WO2001085150A2

WO2001085150A2 - Opioid antagonist containing composition for enchaching the potency or reducing adverse side effects ofopioid agonists

Info

Publication number: WO2001085150A2
Application number: PCT/US2001/014644
Authority: WO
Inventors: Barry Sherman; Mary Remien; Remi Barbier; Kathleen Dumas; Grant Schoenhard
Original assignee: Pain Therapeutics, Inc.; Albert Einstein College Of Medicine Of Yeshiva University
Priority date: 2000-05-05
Filing date: 2001-05-04
Publication date: 2001-11-15
Also published as: EP1280529A2; WO2001085150A3; JP2004501094A; AU5956001A; AU2001259458B2; AU2001259560B2; CA2408098A1

Abstract

0he invention generally relates to novel compositions and methods with an opioid agonist and an opioid antagonist to differentially dose a human subject so as to either enhance analgesic potency without attenuating an adverse side effect of the agonist, or alternatively maintain the analgesic potency of the agonist while attenuating an adverse side effect of the agonist. The invention additionally relates to novel opioid compositions and methods for the gender-based dosing of men and women.

Description

NOVEL COMPOSITIONS AND METHODS FOR

ENHANCING POTENCY OR REDUCING ADVERSE SIDE

EFFECTS OF OPIOID AGONISTS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority of the following U.S. Patent Application Nos. 60/202,227 filed May 5, 2000 (provisional); 60/202,268 filed May 5, 2000 (provisional); 09/756,331 filed January 8, 2001, which is a continuation of 09/566,071 filed May 5, 2000; 60/244,482 filed October 30, 2000 (provisional); 60/245,110 filed November 1, 2000 (provisional); and 60/246,235 filed November 2, 2000 (provisional); and PCT/US00/12493 [WO 00/67739] filed May 5, 2000. The applications cited above are hereby incorporated herein by reference in their entirety to provide continuity of disclosure.

FIELD OF THE INVENTION The present invention relates to novel compositions and methods, including gender-based compositions and methods, for enhancing potency or reducing adverse side effects of opioid agonists in humans. The present invention also relates to novel compositions and methods with an opioid agonist and an opioid antagonist to differentially dose a human subject, including men and/or women, so as to either enhance analgesic potency without attenuating an adverse side effect of the agonist, or alternatively maintain the analgesic potency of the agonist while attenuating an adverse side effect of the agonist.

BACKGROUND OF THE INVENTION Opioid agonists, including morphine sulfate (hereafter called morphine or MS), have been marketed for many years and are widely used for the relief of moderate to' severe acute and chronic pain. The potency of oral morphine is less than that of parenteral morphine, however, the use of the oral product for chronic pain control has increased dramatically in the past decade. An opioid agonist, such as morphine, exerts its primary effects on the central nervous system and organs containing smooth muscle, and acts as an agonist interacting with steriospecific and saturable binding sites or receptors in the brain, spinal cord, and other tissues. The principal therapeutic actions are analgesia and sedation. Opioid antagonists are generally accepted for use in the treatment of human conditions or ailments for reversing opioid toxicity and overdoses, and in preventing abuse of opioid agonists, such as heroin or morphine. For these uses, the antagonist such as naloxone or naltrexone is used in relatively high concentrations in order to effectively block the activity and/or effects of the opioid agonist by antagonizing the opioid agonist at opioid receptors on nociceptive neurons.

Naloxone (4,5-epoxy-3, 14-dihydroxy- 17-(2-prophenyl)morphinan-6-one) was the first of these compounds to be synthesized in 1960 and is considered a "pure" antagonist, i.e., exhibiting virtually no agonist activity. Naloxone became the preferred regime for the treatment of acute opioid toxicity. Since naloxone exhibits a relatively short duration in the body, it became clear that a longer acting agent having similarly pure antagonist character would be even more advantageous. Naltrexone ( 17-(cyclopropylmethyl)-4,5-epoxy-3 , 14-dihydroxy-morphinan-6-one) was developed in 1965 and has greater potency and longer action than its N-allyl cogener, naloxone, and is active when given orally. For example, 50 mg dosage forms of naltrexone, are marketed as ReVia^® in the United States or Trexan in other countries. Nalmefene (6-methylene-6-desoxy-N-cyclopropyl-methyl-14-hydroxydihydroxydihydronor- morphine) was also developed as a long acting, orally available, potent opioid antagonist, and has also been characterized as a pure antagonist. These drugs are presently commercially available in certain dosage forms, and are so far as is known, the only opioid antagonists characterized as pure antagonists which have received governmental approval for administration to humans.

Opioid agonists, such as morphine, are commonly used by clinicians in the treatment of moderate to severe acute and chronic pain. The analgesic activity of these agents contributes to their pharmacological effects on a large number of inhibitory opioid receptors on sensory nerve cells that receive and transmit pain signals in the nervous system; the role of these receptors is to inhibit the transmission of pain signals into the brain. The precise mechanisms of opioid agonists such as morphine are not known, although morphine, for example, is believed to act preferentially at mu-opiate receptors on neurons in the central and peripheral nervous system. In addition to pain relief, other actions of opioid agonists such, as morphine, in human subjects, include adverse side effects such as inhibition of gastrointestinal motility (e.g., leading to constipation), respiratory depression (especially at high-doses), peripheral vasodilation (e.g., leading to orthostatic hypotension), dizziness, sedation/drowsiness, nausea, vomiting, headache, pruritus, dry mouth, difficulty in urination, dependence, mood swings, and clouded sensorium. Opioid antagonists have been widely used in high-doses for the treatment of overdoses of opioid agonists and to prevent abuse of opioid agomsts such as heroin or morphine (e.g., 50 mg naltrexone). For these uses, doses must be relatively high in order to be therapeutically effective (i.e., block) the analgesic potency and the side effects of the opioid agonist, by antagonizing the agonist at opioid receptors on nociceptive neurons .

Grain and Shen fBrain Research 757: 176-190 (1997)) reported that opioid agonists not only activate inhibitory opioid receptors leading to analgesia but also simultaneously activate a smaller group of excitatory opioid receptors on sensory nerve cells. These effects on the excitatory opioid receptors were proposed to weaken opioid induced analgesia and under certain conditions actually enhance pain.

Surprisingly, Grain and Shen (e.g., U.S. Patent No. 5,512,578 reissued as RE 36,457) showed that co-administration of remarkably low-doses of an opioid antagonist, such as naloxone or naltrexone on the order of ng/kg, when administered to mice with morphine or similar opioid agonists selectively blocked their effects on excitatory, but not inhibitory, opioid receptors, thus markedly enhancing the analgesic potency of opioid agonists. These surprising results of Crain and Shen have been described in U.S. Patent Nos. 5,472,943; 5,512,578 reissued as RE 36,457; 5,580,876 and 5,767,125, which are directed to methods for selectively enhancing the analgesic potency of a bimodally-acting opioid agonist and simultaneously attenuating anti- analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects associated with the administration of the bimodally-acting opioid agonist. These methods comprise administering to a subject an analgesic or sub-analgesic amount of a bimodally-acting opioid agonist and an amount of an excitatory opioid receptor antagonist effective to enhance the analgesic potency of the bimodally-acting opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the bimodally-acting opioid agonist. Also included in these patents are methods for treating pain in a subject comprising administering to the subject an analgesic or sub-analgesic amount of a bimodally- acting opioid agonist and an amount of an excitatory opioid receptor antagonist effective to enhance the analgesic potency of the bimodally-acting opioid agonist and simultaneously attenuate anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the bimodally-acting opioid agonist. Also included are methods for treating an opiate addict comprising administering to the opiate addict an amount of an excitatory opioid receptor antagonist either alone or in combination with a bimodally-acting opioid agonist effective to attenuate physical dependence caused by a bimodally-acting opioid agonist and enhance the analgesic potency of a bimodally-acting opioid agonist. Also included are compositions comprising an analgesic or sub-analgesic amount of a bimodally-acting opioid agonist and an amount of an excitatory opioid receptor antagonist effective to enhance the analgesic potency of the bimodally-acting opioid agonist and attenuate the anti- analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the bimodally-acting opioid agonist in a subject administered the composition. In all of these studies, the antagonist simultaneously enhanced potency while attenuating such adverse effects. Two clinical studies on postsurgical hysterectomy patients [Joshi, et al, Anesthesiol. 90: 1007-1011 (1999); Gan et al, Anesthesiol. 87: 1075-1081 (1997)] demonstrated that cotreatment of women with PCA/IN morphine together with a low-dose of the opioid antagomst naloxone (IN) or nalmefene (IN) enhanced potency of morphine in varying cumulative doses of morphine over a 24 hour period. Adverse side effects were attenuated in these studies. Nothing in these studies with women suggested or related to any gender- based effect on either opioid-induced analgesia and/or the adverse effects associated with opioids.

In a recent review of gender differences in pharmacokinetics and pharmacodynamics [Beierle et al, Intl. J. Clin. Pharmacol. Ther. 37 (11): 529-547 (1999)], it was pointed out that until 1993, women were excluded from clinical phase I and early phase II trials. Therefore, for most drugs, including analgesics, there is a real paucity of information on sex differences in the pharmacokinetics as well as in the dose-response relationship or adverse effects of these drugs. The U.S. Food and Drug Administration (FDA) recognized this situation and developed new guidelines for drug research in 1993. Sex-related analgesic responses, including a summary and critique of animal and human studies and discrepancies between such studies were recently reviewed by Levine and his colleagues [Miaskowski et al, Chapter 11, pages 209-230, Editor: Fillingim, IASP Press, Seattle, Sex Gender and Pain (2000)]. In another recent review, Miaskowski and Levine [Pain Forum 8(1): 34-44 (1999)], summarize data from human studies on sex-related differences in responses to opioid analgesics, particularly kappa opioids.

Certain gender-based pain responses have been reported in both animal and human clinical studies [for reviews, see Fillingham and Maixner, Pain Forum 4: 209- 221 (1995); Unruh, Pam 65: 123-167 (1996) Miaskowski et al. (2000), supra.]

Gender-based differences in analgesia and anti-analgesia have recently been shown by Levine and his colleagues in patients with postoperative pain with several kappa opioid agonists, e.g., butorphanol [Gear et al, Nature, 2: 1248-1250 (1996)]; pentazocine [Gear et al, Neuroscience Let., 205: 207-209 (1996)]; nalbuphine [Gear et al., Pain 83: 339-345 (1999)]; and nalbuphine in combination with naloxone, an opioid antagonist [Gear et al, J. Pain, 1: 122-127 (2000)], but not with the mu opioid agonist morphine [Gordon et al, Neuroscience 69(2): 345-349 (1995)]. According to Levine and his colleagues, kappa opioid receptor agonists are unique in their gender- related effects. Studies in rats and mice evaluating the role of mu opioid agonists and antagonists show gender-based effects, although the results of these studies are contradictory and appear to be dependent upon both species and gender (for reviews, see Kest et al, J. Pharmacol. Exper. Therapeutics. 289: 1370-1375 (1999); and Kest et al, Anesthesiόlogy. 93: 539-547 (2000)).

SUMMARY OF THE INVENTION The present invention relates to novel compositions and methods for enhancing potency or reducing adverse side effects of opioid agonists in humans. The present invention is directed to compositions and methods for the differential dosing of human subjects with opioid agonists and low doses of opioid antagonists to yield either (1) enhancement of analgesic potency of the agonist without attenuation (e.g., reduction) or increase of one or more of the adverse side effects associated with that dose of agonist in humans, or (2) maintenance of analgesic potency of the agonist with attenuation (e.g., reduction) of one or more of the adverse side effects associated with that dose of agonist in humans. The present invention is based on surprising results from human clinical trials that demonstrate that the analgesic potency of opioid agonists can be dissociated from the opioid-related adverse side effects in humans. One novel composition and dosing method of the invention utilizes a dose of agonist with a low dose of antagonist that gives more pain relief in men and/or women but with essentially the same adverse side effect(s) of agonist alone. A second novel composition and dosing method of the invention utilizes a dose of agonist with a low dose of antagonist that gives essentially the same pain relief in men and/or women as agonist alone, but with attenuated (e.g., reduced) adverse side effect(s). The maintained potency with attenuated side effect(s) is accomplished without increasing or decreasing the cumulative daily dose of agonist. Thus, at appropriate differential dosing of humans according to the invention, a low dose of antagonist surprisingly can enhance analgesia with no increase in side effects or suppress side effects with no loss in analgesia. The present invention is also directed to novel compositions and methods for gender-based dosing of non-kappa opioid receptor agonists, preferably mu opioid receptor agonists such as morphine sulfate, and/or opioid antagonists such as naltrexone. Such compositions and methods are designed to achieve appropriate and even optimal analgesia, and are useful for treating moderate or severe pain, wherein the pain is either acute or chronic. Appropriate and even optimal analgesia is only possible when pain relief is enhanced, without enhancing and preferably attenuating, adverse side effects of such agonists or antagonists.

The present invention is based in part on additional surprising results from human clinical trials that demonstrate that the analgesic potency and/or the adverse side effects of morphine sulfate, a mu opioid receptor agonist, is gender-specific.

Additionally surprising are gender-specific responses to such agonists, including the discovery of the problem that current methods of treatment with such agomsts result in hypo-analgesia in men, including anti-analgesia, while similar treatment of women results in analgesia but with sigmficant adverse side effects. Compositions and methods described herein provide for the first time a solution to problems related to previously undiscovered differences in drug effects, including pain intensity differences, pain relief or adverse side effects, using such agonists in women and men, including those effects associated with the management of pain.

The present invention is also directed to novel compositions and methods for gender-based dosing of opioid antagonists, such as naltrexone, to avoid hypo- analgesia. This is based in part on surprising results from human clinical trials that the responses to naltrexone, an opioid antagonist, are also gender-specific. Additionally surprising are results that indicate that such an antagonist can act as a partial opioid agonist on opioid receptors differentially in women and men.

The present invention is also directed to novel compositions and methods for gender-based dosing of combinations of non-kappa opioid receptor agonists, preferably mu opioid receptor agonists, with opioid antagonists to achieve optimal analgesia. This is based in part on surprising results from human clinical trials that there are gender-based differences in the interactions between such agonists and antagonists. The present invention provides compositions and methods for administering to a woman, for example, a dose of a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, that alone is analgesic in women but hypo-analgesic in men, while attenuating one or more adverse side effects of such agonists in women. The present invention also provides compositions and methods for administering to a man, for example, a dose of a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, that alone is hypo- analgesic in men but analgesic in women, without substantially enhancing one or more adverse side effects of such agonists in men.

The present invention is also directed to novel compositions and methods for ethnic-based dosing of combinations of opioid receptor agonists, including non-kappa opioid receptor agonists, and preferably mu opioid receptor agonists, with opioid antagonists to achieve optimal analgesia. This is based in part on surprising results from human clinical trials that there are ethnic-based differences in the interactions between such agonists and antagonists.

The present invention provides compositions and methods for administering to a Hispanic man, for example, a dose of opioid receptor agonist, preferably a non- kappa opioid receptor agonist, most preferably a mu opioid receptor agonist, that alone is analgesic in Hispanic men but hypo-analgesic in non-Hispanic men, while attenuating one or more adverse side effects of such agonists in Hispanic men. The present invention also provides compositions and methods for administering to a Black man, for example, a dose of a opioid receptor agonist, preferably a non-kappa opioid receptor agonist, most preferably a mu opioid receptor agonist, that alone is hypo-analgesic in Black men but analgesic in women and/or Hispanic men, without substantially enhancing one or more adverse side effects of such agonists in Black men.

The present invention thus provides compositions and methods for the differential dosing in women and men, for example, with non-kappa opioid receptor agonists, preferably mu opioid receptor agonists, based on co-treatment of such agonists with low doses of opioid receptor antagonists. Specifically provided are compositions and methods of enhancing pain relief or attenuating pain intensity in men comprising administering, for example, to a man a hypo-analgesic dose (including a non-analgesic or anti-analgesic dose) of a mu opioid receptor agonist and a dose of an opioid antagonist that in combination enhances pain relief or attenuates pain intensity. Such compositions and methods convert non-responder human subjects, (e.g., men) into responders. Also specifically provided are compositions and methods of enhancing pain relief or attenuating pain intensity, for example, in women comprising administering to a woman an analgesic dose of a mu opioid receptor agonist and a dose of opioid antagonist that in combination enhances pain relief or attenuates pain intensity comparable to that of the analgesic dose of agonist alone but with attenuation of one or more adverse side effects of the agonist. Thus, compositions and methods for providing, enhancing or maintaining pain relief, as well as for attenuating pain intensity, are specifically provided as gender-specific compositions and methods for women or men.

The present invention provides compositions and methods for the differential dosing in women and men of non-kappa opioid receptor agonists, preferably mu opioid receptor agonists, based on gender-based differences in their pharmacodynamic effects, including pain relief or adverse side effects, from gender- specific interactions of such agonists in women and men. Compositions and methods are provided for administering a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, at a gender-specific compensatory dose based on different pharmacodynamic effects in women and men, wherein such a gender-specific compensatory dose provides enhancement of analgesia and/or attentuation of an adverse side effect of the agonist.

The present invention provides compositions and methods that include a non- kappa opioid receptor agonist, preferably a mu opioid receptor agonist, and an opioid antagonist in amounts that are useful for men only, or for women only, or for both men and women, based on the differences described herein.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the total pain relief (TOTPAR) results at 4 hours (see also Table 4) in the five study groups in Example 1 : placebo; morphine; morphine and low dose (O.Olmg) naltrexone (NTX); morphine and mid dose (0.1 mg) NTX; and morphine and high dose (1.0 mg) NTX.

Figure 2 shows the sum of pain intensity differences (SPID) results at 4 hours (see also Table 5) in the five study groups in Example 1: placebo; morphine; morphine and low dose (O.Olmg) naltrexone (NTX); morphine and mid dose (0.1 mg)

NTX; and morphine and high dose (1.0 mg) NTX.

Figure 3 shows the time to onset of meaningful pain relief results (see also Table 6) in the five study groups in Example 1: placebo; morphine; morphine and low dose (O.Olmg) naltrexone (NTX); morphine and mid dose (0.1 mg) NTX; and morphine and high dose (1.0 mg) NTX.

Figures 4 and 5 show the time to remedication (rescue medication) up to 8 and 24 hours, respectively (see also Table 7) in the five study groups in Example 1: placebo; morphine; morphine and low dose (O.Olmg) naltrexone (NTX); morphine and mid dose (0.1 mg) NTX; and morphine and high dose (1.0 mg) NTX. Figure 6 shows the pain relief results (see also Table 9) for 4 hours in the five study groups in Example 1: placebo represented as small diamonds (0); morphine represented as squares (D); morphine and low dose (0.01 mg) NTX represented as large circles (O); morphine and mid dose (0.1 mg) NTX represented as triangles (Δ); and morphine and high dose (1.0 mg) NTX represented as larger diamonds (0). Figure 7 shows the pain intensity difference (PID) results (see also Table 10) for 4 hours in the five study groups in Example 1: placebo; morphine; morphine and low dose (O.Olmg) naltrexone (NTX); morphine and mid dose (0.1 mg) NTX; and morphine and high dose (1.0 mg) NTX.

Figure 8 shows a summary of adverse side effects of nausea, vomiting, dizziness, headache, somnolence (sedation) or pruritus in the five study groups in Example 1: placebo; morphine; morphine and low dose (O.Olmg) naltrexone (NTX); morphine and mid dose (0.1 mg) NTX; and morphine and high dose (1.0 mg) NTX.

Figures 9B and 9C show the summary of pain intensity difference (SPUD) results at 4 hours (SPID-4) (see also Tables 18A and 18B) for women and men, respectively, in the five study groups as described in Example 2: placebo; morphine (60 mg); morphine and low-dose (0.01 mg) naltrexone (NTX); morphine and mid- dose (0.1 mg) NTX; morphine and high-dose (1.0 mg) NTX.

Figures 10A and 10B show the time to onset of meaningful pain relief results

(see also Tables 19A and 19B) in the five study groups as described in Example 2: placebo; morphine; morphine and low-dose (0.01 mg) naltrexone (NTX); morphine and mid-dose (0.1 mg) NTX; and morphine and high-dose (1.0 mg) NTX, for women and men, respectively.

Figures 11 A and 12A for women, and 11B and 12B for men, show the time to remedication (rescue medication) up to 8 and 24 hours, respectively (see also Tables 20A and 20B) in the five study groups as described in Example 2: placebo; morphine; morphine and low-dose (0.01 mg) naltrexone (NTX); morphine and mid- dose (0.1 mg) NTX; and morphine and high-dose (1.0 mg) NTX, for women and men, respectively.

Figures 13 A for women, and 13B for men, show the pain relief results (see also Tables 22 A and 22B) in the five study groups as described in Example 2: placebo; morphine; morphine and low-dose (0.01 mg) naltrexone (NTX); morphine and mid-dose (0.1 mg) NTX; and morphine and high-dose (1.0 mg) NTX, for women and men, respectively.

Figures 14A for women and 14B for men show the pain intensity difference

(PID) results (see also Tables 23A and 23B) in the five study groups as described in Example 2: placebo; morphine; morphine and low-dose (0.01 mg) naltrexone (NTX); morphine and mid-dose (0.1 mg) NTX; and morphine and high-dose (1.0 mg) NTX, for women and men, respectively. Figures 15A for women (see also Tables 26 A and 26B) and 15B for men (see also Tables 26C and 26D) show a summary of adverse side effects of nausea, vomiting, dizziness, headache, somnolence (sedation) or pruritus in the five study groups as described in Example 2: placebo; morphine (60 mg); morphine and low- dose (0.01 mg) naltrexone (NTX); morphine and mid-dose (0.1 mg) NTX; morphine and high-dose (1.0 mg) NTX.

Figure 16 shows the time to onset of meaningful pain relief results (see also Table 32A) for subjects in the six study groups as described in Example 3: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) naltrexone; morphine and high- dose (0.1 mg) NTX.

Figure 17 shows the time to onset of analgesia results (see also Table 32B) for subjects in the six study groups as described in Example 3: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) naltrexone; morphine and high-dose (0.1 mg)

NTX.

Figure 18 shows the time to remedication (rescue medication) up to 8 hours (see also Table 33) for subjects in the six study groups as described in Example 3: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) naltrexone; morphine and high- dose (0.1 mg) NTX.

Figure 19 shows the time to remedication (rescue medication) up to 8 and 24 hours, (see also Table 33) for subjects in the six study groups as described in Example

3: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) naltrexone; morphine and high-dose (0.1 mg) NTX.

Figure 20 shows the pain relief (PR) results (see also Table 35) for subjects in the six study groups as described in Example 3: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) naltrexone; morphine and high-dose (0.1 mg)

NTX. Figure 21 shows the pain intensity differences (PID) results (see also Table

36) for subjects in the six study groups as described in Example 3: placebo; morphine

(60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) naltrexone; morphine and high-dose (0.1 mg) NTX.

Figure 22 shows the summary of adverse side effects (see also Tables 39A and 39B) of nausea, vomiting, dizziness, headache, somnolence (sedation) or pruritus for subjects in the six study groups as described in Example 3: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) naltrexone; morphine and high-dose (0.1 mg)

NTX.

Figures 23A, 23B and 23C show the summary of pain intensity difference (SPED) results at 4 hours (SPID-4) (see also Tables 44A and 44B) for the total study population, followed by women and men, respectively, in the six study groups as described in Example 4: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) NTX; morphine and high-dose (0.1 mg) NTX.

Figures 24A and 24B show the time to onset of meaningful pain relief results

(see also Tables 45A and 45B) in the six study groups as described in Example 4: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) NTX; morphine and high-dose

(0.1 mg) NTX for men and women respectively.

Figures 25A and 26A for women, and 25B and 26B for men, show the time to remedication (rescue medication) up to 8 and 24 hours, respectively (see also Tables 46A and 46B) in the six study groups as described in Example 4: placebo; morphine; naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) NTX; and morphine and high-dose (0.1 mg) NTX, for women and men, respectively.

Figures 27A for women, and 27B for men, show the pain relief results (see also Tables 48A and 48B) in the six study groups as described in Example 4: placebo; morphine; naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) NTX; and morphine and high- dose (0.1 mg) NTX, for women and men, respectively.

Figures 28A for women and 28B for men show the pain intensity difference (PID) results (see also Tables 49A and 49B) in the six study groups as described in Example 4: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low- dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) NTX; and morphine and high-dose (0.1 mg) NTX, for women and men, respectively.

Figures 29A for women (see also Tables 52A and 52B) and 29B for men (see also Tables 52C and 52D) show a summary of adverse side effects of nausea, vomiting, dizziness, headache, somnolence (sedation) or pruritus in the six study groups described in Example 4: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) NTX; morphine and high-dose (0.1 mg) NTX.

Figure 30 shows the total pain relief (TOTPAR) results (see also Table 56) for subjects in the six study groups as described in Example 5: placebo (A); HC/APAP

(B); HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and 0.1 mg NTX (D); HC/APAP and 0.01 mg NTX (E); HC/APAP and 0.001 mg NTX (F).

Figure 31 shows the summary of pain intensity difference (SPID) results at 4 hours (SPID-4), at 6 hours (SPID-6), and at 8 hours (SPID-8) (see also Table 57) for subjects in the six study groups as described in Example 5: placebo (A); HC/APAP

(B); HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and 0.1 mg NTX (D);

HC/APAP and 0.01 mg NTX (E); HC/APAP and 0.001 mg NTX (F).

Figure 32 shows the time to onset of meaningful pain relief results (see also Table 58 A) for subjects in the six study groups as described in Example 5: placebo (A); HC/APAP (B); HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and 0.1 mg NTX (D); HC/APAP and 0.01 mg NTX (E); HC/APAP and 0.001 mg NTX (F).

Figure 33 shows the time to onset to analgesia results (see also Table 58B) for subjects in the six study groups as described in Example 5: placebo (A); HC/APAP (B); HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and 0.1 mg NTX (D); HC/APAP and 0.01 mg NTX (E); HC/APAP and 0.001 mg NTX (F).

Figure 34 shows the time to remedication (rescue medication) up to 8 hours (see also Table 59) for subjects in the six study groups as described in Example 5: placebo (A); HC/APAP (B); HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and 0.1 mg NTX (D); HC/APAP and 0.01 mg NTX (E); HC/APAP and 0.001 mg NTX (F).

Figure 35 shows the pain relief (PR) results (see also Table 61) for subjects in the six study groups as described in Example 5: placebo (A); HC/APAP (B);

HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and 0.1 mg NTX (D); HC/APAP and 0.01 mg NTX (E); HC/APAP and 0.001 mg NTX (F).

Figure 36 shows the pain intensity differences (PID) results (see also Table 62) for subjects in the six study groups as described in Example 5: placebo (A); HC/APAP (B); HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and 0.1 mg

NTX (D); HC/APAP and 0.01 mg NTX (E); HC/APAP and 0.001 mg NTX (F).

Figure 37 shows the summary of adverse side effects (see also Table 65) of nausea, vomiting, dizziness, headache, somnolence (sedation) or pruritus for subjects in the six study groups as described in Example 5: placebo; HC/APAP; HC/APAP and 1.0 mg naltrexone (NTX); HC/APAP and 0.1 mg NTX; HC/APAP and 0.01 mg

NTX; HC/APAP and 0.001 mg NTX.

Figures 38B and 38C show the summary of pain intensity difference (SPID) results at 4 hours (SPID-4) (see also Tables 69A and 69B) for women and men, respectively, in the six study groups as described in Example 6: placebo; HC (5 mg)/ APAP (500 mg); HC/APAP and 0.001 mg naltrexone (NTX); HC/APAP and 0.01 mg

NTX; HC/APAP and 0.1 mg NTX; HC/APAP and 1.0 mg NTX.

Figures 39A and 39B show the time to remedication (rescue medication) up to

8 hours, for women and men, respectively (see also Tables 72A and 72B) in the six study groups as described in Example 6: placebo (A); HC/APAP (B); HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and 0.1 mg NTX (D); HC/APAP and 0.01 mg NTX (E); HC/APAP and 0.001 mg NTX (F)

Figures 40A for women and 40B for men show a summary of adverse side effects (see also Tables 77A and 77B) of nausea, vomiting, dizziness, headache, somnolence (sedation) or pruritus in the six study groups described in Example 6: placebo; HC (5 mg)/ APAP (500 mg); HC/APAP and 0.001 mg naltrexone (NTX);

HC/APAP and 0.01 mg NTX; HC/APAP and 0.1 mg NTX; HC/APAP and 1.0 mg NTX. Figure 41 shows the total pain relief (TOTPAR) results (see also Table 81) for subjects in the seven study groups as described in Example 7: placebo; morphine (30 mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and NTX (0.1 mg). Figure 42 shows the summary of pain intensity difference (SPID) results at 4 hours (SPID-4) (see also Table 82) for subjects in the seven study groups as described in Example 7: placebo; morphine (30 mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and NTX (0.1 mg). Figure 43 shows the probability to onset of analgesia (see also Table 43) for subjects in the seven study groups as described in Example 7: placebo; morphine (30 mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and NTX (0.1 mg).

Figure 44 shows the probability to remedication (rescue medication) over time up to 24 hours (see also Table 84) for subjects in the seven study groups as described in Example 7: placebo; morphine (30 mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and NTX (0.1 mg).

Figure 45 shows the pain relief (PR) results (see also Table 86) for subjects in the seven study groups as described in Example 7: placebo; morphine (30 mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and NTX (0.1 mg).

Figure 46 shows the pain intensity differences (PID) results (see also Table

87) for subjects in the seven study groups as described in Example 7: placebo; morphine (30 mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 mg); moφhine (60 mg) and NTX (0.1 mg); morphine (90 mg); moφhine (90 mg) and NTX

(0.1 mg).

Figure 47 shows the global evaluations of pain relief (see also Table 89) for subjects in the seven study groups as described in Example 7: placebo; moφhine (30 mg); moφhine (30 mg) and NTX (0.1 mg); moφhine (60 mg); moφhine (60 mg) and

NTX (0.1 mg); moφhine (90 mg); moφhine (90 mg) and NTX (0.1 mg). Figure 48 shows the summary of adverse side effects (see also Table 90) of nausea, vomiting, dizziness, headache, somnolence (sedation) or pruritus for subjects in the seven study groups as described in Example 7: placebo; moφhine (30 mg); moφhine (30 mg) and NTX (0.1 mg); moφhine (60 mg); moφhine (60 mg) and NTX (0.1 mg); moφhine (90 mg); moφhine (90 mg) and NTX (0.1 mg).

Figure 49 shows the day-one mean pain intensity difference (PID) results (see also Table 91) for the three intrathecal moφhine study groups as described in Example 8: placebo, NTX (0.001 mg), and NTX (0.01 mg).

Figure 50 shows the mean pain intensity difference (PID) results (see also Table 92) for days two through seven results for the three intrathecal moφhine study groups as described in Example 8: placebo, NTX (0.001 mg), and NTX (0.01 mg).

Figure 51 shows the day-one pain intensity difference (PID) results moφhine study groups as described in Example 8: Tables 93 A and 93B for days two through eight results for the three intrathecal placebo, NTX (0.001 mg), and NTX (0.01 mg). Figures 52 A and 52B show the mean hourly pain intensity difference (PID) results for women and men, respectively, in the five study groups as described in Example 9: placebo (A); tramadol and placebo (B); tramadol and 1.0 mg naltrexone (NTX) (C); tramadol and 0.1 mg NTX (D); tramadol and 0.01 mg NTX (E).

DETAILED DESCRIPTION

The present invention is directed to novel compositions and methods with opioid agonists and opioid antagonists. Novel combinations of such agonists and antagonists were unexpectedly efficacious in enhancing the analgesic potency of the agonist without attenuating (e.g., reducing, blocking, inhibiting or preventing) the side effects of the agonist in humans, or maintaining the analgesic potency of the agonist while attenuating (e.g., reducing, blocking, inhibiting or preventing) side effects of the agonist in humans.

The present invention is based on suφrising results from clinical trials that the analgesic potency effects of opioid agonists can be dissociated from their adverse effects in humans. Thus, for the first time, the present invention provides compositions and methods to differentially dose or treat humans with opioid agonists and opioid antagonists to specifically either (1) enhance (e.g., increase) analgesic potency of the opioid agonists without substantially reducing or increasing (e.g., maintain) the adverse side effects in humans associated with that dose of agonist; or (2) maintain the analgesic potency (e.g., neither substantially increase or decrease potency) of the opioid agonists while attenuating (e.g., reducing, blocking, inhibiting or preventing) the adverse side effects in humans associated with that dose of agonist.

For compositions and methods of the invention that enhance analgesic potency of the opioid agonist, it is advantageous that adverse side effects are maintained or not increased with that enhanced (e.g., increased) potency. For compositions and methods of the invention that attenuate (e.g., reduce, block or prevent) the adverse side effects of the opioid agonist, it is advantageous that the analgesic potency is maintained without increasing or decreasing the cumulative daily dose of agonist.

The present invention is also directed to novel compositions of and methods using non-kappa opioid receptor agonists, preferably mu opioid receptor agonists, and opioid antagonists for gender-based dosing of the agonist and/or the antagonist in men and women. Such novel combinations of such agonists and antagonists are unexpectedly efficacious in enhancing (e.g., increasing) the analgesic potency of the agomsts without enhancing the side effects of the agonists in men, and in maintaining the analgesic potency of the agonist while attenuating (e.g., reducing, blocking, inhibiting or preventing) the adverse side effects of the agonist in women. The present invention is based on several surprising results from human clinical trials, including that (i) the analgesic potency and/or the adverse side effects of moφhine sulfate, a non-kappa (mu) opioid receptor agonist is gender-specific; (ii) the effects of naltrexone, an opioid antagonist, are gender-specific, and it appears to act as a partial opioid agonist on opioid receptors in women and men, but its partial agonist effects are gender-specific; and (iii) interactions between such a non-kappa

(mu) opioid receptor agonist and an opioid antagonist are gender-specific. Additionally suφrising from these clinical trials is that the analgesic activity, including analgesic potency, of such non-kappa (mu) opioid receptor agonists can be dissociated from their adverse effects in humans based upon gender. Thus, for the first time, the present invention provides compositions and methods for the differential dosing of non-kappa opioid receptor agonists, perferably mu opioid receptor agonists, and/or opioid antagonists in men and women. Compositions and methods according to the invention include those that yield, for example, either (1) analgesia in men using a hypo-analgesic dose (including a non-analgesic or anti- analgesic dose) of a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, and a dose of opioid receptor antagonist that in combination provides or enhances analgesia, thus converting non-responder human subjects (e.g. men) into responder, or (2) analgesia in women using an analgesic dose of a non- kappa opioid receptor agonist, preferably a mu opioid receptor agonist, and a dose of opioid receptor antagonist that in combination maintains the analgesia comparable to that of the against alone, but with attenuation (e.g., in number and/or severity) of one or more of the adverse side effects associated with such an agomst.

For compositions and methods of the invention that provide or enhance (e.g., increase) pain relief or attenuate (e.g., decrease) pain intensity with a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, for example, in men, it is advantageous that the adverse side effects associated with the agonist are not enhanced with the provided or enhanced pain relief or attenuated pain intensity. For compositions and methods of the invention that enhance pain relief or attenuate pain intensity of a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, for example, in women, it is advantageous that the adverse side effects are attenuated. For compositions and methods of the invention that attenuate the adverse side effects (e.g., in number and/or severity) of such agonists, it is advantageous that the analgesic potency be maintained while decreasing the cumulative 24 hour dose of such agonists, thus maintaining responder human subjects (e.g., women) as responders but with attenuation of one or more adverse side effects.

Compositions and methods according to the invention include those with a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, and opioid antagonist in amounts that are useful for men only, useful for women only, or useful for both men and women, taking into account the gender-based differences described and claimed herein. Such compositions and methods are useful to provide or enhance pain relief, attenuate pain intensity, or attenuate one or more of the adverse side effects of the agonist. It will be appreciated that compositions and methods of the invention useful for human subjects (e.g., patients) will be primarily of use in the alleviation or attenuation of established symptoms but prophylaxis is not excluded.

The term "opioid" refers to compounds or compositions including metabolites of such compounds or compositions which bind to specific opioid receptors and have agonist (activation) or antagonist (inactivation) effects at these receptors, such as opioid alkaloids, including the agonist moφhine and its metabolite moφhine-6- glucuronide and the antagonist naltrexone and its metabolite and opioid peptides, including enkephalins, dynoφhins and endoφhins. The opioid can be present as a member selected from an opioid base and an opioid pharmaceutically acceptable salt.

The pharmaceutically acceptable salt embraces an inorganic or an organic salt. Representative salts include hydrobromide, hydrochloride, mucate, succinate, n-oxide, sulfate, malonate, acetate, phosphate dibasic, phosphate monobasic, acetate trihydrate, bi(heplafluorobutyrate), maleate, bi(methylcarbamate), bi(pentafluoropropionate), mesylate, bi(pyridine-3-carboxylate), bi(trifluoroacetate), bitartrate, chlorhydrate, fumarate and sulfate pentahydrate. The term "opiate" refers to drugs derived from opium or related analogs.

