receptoragonist, preferably a mu opioid recep agonist in humans, or maintaining the analgesic potency of tor agonist, and a dose of opioid receptor antagonist that in the agonist while attenuating (e.g., reducing, blocking, inhib combination maintains the analgesia comparable to that of iting or preventing) side effects of the agonist in humans. the against alone, but with attenuation (e.g., in number and/or 0072 The present invention is based on surprising results severity) of one or more of the adverse side effects associated from clinical trials that the analgesic potency effects of opioid with Such an agonist. agonists can be dissociated from their adverse effects in 0075 For compositions and methods of the invention that humans. Thus, for the first time, the present invention pro provide or enhance (e.g., increase) pain relief or attenuate vides compositions and methods to differentially dose or treat (e.g., decrease) pain intensity with a non-kappa opioid recep humans with opioid agonists and opioid antagonists to spe tor agonist, preferably a mu opioid receptor agonist, for cifically either (1) enhance (e.g., increase) analgesic potency example, in men, it is advantageous that the adverse side of the opioid agonists without Substantially reducing or effects associated with the agonist are not enhanced with the increasing (e.g., maintain) the adverse side effects in humans provided or enhanced pain relief or attenuated pain intensity. associated with that dose of agonist; or (2) maintain the anal For compositions and methods of the invention that enhance gesic potency (e.g., neither substantially increase or decrease pain relief or attenuate pain intensity of a non-kappa opioid US 2009/0203722 A1 Aug. 13, 2009 receptoragonist, preferably a mu opioid receptoragonist, for cine, phenadoxone, phenomorphan, phenazocine, phenope example, in women, it is advantageous that the adverse side ridine, pholcodine, piminodine, piritramide, propheptazine, effects are attenuated. For compositions and methods of the promedol, profadol, properidine, propiram, propoxyphene, invention that attenuate the adverse side effects (e.g., in num remifentanil, Sufentanil, tramadol, tilidine, salts thereof, mix ber and/or severity) of Such agonists, it is advantageous that tures of any of the foregoing, mixed mu-agonists/antagonists, the analgesic potency be maintained while decreasing the mu-antagonist combinations, or the like. Preferred opioid cumulative 24 hour dose of Such agonists, thus maintaining agonists for human use are morphine, hydrocodone, oxyc responder human Subjects (e.g., women) as responders but odone, codeine, fentanyl (and its relatives), hydromorphone, with attenuation of one or more adverse side effects. meperidine, methadone, oxymorphone, propoxyphene ortra 0076 Compositions and methods according to the inven madol, or mixtures thereof. Particularly preferred opioidago tion include those with a non-kappa opioid receptor agonist, nists include morphine, hydrocodone, oxycodone or trama preferably a mu opioid receptor agonist, and opioid antago dol. Opioid agonists include exogenous or endogenous nistinamounts that are useful for men only, useful for women opioids. only, or useful for both men and women, taking into account 0080 “Bimodally-acting opioid agonists’ are opioid ago the gender-based differences described and claimed herein. nists that bind to and activate both inhibitory and excitatory Such compositions and methods are useful to provide or opioid receptors on nociceptive neurons which mediate pain. enhance pain relief, attenuate pain intensity, or attenuate one Activation of inhibitory receptors by said agonists causes or more of the adverse side effects of the agonist. analgesia. Activation of excitatory receptors by said agonists 0077. It will be appreciated that compositions and meth results in anti-analgesia, hyperexcitability, hyperalgesia, as ods of the invention useful for human Subjects (e.g., patients) well as development of physical dependence, tolerance and will be primarily of use in the alleviation or attenuation of other undesirable side effects. Bimodally-acting opioid ago established symptoms but prophylaxis is not excluded. nists may be identified by measuring the opioid's effect on the 0078. The term “opioid refers to compounds or compo action potential duration (APD) of dorsal root ganglion sitions including metabolites of Such compounds or compo (DRG) neurons in tissue cultures. In this regard, bimodally sitions which bind to specific opioid receptors and have ago acting opioid agonists are compounds which elicit prolonga nist (activation) or antagonist (inactivation) effects at these tion of the APD of DRG neurons at pM-nM concentrations receptors, such as opioid alkaloids, including the agonist (i.e., excitatory effects), and shortening of the APD of DRG morphine and its metabolite morphine-6-glucuronide and the neurons at LM concentrations (i.e., inhibitory effects). antagonist naltrexone and its metabolite and opioid peptides, I0081. A “non-kappa opioid receptor agonist” or “mor including enkephalins, dynorphins and endorphins. The phine-like opioid receptor agonist’ is an opioid agonist that opioid can be present as a member selected from an opioid primarily binds to and/or interacts with opioid receptors that base and an opioid pharmaceutically acceptable salt. The are not kappa receptors and does not produce its therapeutic pharmaceutically acceptable salt embraces an inorganic oran effects primarily via kappa opioid receptors. Such agonists organic salt. Representative salts include hydrobromide, include mu, delta and sigma opioid receptor agonists and hydrochloride, mucate. Succinate, n-oxide, Sulfate, malonate, specifically exclude kappa opioid receptor agonists. Such acetate, phosphate dibasic, phosphate monobasic, acetate tri agonists exclude, for example, agonists that primarily bind to hydrate, bicheplafluorobutyrate), maleate, biomethylcarbam and interact with kappa opioid receptors, and from Such inter ate), bipentafluoropropionate), mesylate, bipyridine-3-car actions produce their therapeutic effects (e.g., analgesic boxylate), bictrifluoroacetate), bitartrate, chlorhydrate, activity). Such as pentazocine, nalbuphine and butorphanol. fumarate and sulfate pentahydrate. The term “opiate' refers Such agonists include, for example, morphine, hydrocodone, to drugs derived from opium or related analogs. oxycodone, codeine, hydromorphone, levorphanol, meperi 0079 An “opioid receptor agonist' or “opioid agonist' is dine, fentanyl, (and its relatives), oxymorphone, pro an opioid compound or composition including any active poxyphene, methadone or tramadol. A preferred non-kappa metabolite of Such compound or composition that binds to opioid agonist is a mu opioid receptor agonist. According to and activates opioid receptors, for example, on nociceptive the invention, Such agonists include an agonist that exhibits neurons which mediate pain. Such agonists have analgesic non-kappa gender-based effects in men and women as activity (with measurable onset, peak, duration and/or total described and claimed herein. effect) and can produce analgesia. Opioid agonists include: I0082 A“mu opioid receptoragonist' is an opioid agonist alfentanil, allylprodine, alphaprodine, anilleridine, apomor that primarily binds to and/or interacts with mu opioid recep phine, apocodeine, benzylmorphine, bezitramide, buprenor tors and from Such interactions produces its therapeutic phine, butorphanol, clonitaZene, codeine, cyclazocine, cyclo effects (e.g., analgesic activity). Such as morphine, hydroc rphen, cyprenorphine, desomorphine, dextromoramide, odone, and oxycodone, but excluding agonists that primarily dezocine, diampromide, dihydrocodeine, dihydromorphine, bind to and interact with kappa opioid receptors, and from dimenoxadol, dimepheptanol, dimethylthiambutene, Such interactions produce their therapeutic effects (e.g. anal dioxyaphetyl butyrate, dipipanone, eptazocine, ethohep gesic activity). Such as pentazocine, nalbuphine and butor tazine, ethylmethylthiambutene, ethylmorphine, etonitaZene, phanol. fentanyl, heroin, hydrocodone, hydroxymethylmorphinan, I0083. A “delta opioid receptor agonist' is an opioid ago hydromorphone, hydroxypethidine, isomethadone, ketobe nist that primarily binds to and/or interacts with delta opioid midone, levallorphan, levorphanol, levophenacylmorphan, receptors and from Such interactions produces its therapeutic lofentanil, meperidine, meptazinol, metazocine, methadone, effects (e.g., analgesic activity), but excluding agonists that methylmorphine, metopon, morphine, myrophine, nalbu primarily bind to and interact with kappa opioid receptors, phine, narceline, nicomorphine, norlevorphanol, normetha and from such interactions produce their therapeutic effects done, nalorphine, normorphine, norpipanone, ohmefentanyl. (e.g., analgesic activity). Such as pentazocine, nalbuphine and opium, oxycodone, oxymorphone, papaveretum, pentaZo butorphanol. Selective delta opioid receptor agonists include US 2009/0203722 A1 Aug. 13, 2009