An "opioid receptor agonist" or "opioid agonist" is an opioid compound or composition including any active metabolite of such compound or composition that binds to and activates opioid receptors, for example, on nociceptive neurons which mediate pain. Such agonists have analgesic activity (with measurable onset, peak, duration and/or total effect) and can produce analgesia. Opioid agonists include: alfentanil, allylprodine, alphaprodine, anileridine, apomoφhine, apocodeine, benzylmoφhine, bezitramide, buprenoφhine, butoφhanol, clonitazene, codeine, cyclazocine, cycloφhen, cyprenoφhine, desomoφhine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromoφhine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmoφhine, etonitazene, fentanyl, heroin, hydrocodone, hydroxymethylmoφhinan, hydromoφhone, hydroxypethidine, isomethadone, ketobemidone, levalloφhan, levoφhanol, levophenacylmoφhan, lofentanil, meperidine, meptazinol, metazocine, methadone, methylmoφhine, metopon, moφhine, myrophine, nalbuphine, narceine, nicomoφhine, norlevoφhanol, normethadone, naloφhine, normoφhine, noφipanone, ohmefentanyl, opium, oxycodone, oxymoφhone, papaveretum, pentazocine, phenadoxone, phenomoφhan, phenazocine, phenoperidine, pholcodine, piminodine, piritramide, propheptazine, promedol, profadol, properidine, propiram, propoxyphene, remifentanil, sufentanil, tramadol, tilidine, salts thereof, mixtures of any of the foregoing, mixed mu- agonists/antagonists, mu-antagonist combinations, or the like. Preferred opioid agonists for human use are moφhine, hydrocodone, oxycodone, codeine, fentanyl (and its relatives), hydromoφhone, meperidine, methadone, oxymoφhone, propoxyphene or tramadol, or mixtures thereof. Particularly preferred opioid agonists include moφhine, hydrocodone, oxycodone or tramadol. Opioid agomsts include exogenous or endogenous opioids.

"Bimodally-acting opioid agonists" are opioid agonists that bind to and activate both inhibitory and excitatory opioid receptors on nociceptive neurons which mediate pain. Activation of inhibitory receptors by said agonists causes analgesia. Activation of excitatory receptors by said agonists results in anti-analgesia, hyperexcitability, hyperalgesia, as well as development of physical dependence, tolerance and other undesirable side effects. Bimodally-acting opioid agonists may be identified by measuring the opioid's effect on the action potential duration (APD) of dorsal root ganglion (DRG) neurons in tissue cultures. In this regard, bimodally- acting opioid agonists are compounds which elicit prolongation of the APD of DRG neurons at pM-nM concentrations (i.e., excitatory effects), and shortening of the APD of DRG neurons at μM concentrations (i.e., inhibitory effects).

A "non-kappa opioid receptor agonist" or "moφhine-like opioid receptor agonist" is an opioid agonist that primarily binds to and/or interacts with opioid receptors that are not kappa receptors and does not produce its therapeutic effects primarily via kappa opioid receptors. Such agonists include mu, delta and sigma opioid receptor agonists and specifically exclude kappa opioid receptor agonists. Such agonists exclude, for example, agonists that primarily bind to and interact with kappa opioid receptors, and from such interactions produce their therapeutic effects (e-g-, analgesic activity), such as pentazocine, nalbuphine and butoφhanol. Such agonists include, for example, moφhine, hydrocodone, oxycodone, codeine, hydromoφhone, levoφhanol, meperidine, fentanyl, (and its relatives), oxymoφhone, propoxyphene, methadone or tramadol. A preferred non-kappa opioid agonist is a mu opioid receptor agonist. According to the invention, such agonists include an agonist that exhibits non-kappa gender-based effects in men and women as described and claimed herein. A "mu opioid receptor agonist" is an opioid agonist that primarily binds to and/or interacts with mu opioid receptors and from such interactions produces its therapeutic effects (e.g., analgesic activity), such as moφhine, hydrocodone, and oxycodone, but excluding agonists that primarily bind to and interact with kappa opioid receptors, and from such interactions produce their therapeutic effects (e.g., analgesic activity), such as pentazocine, nalbuphine and butoφhanol.

A "delta opioid receptor agonist" is an opioid agonist that primarily binds to and/or interacts with delta opioid receptors and from such interactions produces its therapeutic effects (e.g., analgesic activity), but excluding agonists that primarily bind to and interact with kappa opioid receptors, and from such interactions produce their therapeutic effects (e.g., analgesic activity), such as pentazocine, nalbuphine and butoφhanol. Selective delta opioid receptor agonists include those described by U.S. Patent Nos. 5,389,645 and 5,985,880 hereby incoφorated by reference in its entirety [e.g., a cyclic enkephalin analog [D-Pen , D-Pen ] -(enkephalin) and, heptapeptides of frog skin origin [deltoφhin I and II] (see also U.S. Patent No. 4,518,711 hereby incoφorated by reference in its entirety)].

A "mu-delta opioid receptor agonist" is an opioid agonist that primarily binds to and/or interacts with mu and delta opioid receptors and from such interactions produces its therapeutic effects (e.g., analgesic activity), but excluding agonists that primarily bind to and interact with kappa opioid receptors, and from such interactions produce their therapeutic effects (e.g., analgesic activity), such as pentazocine, nalbuphine and butoφhenal. Selective mu-delta opioid receptor agonists include those described by U.S. Patent No. 5,389,645 hereby incoφorated by reference in its entirety [e.g., tyrosyldiamine amide opioid agonists such as U.S. Patent No. 6,054,557 hereby incoφorated by reference in its entirety; U.S. Patent No. 5,872,097 hereby incoφorated by reference in its entirety; U.S. Patent Nos. 6,568,908, 5,681,830,

5,658,908 and 5,854,249, each and all incoφorated by reference in their entirety [e.g., diarylmethylpiperazines and piperdines such as 3-((α R) - α - ((2S, 5R) - 4 - allyl - 2, 5, - dimethyl - 1 - piperazinyl) -3-hydroxybenzyl) - N, N-diethylbenzamine]; and the synthetic pentapeptide known as DADLE (see, e.g., U.S. Patent No. 5,985,600 hereby incoφorated by reference in its entirety).

A "kappa opioid receptor agonist" is an opioid agonist that primarily binds to and/or interacts with kappa opioid receptors and from such interactions produces its therapeutic effects (e.g., analgesic activity), including, for example, pentazocine, nalbuphine and butoφhenol. Selective kappa opioid agonists include those described by: U.S. Patent No. 4,923,863 hereby incoφorated by reference in its entirety [e.g., moφholine derivatives]; U.S. Patent No. 6,110,947 hereby incoφorated by reference in its entirety [e.g., pyrrolidinyl hydroxamic acid compounds]; U.S. Patent No.

5,965,701 hereby incoφorated by reference in its entirety [e.g., kappa receptor opioid peptides with affinity for the kappa opioid receptor at least 1,000 times greater than its affinity for the mu opioid receptor].

A "sigma opioid receptor agonist" is an opioid agonist that primarily binds to and/or interacts with sigma opioid receptors and from such interactions produces its therapeutic effects (e.g., analgesic activity), but excluding agonists that primarily bind to and interact with kappa opioid receptors, and from such interactions produce their therapeutic effects (e.g., analgesic activity), such as pentazocine, nalbuphine and butoφhanol. Selective sigma opioid agonists include those described by: U.S. Patent Nos. 5,656,633 and 5,556,857, both incoφorated by reference (e.g., carbostyril derivatives).

An "opioid antagonist" is an opioid compound or composition including any active metabolite of such compound or composition that in a sufficient amount attenuates (e.g., blocks, inhibits, or competes with) the action of an opioid agonist. An "effective antagonistic" amount is one which effectively attenuates the analgesic activity of an opioid agonist. An opioid antagonist binds to and blocks (e.g., inhibits) opioid receptors, for example, on nociceptive neurons which mediate pain. Opioid antagonists according to the present invention include: naltrexone, naloxone nalmefene, naloxone methiodide, naloφhine, naloxonazine, nalide, nalmexone, nalbuphine, naloφhine dinicotinate, naltrindole (NTI), naltrindole isothiocyanate,

(NTH), naltriben (NTB), nor-binaltoφhimine (nor-BNI), b-funaltrexamine (b-FNA), BNTX, cyprodime, ICI-174,864, LYl 17413, MR2266, or an opioid antagonist having the same pentacyclic nucleus as nalmefene, naltrexone, naloφhine, nalbuphine, thebaine, levalloφhan, oxymoφhone, butoφhanol, buprenoφhine, levoφhanol, meptazinol, pentazocine, dezocine, or their pharmacologically effective esters or salts. An opioid antagonist with partial agonist activity is cholera toxin B. Preferred opioid antagonists include naltrexone, nalmefene, naloxone, or mixtures thereof. Particularly preferred antagonists include naltrexone and nalmefene. Naltrexone as a most preferred opioid antagonist.

"Excitatory opioid receptor antagomsts" are opioids which bind to and act as antagonists to excitatory but not inhibitory opioid receptors on nociceptive neurons which mediate pain. That is, excitatory opioid receptor antagonists are compounds which bind to excitatory opioid receptors and selectively block excitatory opioid receptor functions of nociceptive types of DRG neurons at 1,000 to 10,000-fold lower concentrations than are required to block inhibitory opioid receptor functions in these neurons. Excitatory opioid receptor antagonists may also be identified by measuring their effect on the action potential duration (APD) of dorsal root ganglion (DRG) neurons in tissue cultures. In this regard, excitatory opioid receptor antagonists are compounds which selectively block prolongation of the APD of DRG neurons (i.e., excitatory effects) but not the shortening of the APD of DRG neurons (i.e., inhibitory effects) elicited by a bimodally-acting opioid receptor agonist. Preferred excitatory opioid receptor antagonists are naltrexone and nalmefene because of their longer duration of action as compared to naloxone and their greater bioavailability after oral administration.

Other compounds and compositions of opioid agonists, including non-kappa opioid receptor agonists, preferably mu opioid receptor agonists, and opioid antagonists are known and will be readily apparent to those skilled in the art, once armed with the present disclosure.

The opioid agonists or opioid antagonists may be provided in the form of free bases or pharmaceutically acceptable acid addition salts. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the therapeutic compound is modified by making acid or base salts thereof.

The pharmaceutically acceptable salt embraces an inorganic or an organic salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the opioid antagonist or opioid agonist. The pharmaceutically acceptable salts include the conventional non-toxic salts made, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and others known to those skilled in the art; and the salts prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, malonic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, glucuronic, and other acids. Other pharmaceutically acceptable salts and variants include mucates, phosphate (dibasic), phosphate (monobasic), acetate trihydrate, bi(heptaflourobutyrate), bi(methylcarbamate), bi(pentaflouropropionate), mesylate, bi(pyridine-3-carboxylate), bi(triflouroacetate), bitartrate, chlorhydrate, and sulfate pentahydrate. An oxide, though not usually referred to by chemists as a salt, is also a "pharmaceutically acceptable salt" for the present puφose. For acidic compounds, the salt may include an amine-based (primary, secondary, tertiary or quaternary amine) counter ion, an alkali metal cation, or a metal cation. Lists of suitable salts are found in texts such as Remington's Pharmaceutical Sciences, 18^th Ed. (Alfonso R. Gennaro, ed.; Mack Publishing

Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy 19^th Ed. (Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3^rd Ed. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc, 1999); the Pharmaceutical Codex: Principles and Practice of Pharmaceutics V Ed. (Walter Lund ed.; Pharmaceutical Press, London, 1994); The United States Pharmacopeia:

The National Formulary (United States Pharmacopeial Convention); and Goodman and Gilman's: the Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill, 1992), the disclosures of which are hereby incoφorated by reference. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ration.

An "adverse side effect" of an opioid agonist is a side effect in humans, typically associated with opioid analgesics such as moφhine, including nausea, vomiting, dizziness, somnolence/sedation, pruritus, reduced gastrointestinal mortality including constipation, difficulty in urination, peripheral vasodilation including leading to orthostatic hypotension, headache, dry mouth, sweating, asthenia, dependence, mood changes (e.g., dysphoria, euphoria), or lightheadedness. An "adverse side effect" also includes a serious adverse side effect such as respiratory depression or also apnea, respiratory arrest, circulatory depression, hypotension or shock.

As demonstrated herein, opioid agonists may produce certain adverse side effects. Among the side effects that have been recognized for products containing moφhine or other opioid agonists are: respiratory depression; depression of the cough reflex; miosis; reduced gastrointestinal motility including constipation; peripheral vasodilation which may result in orthostatic hypotension; and release of histamine. Adverse side effects that are of particular interest in human subjects include nausea, vomiting, dizziness, headache, somnolence (sedation), and pruritus. Some additional adverse side effects are listed in the Physician Desk Reference (PDR) for selected opioid agonists as follows: moφhine: respiratory depression; apnea; circulatory depression; shock respiratory arrest, and cardiac arrest; oxycodone: light-headedness, euphoria, dysphoria, constipation, skin rash; hydrocodone: mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria, dependence, mood changes; constipation; ureteral spasm; spasm of vesical sphincter and urinary retention; and tramadol: seizures; anaphylactoid reactions (lessened resistance to toxins); asthenia; sweating; dyspepsia; dry mouth; dianhea; CNS stimulation ("CNS stimulation" is a composite that can include nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional liability and hallucinations); malaise; vasodilation; anxiety, confusion, coordination disturbance, euphoria, nervousness, sleep disorder; abdominal pain, anorexia, flatulence, hypertonia, rash, visual disturbance, menopausal symptoms, urinary frequency, urinary retention. "Co-administer," "co-administration," "concurrent administration" or "co- treatment" refers to administration of an opioid agonist and an opioid antagonist, in conjunction or combination, together, or before or after each other. The opioid agonist and the opioid antagonist may be administered by different routes. For example, the agonist may be administered orally and the antagonist intravenously, or vice versa. The opioid agonist and opioid antagonist are preferably both administered orally, as immediate or sustained release formulations. The opioid agonist and opioid antagonist may be administered simultaneously or sequentially, as long as they are given in a manner to allow both agents to achieve effective concentrations to yield their desirable therapeutic effects (e.g., analgesia). Optionally, an additional active pharmaceutical ingredient may be co-administered with the opioid agonist and opioid antagonist. For example, other active pharmaceutical ingredients include acetaminophen as shown herein, steroidal drugs or non-steroidal anti-inflammatory drugs (NSAΓDS) such as ibuprofen, COX-1 and/or COX-2 inhibitors such as aspirin, rofecoxib (marketed as VIOXX®), and celcoxib (marketed as CELEBREX™).

"Combination" refers to more than one active compound or active pharmaceutical ingredient (API), including for example, a combination of opioid agonist and opioid antagonist.

"Therapeutic effect" or "therapeutically effective" refers to an effect or effectiveness that is desirable and that is an intended effect associated with the administration of an opioid agonist including the opioid agonist in combination with an opioid antagonist according to the invention, including, for example, analgesia, pain relief, decrease in pain intensity, euphoria or feeling good or calming so as to reduce heart rate, blood pressure or breathing rate. The opioid agonists preferably and the opioid antagomsts for use in the present invention may be in the form of free bases or pharmaceutically acceptable acid addition salts thereof.

The opioid antagonist alone, or in combination with the opioid agonist, may be administered to the human subject by known procedures including but not limited to oral, sublingual, transmucosal (including buccal), intramuscular, subcutaneous, intravenous, intratracheal, or transdermal modes of administration. When a combination of these compounds are administered, they may be administered together in the same composition, or may be administered in separate compositions. If the opioid agonist and the opioid antagonist are administered in separate compositions, they may be administered by similar or different modes of administration, or may be administered simultaneously with one another, or shortly before or after the other. The opioid agonists and the opioid antagonists may be formulated in compositions with a pharmaceutically acceptable carrier. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Examples of suitable pharmaceutical carriers include lactose, sucrose, starch, talc, magnesium stearate, crystalline cellulose, methyl cellulose, carboxymethyl cellulose, glycerin, sodium alginate, gum arabic, powders, saline, water, among others. The formulations may conveniently be presented in unit dosage and may be prepared by methods well- known in the pharmaceutical art, by bringing the active compound into association with a carrier or diluent, as a suspension or solution, or optionally with one or more accessory ingredients, e.g., buffers, flavoring agents, surface active agents, or the like.

The choice of carrier will depend upon the route of administration. "Unit dose form" or "unit dosage form" refers to physically discreet units suitable as unitary doses for human subjects, each unit containing a predetermined quantity of active material (e.g., non-kappa opioid receptor agonist and/or opioid antagonist and/or other active pharmaceutical ingredient) calculated to produce the desired therapeutic effect (e.g., analgesia), in association with a suitable pharmaceutical carrier. Thus, the active ingredients according to the invention (e.g., agonist, antagonist, or other active pharmaceutical ingredient) either each alone or in combination may conveniently be presented to the subject for administration in unit dose form. For oral or sublingual administration, including transmucosal, the formulation may be presented as capsules, tablets, caplets, pills, powders, granules or a suspension, prepared by conventional means with pharmaceutically acceptable excipients, e.g., with conventional additives or fillers such as lactose, mannitol, corn starch or potato starch; with binders or binding agents such as crystalline cellulose, cellulose derivatives, acacia, corn starch (including pregelatinized) or gelatins; with disintegrators or disintegrants such as corn starch, potato starch or sodium carboxymethyl-cellulose; or with lubricants or wetting agents such as talc or magnesium stearate. Tablets may be coated, including by methods well known in the art. The formulation may be presented as an immediate-release or as a slow-release, sustained-release or controlled-release form. The formulation may also be presented as a solid drug matrix, for example, on a handle. Oral dose forms for human administration include: codeine, dihydrocodeine (e.g., SYNALGOS-DC® from

Wyeth-Ayerst Pharmaceuticals), fentanyl (e.g., ACTIQ® from Abbott Laboratories)., hydrocodone (e.g., VICODIN® and VICOPROFEN® from Knoll Laboratories; NORCO® from Watson Laboratories; HYCODAN® from Endo Pharmaceuticals; NORCET® from Abara; ANEXSIA®, HYDROCET®, and LORCET-HD® from Mallinckrodt; LORTAB® from UCB Pharma; HY-PHEN® from Ascher; CO-

GESIC® from Schwarz Pharma; ALLAY® from Zenith Goldline), hydromoφhone (e.g., DILAUDID® from Knoll), levoφhanol (e.g., LEVO-DROMORAN® from ICN Pharmaceuticals), meperidine (e.g., DEMEROL® from Sanofi Pharmaceuticals), methadone (e.g., METHADOSE® from Mallinckrodt; and DOLOPHINE® HCl from Roxane Laboratories), moφhine (e.g., KADIAN® from Faulding Laboratories; MS

CONTIN® from Purdue Frederick; ORAMORPH® SR from Roxane), oxycodone (e.g, PERCOCET® and PERCODAN® from Endo; OXYCET® from Mallinckrodt; OXYCONTLN® from Purdue Frederick; TYLOX® from Ortho-McNeil Pharmaceutical; ROXICODONE®, ROXILOX® and ROXICET® from Roxane), pentazocine (e.g., TALACEN® and TALWIN® from Sanofi Pharmaceuticals), propoxyphene (e.g., DARVOCET-N® and DARVON® from Eli Lilly & Co.; DOLENE® from Lederle; WYGESIC® from Wyeth-Ayerst), and tramadol (e.g., ULTRAM® from Ortho-McNeil Pharmaceutical).

Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Liquid dose forms for human administration include: hydrocodone (e.g., HYDROPHANE® from Halsey), hydromoφhone (e.g., DILAUDID® from Knoll), meperidine (e.g., DEMEROL® from Sanofi), methadone (e.g., DOLOPHINE® from Roxane), oxycodone (e.g., HYCOMLNE® from Knoll; ROXTLOX® from Roxane), and propoxyphene (e.g., DARNON-N® from Eli Lilly). For parenteral administration, including intravenous, intramuscular, or subcutaneous administration, the compounds may be combined with a sterile aqueous solution which is preferably isotonic with the blood of the recipient. Such formulations may be prepared by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride, glycine, or the like, and/or having a buffered pH compatible with physiological conditions to produce an aqueous solution, and/or rendering said solution sterile. The formulations may be present in unit dose forms or multi-dose forms, including in containers such as sealed ampoules or vials. Parenteral dose forms for human administration include: alfentanil (e.g., ALFENTA® from Akorn), buprenoφhine (e.g., BUPRENEX® from Reckitt & Colman Pharmaceuticals), butoφhanol (e.g., STADOL® from Apothecon), dezocine (e.g., DALGAN® from Astrazeneca), fentanyl, hydromoφhone (e.g., DILAUDID-HP® from Knoll), levalloφhan (e.g., LORFAN® from Roche), levoφhanol (e.g., LEVO-DROMORAN® from ICN), meperidine (e.g., DEMEROL® from Sanofi), methadone (e.g., DOLOPHINE® HCl from Roxane), moφhine (e.g, ASTRAMORPH® from Astrazeneca; DURAMORPH® and INFUMORPH® from

Elkins-Sinn), oxymoφhone (e.g., NUMORPHAN® from Endo), nalbuφhine (e.g., NUBAIN® from Endo Pharmaceutical), and pentazocine (TALWLN® from Abbott).

For transdermal administration, the compounds may be combined with skin penetration enhancers such as propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, N-methylpyrrolidone, or the like, which increase the permeability of the skin to the compounds, and permit the compounds to penetrate through the skin and into the bloodstream. The compound/enhancer compositions also may be combined additionally with a polymeric substance such as ethylcellulose, hydroxypropyl cellulose, ethylene/vinylacetate, polyvinyl pyrrolidone, or the like, to provide the composition in gel form, which can be dissolved in solvent such as methylene chloride, evaporated to the desired viscosity, and then applied to backing material to provide a patch. Transdermal dose forms for human administration include fentanyl (e.g., DURAGESIC® from Janssen).

Additional dose forms available as suppositories for human administration include oxymoφhone (e.g., NUMORPHAN® from Endo). "Analgesia" refers to the attenuation, reduction or absence of sensibility to pain, including the provision of pain relief, the enhancement of pain relief, or the attenuation of pain intensity. An "analgesic" amount refers to an amount of the opioid agonist which causes analgesia in a subject administered the opioid agonist alone, and includes standard doses of the agonist which are typically administered to cause analgesia (e.g., mg doses). An "analgesic" amount also refers to an amount that results in analgesic efficacy, for example, as measured by a female or male subject with a pain relief score or a pain intensity difference score, at a given time point, or over time, or as compared to a baseline, and includes calculations based on area under the curve such as TOTPAR or SPID from such pain relief scores or pain intensity difference scores. A "hypo-analgesic" amount is a less-than-analgesic amount, including an amount which is not analgesic or is weakly analgesic in a subject administered the opioid agonist alone, and further includes an "anti-analgesic" or "algesic" amount which is an amount which increases pain. For example, men or women in the opioid antagonist may be administered in an amount effective to provide or enhance the analgesic potency (e.g., as measured by pain relief or pain intensity difference) of the opioid agonist, without substantially increasing (e.g., maintaining) the adverse side effects as compared to the agonist alone. For example, in women or men, the opioid antagonist may be administered in an amount effective to maintain the analgesic potency (e.g., maintain analgesia as measured by pain relief or pain intensity differences) of the opioid against, while attenuating one or more adverse side effects of the agonist. The opioid antagonist may be administered in an amount effective to produce or enhance analgesic potency in combination with, for example, a mu opioid receptor agonist. The optimum amounts, for example, of the opioid agonist and the opioid antagonist administered, will of course depend upon the particular agonist and antagonist used, the carrier chosen, the route of administration, and/or the pharmacokinetic properties of the subject being treated, as well as the desired gender-related effects according to the teachings of the present invention. When the opioid antagonist is administered alone, the amount of the opioid antagonist administered is an amount effective to enhance or maintain the analgesic potency of the opioid agonist and/or attenuate or maintain the adverse side effects of the opioid agonist, according to the teachings of the present invention. Examples 1-9 that follow, describe in detail, results from human clinical trials, including those with a retrospective or prospective gender analysis, that unexpectedly demonstrate that the responses to opioid agonists such as moφhine, hydrocodone, or tramadol and the responses to naltrexone, an opioid antagonist, as well as the responses to the interactions between, such an agonist and antagonist, show suφrising effects in humans, including suφrising clinical benefits from the combination of such agonists and antagonists. Such clinical benefits include enhancing the potency (e.g., increasing pain relief or decreasing pain intensity in humans) of a dose of the opioid agonist, while maintaining the adverse side effects of the agonist at that dose or maintaining the potency of a dose of the opioid agonist while attenuating (e.g., reducing, blocking, inhibiting or preventing) one or more adverse side effects in humans associated with that dose of agonist. The responses to non-kappa opioid receptor agonists, such as moφhine, hydrocodone or tramadol are strikingly different in women and men. By way of example, Examples 1-4 and 7 describe data that have been collected from observations in populations of human patients, wherein males and/or females were subjected to painful stimulation during the course of dental extractions and then treated with naltrexone and/or moφhine. In Examples 1 and 2, subjects had two or more impacted third molars requiring extraction, wherein at least one extracted tooth was a partial or full bony mandibular impaction. hi Examples 3-4 and 7, subjects had three or four full or partial bony impacted third molars requiring extraction. The levels of pain experienced by the subjects, for example, those in

Examples 3-4, are not explicable by the known activity of naltrexone as a pure antagonist of moφhine on nociceptive pathways. Data presented herein relate to novel gender-based differences and the data are consistent with a mechanism whereby an opioid antagonist such as naltrexone can act as a partial agonist on opioid receptors that are responsive to an opioid agonist such as moφhine.

The studies demonstrate a number of gender-related differences, first with respect to the responses of the female and male subjects to the antagonist alone. For example, in females, naltrexone, by itself, acts as a hypo-analgesic agent in that it can cause increased pain in subjects experiencing pain associated with the dental extractions studied. Data from a study are described in Examples 3 and 4 in which female subjects were given an oral dose of 0.01 mg naltrexone. Pain scores were determined as pain intensity differences (PID). A PID score of 0 means no change in. the level of pain, whereas a negative PID score means that pain increased, and a positive PID score indicates analgesia. Within 15 minutes, the PID score in the female subjects decreased below 0, indicating that the subjects experienced increased pain. The response to naltrexone was characterized by three features. First, there was a rapid increase in pain (anti-analgesia), with a peak in pain score of less than -0.3 observed at about 45 minutes after administration of the naloxone. Thereafter, there was a slight attenuation of the pain score (rebound), which lasted about 2 hours, and thereafter, the pain score increased (late phase anti-analgesia) and remained approximately steady (PID score of about -0.3) for the duration of the study (8 hours). In contrast to the results observed for females, naltrexone given to males in the same study had no anti-analgesic or analgesic effects. Data from this study are also shown in Examples 3 and 4 in which males undergoing dental extractions were given an oral dose of 0.01 mg naltrexone. Naltrexone did not change the PID score, which remained at about 0 for the duration of the 8 hours of the study. Thus, there was no rapid anti-analgesia, rebound, or late phase anti-analgesia as observed for the female patients.

Gender-related differences were also observed in the female and male subjects with respect to the agonist alone. As with the responses to the opioid antagonist naltrexone, the responses to the opioid agonist moφhine differed unexpectedly between female and male patients. For example, the results from this study as described in Examples 3 and 4 of the responses of females given an oral dose of 60 mg moφhine, show that the time course of the response to moφhine was slower than the time course of the response to naltrexone, with little or no effect observed at 30 minutes after administration. However, by 60 minutes, substantial analgesia was observed, as indicated by a PID score of greater than about 0.4. A broad peak in analgesia was observed between about 1.5 and about 5 hours, with the PID score remaining at or above about 0.6 for this time period. Thereafter, the PID score slowly fell, and by about 6 hours, the PLD score was at about 0.5. The PLD remained at about 0.5 for the duration of the study. In another study of female patients as described in Examples 1 and 2, a 60 mg oral dose of moφhine was associated with progressive analgesia. In striking contrast to the results observed for females, in the males the same dose of moφhine did not cause any analgesia. In fact, quite unexpectedly, moφhine increased the pain that the men experienced (anti-analgesia). Within the first 15 minutes, the PLD score began to fall below 0, indicating that pain was increased compared to the baseline. PLD decreased to a minimum at about 45 minutes, with the PLD score being about -0.2. Thereafter, the PLD score slowly rose, so that by about 4 hours, the PLD score had returned to about 0, where it remained for the duration of the study. In this study of male patients as described in Examples 1 and 2, moφhine did cause some analgesia, but the analgesia observed was preceded by a period of anti-analgesia.

Gender-related differences were observed in the female and male subjects with respect to combinations of agonist and antagonist, in addition to the differences described above between males and females in the response to naltrexone and moφhine individually. For example, in female patients (Examples 3 and 4), the combination of naltrexone and moφhine at certain times and at certain concentrations caused a decrease in analgesia as compared with moφhine alone. At two hours, the lowest dose of naltrexone (0.001 mg) administered in combination with moφhine decreased the PLD score produced in the presence of moφhine from a peak of about

0.7, to about 0.4. However, by 5 hours and thereafter, naltrexone did not decrease the

PLD score compared to those for moφhine over the same time period. Increasing the dose of naltrexone to 0.01 mg with the moφhine produced somewhat more reduction in PLD than did the lowest combination dose (0.001 mg). However, further increasing the dose of naltrexone to 0.1 mg produced no further decrease in PLD score. Thus, the dose of naltrexone having maximal effect in females when administered with 60 mg moφhine is about 0.01 mg. In another study in female patients (Examples 1 and 2), naltrexone at doses of 0.01 mg and 0.1 mg each potentiated the analgesia associated with moφhine (60 mg). Further increasing the dose of naltrexone to 1.0 mg however, decreased the analgesia associated with moφhine. In male patients, in the study as described in Examples 3 and 4, the lowest dose of naltrexone (0.001 mg) increased analgesia in the presence of 60 mg moφhine. The increase in analgesia was moderate, with an initial analgesic effect observed by about 2 hours after administration. Increasing the dose of naltrexone to 0.01 mg increased the analgesic effect compared to the lowest dose, and further increasing the dose of naltrexone (0.1 mg) increased the analgesia further, with a substantial effect occurring at about 1 hour, and reaching a broad plateau at about 2 hours, and lasting for the duration of the study. The PLD score during this time was greater than about 0.8, with several points above about 0.9. In another study in male patients as described in Examples 1 and 2, naltrexone in combination with moφhine produced more analgesia than did moφhine alone. The effect of naltrexone was dose-dependent with the highest doses (1.0 mg) having the greatest effect.

As shown herein, gender-related differences were 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, respectively, as described herein in Examples.

Gender-based opioid compositions according to the invention may have therapeutic advantages. For example, females can exhibit significant analgesic responses to an opioid agonist such as moφhine, and at certain doses, an opioid antagonist such as naltrexone can potentiate the analgesia induced by moφhine. However, effective doses of an opioid agonist such as moφhine may have undesirable adverse side effects, including nausea, vomiting, other gastrointestinal symptoms, and other serious side effects such as respiratory depression. Additionally, an opioid antagonist such as naltrexone by itself may increase pain in females experiencing pain. In certain embodiments of the invention, compositions are provided for use in females comprising low concentrations of opioid agonists including, by way of example only, moφhine or oxycodone, that by themselves may not produce a desired degree of analgesia, along with doses of naltrexone that are sufficiently low to avoid producing undesirable adverse side effects themselves. By selecting doses of opioid agomst and antagonist, it is now possible to maintain a desirable therapeutic effect such as pain relief, while attenuating undesirable adverse side effects, for example, in females and/or males. Ln certain other embodiments of this invention, compositions are provided for use in males comprising concentrations of moφhine or other opioid agonists that alone are ineffective, along with naltrexone or other opioid antagonists in doses sufficient to potentiate or enhance the analgesic effects of the opioid agonist such as moφhine. Additionally, because an opioid antagonist such as naltrexone can substantially potentiate or enhance the effects of an opioid agonist such as moφhine, it is now possible to reduce the dose of an opioid agonist such as moφhine to well below those doses that cause undesirable side effects, while at the same time, providing substantial pain relief, for example, in females and/or males. Novel pharmaceutical compositions and dosage forms of opioid antagonists are described in U.S. Provisional Application No. 60/202,227, incoφorated by reference herein. Novel compositions and gender-based methods for enhancing potency or reducing adverse side effects of opioid agonists are described in U.S. Provisional Application Nos. 60/244,482, 60/245,110, and 60/246,235, incoφorated by reference herein. Additional human clinical study results with tramadol are described in U.S. Application Nos. 09/566,071 and 09/756,331 as well as PCT/USOO/12493 [WO00/67739], that are all incoφorated by reference herein.

The present invention is described in the following examples which are set forth to aid in the understanding of the invention, and should not be construed to limit in any way the invention as defined in the claims which follow thereafter.

Pharmaceutical active and inactive ingredients used in the preparation of the example formulations were compendial in the USP/NF, when there was an existing monograph.

In the following examples, encapsulated dose forms of naltrexone HCl (NTX) and various opioid agonists were prepared for clinical studies as follows.

Encapsulated dose forms of naltrexone HCl were produced in the following doses and weight concentrations.

A batch of NTX, 0.3% w/w blend was made by first adding naltrexone HCl and other inactive components (e.g., magnesium stearate and microcrystalline cellulose) into a planetary mixer. The inactive components were added in portion- wise steps with mixing between each addition to achieve uniformity of the NTX. The intermediate active blend was transferred from the planetary mixer to a double-cone blender.

An amount of preblended inactive components was used to rinse the planetary mixer. The rinsings were added to the double-cone blender to achieve quantitative recovery of naltrexone HCl. The remaining balance of preblended inactive components were added in portion- wise steps to the double cone blender containing the in-process material. The resulting intermediate and final mixtures were blended for an appropriate time to achieve uniformity.

Less potent formulated blends of naltrexone HCl (e.g., 0.03% w/w/, 0.003 % w/w, and 0.0003% w/w) were prepared from the 0.3% w/w blend by serial dilution with the inactive components. A premeasured portion of the more concentrated active blend were added to the double cone blender. A measured amount of the preblended inactive components was added to achieve the desired dilution. The inactive blend was added in portion-wise steps to the double cone blender, with interim mixing to achieve uniformity. The NTX blends were filled into hard gelatin capsules at a controlled weight to achieve the desired unit dose of NTX.

Encapsulated dose forms of opioid agonists were prepared for clinical studies employing the same inactive components and hard gelatin capsule. Encapsulated dose forms of moφhine were prepared from commercially obtained tablets (Roxane), which contained 15 mg moφhine sulfate pentahydrate and various inactive components. A 60 mg moφhine sulfate strength capsule was made by mixing (e.g., microcrystalline cellulose and magnesium stearate) to form a blend, and this blend and four moφhine sulfate tablets were loaded into a hard gelatin capsule shell to obtain a capsule for clinical studies. Encapsulated dose forms of tramadol were prepared from commercially obtained ULTRAM® tablets (Ortho-McNeil), which contained 50 mg tramadol hydrochloride and various inactive components. A 50 mg tramadol hydrochloride strength capsule was made by mixing inactive components (e.g., microcrystalline cellulose and magnesium stearate) to form a blend, and this blend and one ULTRAM®, immediate release tablet were loaded into a hard gelatin capsule shell to obtain a capsule for clinical studies. Encapsulated dose forms of hydrocodone were prepared from commercially obtained tablets immediate release HYDROCET® capsules (Carnrick Laboratories), which contained hydrocodone bitartrate (5 mg) with acetaminophen (500 mg) and various inactive components. A 5 mg hydrocodone bitartrate/500 mg acetaminophen strength clinical capsule was made from the commercially obtained HYDROCET® capsules in the following manner. The average weight of 20 HYDROCET® capsules was determined, and the hydrocodone/acetaminophen blend contained in a predetermined number of HYDROCET® capsules was emptied into a clean bowl. The total weight of hydrocodone/acetaminophen blend needed to fill the clinical capsules with the same average weight (including 1% overage) was transfereed to a capsule machine. The capsule machine filled clinical capsule shells with the hydrocodone/acetaminophen blend.

EXAMPLE 1

A clinical study was designed as follows: (1) to compare the analgesic activity (onset, peak, duration, and total effect) of three different doses of NTX in combination with MS 60 mg versus MS 60 mg alone in subjects with moderate to severe pain in a postsurgical dental pain model to determine whether NTX enhances the analgesic effect of MS 60 mg; and (2) to evaluate the safety of three different doses of NTX in combination with MS 60 mg versus MS 60 mg alone in subjects with moderate to severe pain in a postsurgical dental pain model to determine whether the addition of NTX reduces the frequency or severity of moφhine-related side effects. Additional objectives of the study included: (1) to compare the analgesic efficacy of MS 60 mg to placebo to establish the assay sensitivity of the study; (2) to compare the analgesic activity (onset, peak, duration, and total effect) of three different doses of NTX in combination with MS 60 mg versus placebo in subjects with moderate to severe pain in a postsurgical dental pain model; and (3) to evaluate the safety of three different doses of NTX in combination with MS 60 mg versus placebo in subjects with moderate to severe pain in a postsurgical dental pain model.

A randomized, double-blind, placebo- and active-controlled, single-dose study was thus designed. There were five treatment groups: three test products, a positive control (MS 60 mg), and a negative control (placebo). Separation of placebo and MS 60 mg were used to determine the assay sensitivity of the study. The active control

(MS 60mg) was used to determine the sensitivity of the clinical endpoints. Placebo was used to control for factors not related to drug treatment. The test products were MS 60 mg with naltrexone (NTX) 1 mg, MS 60 mg with NTX 0.1 mg, and MS 60 mg with NTX 0.01 mg. A single oral dose of one of the treatments was administered when the subject was suffering moderate to severe postoperative pain. The observation period for efficacy was eight hours post treatment. The observation period for safety was 24 hours post treatment.

The Study Population was two hundred male and female outpatients with moderate to severe pain and a pain intensity score of at least 50 mm on the 100 mm Visual Analog Scale (VAS) following extraction of two or more impacted third molars. All subjects remained in the study facility for the eight-hour duration of the single-dose evaluation and then were permitted to leave the study site. Inclusion criteria were as follows:

(1) subjects with two or more impacted third molars requiring extraction and considered to have had surgery significant enough to wanant an opioid analgesic, where at least one extracted tooth was a partial or full bony mandibular impaction; (2) subjects willing and able to complete the pain evaluations;

(3) subjects at least 16 years of age, and if the subject was less than age 18, the subject was emancipated, or the parent or guardian gave written consent.