those described by U.S. Pat. Nos. 5,389,645 and 5,985,880 opioid antagonist having the same pentacyclic nucleus as hereby incorporated by reference in its entirety e.g., a cyclic nalmefene, naltrexone, nalorphine, nalbuphine, thebaine, enkephalin analog (D-Pen, D-Pen-(enkephalin) and, hep levallorphan, oxymorphone, butorphanol, buprenorphine, tapeptides of frog skin origin deltorphin I and III (see also levorphanol, meptazinol, pentazocine, dezocine, or their U.S. Pat. No. 4,518,711 hereby incorporated by reference in pharmacologically effective esters or salts. An opioidantago its entirety). nist with partial agonist activity is cholera toxin B. Preferred 0084. A "mu-delta opioid receptor agonist' is an opioid opioid antagonists include naltrexone, nalmefene, naloxone, agonist that primarily binds to and/or interacts with mu and or mixtures thereof. Particularly preferred antagonists delta opioid receptors and from Such interactions produces its include naltrexone and nalmefene. Naltrexone as a most pre therapeutic effects (e.g., analgesic activity), but excluding ferred opioid antagonist. agonists that primarily bind to and interact with kappa opioid I0088. “Excitatory opioid receptor antagonists' are opioids receptors, and from Such interactions produce their therapeu which bind to and act as antagonists to excitatory but not tic effects (e.g., analgesic activity). Such as pentazocine, nal inhibitory opioid receptors on nociceptive neurons which buphine and butorphenal. Selective mu-delta opioid receptor mediate pain. That is, excitatory opioid receptor antagonists agonists include those described by U.S. Pat. No. 5,389,645 are compounds which bind to excitatory opioid receptors and hereby incorporated by reference in its entirety e.g., tyrosyl selectively block excitatory opioid receptor functions of noci diamine amide opioid agonists such as U.S. Pat. No. 6,054, ceptive types of DRG neurons at 1,000 to 10,000-fold lower 557 hereby incorporated by reference in its entirety; U.S. Pat. concentrations than are required to block inhibitory opioid No. 5,872,097 hereby incorporated by reference in its receptor functions in these neurons. Excitatory opioid recep entirety; U.S. Pat. Nos. 6,568,908, 5,681,830, 5,658,908 and tor antagonists may also be identified by measuring their 5,854.249, each and all incorporated by reference in their effect on the action potential duration (APD) of dorsal root entirety e.g., diarylmethylpiperazines and piperidines Such ganglion (DRG) neurons in tissue cultures. In this regard, as 3-((CR)-O-((2S.5R)-4-allyl-2.5.-dimethyl-1-piperazinyl)- excitatory opioid receptor antagonists are compounds which 3-hydroxybenzyl)-N,N-diethylbenzamine; and the synthetic selectively block prolongation of the APD of DRG neurons pentapeptide known as DADLE (see, e.g., U.S. Pat. No. (i.e., excitatory effects) but not the shortening of the APD of 5.985,600 hereby incorporated by reference in its entirety). DRG neurons (i.e., inhibitory effects) elicited by a bimodally 0085 A“kappa opioid receptor agonist' is an opioid ago acting opioid receptor agonist. Preferred excitatory opioid nist that primarily binds to and/or interacts with kappa opioid receptor antagonists arenaltrexone and nalmefene because of receptors and from such interactions produces its therapeutic their longer duration of action as compared to naloxone and effects (e.g., analgesic activity), including, for example, pen their greater bioavailability after oral administration. tazocine, nalbuphine and butorphenol. Selective kappa opioid I0089. Other compounds and compositions of opioid ago agonists include those described by: U.S. Pat. No. 4,923,863 nists, including non-kappa opioid receptor agonists, prefer hereby incorporated by reference in its entirety e.g., morpho ably mu opioid receptor agonists, and opioid antagonists are line derivatives: U.S. Pat. No. 6,110,947 hereby incorporated known and will be readily apparent to those skilled in the art, by reference in its entirety e.g., pyrrolidinyl hydroxamic acid once armed with the present disclosure. compounds; U.S. Pat. No. 5,965,701 hereby incorporated by 0090 The opioid agonists or opioid antagonists may be reference in its entirety e.g., kappa receptor opioid peptides provided in the form of free bases orpharmaceutically accept with affinity for the kappa opioid receptor at least 1,000 times able acid addition salts. As used herein, "pharmaceutically greater than its affinity for the mu opioid receptor. acceptable salts' refer to derivatives of the disclosed com 0.086 A "sigma opioid receptoragonist' is an opioid ago pounds wherein the therapeutic compound is modified by nist that primarily binds to and/or interacts with sigma opioid making acid or base salts thereof. The pharmaceutically receptors and from Such interactions produces its therapeutic acceptable salt embraces an inorganic or an organic salt. effects (e.g., analgesic activity), but excluding agonists that 0091 Examples of pharmaceutically acceptable salts primarily bind to and interact with kappa opioid receptors, include, but are not limited to, mineral or organic acid salts of and from such interactions produce their therapeutic effects the opioidantagonist or opioid agonist. The pharmaceutically (e.g., analgesic activity). Such as pentazocine, nalbuphine and acceptable salts include the conventional non-toxic salts butorphanol. Selective sigma opioid agonists include those made, for example, from non-toxic inorganic or organic described by: U.S. Pat. Nos. 5,656,633 and 5,556,857, both acids. For example, such conventional non-toxic salts include incorporated by reference (e.g., carboStyril derivatives). those derived from inorganic acids such as hydrochloric, 0087 An “opioid antagonist' is an opioid compound or hydrobromic, Sulfuric, Sulfonic, Sulfamic, phosphoric, nitric composition including any active metabolite of Such com and others known to those skilled in the art; and the salts pound or composition that in a Sufficient amount attenuates prepared from organic acids such as amino acids, acetic, (e.g., blocks, inhibits, or competes with) the action of an propionic, succinic, glycolic, Stearic, lactic, malic, malonic, opioid agonist. An "effective antagonistic' amount is one tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phe which effectively attenuates the analgesic activity of an nylacetic, glutamic, benzoic, Salicylic, Sulfanilic, 2-acetoxy opioidagonist. An opioidantagonist binds to and blocks (e.g., benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane inhibits) opioid receptors, for example, on nociceptive neu disulfonic, oxalic, isethionic, glucoronic, and other acids. rons which mediate pain. Opioid antagonists according to the Other pharmaceutically acceptable salts and variants include present invention include: maltrexone, naloxone nalmefene, mucates, phosphate (dibasic), phosphate (monobasic), naloxone methiodide, nalorphine, naloxonazine, nalide, acetate trihydrate, bicheptafluorobutyrate), biomethylcar nalmexone, nalbuphine, nalorphine dinicotinate, naltrindole bamate), bi?pentafluoropropionate), meSylate, bipyridine-3- (NTI), naltrindole isothiocyanate, (NTII), naltriben (NTB), carboxylate), bictrifluoroacetate), bitartrate, chlorhydrate, nor-binal torphimine (nor-BNI), b-funaltrexamine (b-FNA), and Sulfate pentahydrate. An oxide, though not usually BNTX., cyprodime, ICI-174,864, LY117413, MR2266, or an referred to by chemists as a salt, is also a “pharmaceutically US 2009/0203722 A1 Aug. 13, 2009 acceptable salt for the present purpose. For acidic com lence, hypertonia, rash, visual disturbance, menopausal pounds, the salt may include an amine-based (primary, sec symptoms, urinary frequency, urinary retention. ondary, tertiary or quaternary amine) counter ion, an alkali 0.095 “Co-administer,” “co-administration.” “concurrent metal cation, or a metal cation. Lists of suitable salts are found administration' or "co-treatment” refers to administration of in texts such as Remington's Pharmaceutical Sciences, 18" an opioid agonist and an opioid antagonist, in conjunction or Ed. (Alfonso R. Gennaro, ed.: Mack Publishing Company, combination, together, or before or after each other. The Easton, Pa., 1990); Remington: the Science and Practice of opioidagonist and the opioidantagonist may be administered Pharmacy 19" Ed. (Lippincott, Williams & Wilkins, 1995); by different routes. For example, the agonist may be admin Handbook of Pharmaceutical Excipients, 3" Ed. (Arthur H. istered orally and the antagonist intravenously, or vice versa. Kibbe, ed.: Amer. Pharmaceutical Assoc., 1999); the Phar The opioid agonist and opioid antagonist are preferably both maceutical Codex Principles and Practice of Pharmaceutics administered orally, as immediate or Sustained release formu 12" Ed. (Walter Lund ed.: Pharmaceutical Press, London, lations. The opioid agonist and opioid antagonist may be 1994); The United States Pharmacopeia: The National For administered simultaneously or sequentially, as long as they mulary (United States Pharmacopeial Convention); and are given in a manner to allow both agents to achieve effective Goodman and Gilman's the Pharmacological Basis of concentrations to yield their desirable therapeutic effects Therapeutics (Louis S. Goodman and Lee E. Limbird, eds.; (e.g., analgesia). Optionally, an additional active pharmaceu McGraw Hill, 1992), the disclosures of which are hereby tical ingredient may be co-administered with the opioid ago incorporated by reference. nistand opioidantagonist. For example, other active pharma 0092. The phrase “pharmaceutically acceptable' is ceutical ingredients include acetaminophen as shown herein, employed herein to refer to those compounds, materials, steroidal drugs or non-steroidal anti-inflammatory drugs compositions, and/or dosage forms which are, within the (NSAIDS) such as ibuprofen, COX-1 and/or COX-2 inhibi Scope of sound medical judgment, Suitable for use in contact tors such as aspirin, rofecoxib (marketed as VIOXXR), and with the tissues of human beings and animals without exces celcoxib (marketed as CELEBREXTM). sive toxicity, irritation, allergic response, or other problem or 0096 “Combination” refers to more than one active com complication, commensurate with a reasonable benefit/risk pound or active pharmaceutical ingredient (API), including ration. for example, a combination of opioid agonist and opioid 0093. An “adverse side effect of an opioid agonist is a antagonist. side effect in humans, typically associated with opioid anal (0097. “Therapeutic effect” or “therapeutically effective” gesics Such as morphine, including nausea, Vomiting, dizzi refers to an effect or effectiveness that is desirable and that is ness, somnolence/sedation, pruritus, reduced gastrointestinal an intended effect associated with the administration of an mortality including constipation, difficulty in urination, opioid agonist including the opioid agonist in combination peripheral vasodilation including leading to orthostatic with an opioid antagonist according to the invention, includ hypotension, headache, dry mouth, Sweating, asthenia, ing, for example, analgesia, pain relief, decrease in pain inten dependence, mood changes (e.g., dysphoria, euphoria), or sity, euphoria or feeling good or calming so as to reduce heart lightheadedness. An “adverse side effect” also includes a rate, blood pressure or breathing rate. serious adverse side effect Such as respiratory depression or 0098. The opioid agonists preferably and the opioid also apnea, respiratory arrest, circulatory depression, antagonists for use in the present invention may be in the form hypotension or shock. of free bases or pharmaceutically acceptable acid addition 0094. As demonstrated herein, opioid agonists may pro salts thereof. duce certain adverse side effects. Among the side effects that 0099. The opioid antagonist alone, or in combination with have been recognized for products containing morphine or the opioidagonist, may be administered to the human Subject other opioid agonists are: respiratory depression; depression by known procedures including but not limited to oral, Sub of the cough reflex, miosis; reduced gastrointestinal motility lingual, transmucosal (including buccal), intramuscular, Sub including constipation; peripheral vasodilation which may cutaneous, intravenous, intratracheal, or transdermal modes result in orthostatic hypotension; and release of histamine. of administration. When a combination of these compounds Adverse side effects that are of particular interest in human are administered, they may be administered together in the Subjects include nausea, vomiting, dizziness, headache, Som same composition, or may be administered in separate com nolence (sedation), and pruritus. Some additional adverse positions. If the opioid agonist and the opioid antagonist are side effects are listed in the Physician Desk Reference (PDR) administered in separate compositions, they may be admin for selected opioid agonists as follows: morphine: respiratory istered by similar or different modes of administration, or depression; apnea; circulatory depression; shock respiratory may be administered simultaneously with one another, or arrest, and cardiac arrest; oxycodone: light-headedness, shortly before or after the other. euphoria, dysphoria, constipation, skin rash; hydrocodone: 0100. The opioid agonists and the opioid antagonists may mental clouding, lethargy, impairment of mental and physical be formulated in compositions with a pharmaceutically performance, anxiety, fear, dysphoria, dependence, mood acceptable carrier. The carrier must be “acceptable' in the changes; constipation; ureteral spasm; spasm of vesical sense of being compatible with the other ingredients of the sphincter and urinary retention; and tramadol: seizures; ana formulation and not deleterious to the recipient thereof. phylactoid reactions (lessened resistance to toxins); asthenia; Examples of suitable pharmaceutical carriers include lactose, Sweating; dyspepsia; dry mouth; diarrhea; CNS stimulation Sucrose, starch, talc, magnesium Stearate, crystalline cellu (“CNS stimulation' is a composite that can include nervous lose, methyl cellulose, carboxymethyl cellulose, glycerin, ness, anxiety, agitation, tremor, spasticity, euphoria, emo Sodium alginate, gum arabic, powders, Saline, water, among tional liability and hallucinations); malaise; vasodilation; others. The formulations may conveniently be presented in anxiety, confusion, coordination disturbance, euphoria, ner unit dosage and may be prepared by methods well-known in Vousness, sleep disorder; abdominal pain, anorexia, flatu the pharmaceutical art, by bringing the active compound into US 2009/0203722 A1 Aug. 13, 2009

association with a carrier or diluent, as a Suspension or solu with pharmaceutically acceptable additives Such as Suspend tion, or optionally with one or more accessory ingredients, ing agents (e.g., Sorbitol syrup, methyl cellulose or hydroge e.g., buffers, flavoring agents, surface active agents, or the nated edible fats); emulsifying agents (e.g., lecithin or aca like. The choice of carrier will depend upon the route of cia); non-aqueous vehicles (e.g., methyl or propyl-p- administration. “Unit dose form” or “unit dosage form' refers hydroxybenzoates or Sorbic acid). Liquid dose forms for to physically discreet units suitable as unitary doses for human administration include: hydrocodone (e.g., HYDRO human Subjects, each unit containing a predetermined quan PHANER) from Halsey), hydromorphone (e.g., DILAU tity of active material (e.g., non-kappa opioid receptoragonist DIDR) from Knoll), meperidine (e.g., DEMEROL(R) from and/or opiold antagonist and/or other active pharmaceutical Sanofi), methadone (e.g., DOLOPHINE(R) from Roxane), ingredient) calculated to produce the desired therapeutic oxycodone (e.g., HYCOMINE(R) from Knoll; ROXILOX(R) effect (e.g. analgesia), in association with a suitable pharma from Roxane), and propoxyphene (e.g., DARVON-NR) from ceutical carrier. Thus, the active ingredients according to the Eli Lilly). invention (e.g., agonist, antagonist, or other active pharma 0103 For parenteral administration, including intrave ceutical ingredient) either each alone or in combination may nous, intramuscular, or Subcutaneous administration, the conveniently be presented to the subject for administration in compounds may be combined with a sterile aqueous solution unit dose form. which is preferably isotonic with the blood of the recipient. 0101 For oral or sublingual administration, including Such formulations may be prepared by dissolving solidactive transmucosal, the formulation may be presented as capsules, ingredient in water containing physiologically compatible tablets, caplets, pills, powders, granules or a suspension, pre Substances Such as sodium chloride, glycine, or the like, and/ pared by conventional means with pharmaceutically accept or having a buffered pH compatible with physiological con able excipients, e.g., with conventional additives or fillers ditions to produce an aqueous Solution, and/or rendering said Such as lactose, mannitol, corn starch or potato starch; with solution sterile. The formulations may be present in unit dose binders or binding agents such as crystalline cellulose, cellu forms or multi-dose forms, including in containers such as lose derivatives, acacia, corn starch (including pregelati sealed ampoules or vials. Parenteral dose forms for human nized) or gelatins; with disintegrators or disintegrants such as administration include: alfentanil (e.g., ALFENTAR) from corn starch, potato starch or Sodium carboxymethyl-cellu Akorn), buprenorphine (e.g., BUPRENEX(R) from Reckitt & lose; or with lubricants or wetting agents such as talc or Colman Pharmaceuticals), butorphanol (e.g., STADOL(R) magnesium Stearate. Tablets may be coated, including by from Apothecon), dezocine (e.g., DALGANR) from Astra methods well known in the art. The formulation may be Zeneca), fentanyl, hydromorphone (e.g., DILAUDID-HPR) presented as an immediate-release or as a slow-release, Sus from Knoll), levallorphan (e.g., LORFANR) from Roche), tained-release or controlled-release form. The formulation levorphanol (e.g., LEVO-DROMORANR)from ICN), mep may also be presented as a solid drug matrix, for example, on eridine (e.g., DEMEROL(R) from Sanofi), methadone (e.g., a handle. Oral dose forms for human administration include: DOLOPHINE(R) HCl from Roxane), morphine (e.g., codeine, dihydrocodeine (e.g., SYNALGOS-DC(R) from ASTRAMORPHOR) from AstraZeneca; DURAMORPHOR) and Wyeth-Ayerst Pharmaceuticals), fentanyl (e.g., ACTIOR) INFUMORPHR) from Elkins-Sinn), oxymorphone (e.g., from Abbott Laboratories)., hydrocodone (e.g., VICODINR) NUMORPHANR) from Endo), nalburphine (e.g., NUBAINR) and VICOPROFENR) from Knoll Laboratories: NORCOR) from Endo Pharmaceutical), and pentazocine (TALWINR) from Watson Laboratories: HYCODANR) from Endo Phar from Abbott). maceuticals: NORCETR) from Abara; ANEXSIAR), 0104 For transdermal administration, the compounds HYDROCETR), and LORCET-HDR) from Mallinckrodt: may be combined with skin penetration enhancers such as LORTAB(R) from UCB Pharma: HY-PHENR) from Ascher: propylene glycol, polyethylene glycol, isopropanol, ethanol, CO-GESIC(R) from Schwarz Pharma; ALLAYR from Zenith oleic acid, N-methylpyrrolidone, or the like, which increase Goldline), hydromorphone (e.g. DILAUDID(R) from Knoll), the permeability of the skin to the compounds, and permit the levorphanol (e.g., LEVO-DROMORANR) from ICN Phar compounds to penetrate through the skin and into the blood maceuticals), meperidine (e.g., DEMEROL(R) from Sanofi stream. The compound/enhancer compositions also may be Pharmaceuticals), methadone (e.g., METHADOSE(R) from combined additionally with a polymeric Substance Such as Mallinckrodt; and DOLOPHINE(R) HCl from Roxane Labo ethylcellulose, hydroxypropyl cellulose, ethylene/vinylac ratories), morphine (e.g., KADIANR) from Faulding Labora etate, polyvinyl pyrrolidone, or the like, to provide the com tories; MS CONTINR from Purdue Frederick; positioningel form, which can be dissolved in solvent such as ORAMORPHR SR from Roxane), oxycodone (e.g., PER methylene chloride, evaporated to the desired viscosity, and COCETR) and PERCODANR) from Endo; OXYCETR) from then applied to backing material to provide a patch. Trans Mallinckrodt, OXYCONTINR) from Purdue Frederick; dermal dose forms for human administration include fentanyl TYLOXR) from Ortho-McNeil Pharmaceutical; ROXIC (e.g., DURAGESIC(R) from Janssen). ODONER), ROXILOX(R) and ROXICETR) from Roxane), 0105. Additional dose forms available as suppositories for pentazocine (e.g., TALACENR) and TALWINR) from Sanofi human administration include oxymorphone (e.g. NUMOR Pharmaceuticals), propoxyphene (e.g., DARVOCET-NR) and PHANR) from Endo). DARVONRfrom Eli Lilly & Co.; DOLENER) from Lederle: 0106 “Analgesia' refers to the attenuation, reduction or WYGESIC(R) from Wyeth-Ayerst), and tramadol (e.g., absence of sensibility to pain, including the provision of pain ULTRAMR) from Ortho-McNeil Pharmaceutical). relief, the enhancement of pain relief, or the attenuation of 0102 Liquid preparations for oral administration may pain intensity. An “analgesic' amount refers to an amount of take the form of for example, Solutions, syrups or Suspen the opioidagonist which causes analgesia in a subject admin sions, or they may be presented as a dry product for consti istered the opioid agonist alone, and includes standard doses tution with water or other suitable vehicle before use. Such of the agonist which are typically administered to cause anal liquid preparations may be prepared by conventional means gesia (e.g., mg doses). An “analgesic' amount also refers to US 2009/0203722 A1 Aug. 13, 2009 an amount that results in analgesic efficacy, for example, as molars requiring extraction. The levels of pain experienced measured by a female or male subject with a pain relief score by the Subjects, for example, those in Examples 3-4, are not or a pain intensity difference score, at a given time point, or explicable by the known activity of naltrexone as a pure over time, or as compared to a baseline, and includes calcu antagonist of morphine on nociceptive pathways. Data pre lations based on area under the curve such as TOTPAR or sented herein relate to novel gender-based differences and the SPID from such pain relief scores or pain intensity difference data are consistent with a mechanism whereby an opioid scores. A "hypo-analgesic' amount is a less-than-analgesic antagonist Such as naltrexone can act as a partial agonist on amount, including an amount which is not analgesic or is opioid receptors that are responsive to an opioid agonist Such weakly analgesic in a subject administered the opioid agonist as morphine. alone, and further includes an “anti-analgesic' or "algesic’ 0108. The studies demonstrate a number of gender-related amount which is an amount which increases pain. For differences, first with respect to the responses of the female example, men or women in the opioid antagonist may be and male Subjects to the antagonist alone. For example, in administered in an amount effective to provide or enhance the females, naltrexone, by itself, acts as a hypo-analgesic agent analgesic potency (e.g., as measured by pain relief or pain in that it can cause increased pain in Subjects experiencing intensity difference) of the opioid agonist, without Substan pain associated with the dental extractions studied. Data from tially increasing (e.g., maintaining) the adverse side effects as a study are described in Examples 3 and 4 in which female compared to the agonist alone. For example, in women or subjects were given an oral dose of 0.01 mg naltrexone. Pain men, the opioidantagonist may be administered in an amount scores were determined as pain intensity differences (PID). A effective to maintain the analgesic potency (e.g., maintain PID score of 0 means no change in the level of pain, whereas analgesia as measured by pain relief or pain intensity differ a negative PID score means that pain increased, and a positive ences) of the opioid against, while attenuating one or more PD score indicates analgesia. Within 15 minutes, the PID adverse side effects of the agonist. The opioidantagonist may score in the female subjects decreased below 0, indicating be administered in an amount effective to produce or enhance that the Subjects experienced increased pain. The response to analgesic potency in combination with, for example, a mu maltrexone was characterized by three features. First, there opioid receptoragonist. The optimum amounts, for example, was a rapid increase in pain (anti-analgesia), with a peak in of the opioid agonist and the opioid antagonist administered, pain score of less than -0.3 observed at about 45 minutes after will of course depend upon the particular agonistandantago administration of the naloxone. Thereafter, there was a slight nist used, the carrier chosen, the route of administration, attenuation of the pain score (rebound), which lasted about 2 and/or the pharmacokinetic properties of the subject being hours, and thereafter, the pain score increased (late phase treated, as well as the desired gender-related effects accord anti-analgesia) and remained approximately steady (PID ing to the teachings of the present invention. When the opioid score of about -0.3) for the duration of the study (3 hours). In antagonist is administered alone, the amount of the opioid contrast to the results observed for females, naltrexone given antagonist administered is an amount effective to enhance or to males in the same study had no anti-analgesic or analgesic maintain the analgesic potency of the opioid agonist and/or effects. Data from this study are also shown in Examples 3 attenuate or maintain the adverse side effects of the opioid and 4 in which males undergoing dental extractions were agonist, according to the teachings of the present invention. given an oral dose of 0.01 mg naltrexone. Naltrexone did not 0107 Examples 1-9 that follow, describe in detail, results change the PID score, which remained at about 0 for the from human clinical trials, including those with a retrospec duration of the 8 hours of the study. Thus, there was no rapid tive or prospective gender analysis, that unexpectedly dem anti-analgesia, rebound, or late phase anti-analgesia as onstrate that the responses to opioid agonists such as mor observed for the female patients. phine, hydrocodone, or tramadol and the responses to 0.109 Gender-related differences were also observed in maltrexone, an opioid antagonist, as well as the responses to the female and male Subjects with respect to the agonist alone. the interactions between such an agonistandantagonist, show As with the responses to the opioid antagonist naltrexone, the Surprising effects in humans, including Surprising clinical responses to the opioid agonist morphine differed unexpect benefits from the combination of Such agonists and antago edly between female and male patients. For example, the nists. Such clinical benefits include enhancing the potency results from this study as described in Examples 3 and 4 of the (e.g., increasing pain relief or decreasing pain intensity in responses of females given an oral dose of 60 mg morphine, humans) of a dose of the opioid agonist, while maintaining show that the time course of the response to morphine was the adverse side effects of the agonist at that dose or main slower than the time course of the response to naltrexone, taining the potency of a dose of the opioid agonist while with little or no effect observed at 30 minutes after adminis attenuating (e.g., reducing, blocking, inhibiting or prevent tration. However, by 60 minutes, Substantial analgesia was ing) one or more adverse side effects in humans associated observed, as indicated by a PD score of greater than about 0.4. with that dose of agonist. The responses to non-kappa opioid A broad peak in analgesia was observed between about 1.5 receptor agonists, such as morphine, hydrocodone or trama and about 5 hours, with the PID score remaining at or above dol are strikingly different in women and men. By way of about 0.6 for this time period. Thereafter, the PD score slowly example, Examples 1-4 and 7 describe data that have been fell, and by about 6 hours, the PID score was at about 0.5. The collected from observations in populations of human patients, PD remained at about 0.5 for the duration of the study. In wherein males and/or females were subjected to painful another study of female patients as described in Examples 1 stimulation during the course of dental extractions and then and 2, a 60 mg oral dose of morphine was associated with treated with naltrexone and/or morphine. In Examples 1 and progressive analgesia. In Striking contrast to the results 2, Subjects had two or more impacted third molars requiring observed for females, in the males the same dose of morphine extraction, wherein at least one extracted tooth was a partial did not cause any analgesia. In fact, quite unexpectedly, mor or full bony mandibular impaction. In Examples 3-4 and 7. phine increased the pain that the men experienced (anti-an subjects had three or four full or partial bony impacted third algesia). Within the first 15 minutes, the PID score began to US 2009/0203722 A1 Aug. 13, 2009