(4) female subjects were postmenopausal, or physically incapable of child bearing, or practicing an acceptable method of birth control (IUD, hormones, diaphragm with spermicide, condoms with spermicide, or abstinence), and if practicing an acceptable method of birth control, must also have maintained her normal menstrual pattern for the three months prior to study entry and have had a negative urine pregnancy test performed at screening and immediately prior to surgery; (5) subjects in generally good health;

(6) subjects able to speak and understand English and provide meaningful written informed consent;

(7) subjects able to remain at the study site for the entire eight-hour study period; (8) subjects had an initial pain intensity score of at least 50 mm on a 100 mm visual analog scale and must also describe the initial pain as moderate or severe on a four-point categorical scale; and

(9) subjects willing and able to return to the study site for the post treatment visit five to nine days after surgery. Exclusion criteria for subjects were as follows:

(1) pregnant or breast feeding;

(2) have known allergy or significant reaction to opioids or opioid antagonists;

(3) history of chronic opioid use or opioid abuse within six months prior to study.

(4) have participated in a study of an investigational drug or device within 30 days prior to this study; (5) have taken any of the following drugs within four hours prior to dosing: analgesics, including aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs (NSALDS), opioids, and opioid combinations, minor tranquilizers, muscle relaxants and antihistamines, where exempted from this prohibition were midazolam (Versed), lidocaine (with or without epinephrine), mepivacaine, nitrous oxide, and propofol (Diprivan) given during surgery;

(6) have taken a long-acting analgesic (e.g., long-acting NSALDS) within 12 hours prior to this study;

(7) have taken monoamine oxidase inhibitors or tricyclic antidepressant drugs within four weeks prior to study medication;

(8) have taken serotonin reuptake inhibitors (SSRI) or St. John's wort within four weeks prior to the study unless the subject has been on a stable dose for at least six weeks and the stable dose for St. John's wort must have been no more than lgm/day; (9) have a medical or psychiatric condition that compromises the subject's ability to give informed consent or appropriately complete the pain assessments; and

(10) have a history of seizure, however, subjects with a history of juvenile febrile seizures could be included if there was no seizure history within the past 10 years. Subjects were assigned to treatment groups based on a randomization schedule prepared prior to the study. The randomization was balanced by using equally balanced blocks. Based on the randomization code, the assigned study drug was packaged and labelled for each subject. Subject numbers were preprinted onto the study drug labels and assigned as subjects qualified for the study and were randomized to treatment. In order to achieve balance among treatment groups with respect to starting pain, the study stratified randomization according to initial pain intensity. Subjects with moderate starting pain were assigned medication with the lowest available number. Subjects with severe starting pain were assigned medication with the highest available number. Each subject was assigned one bottle containing two capsules. The label on the bottle consisted of two parts. One part was attached firmly to the bottle and did not contain drug identification. The other part was a tear-off label containing the concealed drug identification. The tear-off label was taped unopened onto the case report form.

NUMBER OF CAPSULES PER BOTTLE FOR EACH TREATMENT GROUP

Included on the open portion of the label was the protocol identification, subject number, number of capsules, directions for use, storage instructions, and cautionary statement about investigational status. The randomization code was not revealed to study subjects, investigators, clinical staff or study monitors until all subjects completed therapy and the data base has been finalized and closed.

Following washout from previous analgesia as stated in the exclusion criteria, and following a suitable recovery from anesthesia after surgery, all subjects who had moderate to severe pain and a score of at least 50 mm on the 100 mm VAS received one dose of study medication, consisting of two capsules. There was one bottle per subject, labeled by subject number, as described above.

The following screening procedures were accomplished within 14 days prior to surgery: (a) review of inclusion and exclusion criteria; (b) informed consent; (c) urine pregnancy test for women of child-bearing potential (at screening and immediately prior to surgery); (d) medical history and demographics; (e) brief physical examination; and (f) vital signs.

Baseline measurements and procedures included: (a) vital signs (prior to dosing); (b) review of medications received within 12 hours prior to dosing; and (c) after a suitable washout period from the anesthesia, the subject's pain level was assessed by a trained observer, and when the pain level was moderate or severe, and the score on the 100 mm VAS was at least 50 mm, the subject was randomized to a treatment group. Provided the subject met the above-referenced criteria, the subject was assigned the next sequential treatment number in ascending or descending order depending upon the starting pain. The subject then took one dose of study medication consisting of two capsules.

Treatment period procedures and measurements included: (a) Following dosing, the subject remained at the study facility for eight hours;

(b) Two stopwatches were started at the time the study medication was taken at baseline and each subject was first instructed, "Stop the first stopwatch when you first feel any paid relief whatsoever. This does not mean you feel completely better, although you might, but when you first feel any difference in the pain you have now." and then the subject was instructed, "Stop the second stopwatch when the pain relief is meaningful to you.";

(c) For treated subjects, vital signs were takn one hour after dosing and at the end of the eight-hour observation period; (d) For treated subjects, pain intensity and pain relief were measured by a trained observer at the following times: 30 minutes, 60 minutes and hourly thereafter through Hour 8 after dosing, and all efficacy assessments were recorded by the subject in a diary in response to questioning by a trained observer, wherein the trained observer questioned the subject for all observations and provided instruction as needed; pain intensity was measured in response to the question, "What is your pain level at this time?" with subject response choices of none=0, mile = 1, moderate=2 and severe=3 on a categorical scale and the pain relief relative to baseline was assessed in response to the question, "How much relief have you had from your starting pain?" with subject response choices of none=0, a little=l, some^, a lot=3, and complete=4;

(e) Subjects not completing at least 90 minutes after dosing were considered not evaluable and were replaced; (f) Adverse events were assessed by non-directed questioning and recorded for the eight hours following dosing;

(g) All concomitant medications (including rescue medications) were recorded for the eight-hour observation period; (h) At the end of eight hours, or at the termination of hourly observations if sooner than eight hours, a global evaluation was made by observer and subject in response to the question, "How do you rate the pain relief?" with response choices of poor=0, fair-=l, good=2, very good=3 and excellent=4; and

(i) Upon discharge from the study facility, the subject was given a diary to take home for recording medications taken and adverse events experienced from the time of discharge until 24 hours after the time of dosing with study medication; a member of the study staff telephoned the patient 24 hours after the time of dosing to query the subject about medications taken, adverse events experienced, and to remind the subject to complete the diary. The study was considered completed after eight hours of evaluation or upon receipt of rescue medication. Subjects could discontinue the study at any time. Subjects who did not get adequate pain relief provided a final set of pain assessments and a global evaluation before taking rescue medication. Subjects were then given a rescue medication and pain assessments were discontinued. Subjects were encouraged to wait at least 90 minutes after administration of the study medication before using rescue medication. Subjects remedicatmg earlier than 90 minutes were not included in the analysis for efficacy.

For subjects who completed eight hours of evaluation without using rescue medication, the time of the first dose of analgesic within 24 hours after dosing with study medication was recorded on the take-home diary.

All subjects who received a dose of study medication returned to the study facility 5 to 9 days after surgery for a post treatment visit. The following was accomplished: (a) brief physical examination; (b) collection and review of subject's diary for 24-hour post-dosing adverse events, and medications (including rescue medications).

Efficacy evaluations were performed using primary and secondary efficacy (outcome) parameters. The primary efficacy paramaters included: (1) 8-hour Total Pain Relief Scores (TOTPAR-8) described below;

(2) 8-Hour Sum of Pain Intensity Difference Scores (SPLD-8) described below;

(3) Time to Rescue; (4) Percent of Subjects Remedicating with Rescue Medication; and

(5) Time to Onset of Meaningful Pain Relief. The secondary efficacy parameters included:

(1) Hourly Pain Relief Scores;

(2) Hourly Pain Intensity Difference Scores; (3) Maximum Pain Relief Scores;

(4) Peak Pain Intensity Difference Scores;

(5) Global Evaluations; and

(6) Time to Onset of First Perceptible Pain Relief.

Safety evaluations included (1) vital signs; and (2) adverse events. All adverse events were recorded on the case report forms (CRF) provided. Serious adverse events were reported promptly to the Institutional Review Board (IRB) and to the sponsor. The investigator transmitted a written report of the circumstances and outcome. All serious adverse events were reported to the FDA in compliance with Federal Regulations. An adverse event (AE) was defined as any untoward, noxious, or unintended event experienced by a subject in a clinical trial of an investigational agent, whether considered related to that investigational agent or not. A treatment- emergent adverse event was defined as an AE that was new in onset or aggravated in severity or frequency following administration of the investigational agent. A serious adverse event was defined as any AE occurring at any dose that resulted in any of the following outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or congenital anomaly or birth defect.

A subject who completed Hour 8 or who completed at least 90 minutes and remedicated before Hour 8 was evaluable for efficacy. In any case, the reason for discontinuation was documented.

For the data analysis, parameters were computed as follows. The extent to which pain changes at each time point was measured by pain relief scores (PR, with 0=none, l=a little, 2=some, 3=a lot, 4=complete), and pain intensity difference scores (PLD, the difference between baseline and the cunent time, with the pain intensity scale consisting of 0=none, l=mild, 2=moderate, 3=severe).

The extent to which pain changes over the entire test period was measured by the total pain relief score (TOTPAR-8), sum of pain intensity differences (SPLD-8), maximum pain relief score (MAXPAR), peak pain intensity difference (PEAKPID), and global evaluation (0=poor, l=fair, 2=good, 3=very good, 4=excellent). TOTPAR- 8 and SPLD-8 are defined as the sum of PR and PJX), respectively, for the entire 8- hour observation period, weighted by the time difference between adjacent points (i.e., area under the curve using the trapezoidal rule). MAXPAR and PEAKPID are defined as the maximum of PR and PJD, respectively.

Where required, the following imputation schemes were employed. Intermediate missing values were replaced by linear inteφolation, whereas missing values after administration of rescue medication or other premature discontinuation were replaced by the last observation carried forward procedure (LOCF).

Further efficacy variables were time to rescue, percent of patients remedicating with rescue medication, time to onset of meaningful pain relief, and time to onset of first perceptible pain relief.

Safety was assessed through vital signs and adverse events (including body systems and prefened terms from the COSTART dictionary).

All testing of statistical significance were two-sided, and a difference resulting in a p-value of less than or equal to 0.05 was considered statistically significant.

Efficacy analyses was conducted on the intent-to-treat (ITT) analysis set, consisting of all randomized patients who received study medication. A second analysis could be done on the evaluable analysis set.

Demographic and baseline characteristics were summarized with descriptive statistics (for continuous variables) or frequencies (for categorical variables).

One-way analysis of variance (ANOVA) by treatment group was performed on PR, PLD, TOTPAR-8, SPLD-8, MAXPAR, PEAKPID, and the global evaluation (with PR and PLD analyzed separately for each time point). Baseline pain intensity was investigated as a possible blocking factor, and baseline pain intensity VAS was investigated as a possible covariate. If the ANOVA treatment effect is significant at the p < 0.05 level, one-sided Fisher's protected least significant difference test (LSD) was performed to investigate pairwise differences. For all pairwise comparisons, the error mean square from the overall analysis of variance with all treatments was used as the estimate of enor variance. Time to rescue (remedication) was analyzed using the Kaplan-Meier estimate to compute the survival distribution function. The distributions were compared among treatment groups using the log rank and Wilcoxon tests. A patient was considered censored at 24 hours if remedication had not occuned. Patients who dropped out because of reasons other than rescue medication were censored at the dropout time. The proportion of patients remedicating were compared among treatment groups using Fisher's exact test or a chi-squared test. Time to onset of meaningful pain relief and time to onset of first perceptible pain relief was analyzed in a similar fashion to time to rescue. Patients who did not achieve meaningful pain relief or perceptible pain relief were considered treatment failures and were assigned a time of 8 hours.

All patients who received study medication were assessed for clinical safety. Vital signs, including changes from baseline, were summarized with descriptive statistics. Adverse event frequencies were tabulated by body system and prefened term, and Fisher's exact test or a chi-squared test was used to test for differences in adverse event frequencies among the treatment groups by body system.

The sample size was estimated from historical data and from practical considerations rather than from calculation of expected measured differences.

A total of 204 subjects were randomized; among them 201 subjects were deemed evaluable. One subject in each of the placebo, MS and MS/0.1 NTX groups was not evaluable because the subject took rescue medication less than 90 minutes after dosing. Table 1 Subject Disposition

The demographic and baseline characteristics were summarized by treatment groups for the ITT population (all randomized patients) and the evaluable population (all randomized patients with at least one efficacy evaluation at 90 minutes or more after dosing) (Table 2). Demographic characteristics included age, race/ethnicity, sex, weight, height, medical history, teeth extracted (impacted and non-impacted), baseline pain intensity, and baseline visual analog scale.

The demographics for the ITT population were comparable across all 5 treatment groups. Subjects ranged in age from 18 to 39 years; 67% were Caucasian and 51% were female. There was comparability among treatment groups regarding the degree of surgical trauma rating. For the evaluable population, but not for the ITT population, there was a difference among treatment groups in the maximum degree of impaction of third molar extracted. Patients in the placebo group had a lesser degree of bony impaction compared to patients in the low-dose group, and patients in both the low-dose and mid-dose groups had a greater degree of impaction compared to patients in the high-dose group. No adjustments in the analyses were made to take into account these differences among treatment groups. These differences had no influence on pain assessments at baseline. Generally, no differences among treatment groups were noted in the number of patients with either a significant medical history or disease of any body system. The baseline pain intensity scores and visual analog scale scores also were comparable across treatment groups (Table 3).

Table 2 Baseline Demographic Characteristics Intent-To-Treat Subjects

[1] ONE-WAY ANALYSIS OF VARIANCE WITH TREATMENT AS THE FACTOR

[2] FISHER'S EXACT TEST.

[3] BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

Table 3A

Summary of Baseline Pain Intensity Scores

Intent-To-Treat Population

NOTE: P-VALUES ARE FROM FISHER'S EXACT TEST.

Table 3B

Summary of Baseline Visual Analog Scale (VAS) Scores

Intent-To-Treat Population

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS. [1] BASELINE PAIN INTENSITY ON THE CATEGORICAL SCALE.

The TOTPAR results (4-hour, 6-hour, 8-hour) are summarized in Table 4 and the 4-hour TOTPAR scores are shown in Figure 1. The placebo treatment group had the lowest mean TOTPAR scores. All 4 of the active treatment groups exhibited mean TOTPAR scores that were numerically higher than placebo. The combination treatments had a reverse dose-response relation in the mean TOTPAR scores, i.e., the highest dose of NTX had the lowest mean TOTPAR scores and the lowest dose of NTX had the highest mean TOTPAR scores. This pattern (low-dose (0.01 mg NTX) > mid-dose (1.0 mg NTX) was observed for all pain relief variables throughout the study. The mean TOTPAR scores for the 0.01-mg NTX and 0.1 -mg NTX combination treatments were higher than that for the MS alone treatment, whereas the

1.0-mg NTX combination treatment mean was comparable to or lower than that for the MS alone treatment (Figure 1).

Analyses of TOTPAR for the evaluable subgroup yielded results similar to those for the ITT population.

Table 4

Total Pain Relief Scores

Intent-To-Treat Po ulation

[1] FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

[2] FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAL INTENSITY AS A BLOCKING FACTOR AND FISHER'S

PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. *, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY. N/A: NOT APPLICABLE

Table 4 (Continued)

Total Pain Relief Scores

Intent-To-Treat Population

TOTAL PALN RELIEF SCORE P-VALUE P-VALUE

TREATMENT N MEAN SD MIN MEDIA MAX SOURCE [1] [2]

N

TOTAL PAIN RELIEF SCORE (0-8 HOURS)

A) Placebo 40 5.12 7.026 0.0 0.25 20.5 TRT

B) MS 60 mg 41 10.73 9.988 0.0 13.50 29.2 BASEPI

C) MS 60 mg /NTX 0.01 mg 41 12.15 9.139 0.0 11.75 27.5 BASEPPTRT

D) MS 60 mg /NTX 0.1 mg 41 11.52 10.130 0.0 10.75 28.3 B-A

E) MS 60 mg /NTX l mg 41 9.14 10.337 0.0 2.75 30.0 C-A

D-A

E-A

C-B

D-B

E-B

[2] FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S

Table 5 summarizes the results of the 4, 6, and 8-hour SPID results. The 4- hour results are also represented in Figure 2. The placebo treatment had the lowest mean 4-hour SPID scores (0.68 + 2.165). All 4 of the active treatment groups exhibited improved profiles in mean SPLD relative to placebo. The mean SPID scores for the 0.01-mg NTX and 0.1 -mg NTX combination treatments were higher than that for the MS alone treatment, whereas the 1.0-mg NTX combination treatment was comparable to that for the MS alone treatment (Figure 2).

The patterns of the 6-hour and 8-hour SPLD scores were similar to those at 4 hours. Analyses of SPLD for the evaluable subgroup also yielded profiles that were similar to 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 0.68 2.165 -3 0.00 5.0 TRT B) MS 60 mg 41 1.91 3.296 -3 2.50 8.0 BASEPI C) MS 60 mg /NTX O.Ol mg 41 3.08 3.309 -3 3.24 10.3 BASEPPTRT D) MS 60 mg /NTX 0.1 mg 41 2.62 2.790 -3 2.48 8.5 B-A

E) MS 60 mg /NTX l mg 41 2.01 3.763 -3 1.25 8.5 C-A

D-A

E-A

C-B

D-B

E-B

[1] PALN INTENSITY DIFFERENCE = PAIN INTENSITY AT BASELINE - PAIN INTENSITY AT CURRENT TIME.

[2] FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER' S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

[3] FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PALN INTENSITY AS A BLOCKING FACTOR AND FISHER'S

Table 5 (Continued)

Summary of Pain Intensity Differences

Intent-To-Treat Population

[2] FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

[3] FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S

Table 5 (Continued)

Summary of Pain Intensity Differences

Lntent-To-Treat Population

Figure 3 is a visual presentation of the summary and analysis of time to onset of meaningful pain relief scores presented in Table 6. The median time to onset of meaningful pain relief was shortest in the 0.01-mg NTX (low-dose) combination treatment group. The placebo treatment had the lower number of subjects who reached meaningful pain relief.

Analyses of times to onset of meaningful pain relief for the evaluable subgroup yielded similar result.

Table 6

•Time To Onset of Meaningful Pain Relief

Intent-To-Treat Population

*, **, ***: P-VALUE < - 0.05, < = 0.01, or < = 0.001 RESPECTIVELY. N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Figures 4 and 5 are a visual presentation of the summary and analysis of time to remedication (rescue medication) up to 8 and 24 hours presented in Table 7. The survival distributions (0-8 hours) were different across treatment groups. The survival distributions were different for the low-dose and mid-dose groups compared to placebo (Figure 4). The median times to administration of rescue medication were longer for the morphine (> 8 hours), low-dose (> 8 hours), and mid-dose (> 8 hours) groups compared to the high-dose (3 hours, 4 minutes) and placebo (2 hours, 18 minutes) groups.

The survival distributions (0-24 hours) were also different across treatment groups, and were also different for the morphine, low-dose, and mid-dose groups compared to the placebo group (Figure 5). Again, the median times to administration of rescue medication were longer for the morphine, low-dose, and mid-dose groups.

Analyses of time to remedication up to 24 hours yielded similar results, however, the data should be viewed with caution because subjects were not under close supervision after 8 hours. Analyses for the evaluable subjects yielded results similar to those for the ITT population.

Table 7

Time To Rescue Medication

Intent-To-Treat Population

Table 8 presents the summary and analysis of percent of subjects who took remedication up to 8 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 conclusions similar to those for the ITT population.

Table 8

Percent of Subjects Rescued

Intent-To-Treat Population

Figures 6 is a visual presentation of the hourly pain relief scores presented in Table 9. The hourly pain relief scores were summarized and analyzed in 2 ways: first as a categorical variable and second as a numerical variable. Because results of these two methods were similar, only the results from the numerical version are presented here. Whereas the hourly pain relief scores for the placebo treatment were less than those for the active treatment groups which improved over time. There was separation between the placebo and the active treatment groups that continued throughout the 8-hour study period. Comparable pain relief was observed (see, e.g., 1-3 hours) in the MS alone group and the high-dose (1.0 mg NTX) combination group (Figure 6). Highest pain relief scores were observed for the low-dose (0.01 mg NTX) combination group (Figure 6).

Table 9 Pain Relief (PR) Scores [1] Intent-To-Treat Population

PROTECTED LEAST SIGNIFICANT DIFFERENCD 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).

Table 9 (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population

[1] PAIN RELIEF (PR) SCORES: 0 = NONE, 1 = A LITTLE, 2 = SOME, 3 = A LOT, 4 = COMPLETE.

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).

Table 9 (Continued) Pain Relief (PR) Scores [1] Lntent-To-Treat Population

[1] PALN RELIEF (PR) SCORES: 0 = NONE, 1 = A LITTLE, 2 = SOME, 3 = A LOT, 4 = COMPLETE.

[3] FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PALN INTENSITY AS A BLOCKING FACTOR AND FISHER' S

Table 9 (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population

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).

Table 9 (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population

Table 9 (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population

Table 9 (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population

Table 9 (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population

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).

The hourly pain intensity difference (PLD) data presented in Table 10 and Figure 7. The hourly PLD scores for the placebo treatment were generally flat while the hourly PLD scores generally improved over time for the active treatment groups. The mean scores for the morphine and morphine/naltrexone groups were higher than the mean PLD scores for the placebo group at each assessment time. The means for the low-dose and mid-dose groups were greater than the means for high-dose and placebo groups. Comparable pain relief as measured by PLD scores was observed (see, e.g., 2-3 hours) in the MS alone group and the high-dose (1.0 mg NTX) combination group (Figure 7). Highest pain relief as measured by PLD scores was observed for the low-dose (0.01 mg NTX) combination group.

Table 10

Pain Intensity Difference (PLD) Scores [1]

Intent-To-Treat Po ulation

[1] PAIN INTENSITY SCORES: 0 = NONE, 1 = MILD, 2 = MODERATE, 3 = SEVERE.

[3] FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER' S 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).

Table 10 (Continued)

Pain Intensity Difference (PLD) Scores [1]

Intent-To-Treat Po ulation

[1] PAIN INTENSITY SCORES: 0 = NONE, 1 = MILD, 2 = MODERATE, 3 = SEVERE.

[3] FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT

Table 10 (Continued)

Pain Intensity Difference (PID) Scores [1]

Intent-To-Treat Po ulation

[1] PAIN INTENSITY SCORES: 0 = NONE, 1 = MILD, 2 = MODERATE, 3 = SEVERE.

Table 10 (Continued)

Pain Intensity Difference (PLD) Scores [1]

Intent-To-Treat Po ulation

[1] PAIN INTENSITY SCORES: 0 = NONE, 1 = MILD, 2 = MODERATE, 3 = SEVERE.

Table 10 (Continued)

Pain Intensity Difference (PLD) Scores [1]

Intent-To-Treat Po ulation

[1] PAIN INTENSITY SCORES: 0 = NONE, 1 = MILD, 2 = MODERATE, 3 = SEVERE.

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).

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

Table 11A

Maximum Pain Relief Scores (MAXPAR)

Intent-To-Treat Population

Table 1 IB

Peak Pain Intensity Difference (PEAKP D)

Intent-To-Treat Population

PEAK PAIN INTENS] [TY DIFFERENCE

TREATMENT N MEAN . SD MIN MEDIAN MAX SOURCE P-VALUE P-VALUE [1] [2]

A) Placebo 40 0.53 0.877 -1 0.0 3 TRT 0.007** 0.004**

B) MS 60 mg 41 1.10 1.068 -1 1.0 3 BASEPI N/A O.001***

C) MS 60 mg /NTX O.Ol mg 41 1.41 1.140 -1 2.0 3 BASEPPTRT N/A 0.073

D) MS 60 mg /NTX 0.1 mg 41 1.17 1.022 -1 1.0 3 B-A 0.019* 0.011*

E) MS 60 mg/NTX l mg 41 1.00 1.304 1.0 3 C-A O.001*** O.001*** D-A 0.008** 0.004** E-A 0.051 0.034* C-B 0.190 0.154 D-B 0.761 0.742 E-B 0.686 0.660 m FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST

Table 12 presents the summary and analysis of global evaluations. The placebo treatment had the highest number 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

[2] FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND ITS FISHER'S

PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. *, **, ***: P-VALUE <= 0.05, + 0.01, OR <=0.001 RESPECTIVELY N/A: NOT APPLICABLE

The majority of adverse events reported were categorized as digestive (nausea or vomiting) or nervous system (dizziness or somnolence) as further shown in Tables 13A or 13B. Figure 8 represents a summary of exemplary adverse side effects attenuated according to methods and compositions of the invention.

Table 13A

Adverse Events By Body System And Severity Safety Population

Total No. Of Total Severity [2]

Body System No. Of Subjects Source P-Value No. Of

Mild Moderate Severe Adverse Events Treatment Subjects W/Event [1] Events (Costart English)

Total Number Of Events Adverse Events (All Body Systems) A) PLACEBO 40 11 ( 27.5%) TRT O.001*** 17 7 ( 41.2%) 5 ( 29.4%) 5 ( 29.4%)

B) MS 60 MG 41 35 ( 85.4%) A-B O.001 *** 82 28 ( 34.1%) 32 ( 39.0%) 22 ( 26.8%)

C) MS 60 MG NTX 0.01 MG 41 36 ( 87.8%) A-C O.001*** 93 22 ( 23.7%) 40 ( 43.0%) 31 ( 33.3%)

D) MS 60 MG/NTX 0.1 MG 41 37 ( 90.2%) A-D O.001*** 102 28 ( 27.5%) 40 ( 39.2%) 34 ( 33.3%)

E) MS 60 MG/NTX 1 MG 41 31 ( 75.6%) A-E O.001*** 64 31 ( 48.4%) 22 ( 34.4%) 11 ( 17.2%)

Body As A Whole All Events A) PLACEBO 40 4 ( 10.0%) TRT 0.675 4 1 ( 25.0%) 3 ( 75.0%) 0

B) MS 60 MG 41 6 ( 14.6%) 7 4 ( 57.1%) 3 ( 42.9%) 0

C) MS 60 MG/NTX 0.01 MG 41 8 ( 19.5%) 8 2 ( 25.0%) 4 ( 50.0%) 2 ( 25.0%)

D) MS 60 MG/NTX 0.1 MG 41 7 ( 17.1%) 10 3 ( 30.0%) 5 ( 50.0%) 2 ( 20.0%)

E) MS 60 MG/NTX 1 MG 41 4 ( 9.8%) 4 2 ( 50.0%) 2 ( 50.0%) 0

Abdominal Pain A) PLACEBO 40 0 TRT 0.512 0 0 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG/NTX 0.01 MG 41 2 ( 4.9%) 2 0 0 2 (100.0%)

D) MS 60 MG/NTX 0.1 MG 41 1 ( 2.4%) 1 0 0 1 (100.0%)

E) MS 60 MG/NTX 1 MG 41 0 0 0 0 0

[1] P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND

SIGNIFICANT PAIRWISE COMPARISONS ONLY. [2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS. *, **, ***: P-VALUE < = 0.05, < = 0.01, OR < = 0.001 RESPECTIVELY.

Table 13A (Continued)

Adverse Events By Body System And Severity

Safety Population

Total No . Of Total Severity [2]

Body System No. Of Subjects Source P-Value No. Of ^"

Mild j TnHftrafp; Severe

Adverse Events Treatment Subjects W/Event [1] Events

(Costart English)

Asthenia

A) PLACEBO 40 0 TRT 1.000 0 0 0 0

B) MS 60 MG 41 1 ( 2.4%) 1 1 (100.0%) 0 0

C) MS 60 MG/NTX 0.01 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

D) MS 60 MG/NTX 0.1 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

E) MS 60 MG NTX 1 MG 41 1 ( 2.4%) 1 1 (100.0%) 0 0

Fever A) PLACEBO 40 1 ( 2.5%) TRT 0.196 1 0 1 (100.0%) 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG/NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG/NTX 0.1 MG 41 0 0 0 0 0

E) MS 60 MG/NTX 1 MG 41 0 0 0 0 0

Headache A) PLACEBO 40 3 ( 7.5%) TRT 0.960 3 1 ( 33.3%) 2 ( 66.7%) 0

B) MS 60 MG 41 5 ( 12.2%) 5 2 ( 40.0%) 3 ( 60.0%) 0

C) MS 60 MG/NTX 0.01 MG 41 3 ( 7.3%) 3 2 ( 66.7%) 1 ( 33.3%) 0

D) MS 60 MG/NTX 0.1 MG 41 4 ( 9.8%) 6 2 ( 33.3%) 3 ( 50.0%) 1 ( 16.7%)

E) MS 60 MG NTX 1 MG 41 3 ( 7.3%) 3 1 ( 33.3%) 2 ( 66.7%) 0

Injection Site A) PLACEBO 40 0 TRT 1.000 0 0 0 0

Hemorrhage B) MS 60 MG 41 1 ( 2.4%) 1 1 (100.0%) 0 0

C) MS 60 MG NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG NTX 0.1 MG 41 0 0 0 0 0

E) MS 60 MG/NTX I MG 41 0 0 0 0 0

SIGNIFICANT PAIRWISE COMPARISONS ONLY. [2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS. P-VALUE < = 0.05, < = 0.01, OR < = 0.001 RESPECTIVELY.

Table 13A (Continued)

Adverse Events By Body System And Severity

Safety Population

Total No. Of Total Severity [2]

Body System No. Of Subjects Source P-Value No. Of ^•

Mild MnAprntf* Severe

Adverse Events Treatment Subjects W/Event [1] Events

(Costart English)

Overdose A) PLACEBO 40 0 TRT 1.000 0 0 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG NTX 0.01 MG 41 1 ( 2.4%) 1 0 1 ( 100.0%) 0

D) MS 60 MG/NTX 0.1 MG 41 0 0 0 0 0

E) MS 60 MG/NTX 1 MG 41 0 0 0 0 0

Pain A) PLACEBO 40 0 TRT 0.512 0 0 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG NTX 0.01 MG 41 1 ( 2.4%) 1 0 1 ( 100.0%) 0

D) MS 60 MG/NTX 0.1 MG 41 2 ( 4.9%) 2 1 ( 50.0%) 1 ( 50.0%) 0

E) MS 60 MG/NTX 1 MG 41 0 0 0 0 0

Cardiovascular

All Events A) PLACEBO 40 0 TRT 0.124 0 0 0 0

B) MS 60 MG 41 3 ( 7.3%) 3 2 ( 66.7%) 1 ( 33.3%) 0

C) MS 60 MG/NTX 0.01 MG 41 4 ( 9.8%) 4 2 ( 50.0%) 1 ( 25.0%) 1 ( 25.0%)

D) MS 60 MG/NTX 0.1 MG 41 5 ( 12.2%) 5 2 ( 40.0%) 3 ( 60.0%) 0

E) MG 60 MG/NTX 1 MG 41 1 ( 2.4%) 1 1 (100.0%) 0 0

Hemorrhage A) PLACEBO 40 0 TRT 1.000 0 0 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG/NTX 0.1 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

E) MG 60 MG/NTX 1 MG 41 0 0 0 0 0

Table 13 A (Continued)

Adverse Events By Body System And Severity

Safety Population

Total No. Of Total Severity [2]

Body System No. Of Subjects Source P-Value No. Of '

Mild

Severe

Adverse Events Treatment Subjects W/Event [1] Events

(Costart English)

Hypertension A) PLACEBO 40 0 TRT 1.000 0 0 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG/NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG/NTX 0.1 MG 41 1 ( 2.4%) 1 1 (100.0%) 0 0

E) MG 60 MG/NTX 1 MG 41 0 0 0 0 0

Vasodilatation A) PLACEBO 40 0 TRT 0.257 0 0 0 0

B) MS 60 MG 41 3 ( 7.3%) 3 2 ( 66.7%) 1 ( 33.3%) 0

C) MS 60 MG/NTX 0.01 MG 41 ( 9.8%) 4 2 ( 50.0%) 1 ( 25.0%) 1 ( 25.0%)

D) MS 60 MG NTX 0.1 MG 41 3 ( 7.3%) 3 1 ( 33.3%) 2 ( 66.7%) 0

E) MS 60 MG NTX 1 MG 41 1 ( 2.4%) 1 1 (100.0%) 0 0

Digestive

All Events A) PLACEBO 40 5 ( 12.5%) TRT O.001*** 8 1 ( 12.5%) 2 ( 25.0%) 5 ( 62.5%)

B) MS 60 MG 41 23 ( 56.1%) A-B O.001*** 40 6 ( 15.0%) 14 ( 35.0%) 20 ( 50.0%)

C) MS 60 MG/NTX 0.01 MG 41 25 ( 61.0%) A-C O.001*** 46 7 ( 15.2%) 15 ( 32.6%) 24 ( 52.2%)

D) MS 60 MG/NTX 0.1 MG 41 29 ( 70.7%) A-D O.001*** 47 8 ( 17.0%) 12 ( 25.5%) 27 ( 57.4%)

E) MS 60 MG/NTX 1 MG 41 16 ( 39.0%) A-E O.010* 25 6 ( 24.0%) 8 ( 32.0%) 11 ( 44.0%)

D-E O.007**

Diarrhea A) PLACEBO 40 0 TRT 0.196 0 0 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG/NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG/NTX 0.1 MG 41 2 ( 4.9%) 2 1 ( 50.0%) 1 ( 50.0%) 0

E) MG 60 MG/NTX I MG 41 0 0 0 0 0

SIGNIFICANT PAIRWISE COMPARISONS ONLY. [2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS. * ** ***. p. VALUE < = 0.05, < = 0.01, OR < = 0.001 RESPECTIVELY.