fall below 0, indicating that pain was increased compared to trointestinal symptoms, and other serious side effects such as the baseline. PID decreased to a minimum at about 45 min respiratory depression. Additionally, an opioid antagonist utes, with the PID score being about -0.2. Thereafter, the PID Such as naltrexone by itself may increase pain in females score slowly rose, so that by about 4 hours, the PID score had experiencing pain. returned to about 0, where it remained for the duration of the 0113. In certain embodiments of the invention, composi study. In this study of male patients as described in Examples tions are provided for use in females comprising low concen 1 and 2, morphine did cause some analgesia, but the analgesia trations of opioid agonists including, by way of example only, observed was preceded by a period of anti-analgesia. morphine or oxycodone, that by themselves may not produce 0110 Gender-related differences were observed in the a desired degree of analgesia, along with doses of naltrexone female and male Subjects with respect to combinations of that are sufficiently low to avoid producing undesirable agonist and antagonist, in addition to the differences adverse side effects themselves. By selecting doses of opioid described above between males and females in the response agonistandantagonist, it is now possible to maintain a desir to naltrexone and morphine individually. For example, in able therapeutic effect such as pain relief, while attenuating female patients (Examples 3 and 4), the combination of nal undesirable adverse side effects, for example, in females and/ trexone and morphine at certain times and at certain concen or males. trations caused a decrease in analgesia as compared with 0114. In certain other embodiments of this invention, morphine alone. At two hours, the lowest dose of naltrexone compositions are provided for use in males comprising con (0.001 mg) administered in combination with morphine centrations of morphine or other opioid agonists that alone decreased the PID score produced in the presence of mor are ineffective, along with naltrexone or other opioid antago phine from a peak of about 0.7, to about 0.4. However, by 5 nists in doses sufficient to potentiate or enhance the analgesic hours and thereafter, naltrexone did not decrease the PD score effects of the opioid agonist Such as morphine. Additionally, compared to those for morphine over the same time period. because an opioid antagonist Such as naltrexone can Substan Increasing the dose of naltrexone to 0.01 mg with the mor tially potentiate or enhance the effects of an opioid agonist phine produced somewhat more reduction in PID than did the Such as morphine, it is now possible to reduce the dose of an lowest combination dose (0.001 mg). However, further opioid agonist Such as morphine to well below those doses increasing the dose of naltrexone to 0.1 mg produced no that cause undesirable side effects, while at the same time, further decrease in PD score. Thus, the dose of naltrexone providing Substantial pain relief, for example, in females having maximal effect in females when administered with 60 and/or males. mg morphine is about 0.01 mg. In another study in female 0115 Novel pharmaceutical compositions and dosage patients (Examples 1 and 2), naltrexone at doses of 0.01 mg forms of opioid antagonists are described in U.S. Provisional and 0.1 mg each potentiated the analgesia associated with Application No. 60/202,227, incorporated by reference morphine (60 mg). Further increasing the dose of naltrexone herein. Novel compositions and gender-based methods for to 1.0 mg however, decreased the analgesia associated with enhancing potency or reducing adverse side effects of opioid morphine. In male patients, in the study as described in agonists are described in U.S. Provisional Application Nos. Examples 3 and 4, the lowest dose of naltrexone (0.001 mg) 60/244,482, 60/245,110, and 60/246,235, incorporated by increased analgesia in the presence of 60 mg morphine. The reference herein. Additional human clinical study results with increase in analgesia was moderate, with an initial analgesic tramadol are described in U.S. application Ser. Nos. 09/566, effect observed by about 2 hours after administration. 071 and 09/756,331 as well as PCT/US00/12493 WO00/ Increasing the dose of naltrexone to 0.01 mg increased the 67739, that are all incorporated by reference herein. analgesic effect compared to the lowest dose, and further 0116. The present invention is described in the following increasing the dose of naltrexone (0.1 mg) increased the anal examples which are set forth to aid in the understanding of the gesia further, with a Substantial effect occurring at about 1 invention, and should not be construed to limit in any way the hour, and reaching a broad plateau at about 2 hours, and invention as defined in the claims which follow thereafter. lasting for the duration of the study. The PID score during this Pharmaceutical active and inactive ingredients used in the time was greater than about 0.8, with several points above preparation of the example formulations were compendial in about 0.9. In another study in male patients as described in the USP/NF, when there was an existing monograph. Examples 1 and 2, naltrexone in combination with morphine 0117. In the following examples, encapsulated dose forms produced more analgesia than did morphine alone. The effect of naltrexone HCl (NTX) and various opioid agonists were of naltrexone was dose-dependent with the highest doses (1.0 prepared for clinical studies as follows. Encapsulated dose mg) having the greatest effect. forms of naltrexone HCl were produced in the following 0111. As shown herein, gender-related differences were doses and weight concentrations. observed in the female and male subjects with respect to combinations of agonist and antagonist, for example, as shown by pain relief (PR) scores, pain intensity difference scores, or adverse side effects for female and male patients, Naltrexone HCI Naltrexone HCl Active Capsule respectively, as described herein in Examples. Capsule Dose Blend Concentration (% w/w) 0112 Gender-based opioid compositions according to the 1.0 mg O.3% invention may have therapeutic advantages. For example, 0.1 mg O.03% females can exhibit significant analgesic responses to an 0.01 mg O.OO3% opioid agonist Such as morphine, and at certain doses, an 0.001 mg O.OOO3% opioid antagonist Such as naltrexone can potentiate the anal gesia induced by morphine. However, effective doses of an 0118 Abatch of NTX, 0.3% w/w blend was made by first opioid agonist Such as morphine may have undesirable adding naltrexone HCl and other inactive components (e.g., adverse side effects, including nausea, vomiting, other gas magnesium Stearate and microcrystalline cellulose) into a US 2009/0203722 A1 Aug. 13, 2009

planetary mixer. The inactive components were added in por with MS 60 mg versus MS 60 mg alone in subjects with tion-wise steps with mixing between each addition to achieve moderate to severe pain in a postSurgical dental pain model to uniformity of the NTX. The intermediate active blend was determine whether NTX enhances the analgesic effect of MS transferred from the planetary mixer to a double-cone 60 mg; and (2) to evaluate the safety of three different doses blender. of NTX in combination with MS 60 mg versus MS 60 mg 0119) An amount of preblended inactive components was alone in Subjects with moderate to severe pain in a postSur used to rinse the planetary mixer. The rinsings were added to gical dental pain model to determine whether the addition of the double-cone blender to achieve quantitative recovery of NTX reduces the frequency or severity of morphine-related maltrexone HC1. The remaining balance of preblended inac tive components were added in portion-wise steps to the side effects. double cone blender containing the in-process material. The I0123. Additional objectives of the study included: (1) to resulting intermediate and final mixtures were blended for an compare the analgesic efficacy of MS 60 mg to placebo to appropriate time to achieve uniformity. establish the assay sensitivity of the study; (2) to compare the 0120 Less potent formulated blends of naltrexone HCl analgesic activity (onset, peak, duration, and total effect) of (e.g., 0.03% w/w/, 0.003% w/w, and 0.0003% w/w) were three different doses of NTX in combination with MS 60 mg prepared from the 0.3% w/w blend by serial dilution with the Versus placebo in Subjects with moderate to severe pain in a inactive components. A premeasured portion of the more postSurgical dental pain model; and (3) to evaluate the safety concentrated active blend were added to the double cone of three different doses of NTX in combination with MS 60 blender. A measured amount of the preblended inactive com mg versus placebo in Subjects with moderate to severe pain in ponents was added to achieve the desired dilution. The inac a postSurgical dental pain model. tive blend was added in portion-wise steps to the double cone 0.124. A randomized, double-blind, placebo- and active blender, with interim mixing to achieve uniformity. The NTX controlled, single-dose study was thus designed. There were blends were filled into hard gelatin capsules at a controlled weight to achieve the desired unit dose of NTX. five treatment groups: three test products, a positive control 0121 Encapsulated dose forms of opioid agonists were (MS 60 mg), and a negative control (placebo). Separation of prepared for clinical studies employing the same inactive placebo and MS 60 mg were used to determine the assay components and hard gelatin capsule. Encapsulated dose sensitivity of the study. The active control (MS 60 mg) was forms of morphine were prepared from commercially used to determine the sensitivity of the clinical endpoints. obtained tablets (Roxane), which contained 15 mg morphine Placebo was used to control for factors not related to drug Sulfate pentahydrate and various inactive components. A 60 treatment. The test products were MS 60 mg with naltrexone mg morphine Sulfate strength capsule was made by mixing (NTX) 1 mg, MS 60 mg with NTX 0.1 mg, and MS 60 mg (e.g., microcrystalline cellulose and magnesium Stearate) to with NTX 0.01 mg. A single oral dose of one of the treatments form a blend, and this blend and four morphine sulfate tablets was administered when the Subject was suffering moderate to were loaded into a hard gelatin capsule shell to obtain a severe postoperative pain. The observation period for efficacy capsule for clinical studies. Encapsulated dose forms of tra was eight hours post treatment. The observation period for madol were prepared from commercially obtained safety was 24 hours post treatment. ULTRAMR tablets (Ortho-McNeil), which contained 50 mg 0.125. The Study Population was two hundred male and tramadol hydrochloride and various inactive components. A 50 mg tramadol hydrochloride strength capsule was made by female outpatients with moderate to severe pain and a pain mixing inactive components (e.g., microcrystalline cellulose intensity score of at least 50mm on the 100 mm Visual Analog and magnesium Stearate) to form a blend, and this blend and Scale (VAS) following extraction of two or more impacted one ULTRAMR), immediate release tablet were loaded into a third molars. All subjects remained in the study facility for the hard gelatin capsule shell to obtain a capsule for clinical eight-hour duration of the single-dose evaluation and then studies. Encapsulated dose forms of hydrocodone were pre were permitted to leave the study site. pared from commercially obtained tablets immediate release 0126 Inclusion criteria were as follows: HYDROCETR) capsules (Carnrick Laboratories), which con I0127 (1) subjects with two or more impacted third molars tained hydrocodone bitartrate (5 mg) with acetaminophen requiring extraction and considered to have had surgery sig (500 mg) and various inactive components. A 5 mg hydroc nificant enough to warrant an opioid analgesic, where at least odone bitartrate/500mg acetaminophen strength clinical cap one extracted tooth was a partial or full bony mandibular sule was made from the commercially obtained HYDRO impaction; CETR) capsules in the following manner. The average weight I0128 (2) subjects willing and able to complete the pain of 20 HYDROCETR) capsules was determined, and the evaluations; hydrocodonefacetaminophen blend contained in a predeter I0129 (3) subjects at least 16 years of age, and if the subject mined number of HYDROCETR) capsules was emptied into was less than age 18, the Subject was emancipated, or the a clean bowl. The total weight of hydrocodone/acetami parent or guardian gave written consent. nophen blend needed to fill the clinical capsules with the same average weight (including 1% overage) was transferred to a 0.130 (4) female subjects were postmenopausal, or physi capsule machine. The capsule machine filled clinical capsule cally incapable of child bearing, or practicing an acceptable shells with the hydrocodone/acetaminophen blend. method of birth control (IUD, hormones, diaphragm with spermicide, condoms with spermicide, or abstinence), and if EXAMPLE1 practicing an acceptable method of birth control, must also have maintained her normal menstrual pattern for the three 0122. A clinical study was designed as follows: (1) to months prior to study entry and have had a negative urine compare the analgesic activity (onset, peak, duration, and pregnancy test performed at Screening and immediately prior total effect) of three different doses of NTX in combination to Surgery; US 2009/0203722 A1 Aug. 13, 2009

0131 (5) subjects in generally good health; 0132 (6) subjects able to speak and understand English and provide meaningful written informed consent; 0.133 (7) subjects able to remain at die study site for the NUMBER OF CAPSULESPER BOTTLE FOREACH entire eight-hour study period; TREATMENT GROUP 0134 (8) subjects had an initial pain intensity score of at Capsules least 50 mm on a 100 mm visual analog scale and must also Treatment Contents MS NTX NTX NTX describe the initial pain as moderate or severe on a four-point Group Treatment 60 mg 1 mg 0.1 mg 0.01 mg Placebo categorical scale; and Group A Placebo O O O O 2 0135 (9) subjects willing and able to return to the study Group B MS 60 mg 1 O O O 1 site for the post treatment visit five to nine days after Surgery. Group C MS 60 mg with 1 O O 1 O 0.136 Exclusion criteria for subjects were as follows: NTX 0.01 mg Group D MS 60 mg with 1 O 1 O O 0.137 (1) pregnant or breast feeding: NTX 0.1 mg 0138 (2) have known allergy or significant reaction to Group E MS 60 mg with 1 1 O O O opioids or opioid antagonists; NTX 1 mg 0139 (3) history of chronic opioid use or opioid abuse within six months prior to study. 0149 Included on the open portion of the label was the 0140 (4) have participated in a study of an investigational protocol identification, Subject number, number of capsules, drug or device within 30 days prior to this study: directions for use, Storage instructions, and cautionary State 0141 (5) have taken any of the following drugs within four ment about investigational status. hours prior to dosing: analgesics, including aspirin, acetami 0150. The randomization code was not revealed to study nophen, nonsteroidal anti-inflammatory drugs (NSAIDS), Subjects, investigators, clinical staff or study monitors until opioids, and opioid combinations, minor tranquilizers, all subjects completed therapy and the data base has been muscle relaxants and antihistamines, where exempted from finalized and closed. this prohibition were midazolam (Versed), lidocaine (with or 0151. Following washout from previous analgesia as without epinephrine), mepivacaine, nitrous oxide, and propo stated in the exclusion criteria, and following a suitable recov fol (Diprivan) given during Surgery; ery from anesthesia after Surgery, all Subjects who had mod 0142 (6) have taken a long-acting analgesic (e.g., long erate to severe pain and a score of at least 50 mm on the 100 acting NSAIDS) within 12 hours prior to this study: mm VAS received one dose of study medication, consisting of 0143 (7) have taken monoamine oxidase inhibitors or tri two capsules. There was one bottle per subject, labeled by cyclic antidepressant drugs within four weeks prior to study subject number, as described above. medication; 0152 The following screening procedures were accom 0144 (8) have taken serotonin reuptake inhibitors (SSRI) plished within 14 days prior to surgery: (a) review of inclu or St. John's wort within four weeks prior to the study unless sion and exclusion criteria; (b) informed consent; (c) urine the subject has been on a stable dose for at least six weeks and pregnancy test for women of child-bearing potential (at the stable dose for St. John's wort must have been no more screening and immediately prior to Surgery); (d) medical than 1 gm/day; history and demographics; (e) brief physical examination; 0145 (9) have a medical or psychiatric condition that and (t) vital signs. compromises the Subject’s ability to give informed consent or 0153. Baseline measurements and procedures included: appropriately complete the pain assessments; and (a) Vital signs (prior to dosing); (b) review of medications 0146 (10) have a history of seizure, however, subjects received within 12 hours prior to dosing; and (c) after a with a history of juvenile febrile seizures could be included if suitable washout period from the anesthesia, the subject's there was no seizure history within the past 10 years. pain level was assessed by a trained observer, and when the 0147 Subjects were assigned to treatment groups based pain level was moderate or severe, and the score on the 100 on a randomization schedule prepared prior to the study. The mm VAS was at least 50 mm, the subject was randomized to randomization was balanced by using equally balanced a treatment group. blocks. Based on the randomization code, the assigned study 0154 Provided the subject met the above-referenced cri drug was packaged and labelled for each Subject. Subject teria, the Subject was assigned the next sequential treatment numbers were preprinted onto the study drug labels and number in ascending or descending order depending upon the assigned as Subjects qualified for the study and were random starting pain. The Subject then took one dose of study medi ized to treatment. In order to achieve balance among treat cation consisting of two capsules. ment groups with respect to starting pain, the study stratified 0155 Treatment period procedures and measurements randomization according to initial pain intensity. Subjects included: with moderate starting pain were assigned medication with 0156 (a) Following dosing, the subject remained at the the lowest available number. Subjects with severe starting study facility for eight hours; pain were assigned medication with the highest available 0157 (b) Two stopwatches were started at the time the number. study medication was taken at baseline and each Subject was 0148. Each subject was assigned one bottle containing two first instructed, “Stop the first stopwatch when you first feel capsules. The label on the bottle consisted of two parts. One any paid relief whatsoever. This does not mean you feel part was attached firmly to the bottle and did not contain drug completely better, although you might, but when you first feel identification. The other part was a tear-off label containing any difference in the pain you have now.” and then the subject the concealed drug identification. The tear-off label was taped was instructed, “Stop the second stopwatch when the pain unopened onto the case report form. relief is meaningful to you.’’: US 2009/0203722 A1 Aug. 13, 2009

0158 (c) For treated subjects, vital signs were taken one 0168 Efficacy evaluations were performed using primary hour after dosing and at the end of the eight-hour observation and secondary efficacy (outcome) parameters. The primary period; efficacy parameters included: 0159 (d) For treated subjects, pain intensity and pain (0169 (1) 8-hour Total Pain Relief Scores (TOTPAR-8) relief were measured by a trained observer at the following described below: times: 30 minutes, 60 minutes and hourly thereafter through (0170 (2) 8-Hour Sum of Pain Intensity Difference Scores Hour 8 after dosing, and all efficacy assessments were (SPID-8) described below: recorded by the Subject in a diary in response to questioning (0171 (3) Time to Rescue: by a trained observer, wherein the trained observer ques 0172 (4) Percent of Subjects Remedicating with Rescue tioned the subject for all observations and provided instruc Medication; and tion as needed; pain intensity was measured in response to the (0173 (5) Time to Onset of Meaningful Pain Relief. question, “What is your pain level at this time?” with subject 0.174. The secondary efficacy parameters included: response choices of none-0, mile=1, moderate=2 and (0175 (1) Hourly Pain Relief Scores; severe 3 on a categorical scale and the pain relief relative to (0176 (2) Hourly Pain Intensity Difference Scores: baseline was assessed in response to the question, “How much relief have you had from your starting pain?' with (0177 (3) Maximum Pain Relief Scores; subject response choices of none-0, a little=1, some=2, a (0178 (4) Peak Pain Intensity Difference Scores; lot-3, and complete=4; (0179 (5) Global Evaluations; and 0160 (e) Subjects not completing at least 90 minutes after 0180 (6) Time to Onset of First Perceptible Pain Relief. 0181 Safety evaluations included (1) vital signs; and (2) dosing were considered not evaluable and were replaced; adverse events. All adverse events were recorded on the case 0161 (f) Adverse events were assessed by non-directed report forms (CRF) provided. Serious adverse events were questioning and recorded for the eight hours following dos reported promptly to the Institutional Review Board (IRB) ing: and to the sponsor. The investigator transmitted a written 0162 (g) All concomitant medications (including rescue report of the circumstances and outcome. All serious adverse medications) were recorded for the eight-hour observation events were reported to the FDA in compliance with Federal period; Regulations. An adverse event (AE) was defined as any unto ward, noxious, or unintended event experienced by a subject 0163 (h) At the end of eight hours, or at the termination of in a clinical trial of an investigational agent, whether consid hourly observations if sooner than eight hours, a global evalu ered related to that investigational agent or not. A treatment ation was made by observer and Subject in response to the emergent adverse event was defined as an AE that was new in question, “How do you rate the pain relief?' with response onset or aggravated in severity or frequency following admin choices of poor=0, fair-–1, good=2, very good=3 and excel istration of the investigational agent. A serious adverse event lent=4; and was defined as any AE occurring at any dose that resulted in 0164 (i) Upon discharge from the study facility, the sub any of the following outcomes: death, a life-threatening ject was given a diary to take home for recording medications adverse drug experience, inpatient hospitalization or prolon taken and adverse events experienced from the time of dis gation of existing hospitalization, a persistent or significant charge until 24 hours after the time of dosing with study disability/incapacity, or congenital anomaly or birth defect. medication; a member of the study staff telephoned the 0182. A subject who completed Hour 8 or who completed patient 24 hours after the time of dosing to query the Subject at least 90 minutes and remedicated before Hour 8 was evalu about medications taken, adverse events experienced, and to able for efficacy. In any case, the reason for discontinuation remind the subject to complete the diary. was documented. 0.165. The study was considered completed after eight 0183 For the data analysis, parameters were computed as hours of evaluation or upon receipt of rescue medication. follows. The extent to which pain changes at each time point Subjects could discontinue the study at any time. Subjects was measured by pain relief scores (PR, with 0-none, 1=a who did not get adequate pain relief provided a final set of little, 2=some, 3-a lot, 4-complete), and pain intensity dif pain assessments and a global evaluation before taking rescue ference scores (PID, the difference between baseline and the medication. Subjects were then given a rescue medication current time, with the pain intensity Scale consisting of and pain assessments were discontinued. Subjects were 0-none, 1-mild, 2-moderate, 3-severe). encouraged to wait at least 90 minutes after administration of 0.184 The extent to which pain changes over the entire test the study medication before using rescue medication. Sub period was measured by the total pain relief score (TOTPAR jects remedicating earlier than 90 minutes were not included 8), sum of pain intensity differences (SPID-8), maximum in the analysis for efficacy. pain relief score (MAXPAR), peak pain intensity difference 0166 For subjects who completed eight hours of evalua (PEAKPID), and global evaluation (0-poor, 1=fair, 2-good, tion without using rescue medication, the time of the first dose 3–very good, 4=excellent). TOTPAR-8 and SPID-8 are of analgesic within 24 hours after dosing with study medica defined as the sum of PR and PD, respectively, for the entire tion was recorded on the take-home diary. 8-hour observation period, weighted by the time difference 0167 All subjects who received a dose of study medica between adjacent points (i.e., area under the curve using the tion returned to the study facility 5 to 9 days after surgery for trapezoidal rule). MAXPAR and PEAKPID are defined as the a post treatment visit. The following was accomplished: (a) maximum of PR and PID, respectively. brief physical examination; (b) collection and review of sub 0185. Where required, the following imputation schemes ject's diary for 24-hour post-dosing adverse events, and medi were employed. Intermediate missing values were replaced cations (including rescue medications). by linear interpolation, whereas missing values after admin US 2009/0203722 A1 Aug. 13, 2009 16 istration of rescue medication or other premature discontinu 0193 All patients who received study medication were ation were replaced by the last observation carried forward assessed for clinical safety. Vital signs, including changes procedure (LOCF). from baseline, were summarized with descriptive statistics. 0186. Further efficacy variables were time to rescue, per Adverse event frequencies were tabulated by body system cent of patients remedicating with rescue medication, time to and preferred term, and Fisher's exact test or a chi-squared onset of meaningful pain relief, and time to onset of first test was used to test for differences in adverse event frequen perceptible pain relief. cies among the treatment groups by body system. 0187 Safety was assessed through vital signs and adverse 0194 The sample size was estimated from historical data events (including body systems and preferred terms from the and from practical considerations rather than from calcula COSTART dictionary). tion of expected measured differences. 0188 All testing of statistical significance were two 0.195 A total of 204 subjects were randomized; among sided, and a difference resulting in a p-value of less than or them 201 subjects were deemed evaluable. One subject in equal to 0.05 was considered statistically significant. each of the placebo, MS and MS/0.1 NTX groups was not 0189 Efficacy analyses was conducted on the intent-to evaluable because the Subject took rescue medication less treat (ITT) analysis set, consisting of all randomized patients than 90 minutes after dosing.