Table 13A (Continued)

Adverse Events By Body System And Severity

Safety Population

Total ] No. Of Total Severity [2]

Body System No. Of c SuDjecrs Source P-Value No. Of

Mild jtyf Hpratp Severe

Adverse Events Treatment Subjects W/Event [1] Events

(Costart English)

Dyspepsia A) PLACEBO 40 1 ( 2.5%) TRT 0.512 1 1 (100.0%) 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG/NTX 0.1 MG 41 0 0 0 0 0

E) -MS 60 MG/NTX 1 MG 41 1 ( 2.4%) 1 1 (100.0%) 0 0

Nausea A) PLACEBO 40 4 ( 10.0%) TRT O.001*** 4 0 2 ( 50.0%) 2 ( 50.0%)

B) MS 60 MG 41 21 ( 51.2%) A-B O.001*** 22 6 ( 27.3%) 14 ( 63.6%) 2 ( 9.1%)

C) MS 60 MG NTX 0.01 MG 41 23 ( 56.1%) A-C O.001*** 26 7 ( 26.9%) 15 ( 57.7%) 4 ( 15.4%)

D) MS 60 MG/NTX 0.1 MG 41 25 ( 61.0%) A-D O.001*** 26 7 ( 26.9%) 11 ( 42.3%) 8 ( 30.8%)

E) MS 60 MG/NTX 1 MG 41 14 ( 34.1%) A-E .014* 15 5 ( 33.3%) 8 ( 53.3%) 2 ( 13.3%) D-E O.026*

Vomiting A) PLACEBO 40 3 ( 7.5%) TRT O.001 *** 3 0 0 3 (100.0%)

B) MS 60 MG 41 18 ( 43.9%) A-B O.001*** 18 0 0 18 (100.0%)

C) MS 60 MG/NTX 0.01 MG 41 20 ( 48.8%) A-C O.001 *** 20 0 0 20 (100.0%)

D) MS 60 MG/NTX 0.1 MG 41 19 ( 46.3%) A-D .001*** 19 0 0 19 (100.0%)

E) MS 60 MG/NTX 1 MG 41 9 ( 22.0%) A-E .020* 9 0 0 9 (100.0%) D-E O.035*

Musculoskeletal

All Events A) PLACEBO 40 0 TRT 1.000 0 0 0 0

B) MS 60 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

C) MS 60 MG/NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG/NTX 0.1 MG 41 0 0 0 0 0

E) MS 60 MG NTX 1 MG 41 0 0 0 0 0

Table 13A (Continued)

Adverse Events By Body System And Severity

Safety Population

Total No. Of Total Severity [2]

Body System No. Of Subjects Source P-Value No. Of Mild Moderate Severe Adverse Events Treatment Subjects W/Event [1] Events (Costart English)

Myalgia A) PLACEBO 40 0 TRT 1.000 0 0 0 0

B) MS 60 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

C) MS 60 MG NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG/NTX 0.1 MG 41 0 0 0 0 0

E) MS 60 MG/NTX 1 MG 41 0 0 0 0 0

Nervous System All Events A) PLACEBO 40 2 ( 5.0%) TRT O.001*** 2 2 (100.0%) 0 0

B) MS 60 MG 41 18 ( 43.9%) A-B O.001 *** 24 11 ( 45.8%) 11 ( 45.8%) 2 ( 8.3%)

C) MS 60 MG NTX 0.01 MG 41 22 ( 53.7%) A-C O.001*** 25 6 ( 24.0%) 15 ( 60.0%) 4 ( 16.0%)

D) MS 60 MG/NTX 0.1 MG 41 22 ( 53.7%) A-D .001*** 29 9 ( 31.0%) 15 ( 51.7%) 5 ( 17.2%)

E) MS 60 MG NTX I MG 41 20 ( 48.8%) A-E O.001*** 26 16 ( 61.5%) 10 ( 38.5%) 0

Anxiety A) PLACEBO 40 0 TRT 1.000 0 0 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG/NTX 0.01 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

D) MS 60 MG/NTX 0.1 MG 41 1 ( 2.4%) 1 1 (100.0%) 0 0

E) MS 60 MG/NTX 1 MG 41 0 0 0 0 0

Dizziness A) PLACEBO 40 2 ( 5.0%) TRT .001*** 2 2 (100.0%) 0 0

B) MS 60 MG 41 15 ( 36.6%) A-B O.001*** 17 9 ( 52.9%) 6 ( 35.3%) 2 ( 11.8%)

C) MS 60 MG/NTX 0.01 MG 41 16 ( 39.0%) A-C O.001 *** 16 5 ( 31.3%) 9 ( 56.3%) 2 ( 12.5%)

D) MS 60 MG NTX 0.1 MG 41 17 ( 41.5%) A-D O.001 *** 20 6 ( 30.0%) 10 ( 50.0%) 4 ( 20.0%)

E) MS 60 MG NTX IMG 41 13 ( 31.7%) A-E O.003** 13 8 ( 61.5%) 5 ( 38.5%) 0

Table 13 A (Continued)

Adverse Events By Body System And Severity

Safety Population

Total No. Of Total Severity [2]

Body System No. Of Subjects Source P-Value No. Of

Adverse Events Treatment Subjects W/Event [1] Events

(Costart English)

Dry Mouth A) PLACEBO 40 0 TRT 0.196 0 0 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG/NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG NTX 0.1 MG 41 0 0 0 0 0

E) MS 60 MG NTX IMG 41 2 ( 4.9%) 2 1 ( 50.0%) 1 ( 50.0%) 0

Euphoria A) PLACEBO 40 0 TRT 0.005** 0 0 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG/NTX 0.01 MG 41 5 ( 12.2%) 5 0 4 ( 80.0%) 1 ( 20.0%)

D) MS 60 MG/NTX 0.1 MG 41 2 ( 4.9%) 2 1 ( 50.0%) 1 ( 50.0%) 0

E) MS 60 MG/NTX IMG 41 0 0 0 0 0

Hallucinations A) PLACEBO 40 0 TRT 1.000 0 0 0 0

B) MS 60 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

C) MS 60 MG/NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG/NTX 0.1 MG 41 0 0 0 0 0

E) MS 60 MG/NTX 1 MG 41 0 0 0 0 0

Hypertonia A) PLACEBO 40 0 TRT 1.000 0 0 0 0

B) MS 60 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

C) MS 60 MG/NTX 0.01 MG 41 1 ( 2.4%) 1 0 0 1 (100.0%)

D) MS 60 MG/NTX 0.1 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

E) MS 60 MG/NTX 1 MG 41 0 0 0 0 0

Table 13 A (Continued)

Adverse Events By Body System And Severity

Safety Population

Total No . Of Total Severity [2]

Body System No. Of Su 1b_jects Source P-Value No. Of

Mild fnHprntp. Severe

Adverse Events Treatment Subjects W/Event [1] Events

(Costart English)

Paresthesia A) PLACEBO 40 0 TRT 0.802 0 0 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG/NTX 0.01 MG 41 1 ( 2.4%) 1 1 (100.0%) 0 0

D) MS 60 MG/NTX 0.1 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

E) MS 60 MG/NTX 1 MG 41 2 ( 4.9%) 2 1 ( 50.0%) 1 ( 50.0%) 0

Somnolence A) PLACEBO 40 0 TRT 0.009** 0 0 0 0

B) MS 60 MG 41 4 ( 9.8%) A-E 0.005** 4 2 ( 50.0%) 2 ( 50.0%) 0

C) MS 60 MG/NTX 0.01 MG 41 1 ( 2.4%) C-E 0.029* 1 0 1 (100.0%) 0

D) MS 60 MG/NTX 0.1 MG 41 3 ( 7.3%) 3 0 2 ( 66.7%) 1 ( 33.3%)

E) MS 60 MG/NTX 1 MG 41 8 ( 19.5%) 8 5 ( 62.5%) 3 ( 37.5%) 0

Tremor A) PLACEBO 40 0 TRT 1.000 0 0 0 0

B) MS 60 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

C) MS 60 MG/NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG/NTX 0.1 MG 41 1 ( 2.4%) 1 1 (100.0%) 0 0

E) MS 60 MG/NTX 1 MG 41 1 ( 2.4%) 1 1 (100.0%) 0 0

Respiratory

All Events A) PLACEBO 40 2 ( 5.0%) TRT 0.335 2 2 (100.0%) 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG NTX 0.01 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

D) MS 60 MG/NTX 0.1 MG 41 0 0 0 0 0

E) MS 60 MG/NTX 1 MG 41 1 ( 2.4%) 1 1 (100.0%) 0 0

Table 13 A (Continued)

Adverse Events By Body System And Severity

Safety Population

Total No. Of Total Severity [2]

Body System No. Of Subjects Source P-Value No. Of

Mild ]yf p.rafp Severe

Adverse Events Treatment Subjects W/Event [1] Events

(Costart English)

Dyspnea A) PLACEBO 40 0 TRT 1.000 0 . 0 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG/NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG/NTX 0.1 MG 41 0 0 0 0 0

E) MS 60 MG/NTX 1 MG 41 1 ( 2.4%) 1 1 (100.0%) . 0 0

Epistaxis A) PLACEBO 40 1 ( 2.5%) TRT 0.512 1 1 (100.0%) 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG/NTX 0.01 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

D) MS 60 MG/NTX 0.1 MG 41 0 0 0 0 0

E) MS 60 MG/NTX 1 MG 41 0 0 0 0 0

Rhinitis A) PLACEBO 40 1 ( 2.5%) TRT 0.196 1 1 (100.0%) 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG/NTX 0.1 MG 41 0 0 0 0 0

E) MS 60 MG/NTX 1 MG 41 0 0 0 0 0

Skin/Appendages

All Events A) PLACEBO 40 0 TRT 0.244 0 0 0 0

B) MS 60 MG 41 4 ( 9.8%) 4 2 ( 50.0%) 2 ( 50.0%) 0

C) MS 60 MG/NTX 0.01 MG 41 4 ( 9.8%) 5 2 ( 40.0%) 3 ( 60.0%) 0

D) MS 60 MG/NTX 0.1 MG 41 4 ( 9.8%) 4 0 4 (100.0%) 0

E) MS 60 MG/NTX 1 MG 41 4 ( 9.8%) 5 3 ( 60.0%) 2 ( 40.0%) 0

SIGNIFICANT PAIRWISE COMPARISONS ONLY. [2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS. *, **, ***: P-VALUE < = 0.05, < - 0.01, OR < - 0.001 RESPECTIVELY.

Table 13A (Continued)

Adverse Events By Body System And Severity Safety Population

Total No. Of Total Severity [2]

Puritus A) PLACEBO 40 0 TRT 0.264 0 0 0 0

B) MS 60 MG 41 2 ( 4.9%) 2 1 ( 50.0%) 1 ( 50.0%) 0

C) MS 60 MG NTX 0.01 MG 41 4 ( 9.8%) 4 2 ( 50.0%) 2 ( 50.0%) 0

D) MS 60 MG/NTX 0.1 MG 41 4 ( 9.8%) 4 0 4 (100.0%) 0

E) MS 60 MG NTX 1 MG 41 2 ( 4.9%) 2 2 (100.0%) 0 0

Rash A) PLACEBO 40 0 TRT 1.000 0 0 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG/NTX 0.01 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

D) MS 60 MG/NTX 0.1 MG 41 0 0 0 0 0

E) MS 60 MG NTX 1 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

Sweating A) PLACEBO 40 0 TRT 0.223 0 0 0 0

B) MS 60 MG 41 2 ( 4.9%) 2 1 ( 50.0%) 1 ( 50.0%) 0

C) MS 60 MG/NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG/NTX 0.1 MG 41 0 0 0 0 0

E) MS 60 MG NTX 1 MG 41 2 ( 4.9%) 2 1 ( 50.0%) 1 ( 50.0%) 0

Special Senses

All Events A) PLACEBO 40 1 ( 2.5%) TRT 0.798 1 1 (100.0%) 0 0

B) MS 60 MG 41 2 ( 4.9%) 2 2 (100.0%) 0 0

C) MS 60 MG/NTX 0.01 MG 41 3 ( 7.3%) 3 3 (100.0%) 0 0

D) MS 60 MG/NTX 0.1 MG 41 4 ( 9.8%) 4 3 ( 75.0%) 1 ( 25.0%) 0

E) MS 60 MG/NTX 1 MG 41 2 ( 4.9%) 2 2 (100.0%) 0 0

SIGNIFICANT PAIRWISE COMPARISONS ONLY. [2] THE DENOMPNATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS. *, **, ***: P-VALUE < - 0.05, < = 0.01, OR < = 0.001 RESPECTIVELY.

Table 13 A (Continued)

Adverse Events By Body System And Severity Safety Population

Total No. Of Total Severity [2]

Body System No. Of Subjects Source P-Value No. Of

Conjunctivitis A) PLACEBO 40 1 ( 2.5%) TRT 0.798 1 , 1 (100.0%) 0 0

B) MS 60 MG 41 2( 4.9%) 2 2 (100.0%) 0 0

C) MS 60 MG/NTX 0.01 MG 41 3 ( 7.3%) 3 3 (100.0%) 0 0

D) MS 60 MG/NTX 0.1 MG 41 4( 9.8%) 4 3 ( 75.0%) 1 ( 25.0%) 0

E) MS 60 MG NTX 1 MG 41 2( 4.9%) 2 2 (100.0%) 0 0

Urogenital All Events A) PLACEBO 40 0 TRT 0.278 0 0 0 0

B) MS 60 MG 41 1 ( 2.4%) 1 1 (100.0%) 0 0

C) MS 60 MG/NTX 0.01 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

D) MS 60 MG NTX 0.1 MG 41 3 ( 7.3%) 3 3 (100.0%) 0 0

E) MS 60 MG NTX 1 MG 41 0 0 0 0 0

Dysuria A) PLACEBO 40 0 TRT 1.000 0 0 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG/NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG NTX 0.1 MG 41 1 ( 2.4%) 1 1 (100.0%) 0 0

E) MS 60 MG NTX 1 MG 41 0 0 0 0 0

Metrorrhagia A) PLACEBO 40 0 TRT 1.000 0 0 0 0

B) MS 60 MG 41 1 ( 2.4%) 1 1 (100.0%) 0 0

C) MS 60 MG/NTX 0.01 MG 41 0 0 0 0 0

D) MS 60 MG/NTX 0.1 MG 41 0 0 0 0 0

E) MS 60 MG/NTX 1 MG 41 0 0 0 0 0

Table 13A (Continued)

Adverse Events By Body System And Severity Safety Population

Total No. Of Total Severity [2]

Urinary Retention A) PLACEBO 40 0 TRT 0.512 0 0 0 0

B) MS 60 MG 41 0 0 0 0 0

C) MS 60 MG/NTX 0.01 MG 41 1 ( 2.4%) 1 0 1 (100.0%) 0

D) MS 60 MG/NTX 0.1 MG 41 2 ( 4.9%) 2 2 (100.0%) 0 0

E) MS 60 MG/NTX 1 MG 41 0 0 0 0 0

[1] P-VALUES ARE FROM_. FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND

Table 13B

SELECTED ADVERSE EVENTS

SAFETY POPULATION

[1] P-VALUE COMPARES THE PROPORTION OF SUBJECTS WITH EVENTS. [2] RELATIONSHIP TO STUDY DRUG = 'SUSPECTED' OR 'PROBABLE'. N/A: NOT APPLICABLE. *, **, ***: P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 13B

SELECTED ADVERSE EVENTS

SAFETY POPULATION

[1] P-VALUE COMPARES THE PROPORTION OF SUBJECTS WITH EVENTS. [2] RELATIONSHIP TO STUDY DRUG = 'SUSPECTED' OR 'PROBABLE'. N/A: NOT APPLICABLE. * ** ***. p.vALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 13B

SELECTED ADVERSE EVENTS

SAFETY POPULATION

Table 13B

SELECTED ADVERSE EVENTS

SAFETY POPULATION

[1] P-VALUE COMPARES THE PROPORTION OF SUBJECTS WITH EVENTS. [2] RELATIONSHIP TO STUDY DRUG - 'SUSPECTED' OR 'PROBABLE'. N/A: NOT APPLICABLE. *, **, ***: P-VALUE <=0.05, <= 0.01, OR<= 0.001 RESPECTIVELY.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of various aspects of the invention. Thus, it is to be understood that numerous modifications may be made in the illustrative embodiments and other arrangements may be devised without departing from the spirit and scope of the invention.

EXAMPLE 2

The results from the clinical study as described in Example 1 were analyzed by gender.

The results for females and males from the Example 1 clinical study are shown in the following Tables and Figures.

A total of 204 subjects were randomized; among them 201 subjects were deemed evaluable. One subject in each of the placebo, MS and MS/0.1 NTX groups was not evaluable because the subject took rescue medication less than 90 minutes after dosing. Tables 14A and 14B show the number of female and male subjects separately.

Table 14A Analysis Po ulations, Female Patients

[1]I ΆTΓENTS WITH DEMOGRAPHIC INFORMATION

Table 14B Analysis Populations, Male Patients

Treatments

Placebo with MS (60 mg) MS (60 mg) MS (60 mg) MS (60 mg) Placebo with Placebo with NTX with NTX with NTX Total (0.01 mg) (0.1 mg) (1.0 mg)

Patients Enrolled [1] 18 18 21 21 21 99

Safety 18 (100.0%) 18 (100.0%) 21 (100.0%) 21 (100.0%) 21 (100.0%) 99 (100.0%)

Intent-To-Treat 18 (100.0%) 18 (100.0%) 21 . (100.0%) 21 (100.0%) 21 (100.0%) 99 (100.0%)

Evaluable 17 ( 94.4%) 17 ( 94.4%) 21 (100.0%) 21 (100.0%) 21 (100.0%) 97 ( 98.0%)

PATIENTS WITH DEMOGR APHIC INFORM ATION.

The demographic and baseline characteristics were summarized by treatment groups for the ITT population (all randomized patients) and the evaluable population (all randomized patients with at least one efficacy evaluation at 90 minutes or more after dosing) (Table 15A for females and Table 15B for males). Demographic characteristics included age, race/ethnicity, sex, weight, height, medical history, teeth extracted (impacted and non-impacted), baseline pain intensity, and baseline visual analog scale.

The demographics for the total ITT population were comparable across all 5 treatment groups. Female subjects (51%) ranged in age from 16 to 35 years; male subjects ranged in age from 16 to 39 years. There were some differences among treatment groups in the maximum degree of impaction of third molar extracted. No adjustments in the analyses were made to take into account these differences among treatment groups. Generally, no differences among overall treatment groups were noted in the number of patients with either a significant medical history or disease of any body system. The baseline pain intensity scores and visual analog scale scores, respectively, are shown in Tables 16A and 16B for females and Tables 16C and 16D for males.

Table 15A

Baseline Characteristics

Intent-To-Treat Po ulation, Female Patients

Table 15A (Continued)

Baseline Characteristics

Intent-To-Treat Po ulation Female Patients

Table 15B

Baseline Characteristics

^"2] Fisher's Exa ct Test.

3] Black, Asian , Hispanic, and O ther are Combir ted into One Catej ory to Derive P-Value. r/11 ^•? nr- Λ/Tr.ι-« T ^■.irA Λ/fr-lαvo ^"Rvf-rα ^"P_

Table 15B (Continued) Baseline Characteristics

[4] 3 or More Third Molars Extracted as One Category to Derive P-Value.

Table 16A Baseline Pain intensity Scores

NOTE: P-VALUES ARE FROM FISHER'S EXACT TEST.

Table 16B Baseline Visual Analog Scale (VAS) Scores Intent-To-Treat Population, Female Patients

BASELINE VAS SCORE P-VALUE FOR PAIRWISE COMPARISONS

TREATMENT Moderate[l] Severe [1] Total MS MS 60 mg MS 60 mg MS 60 mg P-Value for 60 NTX 0.01 NTX 0.1 NTX 1 Overall mg mg mg mg Treatment

N Mean (SD) N Mean (SD) N Mean (SD)

Placebo 65.0 (8.02) 16 80.0 (11.33) 22 75.9 (12.40) 0.256 0.300 0.452 0.776 0.257

MS 60 mg 68.4 (7.67) 15 87.0 (6.80) 23 80.5 (11.42) 0.032 0.736 0.410

MS 60 mg/NTX O.Ol mg 59.0 (8.50) 12 79.9 (13.15) 20 71.6 (15.40) 0.084 0.198

MS 60 mg/NTX 0.1 mg 67.9 (14.61) 11 87.3 (9.22) 19 79.1 (15.07) 0.644

MS 60 mg/ΝTX 1 mg 69.9 (12.19) 11 83.0 (11.93) 20 77.1 (13.50)

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS [1] BASELINE PALN INTENSITY ON THE CATEGORICAL SCALE.

Table 16C

Baseline Pain Intensity Scores

Intent-To-Treat Population, Male Patients

PALN INT ENSITY P-VALUE FOR PAIRWISE COMPARISONS

MS 60 mg MS 60 mg P-VALUE FOR

MS 60 NTX NTX MS 60 mg OVERALL

TREATMENT MODERATE SEVERE mg 0.01 mg 0.1 mg NTX 1 mg TREATMENT

Placebo 10 (55.6%) 8 (44.4%) 1.000 0.527 0.527 0.343 0.749

MS 60 mg 10 (55.6%) 8 (44.4%) 0.527 0.527 0.343

MS 60 mg /NTX 0.01 mg 9 (42.9%) 12 (57.1%) 1.000 1.000

MS 60 mg /NTX 0. l mg 9 (42.9%) 12 (57.1%) 1.000

MS 60 mg /NTX 1 mg 8 (38.1%) 13 (61.9%) E: P-VALUES ARE FROM FISHER'S EXA CT TEST.

Table 16D

Baseline Visual Analog Scale (VAS) Scores

Intent-To-Treat Po ulation, Male Patients

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS [1] BASELINE PAIN INTENSITY ON THE CATEGORICAL SCALE.

The TOTPAR results (4 hour, 6 hour, 8 hour) are summaπzeα m laoies i

for females and 17B for males. The placebo treatment group had the lowest mean TOTPAR scores. All 4 of the active treatment groups exhibited mean TOTPAR scores that were numerically higher than placebo. In females, the mean TOTPAR scores for the 0.01 mg NTX and 0.1 mg NTX combination treatments were higher than that for the MS alone treatment, whereas the 1.0 mg NTX combination treatment mean was comparable to or lower than that for the MS alone. In males, the scores for the 1.0 mg NTX, 0.1 mg NTX, and 0.01 mg combination treatments were higher than that for the MS alone treatment for 4 hour and 6 hour TOTPAR scores, and the 1.0 mg and 0.01 mg NTX combinations were higher than morphine alone for the 8 hour

TOTPAR scores.

Table 17A

Total Pain Relief Scores

Intent-To-Treat Po ulation, Female Patients

[1] FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. *, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Table 17A (Continued)

Total Pain Relief Scores

Intent-To-Treat Population, Female Patients

Table 17B

Total Pain Relief Scores

Intent-To-Treat Po ulation, Male Patients

Table 17B (Continued)

Total Pain Relief Scores

] [ntent-To-Treat Population, Male Patients

TOTAL PALN RELIEF SCORE P-VALUE

TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE rn

TOTAL PAIN RELIEF SCORE (0-8 HOURS)

A) Placebo 18 5.94 7.553 0.0 1.50 20.0 TRT 0.334

B) MS 60 mg 18 9.52 9.168 0.0 10.38 26.1 B-A N/D

C) MS 60 mg /NTX 0.01 mg 21 11.38 9.611 0.0 13.73 27.5 C-A N/D

D) MS 60 mg /NTX 0.1 mg 21 9.48 9.569 0.0 7.25 28.3 D-A N/D

E) MS 60 mg/NTX l mg 21 11.94 11.02 0.0 11.26 30.0 E-A N/D C-B N/D D-B N/D E-B N/D

[1] FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. * ** ***. p.vALUE < - 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Tables 18A for females and 18B for males, summarize the results of the 4, 6, and 8 hour SPTD results and the 4 hour SPED results are shown in Figures 9B for females and 9C for males. Ln females, the placebo treatment had the lowest mean 4, 6 and 8 hour SPLD scores. All 4 of the active treatment groups exhibited improved profiles in mean SPID relative to placebo. The mean SPID scores for the 0.01 mg

NTX and 0.1 mg NTX combination treatments were higher than that for the MS alone treatment. In males, the placebo treatment had the lowest mean 6 and 8 hour SPTD scores. For the 4 hour SPID score, the placebo treatment was similar to the MS alone treatment. The mean SPID scores for the 0.01 mg NTX, 0.1 mg NTX and 1.0 mg combination treatments were higher than that for the MS alone treatment.

Table 18A

Sum of Pain Intensity Differences

Intent-To-Treat Po ulation, Female Patients

[1] PAIN INTENSITY DIFFERENCE = PATN INTENSITY AT BASELINE - PAJN INTENSITY AT CURRENT TIME.

*, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Table 18A (Continued)

Sum of Pain Intensity Differences

Intent-To-Treat Po ulation, Female Patients

[1] PAIN INTENSITY DIFFERENCE = PAIN INTENSITY AT BASELINE - PAJN INTENSITY AT CURRENT TIME.

*, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Table 18B

Sum of Pain Intensity Differences

Intent-To-Treat Po ulation, Male Patients

[1] PAIN INTENSITY DIFFERENCE = PAIN INTENSITY AT BASELINE - PAIN INTENSITY AT CURRENT TIME.

*, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Table 18B (Continued)

Sum of Pain Intensity Differences

Intent-To-Treat Po ulation, Male Patients

[1] PALN INTENSITY DIFFERENCE = PAIN INTENSITY AT BASELINE - PAJN INTENSITY AT CURRENT TIME.

*, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Figures 10A for females and 10B for males are visual presentations of the summary and analysis of time to onset of meaningful pain relief scores presented in Tables 19A for females and 19B for males. In females, the median time to onset of meaningful pain relief was shortest in the 0.01 mg NTX (low-dose) combination treatment group. In males, the median time to onset of meaningful pain relief was shortest for the MS alone treatment, followed by the 1.0 mg NTX combination and then the 0.01 mg NTX combination.

Table 19A

Time To Onset of Meaningful Pain Relief

Intent-To-Treat Po ulation, Female Patients

*, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY. N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Figures 11A and 12 A for females and 11B and 12B for males are visual presentations of the summary and analysis of time to remedication (rescue medication) up to 8 and 24 hours, respectively, presented in Tables 20A for females and 20B for males. The survival distributions (0-8 hours) were different across treatment groups (Figures 11 A and 1 IB). In females, the survival distributions were different for the low-dose and mid-dose groups compared to placebo. The median times to administration of rescue medication were longer for the morphine (> 8 hours), low-dose (> 8 hours), and mid-dose (> 8 hours) groups compared to the high- dose (2 hours, 30 minutes) and placebo (2 hours, 2 minutes) groups. In males, the median times to administration of rescue medication were longer for the placebo (>8 hours), MS alone (>8 hours), low-dose (>8 hours) and high-dose (>8 hours) compared to the mid-dose (3 hours, 6 minutes) group.

The survival distributions (0-24 hours) were also different across treatment groups (Figures 12A and 12B). In females, the median times to administration of rescue medication were longer for the morphine, low-dose, and mid-dose groups. In males, the median times to administration of rescue medication were longest for the low-dose and high-dose groups.

Analyses of time to remedication up to 24 hours yielded similar results, however, the data should be viewed with caution because subjects were not under close supervision after 8 hours.

* *

Table 20B

Time To Rescue Medication

Tables 21 A for females and 2 IB for males present the summary and analysis of percent of subjects who took remedication up to 8 and 24 hours. For females, analysis of the percentage of subjects who remedicated within 8 hours showed the lowest percentage for the low-dose (0.01 mg NTX) and mid-dose (O.lmg NTX) combination groups. In males, the percentage of subjects remedicating (0-8 hours) was comparable across all treatment groups. 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.

Table 21 A

Percent of Subjects Rescued

Intent-To-Treat Po ulation, Female Patients

N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 21B

Percent of Subjects Rescued

Intent-To-Treat Po ulation, Male Patients

ND: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Figures 13 A for females and 13B for males are visual presentations of the hourly pain relief scores presented in Table 22A for females and 22B for males. The hourly pain relief scores were summarized and analyzed in 2 ways: first as a categorical variable and second as a numerical variable. Because results of these two methods were similar, only the results from the numerical version are presented here.

In females, the hourly pain relief scores for the placebo treatment were less than those for the active treatment groups. This was true for males from hour 1 through hour 8. For females and males, there was separation between the placebo and the active treatment groups that continued throughout the 8-hour study period. For females, highest pain relief scores were observed for the low-dose (0.01 mg NTX) and mid- dose (0.1 mg NTX) combination groups (Figure 13 A). For males, highest pain relief scores were observed for the low-dose (0.01 mg NTX) and high-dose (1.0 mg NTX) combination groups.

Table 22A

Pain Relief (PR) Scores [1]

Intent-To-Treat Po ulation, Female Patients

[1] FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. *, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY. N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 22A (Continued) Pain Relief (PR) Scores [1]

Table 22A (Continued) Pain Relief (PR) Scores [1]

Table 22A (Continued) Pain Relief (PR) Scores [1]

Table 22B

Pain Relief (PR) Scores [1]

Intent-To-Treat Population, Male Patients

[1] FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. *, **, ***: P-VALUE < = 0.05, < == 0.01, or < = 0.001 RESPECTIVELY. N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 22B (Continued)

Pain Relief (PR) Scores [1]

Intent-To-Treat Population, Male Patients

Table 22B (Continued)

Pain Relief (PR) Scores [1]

Intent-To-Treat Po ulation, Male Patients

Table 22B (Continued)

Pain Relief (PR) Scores [1]

Intent-To-Treat Population, Male Patients

Table 22B (Continued)

Pain Relief (PR) Scores [1]

Intent-To-Treat Population, Male Patients

The hourly pain intensity difference (PID) data are presented in Table 23 A and Figure 14A for females and in Table 23B and Figure 14B for males. For females, the mean scores for the morphine and morphine/naltrexone combination groups were higher than the mean PID scores for the placebo group at each assessment time. The means for the low-dose (0.01 mg NTX) and mid-dose (0.1 mg NTX) combination groups were greater than the means for high-dose (1.0 mg NTX combination) and placebo groups. Highest pain relief as measured by PID scores was observed for the low-dose (0.01 mg NTX) and mid-dose (0.1 mg NTX) combination groups. In males, the highest PID scores were most often observed for the high dose (1.0 mg NTX) combination group .

Table 23A

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

Table 23A (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

[1] FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. *, **, ***: P-VALUE < = 0.05, < - 0.01, or < = 0.001 RESPECTIVELY. N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 23A (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

Table 23A (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

Table 23 A (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Population, Female Patients

Table 23B

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

Table 23B (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

[1] FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER' S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. *, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY. N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 23B (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

Table 23B (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

[1] FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. *, **, ***: P-VALUE < = 0.05, < = 0.01, or < - 0.001 RESPECTIVELY. N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 23B (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

[11 FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST. *, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY. N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

The mean MAXPAR scores are presented in Table 24A for females and 24C for males. In females, the mean MAXPAR scores were highest for the low-dose (0.01 mg NTX) and mid-dose (0.1 mg NTX) combination groups compared to all other groups. The mean scores for the low-dose and mid-dose groups were greater than the mean score for the morphine group, which in turn, was greater than the mean score for the placebo group. In males, the mean MAXPAR scores were highest for the high-dose (1.0 mg NTX) and low-dose (0.01 mg NTX) combination groups.

The mean PEAKPID scores presented in Table 24B for females and 24D for males were different among treatment groups, and were greater for the morphine/naltrexone groups compared to the placebo group. In females, the mean

PEAKPID scores for the low-dose (0.01 mg NTX) and mid-dose (0.1 mg NTX) combination groups were highest. In males, the high-dose (1.0 mg NTX) and low- dose (0.01 mg NTX) combination groups had the highest mean PEAKPID scores.

Table 24A

Maximum Pain Relief Scores (MAXPAR)

Intent-To-Treat Po ulation, Female Patients

[il

* ** ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Table 24B Peak Pain Intensity Differences (PEAKPID) Intent-To-Treat Population, Female Patients

PEAK PAIN INTENSITY DIFFERENCES P-VALUE

TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE [11

A) Placebo 22 0.50 0.913 -1 0.0 3 TRT O.001***

B) MS 60 mg 23 1.35 1.071 0 1.0 3 B-A 0.005**

C) MS 60 mg /NTX 0.01 mg 20 1.70 0.923 0 2.0 3 C-A O.001***

D) MS 60 mg /NTX 0.1 mg 20 1.40 0.940 0 1.5 3 D-A 0.004**

E) MS 60 mg /NTX l mg 20 0.70 1.174 -1 0.0 3 E-A 0.522

C-B 0.256

D-B 0.866

E-B 0.038*

[11 FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE ' ΓEST. *, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Table 24C Maximum Pain Relief Scores (MAXPAR) Intent-To-Treat Population, Male Patients

-MAXIMUM PAJN RELIEF SCORE P-VALUE

TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE [11

A) Placebo 18 1.33 1.372 0.0 1.0 4.0 TRT 0.674

B) MS 60 mg 18 1.83 1.425 0.0 2.5 4.0 B-A N/D

C) MS 60 mg /NTX 0.01 mg 21 2.00 1.673 0.0 3.0 4.0 C-A N/D

D) MS 60 mg /NTX 0.1 mg 21 1.81 1.401 0.0 2.0 4.0 D-A N/D

E) MS 60 mg /NTX l mg 21 2.00 1.789 0.0 2.0 4.0 E-A N/D

C-B N/D

D-B N/D

E-B N/D

Table 24D

Peak Pain Intensity Differences (PEAKPID)

Intent-To-Treat Population, Male Patients

EST.

*, **, ***: P-VALUE < = 0.05, < - 0.01, or < = 0.001 RESPECTIVELY.

Tables 25A for females and 25B for males present the summary and analysis of global evaluations. For both females and males, the placebo treatment had the highest number of subjects who had poor global evaluation scores based on subject evaluation. For females, the low-dose (0.01 mg NTX) and mid-dose (0.1 mg NTX) combination groups were most often rated as "excellent." For males, the high-dose (1.0 mg NTX) combination group was most often rated as "excellent." The profiles of the global evaluations scores are based on subjects' evaluations.

Table 25A

Global Evaluation of Study Medication

Intent-To-Treat Po ulation, Female Patients

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR <=<0.001 RESPECTIVELY.

Table 25B Global Evaluation of Study Medication

**₅ ***. P-VALUE <= 0.05, <= 0.01, OR <=O.001 RESPECTIVELY.

The majority of adverse events reported were categorized as digestive (nausea or vomiting) or nervous system (dizziness or somnolence) as further shown in Tables 26 A or 26B for females and 26C or 26D for males. Figures 15 A for females and 15B for males represent a summary of exemplary adverse side effects according to methods and compositions of the invention.

In females, the placebo group had the lowest incidence of nausea, vomiting, dizziness and somnolence (sedation). For nausea, vomiting and dizziness, the 1.0 mg NTX combination group had the lowest incidence of adverse events compared to the other active treatment groups. For somnolence, the 0.01 mg NTX combination group had the lowest incidence among the active treatment groups.

In males, the placebo group showed the lowest incidence of adverse events. Among the active treatment groups, the 1.0 mg NTX combination group had the lowest incidence of adverse events. Except for somnolence which was lowest in the 0.1 mgNTX combination group.

Table 26A . ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

(COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE DI Of MILD Moderate SEVERE

Events

TOTAL NUMBER OF EVENTS ADVERSE EVENTS (ALL BODY SYSTEMS)

A) PLACEBO 22 7 (31.8%) Treatment O.OOl*** 12 4 (33.3%) 3 (25.0%) 5 (41.7%

B) MS 60 mg 23 22 (95.7%) A-B O.001*** 55 18 (32.7%) 20 (36.4%) 17 (30.9%

C) MS 60 mg/NTX 0.01 mg 20 19 (95.0%) A-C O.001*** 58 13 (22.4%) 24 (41.4%) 21 (36.2%

D) MS 60 mg/NTX 0.1 mg 20 20 (100.0%) A-D O.001*** 68 17 (25.0%) 25 (36.8%) 26 (38.2%

E) MS 60 mg/NTX 1 mg 20 17 (85.0%) A-E O.001*** 34 16 (47.1%) 10 (29.4%) 8 (23.5%

BODY AS A WHOLE

ALL EVENTS A) PLACEBO 22 3 (13.6%) Treatment 0.284 3 1 (33.3%) 2 (66.7%) 0

B) MS 60 mg 23 4 . (17.4%) 5 2 (40.05) 3 (60.05) 0

C) MS 60 mg/NTX O.Ol g 20 3 (15.0%) 3 1 (33.3%) 1 (33.3%) 1 (33.3%

D) MS 60 mg/NTX 0.1 mg 20 4 (20.0%) 7 1 (14.3%) 4 (57.1%) 2 (28.6%

E) MS 60 mg ΝTX 1 mg 20 0 0 0 0 0

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY

DRUG "SUSPECTED" OR "PROBABLE"

[1] P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND

SIGNIFICANT PAIRWISE COMPARISONS ONLY

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, FEMALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [21

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W EVENT SOURCE [1] Of MILD Moderate SEVERE Events

ABDOMINAL PAIN A) PLACEBO 22 0 Treatment 0.412 0 0 0 0

B) MS 60 mg 23 0 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 20 1 (5.0%) 1 0 0 1 (100.0%

D) MS 60 mg/NTX 0.1 mg 20 1 (5.0%) 1 0 0 1 (100.0%

E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0

ASTHENIA A) PLACEBO 22 0 Treatment 0.571 0 0 0 0

B) MS 60 mg 23 0 0 0 0 0

C) MS 60 mg/ΝTX 0.01 mg 20 0 0 0 0 0

D) MS 60 mg/ΝTX 0.1 mg 20 1 (5.0%) 1 0 1 (100.0%) 0

E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0

HEADACHE A) PLACEBO 22 3 (13.6%) Treatment 0.279 3 1 (33.3%) 2 (66.7%) 0

B) MS 60 mg 23 4 (17.4%) 4 1 (25.0%) 3(75.0%a0 0

C) MS 60 mg/ΝTX 0.01 mg 20 1 (5.0%) 1 K 100.0%) 0 0

D) MS 60 mg/ΝTX 0.1 mg 20 3 (15.0%) 5 1 (20.0%) 3 (60.0%) 1 (20.0%

E) MS 60 mg/ΝTX 1 mg 20 0 0 0 0 0

DRUG "SUSPECTED" OR "PROBABLE"

SIGNIFICANT PAJRWISE COMPARISONS ONLY

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <O.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, FEMALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE [1] Of MILD Moderate SEVERE Events

INJECTION SITE A) PLACEBO 22 0 Treatment 1.000 0 0 0 0 HEMORRHAGE B) MS 60 mg 23 1 (4.3%) 1 1 (100.0%) 0 0

C) MS 60 mg/NTX 0.01 mg 20 0 0 0 0 0

D) MS 60 mg/ΝTX 0.1 mg 20 0 0 0 0 0

E) MS 60 mg/ΝTX 1 mg 20 0 0 0 0 0

PATN A) PLACEBO 22 0 Treatment 0.571 0 0 0 0

B) MS 60 mg 23 0 0 0 0 0

C) MS 60 mg/ΝTX 0.01 mg 20 1 (5.0%) 1 0 1 (100.0%) 0

D) MS 60 mg/ΝTX 0.1 mg 20 0 0 0 0 0

E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0

DRUG "SUSPECTED" OR "PROBABLE"

[11 P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND

SIGNIFICANT PAIRWISE COMPARISONS ONLY

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

* ** ***. P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, FEMALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

(COSTART ENGLISH) TREATMENT UBJECTS W/EVENT SOURCE [1] Of MILD Moderate SEVERE Events

CARDIOVASCULAR

ALL EVENTS A) PLACEBO 22 0 Treatment 0.201 0

B) MS 60 mg 23 2 (8.7%) (50.0%) 1 (50.0%)

C) MS 60 mg/NTX 0.01 mg 20 3 (15.0%) (33.3%) 1 (33.3%) (33.3%)

D) MS 60 mg/NTX 0.1 mg 20 2 (10.0%) (50.0%) 1 (50.0%)a

E) mg 60 mg/NTX 1 mg 20 0 0

VASODILATATION A) PLACEBO 22 0 Treatment 0.201 0

B) MS 60 mg 23 2 (8.7%) 2 (50.0%) 1 (50.0%)

C) MS 60 mg/NTX 0.01 mg 20 3 (15.0%) 3 (33.3%) 1 (33.3%) (33.3

D) MS 60 mg/NTX 0.1 mg 20 2 (10.0%) 2 (50.0%) 1 (50.0%)a

DRUG "SUSPECTED" OR "PROBABLE"

SIGNIFICANT PAIRWISE COMPARISONS ONLY

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, FEMALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS ^• W/EVENT SOURCE [1] Of MILD Moderate SEVERE Events

DIGESTIVE

ALL EVENTS A) PLACEBO 22 4 (18.2%) Treatment .001*** 7 (14.3%) 1 (14.3%) 5 (71.4%)

B) MS 60 mg 23 16 (69.6%) A-B .001*** 30 (13.3%) 10 (33.3%) 16 (53.3%)

C) MS 60 mg/NTX 0.01 mg 20 17 (85.0%) A-C O.001*** 31 (12.9%) 11 (35.5%) 16 (51.6%)

D) MS 60 mg/NTX 0.1 mg 20 18 (90.0%) A-D .001*** 33 (18.2%) 7 (21.2%) 20 (60.6""

E) MS 60 mg/ΝTX 1 mg 20 11 (55.0%) A-E 0.023* 18 (27.8%) 5 (27.8%) 8 (44.4

D-E 0.030*

DIARRHEA A) PLACEBO 22 0 Treatment 0.104 0 0 0 0

B) MS 60 mg 23 0 0 0 0 0

C) MS 60 mg ΝTX 0.01 mg 20 0 0 0 0 0

D) MS 60 mg/ΝTX 0.1 mg 20 2 (10.0%) 2 1 (50.0%) 1 (50.0%) 0

E) MS 60 mg/ΝTX 1 mg 20 0 0 0 0 0

DRUG "SUSPECTED" OR "PROBABLE"

SIGNIFICANT PAIRWISE COMPARISONS ONLY

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, FEMALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

(COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE [1] Of MILD Moderate SEVERE Events

DYSPEPSIA A) PLACEBO ' 22 1 (4.5%) Treatment 0.654 1 1 (100.0%) 0 0

B) MS 60 mg 23 0 0 0 0 0

C) MS 60 mg NTX 0.01 mg 20 0 0 0 0 0

D) MS 60 mg/NTX 0.1 mg 20 0 0 0 0 0

E) MS 60 mg/NTX 1 mg 20 1 (5.0%) 1 1 (100.0%) 0 0

NAUSEA A) PLACEBO 22 3 (13.6%) Treatment O.001*** 3 0 1 (33. 3%) 2 (66.'