TABLE 1. Subject Disposition

Treatments Placebo MS (60 mg) MS (60 mg) MS (60 mg) with with with NTX with NTX MS (60 mg) with Placebo Placebo (0.01 mg) (0.1 mg) NTX (1.0 mg) Total Number of Subjects Screened 40 41 41 41 41 204 Analyzed for Efficacy: 40 41 41 41 41 204 Intent-To-Treat 39 40 41 40 41 2O1 Evaluable Subjects Analyzed for Safety: 40 41 41 41 41 204 Intent-To-Treat who received study medication. A second analysis could be 0196. The demographic and baseline characteristics were done on the evaluable analysis set. summarized by treatment groups for the ITT population (all 0190. Demographic and baseline characteristics were randomized patients) and the evaluable population (all ran Summarized with descriptive statistics (for continuous vari ables) or frequencies (for categorical variables). domized patients with at least one efficacy evaluation at 90 0191) One-way analysis of variance (ANOVA) by treat minutes or more after dosing) (Table 2). Demographic char ment group was performed on PR, PD, TOTPAR-8, SPID-8, acteristics included age, race/ethnicity, sex, weight, height, MAXPAR, PEAKPID, and the global evaluation (with PR medical history, teeth extracted (impacted and non-im and PID analyzed separately for each time point). Baseline pacted), baseline pain intensity, and baseline visual analog pain intensity was investigated as a possible blocking factor, scale. and baseline pain intensity VAS was investigated as a possible 0197) The demographics for the ITT population were covariate. If the ANOVA treatment effect is significant at the comparable across all 5 treatment groups. Subjects ranged in p<0.05 level, one-sided Fisher's protected least significant age from IS to 39 years; 67% were Caucasian and 51% were difference test (LSD) was performed to investigate pairwise female. There was comparability among treatment groups differences. For all pairwise comparisons, the error mean regarding the degree of Surgical trauma rating. For the evalu square from the overall analysis of variance with all treat able population, but not for the ITT population, there was a ments was used as the estimate of error variance. difference among treatment groups in the maximum degree of 0.192 Time to rescue (remedication) was analyzed using impaction of third molar extracted. Patients in the placebo the Kaplan-Meier estimate to compute the survival distribu group had a lesser degree of bony impaction compared to tion function. The distributions were compared among treat ment groups using the log rank and Wilcoxon tests. A patient patients in the low-dose group, and patients in both the low was considered censored at 24 hours if remedication had not dose and mid-dose groups had a greater degree of impaction occurred. Patients who dropped out because of reasons other compared to patients in the high-dose group. No adjustments than rescue medication were censored at the dropout time. in the analyses were made to take into account these differ The proportion of patients remedicating were compared ences among treatment groups. These differences had no among treatment groups using Fisher's exact test or a chi influence on pain assessments at baseline. Generally, no dif squared test. Time to onset of meaningful pain relief and time ferences among treatment groups were noted in the number of to onset of first perceptible pain relief was analyzed in a patients with either a significant medical history or disease of similar fashion to time to rescue. Patients who did not achieve any body system. The baseline pain intensity Scores and meaningful pain relief or perceptible pain relief were consid visual analog scale scores also were comparable across treat ered treatment failures and were assigned a time of 8 hours. ment groups (Table 3). US 2009/0203722 A1 Aug. 13, 2009 17

TABLE 2 Baseline Demographic Characteristics Intent-To-Treat Subjects Treatments

Placebo MS MS MS MS Number of with (60 mg) with (60 mg) with (60 mg) with (60 mg) with Subjects - 204 Placebo Placebo NTX (0.01 mg) NTX (0.1 mg) NTX 1.0 mg) P-Value Sex (N, 9%) Male 18 (45.0%) 18 (43.9%) 21 (51.2%) 21 (51.2%) 21 (51.2%) 0.918 (2) Female 22 (55.0%) 23 (56.1%) 20 (48.8%) 20 (48.8%) 20 (48.8%) Total 40 41 41 41 41 Age (yrs) N 40 41 41 41 41 0.715 (1) Mean 22.1 22.8 22.0 23.1 22.5 SD 2.92 3.87 3.55 S.10 4.28 Median 21.5 22.0 21.0 22.0 22.O Range 18-28 19-32 18-35 16-39 18-39 Height (cm) N 40 41 41 41 41 0.5961) Mean 170.3 170.7 173.8 171.4 171.4 SD 9.70 1222 9.38 10.87 1.O.OS Median 170.2 167.6 172.7 172.7 1715 Range 1524-188.O 1499-1981 1575-193.0 139.7-194.3 1549-188.0 Weight (kg) N 40 41 41 41 41 0.384 (1) Mean 68.8 75.5 72.1 70.8 72.6 SD 13.94 17.39 12.99 14.49 17.34 Median 67.3 75.0 73.2 70.9 69.8 Range 473-106.4 42.7-117.3 SO.9-1. OSS 46.4-104.5 47.3-122.3 Ethnic Origin Caucasian 26 (65.0%) 25 (61.0%) 31 (75.6%) 28 (68.3%) 26 (63.4%) 0.666 [2] Black 4 (10.0%) 4 (9.8%) 1 (2.4%) 1 (2.4%) 3 (7.3%) Hispanic 7 (17.5%) 11 (26.8%) 7 (17.1%) 9 (22.0%) 6 (14.6%) Asian 3 (7.5%) 1 (2.4%) 1 (2.4%) 2 (4.9%) 5 (12.2%) Other 0 (0.0%) 0 (0.0%) 1 (2.4%) 1 (2.4%) 1 (2.4%) Total 40 41 41 41 41 1) ONE-WAY ANALYSIS OF VARIANCE WITH TREATMENT AS THE FACTOR 2 FISHERS EXACT TEST. 3) BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

TABLE 3 Summary of Baseline Pain Intensity Scores Intent-To-Treat Population

P-VALUE FOR PAIRWISE COMPARISONS

P-VALUE FOR PAIN INTENSITY MS 60 mg MS 60 mg MS 60 mg OVERALL TREATMENT MODERATE SEVERE MS 60 mg NTX 0.01 mg NTX 0.1 mg NTX 1 mg TREATMENT

Placebo 16 (40.0%) 24 (60.0%) O822 1.OOO O822 1.OOO O.997 MS 60 mg 18 (43.9%) 23 (56.1%) 1.OOO 1.OOO 1.OOO MS 60 mg/NTX 0.01 mg 17 (41.5%) 24 (58.5%) 1.OOO 1.OOO MS 60 mg/NTX 0.1 mg 18 (43.9%) 23 (56.1%) 1.OOO MS 60 mg/NTX 1 mg 17 (41.5%) 24 (58.5%)

NOTE: P-VALUES ARE FROM FISHERS EXACT TEST. Summary of Baseline Visual Analog Scale (VAS) Scores Intent-To-Treat Population

P-VALUE FOR PAIRWISE COMPARISONS

P-Value BASELINE WASSCORE for

Moderate 1 Severe 1) Total MS 60 mg MS 60 mg MS 60 mg Overall TREATMENT N Mean (SD) N. Mean (SD) N. Mean (SD) MS 60 mg NTX 0.01 mg NTX 0.1 mg NTX 1 mg Treatment Placebo 16 65.5 (7.91) 24 79.4 (9.91) 40 73.9 (11.39) 0.250 O.890 O.296 O966 MS 60 mg 18 68.1 (6.58) 23 84.1 (8.23) 41 77.1 (11.00) O.195 O.922 O.231 US 2009/0203722 A1 Aug. 13, 2009

TABLE 3-continued MS 60 mg/NTX 17 60.7 (9.29) 24 82.5 (10.77) 41 73.5 (14.81) O-234 O.923 0.01 mg MS 60 mg/NTX 17 65.5 (10.62) 23 85.2 (9.18) 40 76.8 (13.83) O.274 0.1 mg MS 60 mg/NTX 17 67.6 (10.53) 24 78.1 (10.23) 41 73.7 (11.48) 1 mg

NOTE: P-VALUES ARE FROM ONE-WAYANALYSIS OF WARIANCE AND ITS CONTRASTS. 1 BASELINE PAIN INTENSITY ON THE CATEGORICAL SCALE.

(0198 The TOTPAR results (4-hour, 6-hour, 8-hour) are This pattern (low-dose (0.01 mg NTX)>mid-dose (1.0 mg summarized in Table 4 and the 4-hour TOTPAR scores are NTX) was observed for all pain relief variables throughout shown in FIG.1. The placebo treatment group had the lowest the study. The mean TOTPAR scores for the 0.01-mg NTX mean TOTPAR scores. All 4 of the active treatment groups and 0.1-mg NTX combination treatments were higher than exhibited mean TOTPAR scores that were numerically higher that for the MS alone treatment, whereas the 1.0-mg NTX than placebo. The combination treatments had a reverse dose combination treatment mean was comparable to or lower than response relation in the mean TOTPAR scores, i.e., the high that for the MS alone treatment (FIG. 1). est dose of NTX had the lowest meanTOTPAR scores and the (0199 Analyses of TOTPAR for the evaluable subgroup lowest dose of NTX had the highest mean TOTPAR scores. yielded results similar to those for the ITT population. TABLE 4

Total Pain Relief Scores Intent-To-Treat Population

TOTAL PAIN RELIEF SCORE P-VALUE P-VALUE

TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 1. 2 TOTAL PAIN RELIEF SCORE (O-4 HOURS) A) Placebo 40 2.2O 2.836 O.O O.25 9.5 TRT O.003** 0.004** B) MS 60 mg 41 4.38 4.O3S O.O 3.75 13.2 BASEPI NA O.312 C) MS 60 mg/NTX 0.01 mg 41 5.50 4.106 (O.O 5.73 14.0 BASEPI* TRT NA O.O81 D) MS 60 mg/NTX 0.1 mg 41 S.09 4.278 O.O 3.25 12.3 B-A 0.014: O.O13: E) MS 60 mg/NTX 1 mg 41 4.18 4.439 O.O 2.75 14.0 C-A 0.001.*** -0.001.*** D-A O.001.** 0.001.** E-A 0.026* O.O24: C-B O.2O3 O.198 D-B O416 O411 E-B O828 O.826 TOTAL PAIN RELIEF SCORE (O-6 HOURS) A) Placebo 40 3.62 4.851 O.O O.25 14.5 TRT O.004** 0.006** B) MS 60 mg 41 7.52 6.962 O.O 8.25 21.2 BASEPI NA O419 C) MS 60 mg/NTX 0.01 mg 41 8.85 6.47O O.O 9.23 20.5 BASEPI* TRT NA O.O44 D) MS 60 mg/NTX 0.1 mg 41 8.25 7.089 O.O 6.75 20.3 B-A O.008** 0.007** E) MS 60 mg/NTX 1 mg 41 6.60 7.277 O.O 2.75 22.0 C-A 0.001.*** -0.001.*** D-A O.001.** 0.001.** E-A 0.043: 0.041: C-B O.359 O.353 D-B O613 O.608 E-B O.S30 O.S24 TOTAL PAIN RELIEF SCORE (O-8 HOURS) A) Placebo 40 S.12 7.026 O.O O.25 20.5 TRT O.007** 0.009** B) MS 60 mg 41 10.73 9.988 O.O 13.50 29.2 BASEPI NA O.470 C) MS 60 mg/NTX 0.01 mg 41 12.15 9.139 O.O 11.75 27.5 BASEPI* TRT NA 0.037: D) MS 60 mg/NTX 0.1 mg 41 1152 10.130 O.O 10.75 28.3 B-A O.007** 0.007** E) MS 60 mg/NTX 1 mg 41 9.14 10.337 O.O 2.75 3O.O C-A 0.001.*** -0.001.*** D-A O.002** 0.002** E-A O.OS6 O.OS3 C-B O496 O489 D-B 0.705 O.701 E-B O442 O436 1) FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHERS PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. 2) FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR ANDFISHERS PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. *, *, ***P-VALUE -<=0.05, <=0.01, or <=0.001 RESPECTIVELY. NA: NOT APPLICABLE US 2009/0203722 A1 Aug. 13, 2009 19