B) MS 60 mg 23 15 (65.2%) A-B O.001*** 16 4 (25.0%) 10 (62. 5%) 2 (12.f

C) MS 60 mg/NTX 0.01 mg 20 15 (75.0%) A-C O.001*** 16 4 (25.0%) 11 (68. 8%) 1 (6.:

D) MS 60 mg/NTX 0.1 mg 20 16 (80.0%) A-D O.001*** 17 5 (29.4%) 6 (35. 3%) 6 (35.:

E) MS 60 mg/NTX 1 mg 20 10 (50.0%) A-E 0.018* 11 (36.4%) 5 (45. 5%) 2 (18.

VOMITING A) PLACEBO 22 3 (13.6%) Treatment O.001*** 3 0 0 3 (100.(

B) MS 60 mg 23 14 (60.9%) A-B O.001** 14 0 0 14(100.0yo

C) MS 60 mg/ΝTX 0.01 mg 20 15 (75.0%) A-C O.001*** 15 0 0 15(100.0%

D) MS 60 mg/NTX 0.1 mg 20 14 (70.0%) A-D O.001*** 14 0 0 14(100.0%

E) MS 60 mg/NTX 1 mg 20 6 (30.0%) C-E 0.010* 6 0 0 6 (100.0%

D-E 0.025*

DRUG "SUSPECTED" OR "PROBABLE"

SIGNIFICANT PAIRWISE COMPARISONS ONLY

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, FEMALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

NERVOUS SYSTEM

ALL EVENTS A) PLACEBO 22 1 (4.5%) Treatment .001*** 1 1 (100.0%) 0 0

B) MS 60 mg 23 10 (43.5%) A-B 0.004** 14 7 (50.0%) 6 (42.9%) 1 (7.1%

C) MS 60 mg/NTX 0.01 mg 20 12 (60.0%) A-C O.001*** 14 4 (28.6%) 7 (50.0%) 3 (21.4%

D) MS 60 mg/ΝTX 0.1 mg 20 12 (60.0%) A-D .001*** 19 6 (31.6%) 9 (47.4%) 4 (21.^{" '}

E) MS 60 mg/ΝTX 1 mg 20 10 (50.0%) A-E O.001** 12 8 (66.7%) 4 (33.3%) 0

DIZZINESS A) PLACEBO 22 1 (4.5%) Treatment 0.022* 1 1 (100.0%) 0 0

B) MS 60 mg 23 7 (30.4%) A-B 0.046* 9 5 (55.6%) 3 (33.3%) 1 (i i.:

C) MS 60 mg/ΝTX O.Ol mg 20 8 (40.0%) A-C 0.007** 8 3 (37.5%) 4 (50.0%) l (12.:

D) MS 60 mg/ΝTX 0.1 mg 20 9 (45.0%) A-D 0.003** 12 5 (41.7%) 4 (33.3%) 3 (25.1

E) MS 60 mg/ΝTX lmg 20 6 (30.0%) A-E 0.040* 6 4 (66.7%) 2 (33.3%) 0

DRUG "SUSPECTED" OR "PROBABLE"

SIGNIFICANT PAIRWISE COMPARISONS ONLY

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, FEMALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

(COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE [1] Of MILD Moderate SEVERE

Events

EUPHORIA A) PLACEBO 22 0 Treatment 0.007** 0 0 0 0

B) MS 60 mg 23 0 A-C 0.043* 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 20 4 (20.0%) B-C 0.039* 4 0 3 (75.0%) 1 (25.0%

D) MS 60 mg/NTX 0.1 mg 20 1 (5.0%) . 1 0 1 (100.0%) 0

E) MS 60 mg/ΝTX 1 mg 20 0 0 0 0 0

HALLUCINATIONS A) PLACEBO 22 0 Treatment 1.000 0 0 0 0

B) MS 60 mg 23 1 (4.3%) 1 0 1 (100.0%) 0

C) MS 60 mg/ΝTX 0.01 mg 20 0 0 0 0 0

D) MS 60 mg/NTX 0.1 mg 20 0 0 0 0 0

E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0

HYPERTONIA A) PLACEBO 22 0 Treatment 0.838 0 0 0 0

B) MS 60 mg 23 1 (4.3%) 1 0 1 (100.0%) 0

C) MS 60 mg/ΝTX 0.01 mg 20 1 (5.0%) 1 0 0 1 (100.0%

D) MS 60 mg/ΝTX 0.1 mg 20 1 (5.0%) 1 0 1 (100.0%) 0

E) MS 60 mg ΝTX 1 mg 20 0 0 0 0 0

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE"

[1] P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS. P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, FEMALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

PARESTHESIA A) PLACEBO 22 0 Treatment 0.549 0 0 0 0

B) MS 60 mg 23 0 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 20 1 (5.0%) 1 K 100.0%) 0 0

D) MS 60 mg/NTX 0.1 mg 20 1 (5.0%) 1 0 1 (100.0%) 0

E) MS 60 mg NTX 1 mg 20 1 (5.0%) 1 0 1 (100.0%) 0

SOMNOLENCE A) PLACEBO 22 0 Treatment 0.021* 0 0 0 0

B) MS 60 mg 23 3 (13.0%) A-E 0.018* 3 2 (66.7%) 1 (33.3%) 0

C) MS 60 mg/ΝTX 0.01 mg 20 0 C-E 0.047* 0 0 0 0

D) MS 60 mg/ΝTX 0.1 mg 20 3 (15.0%) 3 0 2 (66.7%) 1 (33.:

E) MS 60 mg/ΝTX 1 mg 20 5 (25.0%) 5 4 (80.0%) 1 (20.0%) 0

TREMOR A) PLACEBO 22 0 Treatment 0.571 0 0 0 0

B) MS 60 mg 23 0 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 20 0 0 0 0 0

D) MS 60 mg/ΝTX 0.1 mg 20 1 (5.0%) 1 K 100.0%) 0 0

E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0

DRUG "SUSPECTED" OR "PROBABLE"

SIGNIFICANT PAIRWISE COMPARISONS ONLY

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <=0.05, <= 0.01, OR<= 0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, FEMALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

RESPIRATORY

ALL EVENTS A) PLACEBO 22 1 (4.5%) Treatment 0.654 1 1 (100.0%) 0 0

B) MS 60 mg 23 0 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 20 1 (5.0%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.1 mg 20 0 0 0 0 0

E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0

EPISTAXIS A) PLACEBO 22 0 Treatment 0.571 0 0 0 0

B) MS 60 mg 23 0 0 0 0 0

C) MS 60 mg/ΝTX 0.01 mg 20 1 (5.0%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.1 mg 20 0 0 0 0 0

E) MS 60 mg/ΝTX 1 mg 20 0 0 0 0 0

DRUG "SUSPECTED" OR "PROBABLE"

SIGNIFICANT PAIRWISE COMPARISONS ONLY

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, FEMALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE [11 Of MILD Moderate SEVERE Events

RHINITIS A) PLACEBO 22 1 (4.5%) Treatment 0.780 1 1 (100.0%) 0 0

B) MS 60 mg 23 0 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 20 0 0 0 0 0

D) MS 60 mg/NTX 0.1 mg 20 0 0 0 0 0

E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0

SKIN/APPENDAGES

ALL EVENTS A) PLACEBO 22 0 Treatment 0.211 0 0 0 0

B) MS 60 mg 23 1 (4.3%) 1 1 (100.0%) 0 0

C) MS 60 mg/ΝTX 0.01 mg 20 3 (15.0%) 4 1 (25.0%) 3 (75.0%) 0

D) MS 60 mg ΝTX 0.1 mg 20 3 (15.0%) 3 0 3 (100.0%) 0

E) MS 60 mg/ΝTX 1 mg 20 3 (15.0%) 4 3 (75.0%) 1 (25.0%) 0

DRUG "SUSPECTED" OR "PROBABLE"

SIGNIFICANT PAIRWISE COMPARISONS ONLY

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, FEMALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [21

PURITUS A) PLACEBO 22 0 Treatment 0.081 0 0 0 0

B) MS 60 mg 23 0 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 20 3 (15.0%) 3 1 (33.3%) 2 (66.7%) 0

D) MS 60 mg NTX 0.1 mg 20 3 (15.0%) 3 0 3 (100.0%) 0

E) MS 60 mg/NTX 1 mg 20 2 (10.0%) 2 2 (100.0%) 0 0

RASH A) PLACEBO 22 0 Treatment 0.412 0 0 0

B) MS 60 mg 23 0 0 0 0 0

C) MS 60 mgNTX 0.01 mg 20 1 (5.0%) 1 0 1 (100.0%) 0

D) MS 60 mg/ΝTX 0.1 mg 20 0 0 0 0 0

E) MS 60 mg/ΝTX 1 mg 20 1 (5.0%) 1 0 1 (100.0%) 0

SWEATING A) PLACEBO 22 0 Treatment 0.907 0 0 0 0

B) MS 60 mg 23 1 (4.3%) 1 1 (100.0%) 0 0

C) MS 60 mg/ΝTX O.Ol mg 20 0 0 0 0 0

D) MS 60 mg ΝTX 0.1 mg 20 0 0 0 0 0

E) MS 60 mg/ΝTX 1 mg 20 1 (5.0%) 1 1 (100.0%) 0 0

DRUG "SUSPECTED" OR "PROBABLE"

SIGNIFICANT PAJRWISE COMPARISONS ONLY

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [21

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

(COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE [11 Of MILD Moderate SEVERE Events

SPECIAL SENSES ALL EVENTS A) PLACEBO 22 0 Treatment 0.201 0 0 0 0

B) MS 60 mg 23 2 (8.7%) 2 2 (100.0%) 0 0

C) MS 60 mg/NTX 0.01 mg 20 2 (10.0%) 2 2 (100.0%) 0 0

D) MS 60 mg/NTX 0.1 mg 20 3 (15.0%) 3 2 (66.7%) 1 (33.3%) 0

E) MS 60 mg ΝTX 1 mg 20 0 0 0 0 0

CONJUNCTIVITIS A) PLACEBO 22 0 Treatment 0.201 0 0

B) MS 60 mg 23 2 (8.7%) 2 (100.0%) 0 0

C) MS 60 mg/ΝTX 0.01 mg 20 2 (10.0%) 2 (100.0%) 0 0

D) MS 60 mg/ΝTX 0.1 mg 20 3 (15.0%) 2 (66.7%) 0 0

E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0

DRUG "SUSPECTED" OR "PROBABLE"

SIGNIFICANT PAIRWISE COMPARISONS ONLY

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, FEMALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

UROGENITAL

ALL EVENTS A) PLACEBO 22 0 Treatment 0.907 0 0 0 0

B) MS 60 mg 23 1 (4.3%) 1 1 (100.0%) 0 0

C) MS 60 mg/NTX 0.01 mg 20 0 0 0 0 0

D) MS 60 mg/NTX 0.1 mg 20 1 (5.0%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0

METRORRHAGIA A) PLACEBO 22 0 Treatment 1.000 0 0 0 0

B) MS 60 mg 23 1 (4.3%) 1 1 (100.0%) 0 0

C) MS 60 mg/ΝTX 0.01 mg 20 0 0 0 0 0

D) MS 60 mg/ΝTX OX mg 20 0 0 0 0 0

E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0

DRUG "SUSPECTED" OR "PROBABLE"

SIGNIFICANT PAIRWISE COMPARISONS ONLY

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, FEMALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF

URINARY RETENTION A) PLACEBO 22 0 Treatment 0.571 0 0 0 0

B) MS 60 mg 23 0 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 20 0 0 0 0 0

D) MS 60 mg/NTX 0.1 mg 20 1 (5.0%) 1 1 (100.0%) 0 0

E) MS 60 mg/ΝTX 1 mg 20 0 0 0 0 0

DRUG "SUSPECTED" OR "PROBABLE"

SIGNIFICANT PAIRWISE COMPARISONS ONLY

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26B SELECTED ADVERSE EVENTS SAFETY POPULATION, FEMALE PATIENTS

Adverse Event Total No. Of P-Value Number Severity [2]

(English) No. Of Subjects [11 Of

Treatment Subjects W/Event Source Events Mild Moderate Severe

DIZZINESS A) PLACEBO 22 1 (4.5%) Treatment 0.022* 1 l ι (100.0%) 0 0

B) MS 60 mg 23 7 (30.4%) A-B 0.046* 9 5 (55.6%) 3 (33.3%) 1 (11.1%

C) MS 60 mg/NTX 0.01 mg 20 8 (40.0%) A-C 0.007** 8 3 (37.5%) 4 (50.0%) 1 (12.5%

D) MS 60 mg/NTX 0.1 mg 20 9 (45.0%) A-D 0.003** 12 5 (41.7%) 4 (33.3%) 3 (25.0%

E) MS 60 mg/ΝTX 1 mg 20 6 (30.0%) A-E 0.040* 6 4 (66.7%) 2 (33.3%) 0

NAUSEA A) PLACEBO 22 3 (13.6%) Treatment O.001*** 3 0 1 (33.3%) 2 (66.7%

B) MS 60 mg 23 15 (65.2%) A-B O.001*** 16 4 (25.0%) 10 (62.5%) 2 (12.f

C) MS 60 mg/ΝTX 0.01 mg 20 15 (75.0%) A-C O.001*** 16 4 (25.0%) 11 (68.8%) 1 (6.2

D) MS 60 mg/NTX 0.1 mg 20 16 (80.0%) A-D O.001*** 17 5 (29.4%) 6 (35.3%) 6 (35.:

E) MS 60 mg/NTX 1 mg 20 10 (50.0%) A-E 0.018* 11 4 (36.4%) 5 (45.5%) 2 (is.:

SOMNOLENCE A) PLACEBO 22 0 Treatment 0.021* 0 0 0 0

B) MS 60 mg 23 3 (13.0%) A-E 0.018* 3 2 (66.7%) 1 (33.3%) 0

C) MS 60 mg/NTX 0.01 mg 20 0 C-E 0.047* 0 0 0 0

D) MS 60 mg/ΝTX 0.1 mg 20 3 (15.0%) 3 0 2 (66.7%) 1 (33.3%

E) MS 60 mg/ΝTX 1 mg 20 5 (25.0%) 5 4 (80.0%) 1 (20.0%) 0

DRUG "SUSPECTED" OR "PROBABLE"

SIGNIFICANT PAIRWISE COMPARISONS ONLY

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26B (Continued) SELECTED ADVERSE EVENTS SAFETY POPULATION, FEMALE PATIENTS

Adverse Event Total No. Of P-Value Number Severity [2] (English) No. Of Subjects [11 Of

Treatment Subjects W/Event Source Events Mild Moderate Severe

VOMITING A) PLACEBO 22 3 (13.6%) Treatment .001*** 3 0 0 3 (100.0%

B) MS 60 mg 23 14 (60.9%) A-B O.001** 14 0 0 14(100.0%

C) MS 60 mg NTX 0.01 mg 20 15 (75.0%) A-C .001*** 15 0 0 15(100.0%

D) MS 60 mg/NTX 0.1 mg 20 14 (70.0%) A-D O.001*** 14 0 0 14(100.0%

E) MS 60 mg/NTX 1 mg 20 6 (30.0%) C-E 0.010* 6 0 0 6 (100.0% D-E 0.025*

DRUG "SUSPECTED" OR "PROBABLE"

SIGNIFICANT PAIRWISE COMPARISONS ONLY

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <=0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26C

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

(COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE [1] Of MILD Moderate SEVER

Events

TOTAL NUMBER OF EVENTS

ADVERSE EVENTS

(ALL BODY SYSTEMS)

ALL EVENTS A) PLACEBO 18 4 ( 22.2%) Treatment O.001*** 5 3 ( 60.0%) 2 ( 40.0%) 0

B) MS 60 mg 18 13 ( 72.2%) A-B 0.006 ** 27 10 ( 37.0%) 12 ( 44.4%) 5( 18.^C0

C) MS 60 mg/NTX 0.01 mg 21 17 ( 81.0%) A-C O.001*** 35 9 ( 25.7%) . 16 ( 45.7%) 10( 28

D) MS 60 mg/ΝTX 0.1 mg 21 17 ( 81.0%) A-D O.001*** 34 11 ( 32.4%) 15 ( 44.1%) 8( 23.

E)- MS 60 mg/ΝTX 1 mg 21 14 ( 66.7%) A-E 0.009** 30 15 ( 50.0%) 12 ( 40.0%) 3( 10.

BODY AS A WHOLE

ALL EVENTS A) PLACEBO 18 1 ( 5.6%) Treatment 0.624 1 0 1 (100.0%) 0

B) MS 60 mg 18 2 ( 11.1%) 2 2 (100.0%) 0 0

C) MS 60 mg/NTX 0.01 mg 21 5 ( 23.8%) 5 1 ( 20.0%) 3 ( 60.0%) l( 20.

D) MS 60 mg/ΝTX 0.1 mg 21 3 ( 14.3%) 3 2 ( 66.7%) 1 ( 33.3%) 0

E) MS 60 mg/ΝTX 1 mg 21 4 ( 19.0%) 4 2 ( 50.0%) 2 ( 50.0%) 0

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE."

[11 P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

* ** ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26C (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

(COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE [1] Of MILD Moderate SEVER

Events

ABDOMINAL PATN A) PLACEBO 18 0 Treatment 1.000 0 0 0 0

B) MS 60 mg 18 0 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 21 1 ( 4.8%) 1 0 0 1 (100.0%)

D) MS 60 mg/ΝTX 0.1 mg 21 0 0 0 0 0

E) MS 60 mg/NTX 1 mg 21 0 0 0 0 0

ASTHENIA A) PLACEBO 18 0 Treatment 0.940 0 0 0 0

B) MS 60 mg 18 1 ( 5.6%) 1 1 ( 100.0%) 0 0

C) MS 60 mg/ΝTX 0.01 mg 21 1 ( 4.8%) 1 0 1 (100.0%) 0

D) MS 60 mg/ΝTX 0.1 mg 21 0 0 0 0 0

E) MS 60 mg/ΝTX 1 mg 21 1 ( 4.8%) 1 1 ( 100.0%) 0 0

FEVER A) PLACEBO 18 1 ( 5.6%) Treatment 0.363 1 0 1 0

B) MS 60 mg 18 0 0 0 0 0

C) MS 60 mg/ΝTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.1 mg 21 0 0 0 0 0

E) MS 60 mg/ΝTX 1 mg 21 0 0 0 0 0

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PAJRWISE COMPARISONS ONLY.

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26C (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

(COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE [1] Of MILD Moderate SEVER

Events

HEADACHE A) PLACEBO 18 0 Treatment 0.637 0 0 0 0

B) MS 60 mg 18 1 ( 5.6%) 1 1 (100.0%) 0 0

C) MS 60 mg/NTX 0.01 mg 21 2 ( 9.5%) 2 1 ( 50.0%) 1 ( 50.0%) 0

D) MS 60 mg/NTX 0.1 mg 21 1 ( 4.8%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 1 mg 21 3 (14.3%) 3 1 ( 33.0%) 2 ( 66.7%) 0

OVERDOSE A) PLACEBO 18 0 Treatment 1.000 0 0 0 0

B) MS 60 mg 18 0 0 0 0 0

C) MS 60 mg/ΝTX 0.01 mg 21 1 ( 4.8%) 0 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.1 mg 21 0 0 0 0 0

E) MS 60 mg/ΝTX 1 mg 21 0 0 0 0 0

PAIN A) PLACEBO 18 0 Treatment 0.192 0 0 0 0

B) MS 60 mg 18 0 0 0 .0 0

C) MS 60 mg/ΝTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/ΝTX 0.1 mg 21 2 ( 9.5%) 2 1 ( 50.0%) 1 ( 50.0%) 0

E) MS 60 mg/NTX 1 mg 21 0 0 0 0 0

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PATRWISE COMPARISONS ONLY.

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

* ** ***. P-VALUE <= 0.05, <= 0.01, OR<= 0.001 RESPECTIVELY.

Table 26C (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

(COSTART ENGLISH) TREATMENT SUBJECTS W/EVEΝT SOURCE [1] Of MILD Moderate SEVER

Events

CARDIOVASCULAR

ALL EVENTS A) PLACEBO 18 0 Treatment 0.540 0 0 0 0

B) MS 60 mg 18 1 ( 5.6%) 1 1 (100.0%) 0 0

C) MS 60 mg/NTX 0.01 mg 21 1 ( 4.8%) 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.1 mg 21 3 ( 14.3%) 3 . 1 ( 33.3%) 2 ( 66.7%) 0

E) MS 60 mg/NTX 1 mg 21 1 ( 4.8%) 1 1 (100.0%) 0 0

HEMORRHAGE A) PLACEBO 18 0 Treatment 1.000 0 0 0 0

B) MS 60 mg 18 0 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.1 mg 21 1 ( 4.8%) 1 0 1 (100.0%) 0

E) MS 60 mgNTX 1 mg 21 0 0 0 0 0

HYPERTENSION A) PLACEBO 18 0 Treatment 1.000 0 0 0 0

B) MS 60 mg 18 0 0 0 0 0

C) MS 60 mg/ΝTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.1 mg 21 1 ( 4.8%) 1 1 (100.0%) 0 0

E) MS 60 mg/ΝTX 1 mg 21 0 0 0 0 0

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26C (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

VASODILATATION A) PLACEBO 18 0 Treatment 1.000 0 0 0 0

B) MS 60 mg 18 1 ( 5.6%) 1 1 (100.0%) 0 0

C) MS 60 mg/NTX 0.01 mg 21 1 ( 4.8%) 1 1 (100.0%) 0 0 ^• D) MS 60 mg/NTX 0.1 mg 21 1 ( 4.8%) 1 0 1 (100.0%) 0

E) MS 60 mg/NTX 1 mg 21 1 ( 4.8%) 1 1 (100.0%) 0 0

DIGESTIVE

ALL EVENTS A) PLACEBO 18 1 (5.6%) Treatment 0.017* 1 0 1 (100.0%) 0

B) MS 60 mg 18 7 (38.9%) A-B 0.040* 10 2 ( 20.0%) 4 ( 40.0%) 4( 40.(

C) MS 60 mg/NTX O.Ol mg 21 8 (38.1%) A-C 0.023* 15 3 ( 20.0%) 4 9 26.7%) 8( 53.2

D) MS 60 mg/NTX 0.1 mg 21 11 (52.4%) A-D O.001** 14 2 ( 14.3%) 5 ( 35.7%) 7( 50.C

E) MS 60 mg/NTX 1 mg 21 5 (23.8%) 7 1 ( 14.3%) 3 ( 42.9%) 3 ( 42.9%0

DRUG "SUSPECTED" OR "PROBABLE."

[11 P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND

SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26C (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

(COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE [1] Of MILD Moderate SEVER

Events

NAUSEA A) PLACEBO 18 1 (5.6%) Treatment 0.048* 1 0 1 (100.0%) 0

B) MS 60 mg 18 6 (33.3%) 0.023* 6 2 ( 33.3%) 4 ( 66.7%) 0

C) MS 60 mg/NTX 0.01 mg 21 8 (38.1%) 0.010* 10 3 ( 30.0%) 4 ( 40.0%) 3( 30.0%

D) MS 60 mg/NTX 0.1 mg 21 9 (42.9%) 9 2 ( 22.2%) 5 ( 55.6%) 2( 20.2%

E) MS 60 mg/NTX 1 mg 21 4 (19.0%) 4 1 ( 25.0%) 3 (75.0%) 0

VOMITING A) PLACEBO 18 0 Treatment 0.166 0 0 0 ⁰

B) MS 60 mg 18 4 (22.2%) A-C 4 0 0 4 (100.0'

C) MS 60 mg/NTX 0.01 mg 21 5 (23.8%) A-D 5 0 0 5 (100.0'

D) MS 60 mg/NTX 0.1 mg 21 5 (23.8%) 5 0 0 5 (100.0'

E) MS 60 mg/NTX 1 mg 21 3 (14.3%) 3 0 0 3 (100.0%)

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26C (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

MUSCULOSKELETAL

ALL EVENTS A) PLACEBO 18 0 Treatment 0.363 0 0 0

B) MS 60 mg 18 1 ( 5.6%) 1 1 (100.0%) 0

C) MS 60 mg/NTX 0.01 mg 21 0 0 0 0

D) MS 60 mg/NTX 0.1 mg 21 0 0 0 0

E) MS 60 mg NTX 1 mg 21 0 0 0 0

MYALGIA A) PLACEBO 18 0 Treatment 0.363 0 0 0 0

B) MS 60 mg 18 1 ( 5.6%) 1 0 1 (100.0%) 0

C) MS 60 mg/NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.1 mg 21 0 0 0 0 0

E) MS 60 mg/ΝTX 1 mg 21 0 0 0 0 0

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26C (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2J

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

NERVOUS SYSTEM

ALL EVENTS A) PLACEBO 18 1 ( 5.6%) Treatment 0.016* 1 (100.0%) 0

B) MS 60 mg 18 8 ( 44.4%) A-B 0.017* 10 ( 40.0%) ( 50.0%) 1( 10.0%

C) MS 60 mg/NTX 0.01 mg 21 10 ( 47.6%) A-C 0.004** 11 ( 18.2%) 72.7%) 1 ( 9.1%

D) MS 60 mg NTX 0.1 mg 21 10 ( 47.6%) A-D 0.004** 10 ( 30.0%) (60.0%) 1( 10.0%

E) MS 60 mg/NTX l mg 21 10 ( 47.6%) A-E 0.004** 14 ( 57.1%) ( 42.9%) 0

ANXIETY A) PLACEBO 18 0 Treatment 1.000 0 0 0 0

B) MS 60 mg 18 0 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 21 1 ( 4.8%) 1 0 1 (100.0%) 0

D) MS 60 mg/ΝTX 0.1 mg 21 1 ( 4.8%) 1 0 1 (100.0%) 0

E) MS 60 mg/NTX lmg 21 0 0 0 0 0

DIZZINESS A) PLACEBO 18 1 ( 5.6%) Treatment 0.065 1 (100.0%) 0

B) MS 60 mg 18 8 ( 44.4%) A-B 0.017 * 4 ( 50.0%) ( 37.5%) 1( 12.5%

C) MS 60 mg/ΝTX 0.01 mg 21 8 (38.1%) A-C 0.023 * 2 ( 25.0%) ( 62.5%) 1( 12.5%

D) MS 60 mg/ΝTX 0.1 mg 21 8 ( 38.1%) A-D 0.023 * 1 ( 12.5%) ( 75.0%) 1 (12.5%

E) MS 60 mg/ΝTX 1 mg 21 7 ( 33.3%) A-E 0.048 * 4 ( 57.1%) ( 42.9%) 0

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26C (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

(COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE [11 Of MILD Moderate SEVER

Events

DRY MOUTH A) PLACEBO 18 0 Treatment 0.192 0 0 0 0

B) MS 60 mg 18 0 0 0 0 0

C) MS 60 mg/NTX O.Ol mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0. l mg 21 0 0 0 0 0

E) MS 60 mg/ΝTX 1 mg 21 2 ( 9.5%) 2 1 ( 50.0%) 1 i ( 50.0%) 0

EUPHORIA A) PLACEBO 18 0 Treatment 1.000 0 0 0 0

B) MS 60 mg 18 0 0 0 0 0

C) MS 60 mg/ΝTX 0.01 mg 21 1 ( 4.8%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.1 mg 21 1 ( 4.8%) 1 1 (100.0%) 0 0

E) ms 60 mg/ΝTX 1 mg 21 0 0 0 0 0

PARESTHESIA A) PLACEBO 18 0 Treatment 1.000 0 0 0 0

B) MS 60 mg 18 0 0 0 0 0

C) MS 60 mg/ΝTX O.Ol mg 21 0 0 0 0 0

D) MS 60 mg/ΝTX 0.1 mg 21 0 0 0 0 0

E) MS 60 mg/ΝTX 1 mg 21 1 ( 4.8%) 1 1 (100.0%) 0 0

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26C (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

SOMNOLENCE A) PLACEBO 18 0 Treatment 0.265 0 0 0 0

B) MS 60 mg 18 1 ( 5.6%) 1 0 1 (100.0%) 0

C) MS 60 mg/NTX 0.01 mg 21 1 ( 4.8%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.1 mg 21 0 0 0 0 0

E) MS 60 mg/ΝTX 1 mg 21 3 ( 14.3%) 3 1 ( 33.3%) 2 ( 66.7%) 0

TREMOR A) PLACEBO 18 0 Treatment 0.727 0 0 0 0

B) MS 60 mg 18 1 ( 5.6%) 1 0 1 (100.0%) 0

C) MS 60 mg/NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/ΝTX 0.1 mg 21 0 0 0 0 0

E) MS 60 mg/NTX 1 mg 21 1 ( 4.8%) 1 1 (100.0%) 0 0

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26C (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [21

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

(COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE DI Of MILD Moderate SEVERE Events

RESPIRATORY

ALL EVENTS A) PLACEBO 18 1 ( 5.6%) Treatment 0.727 1 1 (100.0) 0 0

B) MS 60 mg 18 0 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg NTX 0.1 mg 21 0 0 0 0 0

E) MS 60 mg/NTX l mg 21 1 ( 4.8%) 1 1 (100.0) 0 0

DYSPNEA A) PLACEBO 18 0 Treatment 1.000 0 0 0 0

B) MS 60 mg 18 0 0 0 0 0

C) MS 60 mg/ΝTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/ΝTX 0.1 mg 21 0 0 0 0 0

E) MS 60 mg/ΝTX 1 mg 21 1 ( 4..8%) 1 1 (100.0%) 0 0

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26C (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [21

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

EPISTAXIS A) PLACEBO 18 1 ( 5.6%) Treatment 0.363 1 (100.0%) 0 0

B) MS 60 mg 18 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 21 0 0 0 0

D) MS 60 mg/ΝTX 0.1 mg 21 0 0 0 0

E) MS 60 mg/ΝTX 1 mg 21 0 0

SKIN/APPENDAGES

ALL EVENTS A) PLACEBO 18 Treatment 0.399 0 0 0 0

B) MS 60 mg 18 ( 16.7%) 3 1 ( 33.3%) 2 ( 66.7%) 0

C) MS 60 mg/ΝTX 0.01 mg 21 ( 4.8%) 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.1 mg 21 ( 4.8%) 1 0 1 (100.0%) 0

E) MS 60 mg/ΝTX 1 mg 21 ( 4.8%) 1 0 1 (100.0%) 0

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

PURITUS A) PLACEBO 18 0 Treatment 0.416 0 0 0 0

B) MS 60 mg 18 2 ( 11.1%) 2 1 ( 50.0%) 1 ( 50.0%) 0

C) MS 60 mg NTX 0.01 mg 21 1 ( 4.8%) 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.1 mg 21 1 ( 4.8%) 1 0 1 (100.0%) 0

E) MS 60 mg/NTX 1 mg 21 0 0 0 0 0

SWEATING A) PLACEBO 18 0 Treatment 0.727 0 0 0 0

B) MS 60 mg 18 1 ( 5.6%) 1 0 1 (100.0%) 0

C) MS 60 mg/ΝTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/ΝTX 0.1 mg 21 0 0 0 0 0

E) MS 60 mg/NTX 1 mg 21 1 ( 4.8%) 1 0 1 (100.0%) 0

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26C (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

SPECIAL SENSES

ALL EVENTS A) PLACEBO 18 1 ( 5.6%) Treatment 0.958 1 (100.0%) 0 0

B) MS 60 mg 18 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 21 1 ( 4.8%) 1 (100.0%) 0 0

D) MS 60 mg/ΝTX 0.1 mg 21 1 ( 4.8%) 1 (100.0%) 0 0

E) MS 60 mg/NTX 1 mg 21 2 ( 9.5%) 2 (100.0%) 0 0

CONJUNCTIVITIS A) PLACEBO 18 1 ( 5.6%) Treatment 0.958 1 (100.0%) 0 0

B) MS 60 mg 18 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 21 1 ( 4.8%) 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.1 mg 21 1 ( 4.8%) 1 (100.0%) 0 0

E) MS 60 mg/NTX 1 mg 21 2 ( 9.5%) 2 (100.0%) 0 0

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26C (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

ADVERSE EVENTS NO. OF SUBJECTS P-Value Number

UROGENITAL

ALL EVENTS A) PLACEBO 18 0 Treatment 0.507 0 0 0

B) MS 60 mg 18 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 21 1 ( 4.8%) 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.1 mg 21 2 ( 9.5%) 2 (100.0%) 0 0

E) MS 60 mg/NTX 1 mg 21 0 0 0 0

DYSURIA A) PLACEBO 18 0 Treatment 1.000 0 0 0

B) MS 60 mg 18 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 21 0 0 0 0

D) MS 60 mg/NTX 0.1 mg 21 1 ( 4.8%) 1 (100.0%) 0 0

E) MS 60 mg/NTX 1 mg 21 0 0 0 0

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

* **, ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26C (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

SAFETY POPULATION, MALE PATIENTS

Severity

BODY SYSTEM TOTAL NO. OF [2]

URINARY RETENTION A) PLACEBO 18 0 Treatment 1.000 0 0 0 0

B) MS 60 mg 18 0 0 0 0 0

C) MS 60 mg/NTX 0.01 mg 21 1 ( 4.8%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.1 mg 21 1 ( 4.8%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 1 mg 21 0 0 0 0 0

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR<= 0.001 RESPECTIVELY.

Table 26D

SELECTED ADVERSE EVENTS

SAFETY POPULATION, MALE PATIENTS

ADVERSE TOTAL NO. OF P-VALUE NUMBER SEVERITY [2]

EVENT NO. OF SUBJECTS [1] OF (ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE EVENTS MILD MODERATE SEVER

DIZZINESS A) PLACEBO 18 1 (5.6%) Treatment 0.065 1 1 (100.0%) 0 0

B) MS 60 mg 18 8 (44.4%) A-B 0.017* 8 4 (50.0%) 3 (37.5%) 1 (12.5

C) MS 60 mg/NTX 0.01 mg 21 8 (38.1%) A-C 0.023* 8 2 (25.0%) 5 (62.5%) 1 (12.5

D) MS 60 mg/ΝTX 0.1 mg 21 8 (38.1%) A-D 0.023* 8 1 (12.5%) 6 (75.0%) 1 (12.5

E) MS 60 mg/ΝTX 1 mg 21 7 (33.3%) A-E 0.048* 7 4 (57.1%) 3 (42.9%) 0

NAUSEA A) PLACEBO 18 1 (5.6%) Treatment 0.048* 1 1 (100.0%) 0

B) MS 60 mg 18 6 (33.3%) 0.023* 6 (33.3%) 4 (66.7%) 0

C) MS 60 mg/ΝTX 0.01 mg 21 8 (38.1%) 0.010* 10 (30.0%) 4 (40.0%) 3 (3(

D) MS 60 mgNTX 0.1 mg 21 9 (42.9%) 9 (22.2%) 5 (55.6%) 2 (2(

E) MS 60 mg/NTX 1 mg 21 4 (19.0%) 4 (25.0%) 3 (75.0%) 0

SOMNOLENCE A) PLACEBO 18 0 Treatment 0.265 0 0 0

B) MS 60 mg 18 1 (5.6%) 1 1 (100.0%) 0

C) MS 60 mg/NTX O.Ol mg 21 1 (4.8%) 1 1 (100.0%) 0

D) MS 60 mg/ΝTX 0.1 mg 21 0 0 0 0

E) MS 60 mg/ΝTX 1 mg 21 3 (14.3%) 3 (33.3%) 2 (66.7%) 0

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[2] THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

Table 26D (Continued)

SELECTED ADVERSE EVENTS

SAFETY POPULATION, MALE PATIENTS

ADVERSE TOTAL NO. OF P-VALUE NUMBER SEVERITY [2]

VOMITING A) PLACEBO 18 0 Treatment 0.166 0 0 0

B) MS 60 mg 18 4 (22.2%) A-C 0 0 4 (100.0

C) MS 60 mg/NTX 0.01 mg 21 5 (23.8%) A-D 0 0 5 (100.0

D) MS 60 mg/ΝTX 0.1 mg 21 5 (23.8%) 0 0 5 (100.0

E) MS 60 mg/NTX 1 mg 21 3 (14.3%) 0 0 3 (100.0

DRUG "SUSPECTED" OR "PROBABLE."

SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, OR <= O.OOl RESPECTIVELY.

EXAMPLE 3

An additional clinical study using morphine alone and in combination with low doses of naltrexone was designed substantially the same as that described in Example 1, with the following differences: (1) six treatment groups (not 5) with three different doses of NTX (0.1 mg, 0.01 mg and 0.001 mg) in combination with MS 60 mg versus MS 60 mg alone, versus NTX 0.01 mg alone, and versus placebo alone, in subjects with moderate to severe pain in a postsurgical dental pain clinical study; (2) each group was 50 patients (not 40) for a total of 300 (not 200); (3) subjects had three or four full or partial bony impacted third molars (not 2 or more impacted third molars); (4) meaningful pain relief only (not meaningful and perceptible pain relief with two stopwatches) was measured using one stopwatch; (5) the primary efficacy variables included TOTPAR-4 and SPID-4 measured through 4 hours (not TOTPAR- 8 and SPID-8 measured through 8 hours); (6) the secondary efficacy variables included 6 and 8 hour Total Pain Relief Scores (TOTPAR-6 AND TOTPAR-8), 6 and 8 hour Sum of Pain Intensity Difference Scores (SPID-6 and SPID-8), and Time to Onset of Analgesia, time to an hourly PID Score of 1, instead of Time to Onset of First Perceptible Pain Relief; (7) additional exclusion criteria were patients with known history of severe hepatic or renal impairment, and midazolam (Versed) was not permissible medication during surgery; and (8) for adverse events, body systems and preferred terms were from the MedDRA (not the COSTART) dictionary.

A total of 304 subjects were randomized; among them 302 subjects were deemed evaluable (Table 27).

[11 PATIENTS WITH DEMOGRAPHIC INFORMATION.

The demographic and baseline characteristics were summarized by treatment groups for the ITT population (all randomized patients) and the evaluable population (all randomized patients with at least one efficacy evaluation at 90 minutes or more after dosing) (Table 28). Demographic characteristics included age, race/ethnicity, sex, weight, height, medical history, teeth extracted (impacted and non-impacted), baseline pain intensity, and baseline visual analog scale.

The demographics for the total ITT population were generally comparable across all 5 treatment groups. Subjects ranged in age from 16 to 49 years; 66.8% were Caucasian and 53.3% were female. There were some differences among treatment groups in the number of third molars extracted and the degree of impaction of third molar extracted. No adjustments in the analyses were made to take into account differences among treatment groups. These differences had little or no influence on pain assessments at baseline. The baseline pain intensity scores (Table 29 A) and visual analog scale scores (Table 29B) were generally comparable across treatment groups.

Table 28

Baseline Characteristics ϊntent-To-Treat Popul ation, All Patients

MS (60 mg) MS (60 mg) MS (60 mg) TOTAL P-Value

Placebo MS NTX 0.01 mg NTX NTX NTX (0.1 [1]

(60 mg) (0.001 mg) (0.01 mg) mg)

Age (yrs) 0.434

N 51 53 51 50 51 48 304

Mean 22.5 23.4 24.0 22.5 24.1 24.0 23.4

SD 3.84 5.85 5.41 4.37 5.97 6.17 5.34

Median 22.0 22.0 23.0 22.0 22.0 21.5 22.0

Range 16-31 16-49 16-41 16-38 16-41 17-40 16-49

Gender 0.126

(n, %) Male 19 (37.3%) 25 (47.2%) 21 (41.2%) 32 (64.0%) 23 (45.1%) 22 (45.8%) 142 (46.7%)

Female 32 (62.7%) 28 (52.8%) 30 (58.8%) 18 (36.0%) 28 (54.9%) 26 (54.2%) 162 (53.3%)

Total 51 53 51 50 51 48 304

Race/Ethnic 0.694

Origin (n, %) Caucasian 31 (60.8%) 35 (66.0%) 34 (66.7%) 31 (62.0%) 37 (72.5%) 35 (72.9%) 203 (66.8%)

[2] Black 8 (15.7%) 8 (15.1%) 7 (13.7%) 7 (14.0%) 8 (15.7%) 5 (10.4%) 43 (14.1%)

Asian 2 (3.9%) 2 (3.8%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (4.2%) 6 (2.0%)

Hispanic 9 (17.6%) 8 (15.1%) 9 (17.6%) 11 (22.0%) 5 (9.8%) 5 (10.4%) 47 (15.5%)

Other 1 (2.0%) 0 (0.0%) 1 (2.0%) 1 (2.0%) 1 (2.0%) 1 (2.1%) 5 (1.6%)

Total 51 53 51 50 51 48 304

[1] FOR AGE, HEIGHT, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR GENDER, RACE/ETHNIC ORIGIN, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

[21 BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

[31 4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

[11 FOR AGE, HEIGH, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR GENDER, RACE/ETHNIC ORIGIN, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

[2] BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

[3] 4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

Table z» ontmued)

[2] BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED JNTO ONE CATEGORY TO DERIVE P-VALUE.

[31 4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

Table 29A

Baseline Pain Intensity Scores

Intent-To-Treat Po ulation, All Patients

Table 29B

Baseline Visual Analog Scale (VAS) Scores

Intent-To-Treat Population, All Patients

[11 BASELINE PAJN INTENSITY ON THE CATEGORICAL SCALE.

The TOTPAR results (e.g., 4 hour, 6 hour, 8 hour) are summarized in Table 30. The 0.01 mg NTX only group and the placebo treatment group had the lowest mean TOTPAR scores. All 4 of the active treatment groups exhibited mean TOTPAR scores that were numerically higher than NTX alone or placebo. The combination treatments had a dose-response relation in the mean TOTPAR scores, i.e., the highest dose of NTX (0.1 mg) had the highest mean TOTPAR scores and the lowest dose of NTX (0.001 mg) had the lowest mean TOTPAR scores. This pattern (high-dose (0.1 mg NTX) > mid-dose (0.01 mg NTX) > low dose (0.001 mg NTX) was generally observed for pain relief variables throughout the study. The mean TOTPAR score for the 0.01 mg NTX combination treatment was higher than that for the MS alone treatment, whereas the 0.001 mg NTX combination treatment mean was comparable to or lower than that for the MS alone treatment.

Table 30

Total Pain Relief Scores

Intent-to-Treat Po ulation, All Patients

[1] P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND

TREATMENT BY SITE INTERACTION AS FACTORS. *, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Table 30 (Continued)

Total Pain Relief Scores

Intent-to-Treat Po ulation, All Patients

Table 30 (Continued)

Total Pain Relief Scores

Intent-to-Treat Po ulation, All Patients

Table 31 summarizes the results of the 4, 6, and 8 hour SPID results. The 4 hour SPID results are also represented in Figure 23 A. The 0.01 mg NTX alone and placebo treatment groups had the lowest mean 4 hour SPID scores. All 4 of the active treatment groups with MS alone or in combination with NTX exhibited improved profiles in mean SPID relative to NTX alone or placebo. The mean 4 hour SPID scores for the 0.01 mg NTX and 0.1 mg NTX combination treatments were higher than that for the MS alone treatment, whereas the 0.001 mg NTX combination treatment was comparable to that for the MS alone treatment (Figure 23 A).

The patterns of the 6 hour and 8 hour SPID scores were similar to those at 4 hours.

Table 31

Sum of Pain Intensity Differences

Intent-To-Treat Po ulation, All Patients

[11 PAIN INTENSITY DIFFERENCE - PATN INTENSITY AT BASELINE - PAJN INTENSITY AT CURRENT TIME.

[21 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND

Table 31 (Continued)

Sum of Pain Intensity Differences

Intent-To-Treat Po ulation, All Patients

[11 PAM MTENSITY DIFFERENCE = PAM MTENSITY AT BASELINE - PAM MTENSITY AT CURRENT TIME.

TREATMENT BY SITE MTERACTION AS FACTORS. *, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Table 31 (Continued)

Sum of Pain Intensity Differences

Intent-To-Treat Po ulation, All Patients

[1] PAM MTENSITY DIFFERENCE = PAM MTENSITY AT BASELME - PAM MTENSITY AT CURRENT TIME.

Figure 16 is a visual presentation of the summary and analysis of time to onset of meaningful pain relief presented in Table 32A. The median time to onset of meaningful pain relief was shortest in the 0.1 mg NTX combination treatment group.

Figure 17 is a visual presentation of the summary and analysis of time to onset of analgesia presented in Table 32B. The median time to onset of analgesia was shortest in the 0.1 mg NTX combination treatment group.

Table 32A Time To Onset of Meaningful Pain Relief Intent-To-Treat Population, All Patients

*, **, ***: P-VALUE < = 0.05, < = 0.001, OR < = 0.001 RESPECTIVELY.

Table 32B Time to Onset of Analgesia Intent-To-Treat Population, All Patients

*, **, ***: P-VALUE < = 0.05, < = 0.001, OR < = 0.001 RESPECTIVELY.

Figures 18 and 19 are a visual presentation of the summary and analysis of time to remedication (rescue medication) up to 8 and 24 hours presented in Table 33. The survival distributions (0-8 hours) were different across treatment groups. The cumulative percent distributions were different for the MS alone or in combination with NTX compared to 0.01 mg NTX alone or placebo (Figure 18). The median times to administration of rescue medication were longer for the MS alone or in combination with NTX treatment groups compared to the 0.01 mg NTX alone and placebo groups. The longest duration of action was observed in the 0.1 mg NTX combination treatment group, followed by the 0.001 mg NTX combination treatment group.

The cumulative percent distributions (0-24 hours) were also different across treatment groups, and were also different for the MS alone or in combination with NTX groups compared to the 0.01 mg NTX alone or placebo group (Figure 19). Again, the median times to administration of rescue medication were longer for the morphine and combination treatment groups.

Analyses of time to remedication up to 24 hours yielded generally similar results, however, the data should be viewed with caution because subjects were not under close supervision after 8 hours.

Table 33 Time To Rescue Medication Intent-To-Treat Po ulation, All Patients

**, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Table 33 (Continued) Time To Rescue Medication Intent-To-Treat Po ulation All Patients

*, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Table 34 presents the summary and analysis of percent of subjects who took rescue medication up to 8 and 24 hours. Approximately 40% of subjects in the high- dose NTX (0.1 mg) combination group and more than 30% of subjects in the mid- dose NTX (0.01 mg) and low-dose NTX (0.001 mg) combination groups did not require rescue medication during 8 hours. Thus, the longest duration of action was observed in the 0.1 mg NTX combination treatment group. Analyses of the percentage of subjects who remedicated within 24 hours indicated that the NTX (0.001 mg, 0.01 mg, 0.1 mg) combination treatment groups were comparable and different from the placebo, 0.01 mg NTX and MS alone treatment groups, however, the data should be interpreted with caution because subjects were not under close supervision after 8 hours.

Table 34

Percent of Patients Rescued

Intent-To-Treat Population, All Patients

RESCUED

TREATMENT YES NO SOURCE P-VALUE [11

EFFICACY OBSERVATION PERIO1 D (0-8 HOURS)

A) Placebo 45 (88.2%) 6 (11.8%) TREATMENT 001***

B) MS 60 mg 40 (75.5%) 13 (24.5%) A-B 0.092

C) NTX 0.01 mg 48 (94.1%) 3 (5.9%) A-C 0.302

D) MS 60 mg /NTX 0.001 mg 34 (68.0%) 16 (32.0%) A-D 0.015*

E) MS 60 mg /NTX 0.01 mg 34 (66.7%) 17 (33.3%) A-E 0.008**

F) MS 60 mg /NTX 0.1 mg 29 (60.4%) 19 (39.6%) A-F 0.001** B-C 0.008** B-D 0.400 B-E 0.322 B-F 0.103 C-D <.001*** C-E <.ooι*** C-F <.ooι*** D-E 0.840 D-F 0.391 E-F 0.532

P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST AD JUSTMG FOR SITE.

Table 34 (Continued)

Percent of Patients Rescued

Intent-To-Treat Po ulation, All Patients

P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTMG FOR SITE.

Figure 20 is a visual presentation of the hourly pain relief scores presented in Table 35. The hourly pain relief scores for the 0.01 mg NTX alone or placebo treatment were less than those for the active treatment groups (MS alone or in combination with NTX) which improved over time. There was separation between the 0.01 mg NTX alone or placebo and the active treatment groups that continued throughout the 8 hour study period. Highest pain relief scores were observed for the 0.1 mg NTX combination group followed by the 0.01 mg NTX combination group (Figure 20).

Table 35 Pain Relief (PR) Scores

[11 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND

TREATMENT BY SITE MTERACTION AS FACTORS. *, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY. N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 35 (Continued) Pain Relief (PR) Scores

Table 35 (Continued) Pain Relief (PR) Scores

Table 35 (Continued) Pain Relief (PR) Scores

TREATMENT BY SITE MTERACTION AS FACTORS. *, **, ***: P-VALUE < = 0.05, < - 0.01, or < = 0.001 RESPECTIVELY. N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 35 (Continued) Pain Relief (PR) Scores

Table 35 (Continued) Pain Relief (PR) Scores

Table 35 (Continued) Pain Relief (PR) Scores

Table 35 (Continued) Pain Relief (PR) Scores

TREATMENT BY SITE MTERACTION AS FACTORS. *, **, ***: P-VALUE < = 0.05, < = 0.01, or < - 0.001 RESPECTIVELY. N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 35 (Continued) Pain Relief (PR) Scores

Table 35 (Continued) Pain Relief (PR) Scores

Table 35 (Continued) Pain Relief (PR) Scores

Table 35 (Continued) Pain Relief (PR) Scores

The hourly pain intensity difference (PID) scores are presented in Table 36 and Figure 21. The hourly PED scores for the 0.01 mg NTX alone and placebo treatment groups were generally flat while the hourly PID scores generally improved over time for the active treatment groups (MS alone or in combination with NTX). The mean scores for the morphine and morphine/naltrexone groups were higher than the mean PID scores for the 0.01 mg NTX alone or placebo group at each assessment time from 1-8 hours. Highest pain relief as measured by mean PED scores was observed for the high-dose (0.1 mg NTX) combination group.

Table 36

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, All Patients

Table 36 (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Po ulation, All Patients

Table 36 (Continued) Pain Intensity Difference (PED) Scores Intent-To-Treat Po ulation, All Patients

Table 36 (Continued)

Pain Intensity Difference (PED) Scores

Intent-To-Treat Po ulation, All Patients

Table 36 (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, All Patients

Table 36 (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, All Patients

TREATMENT BY SITE MTERACTION AS FACTORS. *, **, ***: P-VALUE < - 0.05, < = 0.01, or < = 0.001 RESPECTIVELY. N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 36 (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, All Patients

Table 36 (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, All Patients

TREATMENT BY SITE INTERACTION AS FACTORS. *, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY. N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Tables 37A and 37B present the mean MAXPAR and PEAKPID scores. The mean MAXPAR scores presented in Table 37A varied among treatment groups. The mean MAXPAR score was highest for the 0.1 mg NTX combination treatment group compared to all other groups. The mean scores for the 0.01 mg NTX and 0.001 mg NTX combination treatment groups were comparable to the mean score for the MS alone treatment group, which in turn, was greater than the mean score for the placebo and the 0.01 mg NTX alone treatment groups. The mean PEAKPID scores presented in Table 37B varied among treatment groups, and were greater for the MS alone or NTX combination treatment groups compared to the placebo and the 0.01 mg NTX alone treatment groups. Compared to all other groups, the mean PEAKPID scores were highest for the 0.1 mg NTX combination treatment group.

Table 37A

Maximum Pain Relief Scores (MAXPAR)

Intent-To-Treat Po ulation, All Patients

[il

[2] P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND

Table 37B

Peak Pain Intensity Differences (PEAKPID)

Intent-To-Treat Po ulation, All Patients

TREATMENT BY SITE INTERACTION AS FACTORS. **, ***: P-VALUE < = 0.05, < = 0.01, OR < = 0.001 RESPECTIVELY.

Table 38 presents the summary and analysis of global evaluations. The NTX alone and placebo treatment groups had the highest number of subjects who had "poor" global evaluation scores. The profiles of the global evaluations scores are based on subjects' evaluations.

Table 38 Global Evaluation of Study Medication

[1] FROM COCHRAN-MANTEL-HAENZEL TEST FOR RAW MEAN SCORES DIFFERENCE, ADJUSTMG FOR SITE. *, **, ***: P-VALUE <= 0.05, <= 0.01, OR <= 0.001 RESPECTIVELY.

The majority of adverse events reported were categorized as digestive (nausea or vomiting) or nervous system (dizziness or somnolence) as further shown in Table 39A and 39B. Figure 22 represents a summary of exemplary adverse side effects that maybe attenuated according to methods and compositions of the invention.

Table 39A

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

ALL BODY SYSTEMS

All EVENTS A) PLACEBO 51 29 (56.9%) Treatment <001*** 53 18 (34.0%) 19 (35.8%) 16 (30.2%)

B) MS 60 mg 53 46 (86.8%) A-B 001*** 175 62 (35.4%) 77 (44.0%) 36 (20.6%)

C) NTX 0.01 mg 51 28 (54.9%) A-D 001*** 61 17 (27.9%) 27 (44.3%) 17 (27.9%)

D) MS 60 mg/NTX 0.001 mg 50 46 (92.0%) A-E <001*** 141 47 (33.3%) 58 (41.1%) 36 (25.5%)

E) MS 60 mg/ΝTX 0.01 mg 51 48 (94.1%) A-F <.001*** 161 53 (32.9%) 58 (36.0%) 50 (31.1°/

F) MS 60 mg/ΝTX 0.1 mg 48 44 (91.7%) B-C 001*** 143 43 (30.1%) 61 (42.7%) 39 (27.3°/ C-D < ooι*** C-E <001*** C-F 001***

CARDIAC DISORDERS

ALL EVENTS A) PLACEBO 51 1 (2.0%) Treatment 0.785 1 1 (100.0%) 0 0

B) MS 60 mg 53 2 (3.8%) 2 2 (100.0%) 0 0

C) ΝTX 0.01 mg 51 2 (3.9%) 2 1 (50.0%) 1 (50.0%) 0

D) MS 60 mg/ΝTX 0.001 mg 50 2 (4.0%) 2 1 (50.0%) 1 (50.0%) 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 1 (100.0%) 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

[11 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS. P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source w . Mild Moderate Severe

BRAD YCARDIA NOS A) PLACEBO 51 1 (2.0%) Treatment 0.418 1 1 (100.0%) 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mgNTX 0.1 mg 48 0 0 0 0 0

PALPITATIONS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) ΝTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX O.Ol mg 51 1 (2.0%) 1 1 (100.0%) 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

TACHYCARDIA NOS A) PLACEBO 51 0 Treatment 0.309 0 0 0 0

B) MS 60 mg 53 2 (3.8%) 2 2 (100.0%) 0 0

C) ΝTX 0.01 mg 51 2 (3.9%) 2 1 (50.0%) 1 (50.0%) 0

D) MS 60 mg/ΝTX 0.001 mg 50 2 (4.0%) 2 1 (50.0%) 1 (50.0%) 0

E) MS 60 mg/ΝTX O.Ol mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

[1] P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT

PAJRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

EAR AND LABYRINTH DISORDERS

ALL EVENTS A) PLACEBO 51 3 (5.9%) Treatment 0.305 4 2 (50.0%) 2 (50.0%) 0

B) MS 60 mg 53 1 (1.9%) E-F 0.047* 1 1 (100.0%) 0 0

C) NTX O.Ol mg 51 2 (3.9%) 2 0 2 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 51 4 (7.8%) 4 0 4 (100.0%) 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

EARACHE A) PLACEBO 51 3 (5.9%) Treatment 0.265 4 2 (50.0%) 2 (50.0%) 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 2 (3.9%) 2 0 2 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 51 3 (5.9%) 3 0 3 (100.0%) 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

HEARING IMPAIRED A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 1 (2.0%) 1 0 1 (100.0%) 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

HYPERACUSIS A) PLACEBO 51 0 Treatment 0.446 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 1 (100.0%) 0 0

C) ΝTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [21

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

EYE DISORDERS

ALL EVENTS A) PLACEBO 51 1 (2.0%) Treatment 0.017* 1 0 1 (100.0%) 0

B) MS 60 mg 53 10 (18.9%) A-B 0.005** 10 7 (70 0%) 2 (20.0%) 1 (10.0%)

C) NTX 0.01 mg 51 1 (2.0%) A-D 0.047* 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 50 6 (12.0%) B-C 0.005** 6 5 (83.3%) 0 1 (16.7%)

E) MS 60 mg/ΝTX 0.01 mg 51 4 (7.8%) C-D 0.047 4 3 (75 0%) 0 1 (25.0%)

F) MS 60 mg/ΝTX 0.1 mg 48 4 (8.3%) 4 4 (100.0%) 0 0

AMBLYOPIA NOS A) PLACEBO 51 0 Treatment 0.374 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) ΝTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 1 (2.1%) 1 1 (100. 0%) 0 0

[11 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of m

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

CONJUNCTIVITIS NEC A) PLACEBO 51 0 Treatment 0.068 0 0 0 0

B) MS 60 mg 53 7 (13.2%) A-B 0.007** 7 6 (85. 7%) 1 (14.3%) 0

C) NTX 0.01 mg 51 1 (2.0%) A-D 0.020* 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 50 5 (10.0%) A-E 0.041* 5 5 (100. 0%) 0 0

E) MS 60 mg/NTX 0.01 mg 51 4 (7.8%) B-C 0.031* 4 3 (75. 0%) 0 1 (25.0%)

F) MS 60 mg/NTX 0.1 mg 48 3 (6.3%) 3 3 (100. 0%) 0 0

PHOTOPHOBIA A) PLACEBO 51 1 (2.0%) Treatment 0.418 1 0 1 (100.0%) 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

RED EYE A) PLACEBO 51 0 Treatment 0.446 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 0 0 1 (100.0%)

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

_*

[11 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PΔTRWTQP mM ΔRT.ςfws r r v

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [21

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

TIRED EYES A) PLACEBO 51 0 Treatment 0.404 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 0 0 1 (100.0%)

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

VISION BLURRED A) PLACEBO 51 0 Treatment 0.089 0 0 0 0

B) MS 60 mg 53 2 (3.8%) 2 1 (50.0%) 1 (50.0%) 0

C) ΝTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [21

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

GASTROINTESTINAL DISORDERS

ALL EVENTS A) PLACEBO 51 12 (23.5%) Treatment < ooι*** 16 4 (25.0%) 4 (25.0%) 8 (50.0%)

B) MS 60 mg 53 33 (62.3%) A-B 001*** 61 17 (27.9%) 23 (37.7%) 21 (34.4%)

C) NTX O.Ol mg 51 13 (25.5%) A-D <001*** 19 6 (31.6%) 6 (31.6%) 7 (36.8%)

D) MS 60 mg/NTX 0.001 mg 50 35 (70.0%) A-E < ooι*_** 66 14 (21.2%) 26 (39.4%) 26 (39.4%)

E) MS 60 mg/NTX 0.01 mg 51 34 (66.7%) A-F ooι*_** 62 13 (21.0%) 18 (29.0%) 31 (50.0%)

F) MS 60 mg/NTX 0.1 mg 48 33 (68.8%) B-C <.ooι*** 63 10 (15.9%) 26 (41.3%) 27 (42.9' C-D < ooι*_** C-E < ooι*_** C-F <001***

ABDOMINAL PATN A) PLACEBO 51 1 (2.0%) Treatment 0.439 1 0 0 1 (lOO.OVo,

NOS

B) MS 60 mg 53 2 (3.8%) 2 1 (50.0%) 1 (50.0%) 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 l l (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

ABDOMINAL PAIN A) PLACEBO 51 0 Treatment 0.540 0 0 0 0

UPPER B) MS 60 mg 53 1 (1.9%) 1 0 0 1 (100.0%)

C) NTX 0.0 l mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0. l mg 48 1 (2.1%) 1 0 1 (100.0%) 0

DYSPEPSIA A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol mg 51 1 (2.0%) 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0. l mg 48 0 0 0 0 0

DYSPHAGIA A) PLACEBO 51 1 (2.0%) Treatment 0.208 1 0 0 1 (100.0%)

B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 2 (4.0%) 2 0 1 (50.0%) 1 (50.0%)

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

D Λ TD TCU PnAyTD A ϋTOnXTC ΓVXTT V

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS. *, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

HICCUPS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 0 1 (100.0%) 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

MELAENA A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) ΝTX 0.01 mg 51 1 (2.0%) 1 1 (100.0%) 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of m

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

NAUSEA A) PLACEBO 51 7 (13.7%) Treatment <.001*** 8 3 (37.5%) 2 (25.0%) 3 (37.5%)

B) MS 60 mg 53 27 (50.9%) A-B 001*** 31 12 (38.7%) 15 (48.4%) 4 (12.9%)

C) NTX O.Ol mg 51 9 (17.6%) A-D 001*** 10 3 (30.0%) 5 (50.0%) 2 (20.0%)

D) MS 60 mg/NTX 0.001 mg 50 30 (60.0%) A-E <.001*** 31 9 (29.0%) 16 (51.6%) 6 (19.4%)

E) MS 60 mg/NTX 0.01 mg 51 27 (52.9%) A-F 001*** 31 9 (29.0%) 12 (38.7%) 10 (32.3%)

F) MS 60 mg/ΝTX 0.1 mg 48 26 (54.2%) B-C <001*** 28 7 (25.0%) 19 (67.9%) 2 (7.1%) C-D _< ooι_*** C-E <.ooι*** C-F <.001***

ORAL PATN A) PLACEBO 51 0 Treatment 0.214 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 0 0 1 (100.0%)

C) ΝTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 2 (4.0%) 2 0 0 2 , (100.0%)

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

SORE THROAT NOS A) PLACEBO 51 2 (3.9%) Treatment 0.217 2 0 2 (100.0%) 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

STOMATITIS A) PLACEBO 51 0 Treatment 0.524 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) ΝTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 1 (2.0%) 1 0 0 1 (100.0%;

F) MS 60 mg/NTX 0.1 mg 48 1 (2.1%) 1 0 0 1 (100.0%)

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

VOMITING NOS A) PLACEBO 51 4 (7.8%) Treatment < ooι*** 4 1 (25.0%) 0 3 (75.0%)

B) MS 60 mg 53 25 (47.2%) A-B < ooι*** 26 4 (15.4%) 7 (26.9%) 15 (57.7%)

C) NTX 0.01 mg 51 7 (13.7%) A-D 001*** 7 1 (14.3%) 1 (14.3%) 5 (71.4%)

D) MS 60 mg/NTX 0.001 mg 50 27 (54.0%) A-E 001*** 29 3 (10.3%) 9 (31.0%) 17 (58.6%)

E) MS 60 mg/NTX 0.01 mg 51 25 (49.0%) A-F _< ooι_*** 29 4 (13.8%) 5 (17.2%) 20 (69.0%)

F) MS 60 mg/NTX 0.1 mg 48 27 (56.3%) B-C 33 3 (9.1%) 6 (18.2%) 24 (72.7%) C-D C-E C-F

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

ALL EVENTS A) PLACEBO 51 5 (9.8%) Treatment 0.139 5 2 (40.0%) 2 (40.0%) 1 (20.0%)

B) MS 60 mg 53 13 (24.5%) A-B 0.047* 13 5 (38.5%) 7 (53.8%) 1 (7.7%)

C) NTX 0.01 mg 51 4 (7.8%) B-C 0.021* 5 1 (20.0%) 2 (40.0%) 2 (40.0%)

D) MS 60 mg/NTX 0.001 mg 50 7 (14.0%) B-E 0.047* 7 4 (57.1%) 3 (42.9%) 0

E) MS 60 mg/NTX 0.01 mg 51 5 (9.8%) 8 4 (50.0%) 2 (25.0%) 2 (25.0%)

F) MS 60 mg/NTX 0.1 mg 48 6 (12.5%) 6 4 (66.7%) 2 (33.3%) 0

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF V V V V E o o o oVENTS. P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY. o o o o

* * * * * * * * * * * *

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [11 Mild Moderate Severe

ASTHENIA A) PLACEBO 51 0 Treatment 0.001** 0 0 0 0

B) MS 60 mg 53 6 (11.3%) A-B 0.013* 6 3 (50.0%) 3 (50.0%) 0

C) NTX O.Ol mg 51 0 B-C 0.013* 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) B-F 0.016* 1 0 1 (100.0%) 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 2 1 (50.0%) 0 1 (50.0%)

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

FATIGUE A) PLACEBO 51 0 Treatment 0.446 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 0 K ;ιoo.o%) 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

FEELING ABNORMAL A) PLACEBO 51 0 Treatment 0.446 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 0 0 1 (100.0%)

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS. P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

FEELING HOT A) PLACEBO 51 0 Treatment 0.542 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 1 (2.0%) 1 0 0 1 (100.0%)

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

FEELING JITTERY A) PLACEBO 51 0 Treatment 0.548 0 0 0 0

B) MS 60 mg 53 2 (3.8%) 2 1 (50.0%) 1 (50.0%) 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 2 (4.0%) 2 1 (50.0%) 1 (50.0%) 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX 0.1 mg 48 1 (2.1%) 1 0 K ;ιoo.o%) 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued) ^' ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [21

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

PAIN IN FACE A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 0 0 1 (100.0%)

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

PAIN NOS A) PLACEBO 51 1 (2.0%) Treatment 0.960 1 0 0 1 (100.0°/

B) MS 60 mg 53 1 (1.9%) 1 0 1 (100.0%) 0

C) NTX O.Ol mg 51 1 (2.0%) 1 0 0 1 (100.0°/

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 1 (2.1%) 1 0 1 (100.0%) 0

PYREXIA A) PLACEBO 51 2 (3.9%) Treatment 0.975 2 2 (100.0%) 0 0

B) MS 60 mg 53 2 (3.8%) 2 1 (50.0%) 1 (50.0%) 0

C) NTX 0.01 mg 51 1 (2.0%) 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 51 2 (3.9%) 2 1 (50.0%) 1 (50.0%) 0

F) MS 60 mg/NTX 0.1 mg 48 2 (4.2%) 2 2 (100.0%) 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

RIGORS A) PLACEBO 51 2 (3.9%) Treatment 0.623 2 0 2 (100.0%) 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 1 (2.0%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 0 1 (100.0%) 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 1 (2.1%) 1 1 (100.0%) 0 0

SHΓVΈRΓNG A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol g 51 1 (2.0%) 1 0 1 (100.0%) 0

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

WEAKNESS A) PLACEBO 51 0 Treatment 0.211 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 2 (3.9%) 2 1 (50.0%) 1 (50.0%) 0

F) MS 60 mg/ΝTX 0.1 mg 48 1 (2.1%) 1 1 (100.0%) 0 0

HEPATO-BΓLIARY DISORDERS

ALL EVENTS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS^'όO mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 0 0 1 (100.0%)

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

PAJRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of m

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

CHOLELITHIASIS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 . 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 0 0 1 (100.0%)

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

INFECTIONS AND INFESTATIONS

ALL EVENTS A) PLACEBO 51 8 (15.7%) Treatment 0.606 10 4 (40.0%) 1 (10.0%) 5 (50.0°/

B) MS 60 mg 53 6 (11.3%) 7 1 (14.3%) 3 (42.9%) 3 (42.9°/

C) NTX 0.01 mg 51 9 (17.6%) 10 1 (10.0%) 5 (50.0%) 4 (40.0°/

D) MS 60 mg/NTX 0.001 mg 50 6 (12.0%) 6 0 1 (16.7%) 5 (83.3%^

E) MS 60 mg/NTX 0.01 mg 51 4 (7.8%) 5 0 0 5 (100.0%)

F) MS 60 mg/NTX 0.1 mg 48 4 (8.3%) 5 0 2 (40.0%) 3 (60.0%)

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

CELLULITIS A) PLACEBO 51 0 Treatment 0.211 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol mg 51 2 (3.9%) 2 0 0 2 (100.0%)

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 1 (2.1%) 1 0 0 1 (100.0%)

DRY SOCKET NOS A) PLACEBO 51 3 (5.9%) Treatment 0.848 3 0 1 (33.3%) 2 (66.7°

B) MS 60 mg 53 3 (5.7%) 3 0 1 (33.3%) 2 (66.7°

C) ΝTX O.Ol mg 51 4 (7.8%) 4 0 3 (75.0%) 1 (25.0°

D) MS 60 mg/ΝTX 0.001 mg 50 4 (8.0%) 4 0 0 4 (100.0°

E) MS 60 mg/ΝTX 0.01 mg 51 3 (5.9%) 3 0 0 3 (100.0%)

F) MS 60 mg/ΝTX 0.1 mg 48 1 (2.1%) 2 0 0 2 (100.0%)

NASOPHARYNGITIS A) PLACEBO 51 0 Treatment 0.446 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 0 0 1 (100.0%)

C) ΝTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of ra

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

ORAL INFECTION NEC A) PLACEBO 51 0 Treatment 0.542 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 0 1 (100.0%) 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 0 0 1 (100.0%)

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

PHARYNGITIS NOS A) PLACEBO 51 4 (7.8%) Treatment 0.546 6 3 (50.0%) 0 3 (50.0°/

B) MS 60 mg 53 2 (3.8%) 3 1 (33.: 3%) 2 (66.7%) 0

C) ΝTX 0.01 mg 51 3 (5.9%) 4 1 (25.ι 0%) 2 (50.0%) 1 (25.0°/

D) MS 60 mg ΝTX 0.001 mg 50 1 (2.0%) 1 0 0 1 (100.0°/

E) MS 60 mg/ΝTX 0.01 mg 51 1 (2.0%) 1 . 0 0 1 (100.0%;

F) MS 60 mg/ΝTX 0.1 mg 48 1 (2.1%) 1 0 1 (100.0%) 0

TOOTH INFECTION A) PLACEBO 51 0 Treatment 0.374 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) ΝTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 1 (2.1%) 1 0 1 (100.0%) 0

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

UPPER RESPIRATORY A) PLACEBO 51 1 (2.0%) Treatment 0.418 1 1 (100.0%) 0 0

TRACT INFECTION B) MS 60 mg 53 0 0 0 0 0

NOS C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

INJURY AND POISONING

ALL EVENTS A) PLACEBO 51 1 (2.0%) Treatment 0.418 1 0 1 (100.0%) 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

* ** ***. p_ VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w Event Source [1] Mild Moderate Severe

HYPOTHERMIA A) PLACEBO 51 1 (2.0%) Treatment 0.418 1 0 1 (100.0%) 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

INVESTIGATIONS

ALL EVENTS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

HAEMATURIA A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

.PRESENT B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

MUSCULOSKELETAL, CONNECTIVE TISSUE AND BONE DISORDERS

ALL EVENTS A) PLACEBO 51 0 Treatment 0.068 0 0 0 0

B) MS 60 mg 53 3 (5.7%) 5 0 4 (80.0%) 1 (20.0°

C) ΝTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 2 (3.9%0 2 1 (50.0%) 1 (50.0%) 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

* ** ***. p.vALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

JOINT DISORDER NOS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 0 1 (100.0%) 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

MUSCLE TWITCHING A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) ΝTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 1 (2.0%) 1 1 (100.0%) 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

MYALGIA A) PLACEBO 51 0 Treatment 0.446 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 0 1 (100.0%) 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of m

Adverse Events No. of Patients P-Value Events

Treatment Patients w Event Source [1] Mild Moderate Severe

NECK STIFFNESS A) PLACEBO 51 0 Treatment 0.446 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 0 1 (100.0%) 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

SENSATION OF A) PLACEBO 51 0 Treatment 0.089 0 0 0 0

HEAVINESS B) MS 60 mg 53 2 (3.8%) 3 0 2 (66.7%) 1 (33.3?

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

NEOPLASMS BENIGN AND MALIGNANT (INCLUDING CYSTS AND POLYPS)

ALL EVENTS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 1 (2.0%) 1 0 0 1 (100.0%)

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

ADENOMA BENIGN A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

NOS B) MS 60 mg 53 0 0 0 0 0

C) ΝTX 0.01 mg 51 1 (2.0%) 1 0 0 1 (100.0°

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of m

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

NERVOUS SYSTEM DISORDERS

ALL EVENTS A) PLACEBO 51 13 (25.5%) Treatment 001*** 13 5 (38.5%) 6 (46.2%) 2 (15.4%)

B) MS 60 mg 53 33 (62.3%) A-B <.ooι*** 52 12 (23.1%) 34 (65.4%) 6 (11.5%)

C) NTX O.Ol mg 51 14 (27.5%) A-D < ooι*** 15 5 (33.3%) 8 (53.3%) 2 (13.3%)

D) MS 60 mg/NTX 0.001 mg 50 31 (62.0%) A-E <.001*** 40 16 (40.0%) 21 (52.5%) 3 (7.5%)

E) MS 60 mg/NTX 0.01 mg 51 33 (64.7%) A-F < ooι*** 50 21 (42.0%) 23 (46.0%) 6 (12.0%)

F) MS 60 mg/NTX 0.1 mg 48 30 (62.5%) B-C ooι*** 45 19 (42.2%) 20 (44.4%) 6 (13.3°/ C-D < ooι*** C-E < ooι*** C-F <001***

DIZZINESS (EXC A) PLACEBO 51 2 (3.9%) Treatment <ooι_*** 2 0 2 (100.0%) 0

VERTIGO) B) MS 60 mg 53 19 (35.8%) A-B <001*** 21 4 (19.0%) 14 (66.7%) 3 (14.3%)

C) NTX O.Ol mg 51 2 (3.9%) A-D < ooι*** 2 2 ι (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 50 18 (36.0%) A-E <001*** 19 7 (36.8%) 11 (57.9%) 1 (5.3%)

E) MS 60 mg/NTX 0.01 mg 51 20 (39.2%) A-F < ooι*** 23 10 (43.5%) 12 (52.2%) 1 (4.3%)

F) MS 60 mg/NTX 0.1 mg 48 16 (33.3%) B-C <.001*** 19 7 (36.8%) 9 (47.4%) 3 (15.8%) C-D _< ooi_*** C-E < ooι*** C-F <001***

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

HEADACHE NOS A) PLACEBO 51 9 (17.6%) Treatment 0.905 9 4 (44.4%) 3 (33.3%) 2 (22.2%)

B) MS 60 mg 53 11 (20.8%) 12 3 (25.0%) 9 (75.0%) 0

C) NTX 0.01 mg 51 8 (15.7%) 8 2 (25.0%) 4 (50.0%) 2 (25.0%)

D) MS 60 mg/NTX 0.001 mg 50 8 (16.0%) 9 1 (11.1%) 6 (66.7%) 2 (22.2%)

E) MS 60 mg/NTX 0.01 mg 51 8 (15.7%) 8 2 (25.0%) 4 (50.0%) 2 (25.0%)

F) MS 60 mg/NTX 0.1 mg 48 11 (22.9%) 11 5 (45.5%) 5 (45.5%) 1 (9.1%)

HYPERTONIA A) PLACEBO 51 0 Treatment 0.551 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol mg 51 1 (2.0%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

HYPOAESTHESIA A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 1 (100.0%) 0 0

F) MS 60 mg ΝTX 0.1 mg 48 . 0 0 0 0 0

[1] P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT τ> A TD TCTJ nrw ΛD Λ UTC r.xrc

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

HYPOTONIA A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 0 1 (100.0%) 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

MIGRAINE NOS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) ΝTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 MG 51 1 (2.0%) 1 0 0 1 (100.0%

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

MUSCLE SPASTICITY A) PLACEBO 51 0 Treatment 0.446 0 0 0 0

B) MS 60 mg 53 1 ^• ^: (1.9%) 1 1 (100.0%) 0 0

C) NTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

[1] P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PATRWTSF. COMPARISONS ONLY.