0200 Table 5 summarizes the results of the 4, 6, and for the MS alone treatment, whereas the 1.0-mg NTX com 8-hour SPID results. The 4-hour results are also represented bination treatment was comparable to that for the MS alone in FIG. 2. The placebo treatment had the lowest mean 4-hour treatment (FIG. 2). SPID scores (0.68+2.165). All 4 of the active treatment 0201 The patterns of the 6-hour and 8-hour SPID scores groups exhibited improved profiles in mean SPID relative to were similar to those at 4 hours. Analyses of SPID for the placebo. The mean SPID scores for the 0.01-mg NTX and evaluable subgroup also yielded profiles that were similar to 0.1-mg NTX combination treatments were higher than that those found in the ITT population.

TABLE 5

Summary of Pain Intensity Differences Intent-To-Treat Population

SUM OF PAIN INTENSITY DIFFERENCES 1 P-VALUE P-VALUE

TREATMENT N MEAN SD MIN MEDIAN MAX SOUCRE 2 3)

SUMMARY OF PAIN INTENSITY DIFFERENCES (0-4 HOURS)

A) Placebo 40 O.68 2.165 -3.8 O.OO 5.0 TRT O.009** 0.003** B) MS 60 mg 41 1.91 3.296 -3.8 2.50 8.0 BASEPI NA 0.001.*** C) MS 60 mg/NTX 0.01 mg 41 3.08 3.309 -3.8 3.24 10.3 BASEPI* TRT NA 0.040: D) MS 60 mg/NTX 0.1 mg 41 2.62 2.790 -3.8 2.48 8.5 B-A 0.077 0.048* E) MS 60 mg/NTX 1 mg 41 2.01 3.763 -3.8 1.25 8.5 C-A 0.001.*** -0.001.*** D-A O.005** 0.001.** E-A 0.054* 0.031: C-B O.O90 O.OS8 D-B O.302 O.248 E-B 0.875 O.860 SUMMARY OF PAIN INTENSITY DIFFERENCES (O-6 HOURS)

A) Placebo 40 115 3.435 -5.8 O.OO 8.3 TRT O.O13: 0.004** B) MS 60 mg 41 3.33 S.S10 -5.8 4SO 12.0 BASEPI NA 0.001.*** C) MS 60 mg/NTX 0.01 mg 41 4.86 S.O69 -5.8 5.25 15.3 BASEPI* TRT NA 0.0218 D) MS 60 mg/NTX 0.1 mg 41 4.36 4.606 -5.8 4.48 14.5 B-A O.OS3 0.031: E) MS 60 mg/NTX 1 mg 41 320 6.136 -5.8 1.25 14.5 C-A O.001.** -0.001.*** D-A O.004** 0.001.** E-A O.O68 0.042* C-B O.170 O.127 D-B 0.355 O.303 E-B O.911 O.901 SUMMARY OF PAIN INTENSITY DIFFERENCES (O-8 HOURS)

A) Placebo 40 1.65 4.781 -7.8 O.OO 12.8 TRT O.O19* 0.007** B) MS 60 mg 41 4.80 7.821 -7.8 6.50 17.3 BASEPI NA 0.001.*** C) MS 60 mg/NTX 0.01 mg 41 6.62 7.090 -7.8 7.25 19.8 BASEPI* TRT NA O.O16* D) MS 60 mg/NTX 0.1 mg 41 6.18 6.581 -7.8 6.49 20.5 B-A 0.048* 0.0288 E) MS 60 mg/NTX 1 mg 41 4.54 8.716 -7.8 1.25 2O.O C-A O.001.** -0.001.*** D-A O.004** 0.001.** E-A O.069 0.043: C-B O.248 O.199 D-B O.380 O.329 E-B O.870 0.855

1) PAIN INTENSITY DIFFERENCE = PAIN INTENSITY AT BASELINE - PAIN INTENSITY AT CURRENT TIME. 2) FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHERS PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. (3) FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR ANDFISHERS PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. *, *, ***P-VALUE -<=0.05, <=0.01, or <=0.001 RESPECTIVELY. NA: NOT APPLICABLE US 2009/0203722 A1 Aug. 13, 2009 20

0202 FIG. 3 is a visual presentation of the summary and median times to administration of rescue medication were analysis of time to onset of meaningful pain relief scores longer for the morphine (>8 hours), low-dose (>8 hours), and presented in Table 6. The median time to onset of meaningful mid-dose (>8 hours) groups compared to the high-dose (3 pain relief was shortest in the 0.01-mg NTX (low-dose) com bination treatment group. The placebo treatment had the hours, 4 minutes) and placebo (2 hours, 18 minutes) groups. lower number of Subjects who reached meaningful pain 0205 The survival distributions (0-24 hours) were also relief. different across treatment groups, and were also different for 0203 Analyses of times to onset of meaningful pain relief the morphine, low-dose, and mid-dose groups compared to for the evaluable subgroup yielded similar result. the placebo group (FIG. 5). Again, the median times to

TABLE 6 Time To Onset of Meaningful Pain Relief Intent-To-Treat Population

MEDIAN 95% CONFIDENCE TIME INTERVAL TEST OF SURVIVAL CURVES TREATMENT N (hh:mm) (hh:mm) SOURCE LOG-RANK WILCOXON A) Placebo 40 s8:00 (>8:00, >8:00) TREATMENT O.O29* O.O62 B) MS 60 mg 41 2:37 (1:07, 8:00) B-A 0.006** ND C) MS 60 mg/NTX 0.01 mg 41 2:23 (1:12, >8:00) C-A 0.001.** ND D) MS 60 mg/NTX 0.1 mg 41 3:10 (1:33, 8:00) D-A 0.007** ND E) MS 60 mg/NTX 1 mg 41 >8:00 (2:00, 8:00) E-A 0.0303 ND C-B 0.725 ND D-B O.830 ND E-B O.S92 ND *, **, ***P-VALUE -<=0.05, <=0.01, or <=0.001 RESPECTIVELY. N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

0204 FIGS. 4 and 5 are a visual presentation of the sum administration of rescue medication were longer for the mor mary and analysis of time to remedication (rescue medica phine, low-dose, and mid-dose groups. tion) up to 8 and 24 hours presented in Table 7. The survival 0206 Analyses of time to remedication up to 24 hours yielded similar results, however, the data should be viewed distributions (0-8 hours) were different across treatment with caution because Subjects were not under close Supervi groups. The survival distributions were different for the low sion after 8 hours. Analyses for the evaluable subjects yielded dose and mid-dose groups compared to placebo (FIG. 4). The results similar to those for the ITT population.

TABLE 7

Time To Rescue Medication Intent-To-Treat Population

MEDIAN 95% CONFIDENCE TIME INTERVAL TEST OF SURVIVAL CURVES TREATMENT N (hh:mm) (hh:mm) SOURCE LOG-RANK WILCOXON EFFICACY OBSERVATION PERIOD (0-8 HOURS) A) Placebo 40 2:18 (2:02, 4:05) TREATMENT 0.047: 0.014: B) MS 60 mg 41 >8:00 (2:33, 8:00) B-A O.O92 O. 114 C) MS 60 mg/NTX 0.01 mg 41 >8:00 (6:03, 8:00) C-A 0.011: 0.002** D) MS 60 mg/NTX 0.1 mg 41 >8:00 (3:06, 8:00) D-A O.O2O: 0.010: E) MS 60 mg/NTX 1 mg 41 3:04 (2:00, 8:00) E-A O.S.06 O.471 C-B O.S.06 O.234 D-B O.6OS O422 E-B O.285 O.347 SAFETY OBSERVATION PERIOD (0-24 HOURS) A) Placebo 40 2:18 (2:02, 4:05) TREATMENT O.O15* 0.003: B) MS 60 mg 41 8:37 (2:33, 13:28) B-A O.O29* 0.043: C) MS 60 mg/NTX 0.01 mg 41 9:14 (6:03, 20:59) C-A 0.001.** 0.001.*** D) MS 60 mg/NTX 0.1 mg 41 8:26 (3:06, 18:17) D-A 0.005** 0.003** E) MS 60 mg/NTX 1 mg 41 3:04 (2:00, 9:09) E-A O.169 O.266 C-B O.388 O.167 D-B O.S39 O424 E-B O.S62 O.427

*, *, ***P-VALUE -<=0.05, <=0.01, or <=0.001 RESPECTIVELY. US 2009/0203722 A1 Aug. 13, 2009 21

0207 Table 8 presents the summary and analysis of per cent of Subjects who took remedication up to 5 and 24 hours. Analyses of the percentage of Subjects who remedicated within 24 hours indicated that all 5 treatment groups were comparable, however, the data should be interpreted with caution because Subjects were not under close Supervision after 8 hours. Analyses for the evaluable subjects led to con clusions similar to those for the ITT population.

TABLE 8 Percent of Subjects Rescued Intent-To-Treat Population RESCUED

TREATMENT YES NO SOURCE P-VALUE 1) EFFICACY OBSERVATION PERIOD (0-8 HOURS) A) Placebo 27 (67.5%) 13 (32.5%) TREATMENT O.193 B) MS 60 mg 20 (48.8%) 21 (51.2%) B-A ND C) MS 60 mg/NTX 0.01 mg 19 (46.3%) 22 (53.7%) C-A ND D) MS 60 mg/NTX 0.1 mg 19 (46.3%) 22 (53.7%) D-A ND E) MS 60 mg/NTX 1 mg 25 (61.0%) 16 (39.0%) E-A ND C-B ND D-B ND E-B ND SAFETY OBSERVATION PERIOD (0-24 HOURS) A) Placebo 37 (92.5%) 3 (7.5%) TREATMENT O.S36 B) MS 60 mg 35 (85.4%) 6 (14.6%) B-A ND C) MS 60 mg/NTX 0.01 mg 33 (80.5%) 8 (19.5%) C-A ND D) MS 60 mg/NTX 0.1 mg 33 (80.5%) 8 (19.5%) D-A ND E) MS 60 mg/NTX 1 mg 35 (85.4%) 6 (14.6%) E-A ND C-B ND D-B ND E-B ND N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

0208 FIG. 6 is a visual presentation of the hourly pain which improved over time. There was separation between the relief scores presented in Table 9. The hourly pain relief placebo and the active treatment groups that continued scores were Summarized and analyzed in 2 ways: first as a throughout the S-hour study period. Comparable pain relief categorical variable and second as a numerical variable. Because results of these two methods were similar, only the was observed (see, e.g., 1-3 hours) in the MS alone group and results from the numerical version are presented here. the high-dose (1.0 mg NTX) combination group (FIG. 6). Whereas the hourly pain relief scores for the placebo treat Highest pain relief scores were observed for the low-dose ment were less than those for the active treatment groups (0.01 mg NTX) combination group (FIG. 6).

TABLE 9

Pain Relief (PR) Scores 1 Intent-To-Treat Population PAIN RELIEF SCORE (PR)

TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE P-VALUE 2 P-VALUE 3)

3OMINUTES

A) Placebo 40 O.38 0.628 O O.OO 2 TRT O.S22 0.552 B) MS 60 mg 41 O.S6 0.923 O O.OO 4 BASEPI NA 0.535 C) MS 60 mg/NTX 0.01 mg 41 0.63 0.888 O O.OO 3 BASEPI* TRT NA O.959 D) MS 60 mg/NTX 0.1 mg 41 O.61 O.997 O O.OO 3 B-A ND ND E) MS 60 mg/NTX 1 mg 41 O.71 O.929 O O.OO 3 C-A ND ND D-A ND ND E-A ND ND C-B ND ND D-B ND ND E-B ND ND

US 2009/0203722 A1 Aug. 13, 2009 23

TABLE 9-continued Pain Relief (PR) Scores 1 Intent-To-Treat Population

PAIN RELIEF SCORE (PR

TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE P-VALUE 2 P-VALUE (3) C-B O.940 O.939 D-B 1.OOO 1.OOO E-B O.261 O.253 7 HOURS

A) Placebo 40 O.7S 1.127 O O.OO 3 TRT 0.026* O.O29* B) MS 60 mg 41 1.61 1595 O 1.00 4 BASEPI NA O616 C) MS 60 mg/NTX 0.01 mg 41 1.71 1.569 O 1.00 4 BASEPI* TRT NA 0.036* D) MS 60 mg/NTX 0.1 mg 41 166 1622 O 1.00 4 B-A 0.011: 0.010: E) MS 60 mg/NTX 1 mg 41 1.27 1613 O O.OO 4 C-A 0.005** O.004** D-A 0.007** O.OO6** E-A O.126 O.120 C-B 0.771 O.768 D-B O.884 O.882 E-B O.309 O.303 8 HOURS

A) Placebo 40 O.78 1.187 O O.OO 4 TRT O.OS6 OO67 B) MS 60 mg 41 1.61 1595 O 1.00 4 BASEPI NA O.709 C) MS 60 mg/NTX 0.01 mg 41 1.63 1.577 O 1.00 4 BASEPI* TRT NA O.O88 D) MS 60 mg/NTX 0.1 mg 41 161 1,611 O 1.00 4 B-A ND ND E) MS 60 mg/NTX 1 mg 41 1.29 1632 O O.OO 4 C-A ND ND D-A ND ND E-A ND ND C-B ND ND D-B ND ND E-B ND ND 1) PAIN RELIEF (PR) SCORES: O = NONE, 1 = A LITTLE, 2 = SOME, 3 = A LOT, 4 = COMPLETE. 2) FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHERS PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. (3) FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISH ERS PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. *, **, ***P-VALUE -<=0.05, <=0.01, or <=0.001 RESPECTIVELY. N/A: NOT APPLICABLE, N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

0209. The hourly pain intensity difference (PID) data pre low-dose and mid-dose groups were greater than the means sented in Table 10 and FIG. 7. The hourly PID scores for the for high-dose and placebo groups. Comparable pain relief as placebo treatment were generally flat while the hourly PD measured by PID scores was observed (see, e.g., 2-3 hours) in scores generally improved over time for the active treatment the MS alone group and the high-dose (1.0 mg NTX) combi groups. The mean scores for the morphine and morphine? nation group (FIG. 7). Highest pain reliefas measured by PID maltrexone groups were higher than the mean PID scores for scores was observed for the low-dose (0.01 mg NTX) com the placebo group at each assessment time. The means for the bination group.

TABLE 10 Pain Intensity Difference (PID) Scores 1 Intent-To-Treat Population

PAIN RELIEF SCORE (PR

TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE P-VALUE 2 P-VALUE 3)

3OMINUTES

A) Placebo 40 O.O8 O572 -1 O.OO 1 TRT O.367 O.317 B) MS 60 mg 41 O.17 O.667 -1 O.OO 2 BASEPI NA 0.001.*** C) MS 60 mg/NTX 0.01 mg 41 0.34 0.762 –1 O.OO 2 BASEPI* TRT NA 0.854 D) MS 60 mg/NTX 0.1 mg 41 O.32 0.650 -1 O.OO 2 B-A ND ND E) MS 60 mg/NTX 1 mg 41 O.29 O.782 -1 O.OO 2 C-A ND ND D-A ND ND E-A ND ND C-B ND ND D-B ND ND E-B ND ND

US 2009/0203722 A1 Aug. 13, 2009 25

TABLE 10-continued Pain Intensity Difference (PID) Scores 1 Intent-To-Treat Population

PAIN RELIEF SCORE (PR

TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE P-VALUE 2 P-VALUE (3)

C-B O.474 O433 D-B O.474 O433 E-B O.682 O.654 7 HOURS

A) Placebo 40 O2S O.707 - 1 O.OO 2 TRT O.OS2 O.027% B) MS 60 mg 41 O.76 1220 -1 1.00 3 BASEPI NA 0.001.*** C) MS 60 mg/NTX 0.01 mg 41 0.90 1.136 -1 1.00 3 BASEPI* TRT NA O.017% D) MS 60 mg/NTX 0.1 mg 41 O.93 1.058 -1 1.00 3 B-A ND O.027% E) MS 60 mg/NTX 1 mg 41 O.68 1368 -1 O.OO 3 C-A ND O.004** D-A ND O.003** E-A ND O.O59 C-B ND O.S19 D-B ND O452 E-B ND 0.747 8 HOURS

A) Placebo 40 O28 O.784 -1 O.OO 3 TRT O.09S O.OS6 B) MS 60 mg 41 O.71 1230 -1 1.00 3 BASEPI NA 0.001.*** C) MS 60 mg/NTX 0.01 mg 41 0.88 1.144 -1 1.00 3 BASEPI* TRT NA O.O29* D) MS 60 mg/NTX 0.1 mg 41 O.90 1044 -1 1.00 3 B-A ND ND E) MS 60 mg/NTX 1 mg 41 O.68 1350 -1 O.OO 3 C-A ND ND D-A ND ND E-A ND ND C-B ND ND D-B ND ND E-B ND ND

1) PAIN INTENSITY SCORES: O = NONE, 1 = MILD, 2 = MODERATE, 3 = SEVERE. 2) FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHERS PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. (3) FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISH ERS PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. *, **, ***P-VALUE -<=0.05, <=0.01, or <=0.001 RESPECTIVELY. N/A: NOT APPLICABLE, N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

0210. The mean MAXPAR scores presented in Table 1 1A mean score for the placebo group. The mean PEAKPID were different among treatment groups. The mean MAXPAR scores presented in Table 11B were different among treat scores were highest for the low-dose and mid-dose groups ment groups, and were greater for the morphine/naltrexone compared to all other groups. The mean scores for the low groups compared to the placebo group. Compared to all other dose and mid-dose groups were greater than the mean score groups, the mean PEAKPID scores were higher for the low for the morphine group, which in turn, was greater than the dose and mid-dose groups.

TABLE 11 A

Maximum Pain Relief Scores (MAXPAR) Intent-To-Treat Population

MAXIMUM PAIN RELIEF SCORE (PR)

TREATMENT N MEAN SD MIN MEDIAN MAX SOUCRE P-VALUE (1) P-VALUE 2

A) Placebo 40 110 1.355 O.O O.S 4.0 TRT 0.002** 0.004** B) MS 60 mg 41 1.9S 1.532 O.O 3.0 4.0 BASEPI NA O.S69 C) MS 60 mg/NTX 0.01 mg 41 2.39 1.531 0.0 3.0 4.0 BASEPI* TRT NA O.100 D) MS 60 mg/NTX 0.1 mg 41 2.1O 1463 O.O 2.O 4.0 B-A 0.011: 0.0118 E) MS 60 mg/NTX 1 mg 41 1.71 1.632 O.O 1.O 4.0 C-A 0.001.*** 0.001.*** D-A 0.003** 0.003** E-A O.O71 O.O68 US 2009/0203722 A1 Aug. 13, 2009 26

TABLE 11 A-continued Maximum Pain Relief Scores (MAXPAR) Intent-To-Treat Population

MAXIMUMPAIN RELIEF SCORE (PR

TREATMENT N MEAN SD MIN MEDIAN MAX SOUCRE P-VALUE (1) P-VALUE 2 C-B O.188 O.184 D-B O660 0.657 E-B O464 O460 1) FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHERS PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. 2) FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISH ERS PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. *, **, ***P-VALUE -<=0.05, <=0.01, or <=0.001 RESPECTIVELY. NA: NOT APPLICABLE

TABLE 11B Peak Pain Intensity Difference (PEAKPID) Intent-To-Treat Population

PEAK PAIN INTENSITY DIFFERENCE

TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE P-VALUE (1) P-VALUE 2 A) Placebo 40 O.S3 0.877 - 1 O.O 3 TRT O.007** O.004** B) MS 60 mg 41 1.10 1,068 -1 1.O 3 BASEPI NA 0.001.*** C) MS 60 mg/NTX 0.01 mg 41 1.41 1.140 -1 2.0 3 BASEPI* TRT NA 0.073 D) MS 60 mg/NTX 0.1 mg 41 1.17 1022 -1 1.O 3 B-A O.O19* 0.0118 E) MS 60 mg/NTX 1 mg 41 1.OO 1304 -1 1.O 3 C-A 0.001.*** 0.001.*** D-A O.008** O.004** E-A O.OS1 O.O34: C-B O.190 O.154 D-B O.761 O.742 E-B O686 O660 1) FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHERS PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. 2) FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISH ERS PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. *, **, ***P-VALUE -<=0.05, <=0.01, or <=0.001 RESPECTIVELY. NA: NOT APPLICABLE

0211 Table 12 presents the summary and analysis of glo bal evaluations. The placebo treatment had the highest num ber of subjects who had poor global evaluation scores based on subject evaluation. The profiles of the global evaluations scores are based on Subjects evaluations. Analyses of global evaluations for the evaluable subgroup also yielded similar results.

TABLE 12

Global Evaluation of Study Medication Intent-To-Treat Population

VERY EXCELLENT GOOD GOOD FAIR POOR. MEAN P-VALUE P-VALUE TREATMENT N (1) (2) (3) (4) (5) (SE) SOURCE 1. 2

A) Placebo 40 0 (0.0%) 6 (15.0%) 4 (10.0%) 2 (5.0%) 28 (70.0%) 0.7 (1.16) TRT O.004** 0.010: B) MS 60 mg 41 3 (7.3%) 10 (24.4%) 8 (19.5%) 3 (7.3%) 17 (41.5%) 1.5 (1.43) BASEPI NA O.958 C) MS 60 41 3 (7.3%) 14 (34.1%) 9 (22.0%) 3 (7.3%) 11 (26.8%) 1.9 (1.36) BASEPI* TRT N/A O.O29* mg/NTX 0.01 mg D) MS 60 41 3 (7.3%) 9 (22.0%) 7 (17.1%) 8 (19.5%) 14 (34.1%) 1.5 (1.36) B-A O.008** mg/NTX 0.1 mg