Table 39A (Continued)

■ ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

PARAESTHESIA A) PLACEBO 51 0 Treatment 0.404 0 0 0 0

CΓRCUMORAL B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

PARAESTHESIA NEC A) PLACEBO 51 2 (3.9%) Treatment 0.993 2 1 (50.0%) 1 (50.0%) 0

B) MS 60 mg 53 3 (5.7%) 5 2 (40.0%) 2 (40.0%) 1 (20.0°/

C) NTX O.Ol mg 51 3 (5.9%) 3 1 (33.3%) 2 (66.7%) 0

D) MS 60 mg/NTX 0.001 mg 50 3 (6.0%) 3 3 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 51 3 (5.9%) 3 2 (66.7%) 1 (33.3%) 0

F) MS 60 mg/NTX 0.1 mg 48 2 (4.2%) 2 1 (50.0%) 1 (50.0%) 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [11 Mild Moderate Severe

SOMNOLENCE A) PLACEBO 51 0 Treatment <.001*** 0 0 0 0

B) MS 60 mg 53 11 (20.8%) A-B <.001*** 13 2 (15, 4%) 9 (69.2%) 2 (15.4%)

C) NTX 0.01 mg 51 0 A-D 0.005** 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 7 (14.0%) A-E 0.003** 8 4 (50. 0%) 4 (50.0%) 0

E) MS 60 mg/NTX 0.01 mg 51 8 (15.7%) A-F < ooι*** 8 4 (50. 0%) 4 (50.0%) 0

F) MS 60 mg/NTX 0.1 mg 48 12 (25.0%) B-C < ooι*** 12 6 (50. 0%) 5 (41.7%) 1 (8.3%) C-D 0.005** C-E 0.003** C-F < ooι_***

SYNCOPE A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 0 0 1 (100.0%)

F) MS 60 mg/NTX 0. l mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

able 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

TASTE LOSS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 1 (2.0%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 . 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

TENSION HEADACHES A) PLACEBO 51 0 Treatment 0.374 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol g 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg NTX 0. l mg 48 1 (2.1%) 1 0 0 1 (100.0%)

TREMOR NEC A) PLACEBO 51 0 Treatment 0.010* 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 _.0 0 0

E) MS 60 mg/NTX 0.01 mg 51 3 (5.9%) 3 1 (33.3%) 1 (33.3%) 1 (33.3%)

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

[1] P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT Tj Λ TDΛϊrrcTJ nrw/ro Λ T>TCΓ\ ΓC π\π v

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

PREGNANCY, PUERPEPJUM AND PERINATAL CONDITIONS

ALL EVENTS A) PLACEBO 51 0 Treatment 0.446 0 0 0 0

B) MS 60mg 53 1 (1.9%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

PREGNANCY NOS A) PLACEBO 51 0 Treatment 0.446 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 1 (100.0%) 0 0

C) ΝTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

PSYCHIATRIC DISORDERS

ALL EVENTS A) PLACEBO 51 1 (2.0%) Treatment 0.179 1 0 1 (100.0%) 0

B) MS 60 mg 53 6 (11.3%) 7 2 (28.6%) 2 (28.6%) 3 (42.9%)

C) NTX O.Ol mg 51 1 (2.0%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 50 2 (4.0%) 2 0 2 (100.0%) 0

E) MS 60 mg/NTX 0.01 mg 51 4 (7.8%) 4 4 (100.0%) 0 0

F) MS 60 mg/NTX 0.1 mg 48 5 (10.4%) 7 2 (28.6%) 4 (57.1%) 1 (14.3°/

ANXIETY NEC A) PLACEBO 51 0 Treatment 0.446 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 0 0 1 (100.0°/

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, = 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

CONFUSION A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

DEPERSONALISATION A) PLACEBO 51 0 Treatment 0.540 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 0 0 1 (100.0°/

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 1 (2.1%) 1 1 (100.0%) 0 0

DISORIENTATION A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg ^■ 53 0 0 0 0 0

C) ΝTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 1 (2.0%) 1 1 (100.0%) 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

[11 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT TJ A TDWTCTJ

ΓVKΓT V

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [11 Mild Moderate Severe

DISSOCIATION A) PLACEBO 51 0 Treatment 0.056 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 2 (4.2%) 2 0 1 (50.0%) 1 (50.0%)

EUPHORIC MOOD A) PLACEBO 51 0 Treatment 0.130 0 0 0 0

B) MS 60 mg 53 2 (3.8%) 2 1 (50.0%) 0 1 (50.0¹

C) NTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 0 1 (100.0%) 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0. l mg 48 3 (6.3%) 3 1 (33.3%) 2 (66.7%) 0

NERVOUSNESS A) PLACEBO 51 1 (2.0%) Treatment θ!827 1 0 1 (100.0%) 0

B) MS 60 mg 53 3 (5.7%) 3 1 (33.3%) 2 (66.7%) 0

C) NTX 0.01 mg 51 1 (2.0%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 0 1 (100.0%) 0

E) MS 60 mg/NTX 0.01 mg 51 2 (3.9%) 2 2 ( ;ιoo.o%) 0 0

F) MS 60 mg/NTX 0.1 mg 48 1 (2.1%) 1 0 1 (100.0%) 0

[11 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT A R Ts.P rniw ART.ςnNrs ΓΎMT V

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

RENAL AND URINARY DISORDERS

ALL EVENTS A) PLACEBO 51 0 Treatment 0.226 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 1 (100.1 0%) 0 0

C) NTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 2 (3.9%) 2 0 2 (100.0%) 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

URINARY RETENTION A) PLACEBO 51 0 Treatment 0.226 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 1 (IOO 0%) 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 2 (3.9%) 2 0 2 (100.0%) 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

REPRODUCTIVE SYSTEM AND BREAST DISORDERS

ALL EVENTS A) PLACEBO 51 0 Treatment 0.542 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg NTX 0.001 mg 50 1 (2.0%) 1 0 0 1 (100.0%)

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 2 0 1 (50.0%) 1 (50.0%)

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

DYSMENORRHOEA A) PLACEBO 51 0 Treatment 0.404 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) ΝTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 0 0 1 (100.0%;

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total Nc ). 0f No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

PROSTATIC A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

DISORDER NOS B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 0 1 (100.0%) 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

TESTICULAR A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

DISORDER NOS B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 1 (2.0%) 1 0 0 1 (100.0", „,

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

ALL EVENTS A) PLACEBO 51 0 Treatment 0.796 0 0 0 0

B) MS 60 mg 53 2 (3.8%) 2 2 (100.0%) 0 0

C) NTX 0.01 mg 51 2 (3.9%) 2 1 (50.0%) 0 1 (50.0%)

D) MS 60 mgNTX 0.001 mg 50 1 (2.0%) 1 1 (100.0%) 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 1 (2.0%) 2 0 0 2 (100.0%)

F) MS 60 mg/NTX 0.1 mg 48 1 (2.1%) 1 1 (100.0%) 0 0

COUGH A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) ΝTX 0.01 mg 51 1 (2.0%) 1 0 0 1 (100.0°/

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [11 Mild Moderate Severe

EPISTAXIS A) PLACEBO 51 0 Treatment 0.542 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol mg. 51 1 (2.0%) 1 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 l ! (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

NECK TIGHTNESS A) PLACEBO 51 0 Treatment 0.374 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 1 (2.1%) 1 l i (100.0%) 0 0

RHINITIS NOS A) PLACEBO 51 0 Treatment 0.243 0 0 0 0

B) MS 60 mg 53 2 (3.8%) 2 2 ι (100.0%) 0 0

C) ΝTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 1 (2.0%) 1 0 0 1 (100.0%)

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

[1] P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

* ** ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of m Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [11 Mild Moderate Severe

SINUS CONGESTION A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 0 0 1 (100.0%)

F) MS 60 mgNTX 0. l mg 48 0 0 0 0 0

SKIN & SUBCUTANEOUS TISSUE DISORDERS

ALL EVENTS A) PLACEBO 51 0 Treatment 0.062 0 0 0 0

B) MS 60 mg 53 4 (7.5%) A-B 0.045* 6 5 (83.3%) 1 (16.7%) 0

C) NTX O.Ol mg 51 1 (2.0%) A-E 0.006** 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 50 3 (6.0%) C-E 0.027* 5 2 (40.0%) 3 (60.0%) 0

E) MS 60 mg/NTX 0.01 mg 51 7 (13.7%) 8 4 (50.0%) 3 (37.5%) 1 (12.5%)

F) MS 60 mg/NTX 0.1 mg 48 3 (6.3%) 4 0 2 (50.0%) 2 (50.0%)

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [11 Mild Moderate Severe

DERMATITIS NOS A) PLACEBO 51 0 Treatment 0.567 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 l l (100.0%) 0 0

C) NTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 l l (100.0%) 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

ECCHYMOSIS A) PLACEBO 51 0 Treatment 0.404 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) 1 l i (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

ERYTHEMA NEC A) PLACEBO 51 0 Treatment 0.446 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 l i (100.0%) 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

PHOTOSENSITΓVΠΎ A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

REACTION NOS B) MS 60 mg 53 0 0 0 0 0

C) ΝTX O.Ol mg 51 0 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 1 (2.0%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

PRURITUS NOS A) PLACEBO 51 0 Treatment 0.056 0 0 0 o

B) MS 60 mg 53 1 (1.9%) A-E 0.021* 1 0 1 1 (100.0%) 0

C) ΝTX O.Ol mg 51 0 C-E 0.021* 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 3 (6.0%) 4 1 (25.0%) 3 (75.0%) 0

E) MS 60 mg/ΝTX 0.01 mg 51 5 (9.8%) 5 1 (20.0%) 3 (60.0%) 1 (20.0%)

F) MS 60 mg/NTX 0.1 mg 48 2 (4.2%) 2 0 0 2 (100.0%)

SWEATING A) PLACEBO 51 0 Treatment 0.845 0 0 0 0

INCREASED B) MS 60 mg 53 1 (1.9%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 51 1 (2.0%) 1 0 l ! (100.0%) 0

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 1 (2.0%) 1 1 (100.0%) 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 1 (2.1%) 1 0 1 (100.0%) 0

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of m Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

URTICARIA NOS A) PLACEBO 51 0 Treatment 0.540 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 2 2 (100.0%) 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 1 (2.1%) 1 0 1 (100.0%) 0

VASCULAR DISORDERS

ALL EVENTS A) PLACEBO 51 1 (2.0%) Treatment 0.153 1 0 1 (100.0%) 0

B) MS 60 mg 53 7 (13.2%) A-B 0.031* 7 6 (85.7%) 1 (14.3%) 0

C) NTX 0.01 mg 51 2 (3.9%) A-F 0.021* 2 2 (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 50 ^■4 (8.0%) 4 3 (75.0%) 1 (25.0%) 0

E) MS 60 mg/ΝTX 0.01 mg 51 5 (9.8%) 5 1 (20.0%) 4 (80.0%) 0

F) MS 60 mg/NTX 0.1 mg 48 7 (14.6%) 8 3 (37.5%) 5 (62.5%) 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [1] Mild Moderate Severe

FLUSHING A) PLACEBO 51 0 Treatment 0.418 0 0 0 0

B) MS 60 mg 53 0 0 0 0 0

C) NTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 51 1 (2.0%) 1 1 (100.0%) 0 0

F) MS 60 mg/ΝTX 0.1 mg 48 0 0 0 0 0

HOT FLUSHES NOS A) PLACEBO 51 0 Treatment 0.540 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 0 1 (100.0%) 0

C) ΝTX 0.01 mg 51 0 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 51 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 48 1 (2.1%) 1 0 1 (100.0%) 0

HYPERTENSION NOS A) PLACEBO 51 0 Treatment 0.500 0 0 0 0

B) MS 60 mg 53 1 (1.9%) 1 1 (100.0%) 0 0

C) ΝTX 0.01 mg 51 1 (2.0%) 1 1 (100.0%) 0 0

D) MS 60 mg/ΝTX 0.001 mg 50 3 (6.0%) 3 2 (66.7%) 1 (33.3%) 0

E) MS 60 mg/ΝTX 0.01 mg 51 1 (2.0%) 1 0 1 (100.0%) 0

F) MS 60 mg/NTX 0.1 mg 48 1 (2.1%) 1 1 (100.0%) 0 0

[11 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT P ΔTRWTNMR ΓO PAPTSONΓS ΠNΓT V

Table 39A (Continued)

ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY

MTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2]

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source [11 Mild Moderate Severe

VASODILATATION A) PLACEBO 51 1 (2.0%) Treatment 0.087 1 0 1 (100.0%) 0

B) MS 60 mg 53 5 (9.4%) A-F 0.040* 5 5 (100.0%) 0 0

C) NTX 0.01 mg 51 1 (2.0%) C-F 0.040* 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 50 1 (2.0%) D-F 0.043* 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 51 3 (5.9%) 3 0 3 (100.0%) 0

F) MS 60 mg/NTX 0.1 mg 48 6 (12.5%) 6 2 (33.3%) 4 (66.7%) 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39B

SELECTED ADVERSE EVENTS

MTENT-TO-TREAT POPULATION, ALL PATIENTS

Body System Total No. of No. of -

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source Mild Moderate Severe

[1]

DIZZINESS A) PLACEBO 51 2 (3.9%) Treatment < ooι*** 2 0 2 | (100.0%) 0

(EXC B) MS 60 mg 53 19 (35.8%) A-B 001*** 21 4 (19.0%) 14 (66.7%) 3 (14.3%)

VERTIGO) C) NTX 0.01 mg 51 2 (3.9%) A-D <.001*** 2 2 ι (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 50 18 (36.0%) A-E < ooι*** 19 7 (36.8%) 11 (57.9%) 1 (5.3%)

E) MS 60 mg/ΝTX 0.01 mg 51 20 (39.2%) A-F < ooι*** 23 10 (43.5%) 12 (52.2%) 1 (4.3%)

F) MS 60 mg/NTX 0.1 mg 48 16 (33.3%) B-C <001*** 19 7 (36.8%) 9 (47.4%) 3 (15.8%) C-D < ooι***

C-E <.001*** C-F <.001***

NAUSEA A) PLACEBO 51 7 (13.7%) Treatment < ooι*** 8 3 (37.5%) 2 (25.0%) 3 (37.5%)

B) MS 60 mg 53 27 (50.9%) A-B <.001*** 31 12 (38.7%) 15 (48.4%) 4 (12.9%)

C) ΝTX 0.01 mg 51 9 (17.6%) A-D < ooι*** 10 3 (30.0%) 5 (50.0%) 2 (20.0%)

D) MS 60 mg/ΝTX 0.001 mg 50 30 (60.0%) A-E <.001*** 31 9 (29.0%) 16 (51.6%) 6 (19.4%)

E) MS 60 mg/ΝTX 0.01 mg 51 27 (52.9%) A-F <.ooι*** 31 9 (29.0%) 12 (38.7%) 10 (32.3%)

F) MS 60 mgNTX 0.1 mg 48 26 (54.2%) B-C <.001*** 28 7 (25.0%) 19 (67.9%) 2 (7.1%) C-D 001*** C-E < ooι_*** C-F <.001***

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 39B (Continued)

SELECTED ADVERSE EVENTS

MTENT-TO-TREAT POPULATION, ALL PATIENTS

Body System Total No. of No. of -

Adverse Events No. of Patients P-Value Events

Treatment Patients w/Event Source Mild Moderate Severe

[1]

SOMNOLENCE A) PLACEBO 51 0 Treatment <.ooι*** 0 0 0 0

B) MS 60 mg 53 11 (20.8%) A-B < ooι*** 13 2 (15.4%) 9 (69.2%) 2 (15.4%)

C) NTX 0.01 mg 51 0 A-D 0.005** 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 50 7 (14.0%) A-E 0.003** 8 4 (50.0%) 4 (50.0%) 0

E) MS 60 mg/NTX 0.01 mg 51 8 (15.7%) A-F < ooι*** 8 4 (50.0%) 4 (50.0%) 0

F) MS 60 mg/ΝTX 0.1 mg 48 12 (25.0%) B-C <.ooι*** 12 6 (50.0%) 5 (41.7%) 1 (8.3%) C-D 0.005** C-E 0.003** C-F <.001***

VOMITING NOS A) PLACEBO 51 4 (7.8%) Treatment <001*** 4 1 (25.0%) 0 3 (75.0%)

B) MS 60 mg 53 25 (47.2%) A-B < ooi*** 26 4 (15.4%) 7 (26.9%) 15 (57.7%)

C) ΝTX 0.01 mg 51 7 (13.7%) A-D <ooι*** 7 1 (14.3%) 1 (14.3%) 5 (71.4%)

D) MS 60 mg/ΝTX 0.001 mg 50 27 (54.0%) A-E 001*** 29 3 (10.3%) 9 (31.0%) 17 (58.6%)

E) MS 60 mg/ΝTX 0.01 mg 51 25 (49.0%) A-F < ooι*** 29 4 (13.8%) 5 (17.2%) 20 (69.0%)

F) MS 60 mg/ΝTX 0.1 mg 48 27 (56.3%) B-C 33 3 (9.1%) 6 (18.2%) 24 (72.7%) C-D

C-E C-F

PAIRWISE COMPARISONS ONLY. V V V V

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF E o o o o o o o oVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY. * * ^# * ^# * * * * * * *

EXAMPLE 4

The results from the clinical study using morphine alone and in combination with low doses of naltrexone as described in Example 3 were analyzed by gender.

The results for females and males from the Example 3 clinical study are shown in the following Tables and Figures.

A total of 304 subjects were randomized; among them 302 subjects were deemed evaluable. Tables 40A and 40B show the number of female and male subjects separately.

Table 40A Analsis Po ulations, Female Patients

[1] PATIENTS WITH DEMOGRAPHIC INFORMATION.

Table 40B Anal sis Po ulations, Male Patients

[1] PATIENTS WITH DEMOGRAPHIC INFORMATION.

The demographic and baseline characteristics were summarized by treatment groups as shown in Table 41 A for females and Table 41B for males.

The baseline pain intensity scores and visual analog scores are shown in Tables 42A and 42C for females and Tables 42B and 42D for males.

Table 41 A Baseline Characteristics

Intent-To-Treat Population, Female Patients

MS (60 mg) MS (60 mg) MS (60 mg) TOTAL P-Value

Placebo MS NTX 0.01 mg with NTX with NTX with NTX [1] (60 mg) (0.001 mg) (0.01 mg) (O.lmg)

Age (yrs) 0.315

N 32 28 30 18 28 26 162

Mean 23.2 23.8 22.1 21.4 22.2 24.2 22.9

SD 3.82 6.46 3.99 3.26 3.27 6.51 4.80

Median 23.0 23.0 21.0 21.0 22.0 22.0 22.0

Range 16-31 17-49 16-34 16-28 16-28 17-40 16-49

Race/Ethnic 0.518 Origin Caucasian 17 (53.1%) 18 (64.3%) 20 (66.7%) 11 (61.1%) 21 (75.0%) 19 (73.1%) 106 (65.4%) (N, %) [2] Black 6 (18.8%) 4 (14.3%) 5 (16.7%) 3 (16.7%) 3 (10.7%) 3 (11.5%) 24 (14.8%)

Asian 2 (6.3%) 1 (3.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (7.7%) 5 (3.1%)

Hispanic 7 (21.9%) 5 (17.9%) 5 (16.7%) 4 (22.2%) 4 (14.3%) 2 (7.7%) 27 (16.7%)

Total 32 28 30 18 28 26 162

[l] FORAG E, HEIGff r, WEIGHT, AI ^D TIME BET\ VEEN END Ol ? SURGERY AND STUDY MEDICATION, P-VALUES ARE

FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR RACE/ETHNIC ORIGM, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST AD JUSTMG FOR SITE.

[21 BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED MTO ONE CATEGORY TO DERIVE P-VALUE.

[3] 4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

[1] FOR AGE, HEIGHT, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR RACE/ETHNIC ORIGM, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST AD JUSTMG FOR SITE.

[31 4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

Table 41 A (Continued) Baseline Characteristics

[11 FOR AGE, HEIGHT, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR RACE/ETHNIC ORIGM, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTMG FOR SITE.

[31 4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

[2] BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED MTO ONE CATEGORY TO DERIVE P-VALUE.

[3] 4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

[1] FOR AGE, HEIGHT, WEIGHT, AND TLME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR RACE/ETHNIC ORIGM, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTMG FOR SITE.

[31 4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

Table 41B (Continued)

Baseline Characteristics

Intent-To-Treat Po ulation, Male Patients

[1] FOR AGE, HEIGHT, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR RACE/ETHNIC ORIGM, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTMG FOR SITE.

[3] 4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

Table 42A

Baseline Pain Intensity Scores

Intent-To-Treat Po ulation, Female Patients

NOTE: P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTMG FOR SITE.

Table 42B

NOTE: P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTMG FOR SITE.

Table 42C Baseline Visual Analog Scale (VAS) Scores Intent-To-Treat Po ulation, Female Patients

NOTE: P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS. [1] BASELINE PAM MTENSITY ON THE CATEGORICAL SCALE.

NOTE: P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS. [11 BASELINE PAM MTENSITY ON THE CATEGORICAL SCALE.

The TOTPAR results (4 hour, 6 hour, 8 hour) are summarized in Tables 43A for females and 43B for males. In females, all of the active treatment groups exhibited mean TOTPAR scores that were higher than the placebo group score, except for the 8 hour TOTPAR for NTX 0.01 mg alone which was comparable to placebo. The morphine alone group had the highest mean TOTPAR scores, followed by the 0.1 mg NTX and the 0.01 mg NTX combination groups. In males, the mean TOTPAR scores for the 0.001 mg NTX, 0.01 mg NTX, and 0.1 mg NTX combination groups were higher than the mean TOTPAR score for MS alone.

Table 43A

Total Pain Relief Scores

Intent-to-Treat Po ulation, Female Patients

AND TREATMENT BY SITE MTERACTION AS FACTORS.

*, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY

Table 43A (Continued)

Total Pain Relief Scores

Intent-to-Treat Population, Female Patients

TOTAL PAM RELIEF SCORE P-VALUE

TREATMENT N MEAN SD MM MEDIAN MAX SOURCE [11

TOTAL PAM RELIEF SCORE (0-6 HOURS)

A) Placebo 32 2.04 4.118 0.0 0.00 13.4 TREATMENT .OOl ***

B) MS 60 mg 28 8.64 6.015 0.0 10.06 18.4 SITE 0.147

C) NTX O.Ol mg 30 2.17 3.836 0.0 0.00 16.4 TREATMENT BY SITE 0.407

D) MS 60 mg/NTX 0.001 mg 18 6.57 7.369 0.0 3.88 20.3 A-B 0.001 ***

E) MS 60 mg/NTX 0.01 mg 28 6.94 5.805 0.0 6.06 17.1 A-C 0.793

F) MS 60 mg/NTX O.l mg 26 6.79 5.144 0.0 5.38 15.9 A-D 0.001 ** A-E 0.001 *** A-F 0.001 ** B-C 0.001 *** B-D 0.513 B-E 0.247 B-F 0.175 C-D 0.002 ** D-E 0.727 D-F 0.586 E-F 0.813

[1] P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE,

AND TREATMENT BY SITE MTERACTION AS FACTORS.

*, **, ***: P-VALUE < = 0.05, < = 0.0 l, or < = 0 .001 RES PECTI VELY

Table 43A (Continued)

Total Pain Relief Scores

Intent-to-Treat Po ulation, Female Patients

AND TREATMENT BY SITE MTERACTION AS FACTORS.

*, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY

Table 43B

Total Pain Relief Scores

Intent-to-Treat Population, Male Patients

TOTAL PAM RELIEF SCORE P-VALUE

TREATMENT N MEAN SD MM MEDIAN MAX SOURCE [11

TOTAL PAM RELIEF SCORE (0-4 HOURS)

A) Placebo 19 2.31 2.931 0.0 1.38 11.3 TREATMENT 0.009 **

B) MS 60 mg 25 2.17 2.505 0.0 0.88 7.5 SITE 0.408

C) NTX 0.01 mg 21 1.36 2.551 0.0 0.00 7.8 TREATMENT BY SITE 0.226

D) MS 60 mg NTX 0.001 mg 32 3.12 3.658 0.0 2.56 12.5 A-B 0.800

E) MS 60 mg/NTX 0.01 mg 23 4.15 4.528 0.0 3.63 14,5 A-C 0.337

F) MS 60 mg/NTX O.l mg 22 5.41 4.727 0.0 5.88 14.5 A-D 0.631 A-E 0.123 A-F 0.021 * B-C 0.442 B-D 0.418 B-E 0.055 B-F 0.006 ** C-D 0.115 C-E 0.010 * C-F 0.001 *** D-E 0.214 D-F 0.035 * E-F 0.413

[11 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE,

AND TREATMENT BY SITE MTERACTION AS FACTORS.

*, **, ***: P-VALUE < = 0.05, < = 0.0 l, or < = 0 .001 RES PECTI VELY

Table 43B (Continued)

Total Pain Relief Scores

Intent-to-Treat Population, Male Patients

TOTAL PAM RELIEF SCORE P-VALUE

TREATMENT N MEAN SD MM MEDIAN MAX SOURCE [11

TOTAL PAM RELIEF SCORE (0-6 HOURS)

A) Placebo 19 4.05 5.205 0.0 1.38 19.3 TREATMENT 0.008 **

B) MS 60 mg 25 3.73 4.616 0.0 0.88 13.5 SITE 0.319

C) NTX O.Ol mg 21 2.10 4.078 0.0 0.00 11.8 TREATMENT BY SITE 0.223

D) MS 60 mg NTX 0.001 mg 32 5.46 6.292 0.0 3.81 20.5 A-B 0.786

E) MS 60 mg/NTX 0.01 mg 23 6.89 7.329 0.0 5.88 22.5 A-C 0.261

F) MS 60 mg/NTX O.l mg 22 9.26 7.843 0.0 10.69 22.5 A-D 0.601

A-E 0.168 A-F 0.022 * B-C 0.354 B-D 0.381 B-E 0.078 B-F 0.006 ** C-D 0.072 C-E 0.010 * C-F 0.001 *** D-E 0.312 D-F 0.041 * E-F 0.328

AND TREATMENT BY SITE MTERACTION AS FACTORS.

*, **, ***: P-VALUE < = 0.05, < = 0.0 l, or < = 0 .001 RES .PECTI VELY

Table 43B (Continued)

Total Pain Relief Scores

Intent-to-Treat Po ulation Male Patients

AND TREATMENT BY SITE MTERACTION AS FACTORS.

*, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Tables 44A for females and 44B for males summarize the results of the 4, 6, and 8 hour SPTD results and the 4 hour SPID results are shown in Figures 23B for females and 23C for males. In females, the NTX 0.01 mg alone and the placebo groups had the lowest mean SPID scores for 4, 6, and 8 hours. The MS alone and the 0.001 mg NTX combination groups had the highest mean SPID scores.

In males, the MS alone group had the lowest mean SPID scores. All of the combination groups had higher mean SPID scores than the MS alone, placebo, or NTX alone groups, and the 0.1 mg NTX combination group had the highest mean scores.

Table 44A

Sum of Pain Intensity Differences

Intent-To-Treat Po ulation, Female Patients

[1] P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE

INTERACTION AS FACTORS. [2] P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE

INTERACTION AS FACTORS *, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY

Table 44A (Continued)

Sum of Pain Intensity Differences

Intent-To-Treat Po ulation, Female Patients

Table 44A (Continued)

Sum of Pain Intensity Differences

Intent-To-Treat Po ulation, Female Patients

Table 44B

Sum of Pain Intensity Differences

Intent-To-Treat Po ulation, Male Patients

Table 44B (Continued)

Sum of Pain Intensity Differences

Intent-To-Treat Po ulation, Male Patients

Table 44B (Continued)

Sum of Pain Intensity Differences

Intent-To-Treat Po ulation, Male Patients

Figures 24A for females and 24B for males are visual presentations of the summary and analysis of time to onset of meaningful pain relief scores presented in Tables 45 A for females and 45B for males. In females, the median time to onset of meaningful pain relief was shortest for the MS alone group and comparable for all other groups. In males, the 0.1 mg NTX combination group had the shortest median time to onset of meaningful pain relief while all other groups were comparable.

Table 45A

Time To Onset of Meaningful Pain Relief

Intent-To-Treat Po ulation, Female Patients

* **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Table 45B Time To Onset of Meaningful Pain Relief Intent-To-Treat Po ulation, Male Patients

Figures 25A and 26A for females and 25B and 26B for males are visual presentations of the summary and analysis of time to remedication (rescue medication) up to 8 and 24 hours presented in Tables 46A for females and 46B for males. In females, the median time to remedication was longer for the NTX combination groups and the morphine alone group than the placebo and NTX alone groups. This was true at both 8 and 24 hours. In males, the median time to rescue medication was longest in the O.lmg NTX combination group and was similar for all other groups. This was true at both 8 and 24 hours.

Table 46B

Table 46B (Continued)

Time To Rescue Medication

Intent-To-Treat Po ulation Male Patients

**₅ ***. p_VALUE < - 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Tables 47A for females and 47B for males present the summary and analysis of percent of subjects who took remedication (rescued) up to 8 and 24 hours. In females, the 0.001 mg NTX combination group had the lowest percentage of patients remedicating both at 8 and 24 hours. Ln males, at 8 hours, all three NTX combination groups had lower percentages of patients remedicating than the MS alone, NTX alone, or placebo groups. The 0.1 mg NTX combination group had the lowest percentage remedicating. At 24 hours, all groups were comparable except the MS and NTX 0.01 mg NTX and 0.1 mg NTX combination groups which had fewer patients remedicating.

Table 47A

Percent of Patients Rescued

Intent-To-Treat Po ulation Female Patients

[1] P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTMG FOR SITE.

Table 47A (Continued)

Percent of Patients Rescued

Intent-To-Treat Po ulation, Female Patients

[1] P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTMG FOR SITE.

Table 47B

Percent of Patients Rescued

Intent-To-Treat Po ulation, Male Patients

[1] P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTMG FOR SITE.

Figures 27A for females and 27B for males are visual presentations of the mean pain relief scores presented in Tables 48A for females and 48B for males. In females, from 45 minutes to 8 hours all three NTX combination groups, as well as the MS alone group, have higher mean pain relief scores than the placebo group. In males, the pain relief score of the MS alone group is not statistically different from the placebo group. All three NTX combination groups have higher mean pain relief scores than the placebo or morphine groups from 15 minutes to 8 hours. The 0.01 mg NTX and the 0.1 mg NTX combination groups have the highest pain relief scores.

Table 48A

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Female Patients

[1] P- Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors. *, **, ***: P-Value < = 0.05, < = 0.01, or < = 0.001 respectively. N/D: Not done (because overall P-Value not significant).

Table 48A (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Female Patients

Table 48A (Continued)

Pain Relief (PR) Scores

Iritent-To-Treat Po ulation, Female Patients

Table 48A (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Female Patients

[1] P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors. *, **, ***: P-Value < = 0.05, < = 0.01, or < = 0.001 respectively. ND: Not done (because overall P-Value not significant).

Table 48A (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Female Patients

Table 48A (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Female Patients

[1] P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors. *, **, ***: P-Value < = 0.05, < = 0.01, or < = 0.001 respectively. N/D: Not done (because overall P-Value not significant).

Table 48A (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Female Patients

Table 48A (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Female Patients

Table 48A (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Female Patients

Table 48A (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Female Patients

Table 48 A (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation Female Patients

Table 48A (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Female Patients

Table 48B

Pain Relief (PR) Scores

Intent-To-Treat Po ulation Male Patients

Table 48B (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Male Patients

Table 48B (Continued)

Pain Relief (PR) Scores fritent-To-Treat Po ulation, Male Patients

Table 48B (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation Male Patients

Table 48B (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Male Patients

Table 48B (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation Male Patients

Table 48B (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Male Patients

Table 48B (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Male Patients

Table 48B (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Male Patients

Table 48B (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Male Patients

[11 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors. *, **, ***: P-Value < = 0.05, < = 0.01, or < = 0.001 respectively. N/D: Not done (because overall P-Value not significant).

Table 48B (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation Male Patients

Table 48B (Continued)

Pain Relief (PR) Scores

Intent-To-Treat Po ulation, Male Patients

[11 P- Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors. *, **, ***: P-Value < = 0.05, < = 0.01, or < = 0.001 respectively. N/D: Not done (because overall P-Value not significant).

The hourly pain intensity difference (PID) data presented in Table 49A and Figure 28A for females and Table 49B and Figure 28B for males. In females, the mean PID scores for 45 minutes to 8 hours are higher for all three NTX combination groups and the MS group than for the placebo group. In males, all three NTX combination groups have higher mean PID scores than the placebo and MS alone groups for 45 minutes to 8 hours. The 0.1 mg NTX combination group has the highest mean PID scores.

Table 49A

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

[11 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors. *, **, ***: P-Value < = 0.05, < = 0.01, or < = 0.001 respectively. N/D: Not done (because overall p-value not sigmficant).

Table 49A (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

Table 49A (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

Table 49A (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

Table 49A (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

Table 49A (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

Table 49A (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

Table 49A (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

Table 49A (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

Table 49A (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

Table 49A (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

[1] P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors. *, **, ***: P-Value < = 0.05, < = 0.01, or < = 0.001 respectively. N D: Not done (because overall p-value not significant).

Table 49A (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Female Patients

Table 49B

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

Table 49B (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

Table 49B (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

[1] P- Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors. *, **, ***: P-Value < = 0.05, < = 0.01, or < = 0.001 respectively. N D: Not done (because overall p-value not significant).

Table 49B (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

Table 49B (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

Table 49B (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

Table 49B (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

Table 49B (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

Table 49B (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

Table 49B (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

Table 49B (Continued)

Pain Intensity Difference (PID) Scores

Intent-To-Treat Po ulation, Male Patients

Table 49B (Continued)

Pain Intensity Difference (PED) Scores

[11 - aues are om two-way anayss o va ance an ts contrasts wth treatment, ste, an treatment y ste nteracton as actors. *, **, ***: P-Value < = 0.05, < = 0.01, or < = 0.001 respectively. N/D: Not done (because overall p-value not significant).

Tables 50A and 50B for females and Tables 50C and 50D for males present the mean MAXPAR and PEAKPID scores. In females, the mean MAXPAR and PEAKPID scores were higher for the MS alone and the NTX combination groups than for the placebo group. In males, the three NTX combination groups had higher mean MAXPAR and PEAKPID scores than the placebo or MS alone groups. The 0.1 mg NTX combination group had the highest mean score for MAXPAR and PEAKPID.

Tables 51 A for females and 5 IB for males present the summary and analysis of global evaluations. For both females and males, the placebo treatment had the highest number of subjects who had poor global evaluation scores based on subject evaluation. For females, the morphine and high-dose (0.1 mg NTX) combination groups were most often rated as "excellent." For males, the mid-dose (0.01 mg NTX ) and high-dose (0.1 mg NTX) combination groups were most often rated as "excellent."

Table 50A

Maximum Pain Relief Scores (MAXPAR)

Intent-To-Treat Po ulation, Female Patients

[11 Pain Relief (PR) Scores 0 = None, 1 = A Little, 2 = Some, 3 = A Lot, 4 = Complete. [2] P- Values are from Two- Way Analysis of Variance and its Contrasts with Treatment, Site, and Treatment by Site Interaction as Factors. *, **, ***: P-VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Table 50B

Peak Pain Intensity Differences (PEAKPID)

Intent-To-Treat Population, Female Patients

PEAK PAM Ml ΕNSITY DIFFERENCES (PEAKPID) P-VALUE

TREATMENT N MEAN SD MM MEDIAN MAX SOURCE [11

A) Placebo 32 0.25 0.672 -1 0.00 2 TREATMENT O.OOl ***

B) MS 60 mg 28 1.04 0.881 -1 1.00 3 SITE 0.707

C) NTX 0.01 mg 30 0.10 0.548 -1 0.00 1 TREATMENT BY SITE 0.384

D) MS 60 mg/NTX 0.001 mg 18 0.89 0.963 0 1.00 3 A-B 0.001 ***

E) MS 60 mg/NTX 0.01 mg 28 0.68 1.090 -1 0.50 3 A-C 0.579

F) MS 60 mg/NTX O.l mg 26 0.77 0.765 0 1.00 2 A-D 0.007 ** A-E 0.086 A-F 0.038 * B-C 0.001 *** B-D 0.728 B-E 0.076 B-F 0.182 C-D 0.002 ** C-E 0.028 * C-F 0.012 * D-E 0.231 D-F 0.406 E-F 0.690

[1] P-Values are from Two-Way Analysis of Variance and its Contrasts with Treatment, Site, and Treatment by Site Interaction as Factors.

*, **, ***: P-VALUE < = 0.05 , < = O.01, or < = 0.001 E ESPEC ΓIVELY.

Table 50C Maximum Pain Relief Scores (MAXPAR) Intent-To-Treat Po ulation Male Patients

* ** ***. .VALUE < = 0.05, < = 0.01, or < = 0.001 RESPECTIVELY.

Table 50D

Peak Pain Intensity Differences (PEAKPID)

Intent-To-Treat Po ulation, Male Patients

[1] P-Values are from Two -Way Analysis of Variance and its Contrasts with Treatment, Site, and Treatment by Site Interaction as Factors. * **, ***: P-VALUE < = 0.05 < = 0.01, or < = 0.001 RESPECTIVELY.

Table 51 A

*,**,***: P-VALUE <= 0.05, <= 0 .01,OR<=0.00 1 RESPECTI VELY.

Table 5 IB

*, **, ***: P-VALUE <= 0.05, <= 0 .01,OR<=0.00 1 RESPECTI VELY.

The majority of adverse events reported were categorized as digestive (nausea or vomiting) or nervous system (dizziness or somnolence) as further shown in Tables 52A and 52B for females and Tables 52C and 52D for males. Figures 29A for females and 29B for males represent a summary of exemplary adverse side effects according to methods and compositions of the invention. In females, the placebo group has the lowest incidence of adverse events for nausea, vomiting, and dizziness. For somnolence (sedation), both the placebo group and the NTX alone group have the lowest incidence. In males, the NTX alone group has the lowest incidence of nausea, vomiting and dizziness. For somnolence (sedation), the placebo group and the NTX alone group have the lowest incidence.

Table 52A Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients

Severity [2]

Total No. Of

Body System No. Of ] Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

TOTAL NUMBER OF EVENTS

ADVERSE EVENTS

(ALL BODY SYSTEMS)

All EVENTS A) PLACEBO 32 16 (50.0%) Treatment O.001*** 27 8 (29.6%) 7 (25.9%) 12 (44.4%)

B) MS 60 mg 28 26 (92.9%) A-B O.001*** 116 32 (27.6%) 55 (47.4%) 29 (25.0%)

C) NTX O.Ol mg 30 21 (70.0%) A-D .001 *** 48 12 (25.0%) 21 (43.8%) 15 (31.3%)

D) MS 60 mg/NTX 0.001 mg 18 18 (100.0%) A-E O.001*** 66 15 (22.7%) 29 (43.9%) 22 (33.3%)

E) MS 60 mg NTX 0.01 mg 28 28 (100.0%) A-F O.001*** 103 33 (32.0%) 38 (36.9%) 32 (31.1%)

F) MS 60 mg/NTX O.l mg 26 24 (92.3%) B-C 0.026* 86 22 (25.6%) 40 (46.5%) 24 (27.9%) C-D 0.009** C-E 0.001** C-F 0.036*

CARDIAC DISORDERS

ALL EVENTS A) PLACEBO 32 0 Treatment 0.328 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 30 1 (3.3%) 1 0 1 (100.0%) 0

D) MS 60 mg NTX 0.001 mg 18 2 (11.1%) 2 1 (50.0%) 1 (50.0%) 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52A (Continued)

Adverse Events By Body System And Severity

Intent-To-Treat Population, Female Patients

Severity [2]

Total No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

PALPITATIONS A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

TACHYCARDIA NOS A) PLACEBO 32 0 Treatment 0.156 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 30 1 (3.3%) 1 0 1 (100.0%) 0

D) MS 60 mg NTX 0.001 mg 18 2 (11.1%) 2 1 (50.0%) 1 (50.0%) 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0

EAR AND LABYRINTH DISORDERS

ALL EVENTS A) PLACEBO 32 2 (6.3%) Treatment 0.454 3 2 (66.7%) 1 (33.3%) 0

B) MS 60 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 30 2 (6.7%) 2 0 2 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 3 (10.7%) 3 0 3 (100.0%) 0

F) MS 60 mg NTX O.l mg 26 0 0 0 0 0

Table 52A . (Continued)

Adverse Events By Body System And Severity

Intent-To-Treat Population, Female Patients

Severity [2]

Total No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

EARACHE A) PLACEBO 32 2 (6.3%) Treatment 0.413 3 2 (66.7%) 1 (33.3%) 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 2 (6.7%) 2 0 2 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 28 2 (7.1%) 2 0 2 (100.0%) 0

F) MS 60 mg NTX O.l mg 26 0 0 0 0 0

HEARING IMPAIRED A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 0 1 (100.0%) 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

HYPERACUSIS A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l g 26 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients

Severity [2]

Total ] No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

EYE DISORDERS

ALL EVENTS A) PLACEBO 32 0 Treatment 0.008** 0 0 0 0

B) MS 60 mg 28 6 (21.4%) A-B 0.005** 6 3 (50.0%) 2 (33.3%) 1 (16.7%)

C) NTX 0.01 mg 30 0 A-F 0.048* 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 1 (5.6%) B-C 0.007** 1 1 (100.0%) 0 0

E) MS 60 mg NTX 0.01 mg 28 1 (3.6%) B-E 0.043* 1 1 (100.0%) 0 0

F) MS 60 mg/NTX 0.1 mg 26 3 (11.5%) 3 3 (100.0%) 0 0

AMBLYOPIA NOS A) PLACEBO 32 0 Treatment 0.384 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 1 (3.8%) 1 1 (100.0%) 0 0

CONJUNCTIVITIS A) PLACEBO 32 0 Treatment 0.109 0 0 0 0

NEC B) MS 60 mg 28 4 (14.3%) A-B 0.026* 4 3 (75.0%) 1 (25.0%) 0

C) NTX 0.01 mg 30 0 B-C 0.031* 0 0 0 0

D) MS 60 mg NTX 0.001 mg 18 1 (5.6%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

F) MS 60 mg NTX 0.1 mg 26 2 (7.7%) 2 2 (100.0%) 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Severity [2]

Total No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

RED EYE A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 0 0 1 (100.0%)

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg NTX O.l mg 26 0 0 0 0 0

VISION BLURRED A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 0 1 (100.0%) 0

C) NTX O.Ol mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

GASTROINTESTINAL DISORDERS

ALL EVENTS A) PLACEBO 32 9 (28.1%) Treatment O.00I*** 11 3 (27. 3%) 3 (27.3%) 5 (45.5%)

B) MS 60 mg 28 22 (78.6%) A-B O.001*** 40 6 (15.0%) 17 (42.5%) 17 (42.5%)

C) NTX 0.01 mg 30 13 (43.3%) A-D O.001*** 19 6 (31.6%) 6 (31.6%) 7 (36.8%)

D) MS 60 mg NTX 0.001 mg 18 17 (94.4%) A-E O.001 *** 35 5 (14. 3%) 13 (37.1%) 17 (48.6%)

E) MS 60 mg/NTX 0.01 mg 28 24 (85.7%) A-F O.001*** 44 10 (22. 7%) 13 (29.5%) 21 (47.7%)

F) MS 60 mg/NTX 0.1 mg 26 20 (76.9%) B-C 0.006** 40 3 (7. 5%) 20 (50.0%) 17 (42.5%) C-D O.001 *** C-E 0.001 *** C-F 0.010*

Severity [2]

Total No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

ABDOMINAL PAIN A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 UPPER B) MS 60 mg 28 1 (3-6%) 1 0 0 1 (100.0%)

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

DYSPEPSIA A) PLACEBO 32 0 Treatment 0.489 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 1 (3.3%) 1 1 (100.0%) 0 0

D) MS 60 mg NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg NTX 0.1 mg 26 0 0 0 0 0

DYSPHAGIA A) PLACEBO 32 0 Treatment 0.153 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX O.Ol mg 30 0 0 0 0 0

D) MS 60 mg NTX 0.001 mg 18 1 (5.6%) 1 0 1 (100.0%) 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Severity [2]

Total No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

MELAENA A) PLACEBO 32 0 Treatment 0.489 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 1 (3.3%) 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0

NAUSEA A) PLACEBO 32 5 (15.6%) Treatment .001*** 6 2 (33.3%) 1 (16.7%) 3 (50.0%)

B) MS 60 mg 28 17 (60.7%) A-B O.001*** 21 5 (23.8%) 12 (57.1%) 4 (19.0%)

C) NTX 0.01 mg 30 9 (30.0%) A-D O.001*** 10 3 (30.0%) 5 (50.0%) 2 (20.0%)

D) MS 60 mg/NTX 0.001 mg 18 16 (88.9%) A-E O.001 *** 16 4 (25.0%) 9 (56.3%) 3 (18.8%)

E) MS 60 mg/NTX 0.01 mg 28 21 (75.0%) A-F O.001*** 25 7 (28.0%) 10 (40.0%) 8 (32.0%)

F) MS 60 mg/NTX O.l mg 26 16 (61.5%) B-C 0.018* 18 1 (5.6%) 15 (83.3%) 2 (11.1%) B-D 0.038* C-D O.001*** C-E O.001 *** C-F 0.017* D-F 0.045*

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Severity [2]

Total ] No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

ORAL PAIN A) PLACEBO 32 0 Treatment 0.048* 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 0 0 1 (100.0%)

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 2 (11.1%) 2 0 0 2 (100.0%)

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg NTX 0.1 mg 26 0 0 0 0 0

SORE THROAT A) PLACEBO 32 2 (6.3%) Treatment 0.144 2 0 2 (100.0%) 0

NOS B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

STOMATITIS A) PLACEBO 32 0 Treatment 0.541 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 0 0 1 (100.0%)

F) MS 60 mg/NTX O.l mg 26 1 (3.8%) 1 0 0 1 (100.0%)

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Severity [2]

Total ^'. No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

VOMITING NOS A) PLACEBO 32 3 (9.4%) Treatment O.001*** 3 1 (33.3%) 0 2 (66.7%)

B) MS 60 mg 28 16 (57.1%) A-B O.001*** 17 1 (5.9%) 5 (29.4%) 11 (64.7%)

C) NTX O.Ol mg 30 7 (23.3%) A-D O.001 *** 7 1 (14.3%) 1 (14.3%) 5 (71.4%)

D) MS 60 mg/NTX 0.001 mg 18 15 (83.3%) A-E .001 *** 16 1 (6.3%) 3 (18.8%) 12 (75.0%)

E) MS 60 mg/NTX 0.01 mg 28 17 (60.7%) A-F O.001*** 18 3 (16.7%) 3 (16.7%) 12 (66.7%)

F) MS 60 mg NTX O.l mg 26 16 (61.5%) B-C 0.008** 21 2 (9.5%) 5 (23.8%) 14 (66.7%) C-D O.001*** C-E 0.003** C-F 0.003**

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

ALL EVENTS A) PLACEBO 32 2 (6.3%) Treatment 0.214 2 1 (50.0%) 0 1 (50.0%)

B) MS 60 mg 28 8 (28.6%) A-B 0.020* 8 3 (37.5%) 5 (62.5%) 0

C) NTX O.Ol mg 30 3 (10.0%) 3 1 (33.3%) 1 (33.3%) 1 (33.3%)

D) MS 60 mg/NTX 0.001 mg 18 3 (16.7%) 3 1 (33.3%) 2 (66.7%) 0

E) MS 60 mg NTX 0.01 mg 28 5 (17.9%) 8 4 (50.0%) 2 (25.0%) 2 (25.0%)

F) MS 60 mg/NTX O.l mg 26 3 (11.5%) 3 2 (66.7%) 1 (33.3%) 0

ASTHENIA A) PLACEBO 32 0 Treatment 0.124 0 0 0 0

B) MS 60 mg 28 3 (10.7%) 3 2 (66.7%) 1 (33.3%) 0

C) NTX O.Ol mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 1 (5.6%) 1 0 1 (100.0%) 0

E) MS 60 mg/NTX O.Ol mg 28 1 (3.6%) 2 1 (50.0%) 0 1 (50.0%)

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52A (Continued)

Adverse Events ; By Body System And Severity

Intent-To- -Treat Population, Female Patients

Severity [2]

Total No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

FATIGUE - A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 0 1 (100.0%) 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg NTX O.l mg 26 0 0 0 0 0

FEELING JITTERY A) PLACEBO 32 0 Treatment 0.298 0 0 0 0

B) MS 60 mg 28 2 (7.1%) 2 1 (50.0%) 1 (50.0%) 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg NTX 0.001 mg 18 2 (11.1%) 2 1 (50.0%) 1 (50.0%) 0

E) MS 60 mg NTX 0.01 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX O.l mg 26 1 (3.8%) 1 0 1 (100.0%) 0

PAIN IN FACE A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 0 0 1 (100.0%)

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Severity [2]

Total No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart Eng ;lliisshh)) Treatment Patients W/Event Source [1] Events

PAIN NOS A) PLACEBO 32 1 (3.1%) Treatment 0.782 1 0 0 1 (100.0%)

B) MS 60 mg 28 1 (3.6%) 1 0 1 (100.0%) 0

C) NTX 0.01 mg 30 1 (3.3%) 1 0 0 1 (100.0%)

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

PYREXIA A) PLACEBO 32 1 (3.1%) Treatment 0.893 1 1 (100.0%) 0 0

B) MS 60 mg 28 1 (3.6%) 1 0 1 (100.0%) 0

C) NTX 0.01 mg 30 1 (3.3%) 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 2 (7.1%) 2 1 (50.0%) 1 (50.0%) 0

F) MS 60 mg NTX O.l mg 26 1 (3.8%) 1 1 (100.0%) 0 0

RIGORS A) PLACEBO 32 0 Treatment 0.384 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 1 (3.8%) 1 1 (100.0%) 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Severity [2]

Total ] No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

SHIVERING A) PLACEBO 32 0 Treatment 0.489 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 1 (3.3%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

WEAKNESS A) PLACEBO 32 0 Treatment 0.084 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 2 (7.1%) 2 1 (50.0%) 1 (50.0%) 0

F) MS 60 mg NTX O.l mg 26 0 0 0 0 0

HEPATO-BILIARY DISORDERS

ALL EVENTS A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 0 0 1 (100.0)

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

Severity [2]

Total j No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate < Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

CHOLELITHIASIS A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 0 0 1 (100.0%)

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

INFECTIONS AND INFESTATIONS

ALL EVENTS A) PLACEBO 32 4 (12.5%) Treatment 0.400 4 0 0 4 (100.0%)

B) MS 60 mg 28 4 (14.3%) 5 1 (20.0%) 3 (60.0%) 1 (20.0%)

C) NTX 0.01 mg 30 7 (23.3%) 8 1 (12.5%) 3 (37.5%) 4 (50.0%)

D) MS 60 mg/NTX 0.001 mg 18 4 (22.2%) 4 0 1 (25.0%) 3 (75.0%)

E) MS 60 mg/NTX 0.01 mg 28 2 (7.1%) 2 0 0 2 (100.0%)

F) MS 60 mg/NTX O.l mg 26 2 (7.7%) 3 0 1 (33.3%) 2 (66.7%)

CELLULITIS A) PLACEBO 32 0 Treatment 0.112 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX O.Ol mg 30 2 (6.7%) 2 0 0 2 (100.0%)

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52A (Continued)

Adverse Events By Body System And Severity

Intent-To-Treat Population, Female Patients

Severity [2]

Total ] No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

DRY SOCKET A) PLACEBO 32 2 (6.3%) Treatment 0.868 2 0 0 2 (100.0%)

NOS B) MS 60 mg 28 2 (7-1%) 2 0 1 (50.0%) 1 (50.0%)

C) NTX 0.01 mg 30 3 (10.0%) 3 0 2 (66.7%) 1 (33.3%)

D) MS 60 mg/NTX 0.001 mg 18 2 (11.1%) 2 0 0 2 (100.0%)

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 0 0 1 (100.0%)

F) MS 60 mg NTX O.l mg 26 1 (3.8%) 2 0 0 2 (100.0%)

ORAL INFECTION A) PLACEBO 32 0 Treatment 0.153 0 0 0 0

NEC B) MS 60 g 28 0 0 0 0 0

C) NTX O.Ol mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 1 (5.6%) 1 0 1 (100.0%) 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg NTX O.l mg 26 0 0 0 0 0

PHARYNGITIS A) PLACEBO 32 2 (6.3%) Treatment 0.988 2 0 0 2 (100.0%)

NOS B) MS 60 mg 28 2 (7.1%) 3 1 (33.3%) 2 (66.7%) 0

C) NTX O.Ol mg 30 2 (6.7%) 3 1 (33.3%) 1 (33.3%) 1 (33.3%)

D) MS 60 mg NTX 0.001 mg 18 1 (5.6%) 1 0 0 1 (100.0%)

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 0 0 1 (100.0%)

F) MS 60 mg/NTX O.l mg 26 1 (3.8%) 1 0 1 (100.0%) 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52A (Continued)

Adverse Events By Body System And Severity ϊntent-To -Treat Population, Female Patients

Severity [2]

Total No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W Event Source fl] Events

MUSCULOSKELETAL, CONNECTIVE TISSUE AND BONE DISORDERS

ALL EVENTS A) PLACEBO 32 0 Treatment 0.238 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 3 0 2 (66.7%) 1 (33.3%)

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 2 (7.1%) 2 1 (50.0%) 1 (50.0%) 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

JOINT DISORDER NOS A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX O.Ol mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 0 1 (100.0%) 0

F) MS 60 mg NTX O.l g 26 0 0 0 0 0

MUSCLE A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

TWITCHING B) MS 60 g 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

Severity [2]

Total 1 No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

MYALGIA A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 0 1 (100.0%) 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0

SENSATION OF A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

HEAVINESS B) MS 60 mg 28 1 (3.6%) 2 0 1 (50.0%) 1 (50.0%)

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

NEOPLASMS BENIGN AND MALIGNANT (INCLUDING CYSTS AND POLYPS)

ALL EVENTS A) PLACEBO 32 0 Treatment 0.489 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 1 (3.3%) 1 0 0 1 (100.0%)

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52A . (Continued)

Adverse Events By Body System And Severity

Intent-To -Treat Population, Female Patients

Severity [2]

Total No. Of

Body System No. Of ] Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

ADENOMA BENIGN A) PLACEBO 32 0 Treatment 0.489 0 0 0 0

NOS B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 1 (3.3%) 1 0 0 1 (100.0%)

D) MS 60 mg NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

NERVOUS SYSTEM DISORDERS

ALL EVENTS A) PLACEBO 32 7 (21.9%) Treatment O.001*** 7 2 (28.6%) 3 (42.9%) 2 (28.6%)

B) MS 60 mg 28 20 (71.4%) A-B O.001*** 37 7 (18.9%) 24 (64.9%) 6 (16.2%)

C) NTX 0.01 mg 30 10 (33.3%) A-D 0.005** 11 3 (27. 3%) 7 (63.6%) 1 (9.1%)

D) MS 60 mg/NTX 0.001 mg 18 11 (61.1%) A-E O.001*** 14 4 (28. 6%) 9 (64.3%) 1 (7.1%)

E) MS 60 mg/NTX 0.01 mg 28 19 (67.9%) A-F 0.005** 29 10 (34.5%) 16 (55.2%) 3 (10.3%)

F) MS 60 mg NTX 0.1 mg 26 15 (57.7%) B-C 0.003** 24 10 (41. 7%) 10 (41.7%) 4 (16.7%)

C-E 0.008**

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Severity [2]

Total No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

DIZZINESS A) PLACEBO 32 1 (3.1%) Treatment O.001 *** 1 0 1 (100.0%) 0

(EXC VERTIGO) B) MS 60 mg 28 16 (57.1%) A-B O.001 *** 18 3 (16.7%) 12 (66.7%) 3 (16.7%)

C) NTX 0.01 mg 30 2 (6.7%) A-D .001 *** 2 2 (100.0%) 0 0

D) MS 60 mg NTX 0.001 mg 18 9 (50.0%) A-E .001*** 9 3 (33.3%) 6 (66.7%) 0

E) MS 60 mg/NTX 0.01 mg 28 12 (42.9%) A-F 0.001** 14 5 (35.7%) 8 (57.1%) 1 (7.1%)

F) MS 60 mg NTX 0.1 mg 26 9 (34.6%) B-C .001 *** 10 3 (30.0%) 5 (50.0%) 2 (20.0%) C-D O.001*** C-E 0.001 ** C-F 0.008**

HEADACHE NOS A) PLACEBO 32 6 (18.8%) Treatment 0.966 6 2 (33.3%) 2 (33.3%) 2 (33.3%)

B) MS 60 mg 28 5 (17.9%) 5 1 (20.0%) 4 (80.0%) 0

C) NTX 0.01 mg 30 5 (16.7%) 5 1 (20.0%) 3 (60.0%) 1 (20.0%)

D) MS 60 mg/NTX 0.001 mg 18 2 (11.1%) 2 0 1 (50.0%) 1 (50.0%)

E) MS 60 mg/NTX 0.01 mg 28 6 (21.4%) 6 1 (16.7%) 4 (66.7%) 1 (16.7%)

F) MS 60 mg/NTX O.l mg 26 4 (15.4%) 4 1 (25.0%) 2 (50.0%) 1 (25.0%)

HYPERTONIA A) PLACEBO 32 0 Treatment 0.489 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 1 (3.3%) 1 0 1 (100.0%) 0

D) MS 60 mg NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

PAJRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52A (Continued) ^' Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients

Severity [2]

Total No. Of

HYPOTONIA A) PLACEBO 32 0 Treatment 0.438 0

B) MS 60 mg 28 0 0

C) NTX 0.01 mg 30 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 (100.0%)

F) MS 60 mg/NTX O.l mg 26 0 0

PARAESTHESIA A) PLACEBO 32 0 Treatment 0.657 NEC B) MS 60 mg 28 3 (10.7%) (40.0%) (40.0%) (20.0%)

C) NTX 0.01 mg 30 2 (6.7%) (100.0%)

D) MS 60 mg/NTX 0.001 mg 18 1 (5.6%) (100.0%)

E) MS 60 mg/NTX 0.01 mg 28 2 (7.1%) (50.0%) (50.0%)

F) MS 60 mg NTX O.l mg 26 2 (7.7%) (50.0%) (50.0%)

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Severity [2]

Total ] No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

SOMNOLENCE A) PLACEBO - 32 0 Treatment .001 *** 0 0 0 0

B) MS 60 mg 28 8 (28.6%) A-B 0.001** 9 1 (11.1%) 6 (66.7%) 2 (22.2%)

C) NTX 0.01 mg 30 0 A-E 0.012* 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 2 (11.1%) A-F .001*** 2 0 2 (100.0%) 0

E) MS 60 mg/NTX 0.01 mg 28 5 (17.9%) B-C 0.001** 5 3 (60.0%) 2 (40.0%) 0

F) MS 60 mg/NTX O.l g 26 8 (30.8%) C-E 0.015* 8 5 (62.5%) 2 (25.0%) 1 (12.5%) C-F 0.001**

TASTE LOSS A) PLACEBO 32 0 Treatment 0.489 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX O.Ol mg 30 1 (3.3%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg NTX O.l g 26 0 0 0 0 0

TREMOR NEC A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 0 0 1 (100.0%)

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Severity [2]

Total No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

PREGNANCY, PUERPERIUM AND PERINATAL CONDITIONS

ALL EVENTS A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0

PREGNANCY NOS A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0

PSYCHIATRIC DISORDERS

ALL EVENTS A) PLACEBO 32 0 Treatment 0.156 0 0 0 0

B) MS 60 mg 28 4 (14.3%) A-B 0.026* 5 1 (20.0%) 1 (20.0%) 3 (60.0%)

C) NTX 0.01 mg 30 1 (3.3%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 3 (10.7%) 3 3 (100.0%) 0 0

F) MS 60 mg/NTX O.l mg 26 2 (7.7%) 4 1 (25.0%) 3 (75.0%) 0

PAIRWISE COMPARISONS ONLY.

Severity [2]

Total ] No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

ANXIETY NEC A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 0 0 1 (100.0%)

C) NTX 0.01 mg 30 0 0 0. 0 0

D) MS 60 mg NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

CONFUSION A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

DEPERSONALISATION A) PLACEBO 32 0 Treatment 0.541 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 0 0 1 (100.0%)

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 26 1 (3.8%) 1 1 (100.0%) 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Severity [2]

Total No. Of

DISSOCIATION A) PLACEBO 32 0 Treatment 0.384 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 1 (3.8%) 1 0 1 (100.0%) 0

EUPHORIC MOOD A) PLACEBO 32 0 Treatment 0.541 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 0 1 (100.0%)

C) NTX 0.01 mg 30 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 1 (3.8%) 1 0 (100.0%) 0

NERVOUSNESS A) PLACEBO 32 0 Treatment 0.579 0 0 0

B) MS 60 mg 28 2 (7.1%) 2 1 (50.0%) (50.0%) 0

C) NTX 0.01 mg 30 1 (3.3%) 1 0 (100.0%) 0

D) MS 60 mg NTX 0.001 mg 18 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 2 (7.1%) 2 2 (100.0%) 0

F) MS 60 mg/NTX O.l mg 26 1 (3.8%) 1 0 (100.0%) 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Severity [2]

Total ] No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

RENAL AND URINARY DISORDERS

ALL EVENTS A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 g 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 0 1 (100.0%) 0

F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0

URINARY A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

RETENTION

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 0 1 (100.0%) 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

REPRODUCTIVE SYSTEM AND BREAST DISORDERS

ALL EVENTS A) PLACEBO 32 0 Treatment 0.153 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 1 (5.6%) 1 0 0 1 (100.0%)

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Severity [2]

Total ] No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

DYSMENORRHOEA A) PLACEBO 32 0 Treatment 0.153 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg NTX 0.001 mg 18 1 (5.6%) 1 0 0 1 (100.0%)

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

ALL EVENTS A) PLACEBO 32 0 Treatment 0.768 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 1 (100. 0%) 0 0

C) NTX 0.01 mg 30 1 (3.3%) 1 0 0 1 (100.0%)

D) MS 60 mg NTX 0.001 mg 18 1 (5.6%) 1 1 (100. 0%) 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 2 0 0 2 (100.0%)

F) MS 60 mg NTX O.l mg 26 0 0 0 0 0

COUGH A) PLACEBO 32 0 Treatment 0.489 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 1 (3.3%) 1 0 0 1 (100.0%)

D) MS 60 mg NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

* **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Severity [2]

Total ] No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

EPISTAXIS A) PLACEBO 32 0 Treatment 0.153 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 1 (5.6%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

RHINITIS NOS A) PLACEBO 32 0 Treatment 0.573 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 0 0 1 (100.0%)

F) MS 60 mg NTX O.l g 26 0 0 0 0 0

SINUS CONGESTION A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 0 0 1 (100.0%)

F) MS 60 mg/NTX O.l g 26 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52A (Continued)

Adverse Events By Body System And Severity

Intent-To-Treat Population, Female Patients

Severity [2]

Total No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

SKIN & SUBCUTANEOUS TISSUE DISORDERS

ALL EVENTS A) PLACEBO 32 0 Treatment 0.087 0 0 0 0

B) MS 60 mg 28 2 (7.1%) A-D 0.017* 4 3 (75.0%) 1 (25.0%) 0

C) NTX 0.01 mg 30 0 C-D 0.020* 0 0 0 0

D) MS 60 mg NTX 0.001 mg 18 3 (16.7%) 5 2 (40.0%) 3 (60.0%) 0

E) MS 60 mg/NTX 0.01 mg 28 3 (10.7%) 3 2 (66.7%) 0 1 (33.3%)

F) MS 60 mg/NTX O.l mg 26 1 (3.8%) 2 0 1 (50.0%) 1 (50.0%)

DERMATITIS NOS A) PLACEBO 32 0 Treatment 0.573 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

ECCHYMOSIS A) PLACEBO 32 0 Treatment 0.153 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 1 (5.6%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg NTX O.l mg 26 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52A (Continued)

Adverse Events By Body System . And Severity

Intent-To-Treat Population, Female Patients

Severity [2]

Total ] No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [11 Events

PRURITUS NOS A) PLACEBO 32 0 Treatment 0.074 0 0 0 0

B) MS 60 mg 28 1 (3.6%) A-D 0.017* 1 0 1 (100.0%) 0

C) NTX 0.01 mg 30 0 C-D 0.020* 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 3 (16.7%) 4 1 (25.0%) 3 (75.0%) 0

E) MS 60 mg/NTX 0.01 mg 28 2 (7.1%) 2 1 (50.0%) 0 1 (50.0%)

F) MS 60 mg/NTX O.l mg 26 1 (3.8%) 1 0 0 1 (100.0%)

URTICARIA NOS A) PLACEBO 32 0 Treatment 0.541 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 2 2 (100.0%) 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 1 (3.8%) 1 0 1 (100.0%) 0

VASCULAR DISORDERS

ALL EVENTS A) PLACEBO 32 0 Treatment 0.015* 0 0 0 0

B) MS 60 mg 28 4 (14.3%) A-B 0.026* 4 4 (100.0%) 0 0

C) NTX 0.01 mg 30 1 (3.3%) A-F 0.004** 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 C-F 0.025* 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 3 (10.7%) D-F 0.028* 3 1 (33.3%) 2 (66.7%) 0

F) MS 60 mg/NTX 0: l mg 26 6 (23.1%) 7 3 (42.9%) 4 (57.1%) 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE : <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY

Table 52A (Continued)

Adverse Events By Body System And Severity

Intent-To-Treat Population, Female Patients

Severity [2]

Total ] No. Of

Body System No. Of Patients P-Value No. Of Mild Moderate Severe

Adverse Events (Costart English) Treatment Patients W/Event Source [1] Events

FLUSHING A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0

HOT FLUSHES NOS A) PLACEBO 32 0 Treatment 0.384 0 0 0 0

B) MS 60 mg 28 0 0 0 0 0

C) NTX 0.01 mg 30 0 0 0 0 0

D) MS 60 mg NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 1 (3.8%) 1 0 1 (100.0%) 0

HYPERTENSION NOS A) PLACEBO 32 0 Treatment 0.721 0 0 0 0

B) MS 60 mg 28 1 (3.6%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 30 1 (3.3%) 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 28 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 26 1 (3.8%) 1 1 (100.0%) 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Severity [2]

Total No. Of

VASODILATATION A) PLACEBO 32 0 Treatment 0.015* 0 0 0 0

B) MS 60 mg 28 3 (10.7%) A-F 0.009** 3 3 (100.0%) 0 0

C) NTX 0.01 mg 30 0 C-F 0.011* 0 0 0 0

D) MS 60 mg NTX 0.001 mg ; 18 0 D-F 0.048* 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 28 2 (7.1%) 2 0 2 (100.0%) 0

F) MS 60 mg/NTX 0.1 mg 26 5 (19.2%) 5 2 (40.0%) 3 (60.0%) 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52B Selected Adverse Events Intent-To-Treat Population, Female Patients

TOTAL NO. OF NO. SEVERITY [2]

BODY SYSTEM NO. OF SUBJECTS P-VALUE OF

ADVERSE EVENTS TREATMENT SUBJECTS W EVENT SOURCE [1] EVENTS Mild Moderate Severe

DIZZINESS A) PLACEBO 32 1 (3.1%) Treatment O.001*** 1 0 1 (100.0%) 0

C) NTX 0.01 mg 30 2 (6.7%) A-D O.001 *** 2 2 (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 18 9 (50.0%) A-E O.001*** 9 3 (33.3%) 6 (66.7%) 0

F) MS 60 mg/NTX 0.1 mg 26 9 (34.6%) B-C O.001*** 10 3 (30.0%) 5 (50.0%) 2 (20.0%) C-D O.001 *** C-E 0.001** C-F 0.008**

NAUSEA A) PLACEBO 32 5 (15.6%) Treatment .001 *** 6 2 (33.3%) 1 (16.7%) 3 (50.0%)

B) MS 60 mg 28 17 (60.7%) A-B O.001 *** 21 5 (23.8%) 12 (57.1%) 4 (19.0%)

C) NTX 0.01 mg 30 9 (30.0%) A-D O.001*** 10 3 (30.0%) 5 (50.0%) 2 (20.0%)

D) MS 60 mg/NTX 0.001 mg 18 16 (88.9%) A-E .001 *** 16 4 (25.0%) 9 (56.3%) 3 (18.8%)

E) MS 60 mg/NTX 0.01 mg 28 21 (75.0%) A-F .OOl *** 25 7 (28.0%) 10 (40.0%) 8 (32.0%)

F) MS 60 mg/NTX 0.1 mg 26 16 (61.5%) B-C 0.018* 18 1 (5.6%) 15 (83.3%) 2 (11.1%) B-D 0.038* C-D O.001*** C-E O.001*** C-F 0.017* D-F 0.045*

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG = 'SUSPECT' OR 'PROBABLE'.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52B (Continued)

Selected Adverse Events

Intent-To-Treat Population, Female Patients

TOTAL NO. OF NO. SEVERITY [2]

BODY SYSTEM NO. OF SUBJECTS P-VALUE OF

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT SOURCE [1] EVENTS Mild Moderate Severe

SOMNOLENCE A) PLACEBO 32 0 Treatment O.001*** 0 0 0 0

B) MS 60 mg 28 8 (28.6%) A-B 0.001** 9 1 (11.1%) 6 (66.7%) 2 (22.2%)

C) NTX 0.01 mg 30 0 A-E 0.012* 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 18 2 (11.1%) A-F O.001*** 2 0 2 (100.0%) 0

E) MS 60 mg/NTX 0.01 mg 28 5 (17.9%) B-C 0.001** 5 3 (60.0%) 2 (40.0%) 0

F) MS 60 mg/NTX O.l mg 26 8 (30.8%) C-E 0.015* 8 5 (62.5%) 2 (25.0%) 1 (12.5%)

, C-F 0.001**

VOMITING A) PLACEBO 32 3 (9.4%) Treatment O.001*** 3 1 (33.3%) 0 2 (66.7%)

NOS B) MS 60 mg 28 16 (57.1%) A-B O.001 *** 17 1 (5.9%) 5 (29.4%) 11 (64.7%)

C) NTX 0.01 mg 30 7 (23.3%) A-D O.001 *** 7 1 (14.3%) 1 (14.3%) 5 (71.4%)

D) MS 60 mg/NTX 0.001 mg 18 15 (83.3%) A-E .001*** 16 1 (6.3%) 3 (18.8%) 12 (75.0%)

F) MS 60 mg/NTX O.l mg 26 16 (61.5%) B-C 0.008** 21 2 (9.5%) 5 (23.8%) 14 (66.7%) C-D O.001*** C-E 0.003** C-F 0.003**

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52C Adverse Events By Body System And Intent-To-Treat Population, Male Patients

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of m

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

TOTAL NUMBER OF EVENTS ADVERSE EVENTS (ALL BODY SYSTEMS)

All EVENTS A) PLACEBO 19 13 ( 68.4%) Treatment 0.001 *** 26 10 ( 38.5%) 12 (46.2%) 4 (15.4%)

B) MS 60 mg 25 20 ( 80.0% A-C 0.026 * 59 30 (50.8%) 22 (37.3%) 7 (11.9%)

C) NTX 0.01 mg 21 7 ( 33.3%) B-C 0.001 ** 13 5 ( 38.5%) 6 (46.2%) 2 (15.4%)

D) MS 60 mg/NTX 0.001 mg 32 28 (87.5%) C-D 0.001 *** 75 32 ( 42.7%) 29 (38.7%) 14 . (18.7%)

E) MS 60 mg/NTX 0.001 mg 23 20 (87.0%) C-E 0.001 *** 58 20 (34.5%) 20 (34.5%) 18 (31.0%)

F) MS 60 mg/NTX 0.1 mg 22 20 ( 90.9%) C-F 0.001 *** 57 21 ( 36.8%) 21 (36.8%) 15 (26.3%)

CARDIAC DISORDERS ALL EVENTS A) PLACEBO 19 1 ( 5.3%) Treatment 0.590 1 1 (100.0%) 0 0

B) MS 60 mg 25 1 ( 4.0%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 21 1 ( 4.8%) 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52C (Continued)

Adverse Events By Body System And

Intent-To-Treat Population, Male Patients

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of m

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

BRAD YCARDIA NOS A) PLACEBO 19 1 ( 5.3%) Treatment 0.258 1 1 (100.0%) 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0

TACHYCARDIA NOS A) PLACEBO 19 0 Treatment 0.509 0 0 0 0

B) MS 60 mg 25 1 (4.0%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 21 1 (4.8%) 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

EAR AND LABYRINTH DISORDERS

ALL EVENTS A) PLACEBO 19 1 (5.3%) Treatment 0.685 1 0 1 (100.0%) 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 1 (3.1%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 23 1 (4.3%) 1 0 1 (100.0%) 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG - 'SUSPECT' OR 'PROBABLE'.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of J2L

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] rents

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

EARACHE A) PLACEBO 19 1 (5.3%) Treatment 0.685 1 0 1 (100.0%) 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 1 (3.1%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 23 1 (4.3%) 1 0 1 (100.0%) 0

F) MS 60 mg NTX O.l mg 22 0 0 0 0 0

EYE DISORDERS

ALL EVENTS A) PLACEBO 19 1 (5.3%) Treatment 0.555 1 0 1 (100.0%) 0

B) MS 60 mg 25 4 (16.0%) 4 4 (100.0%) 0 0

C) NTX 0.01 mg 21 1 (4.8%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 32 5 (15.6%) 5 4 (80.0%) 0 1 (20.0%)

E) MS 60 mg NTX 0.01 mg 23 3 (13.0%) 3 2 (66.7%) 0 1 (33.3%)

F) MS 60 mg/NTX 0.1 mg 22 1 (4.5%) 1 1 (100.0%) 0 0

CONJUNCTIVITIS A) PLACEBO 19 0 Treatment 0.511 0 0 0 0

NEC B) MS 60 mg 25 3 (12.0%) 3 3 (100.0%) 0 0

C) NTX 0.01 mg 21 1 (4.8%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 32 4 (12.5%) 4 4 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 23 3 (13.0%) 3 2 (66.7%) 0 1 (33.3%)

F) MS 60 mg/NTX O.l g 22 1 (4.5%) 1 1 (100.0%) 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

PHOTOPHOBIA A) PLACEBO 19 1 (5.3%) Treatment 0.258 1 0 (100.0%) 0

B) MS 60 mg 25 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 - 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0

TIRED EYES A) PLACEBO 19 0 Treatment 0.629 0 0 0

B) MS 60 mg 25 0 0 0 0

C) NTX O.Ol mg 21 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 1 (3.1%) 1 0 1 (100.0%)

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0

VISION BLURRED A) PLACEBO 19 0 Treatment 0.451 0 0 0

B) MS 60 mg 25 1 (4.0%) 1 1 (100.0%) 0

C) NTX 0.01 mg 21 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

* ** ***. .vALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52C (Continued)

Adverse Events By Body System And

Intent-To-Treat Population, Male Patients

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of m

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

GASTROINTESTINAL DISORDERS

ALL EVENTS A) PLACEBO 19 3 (15.8%) Treatment O.001*** 5 1 (20.0%) 1 (20.0%) 3 (60.0%)

B) MS 60 mg 25 11 (44.0%) A-B 0.046* 21 11 (52.4%) 6 (28.6%) 4 (19.0%)

C) NTX O.Ol mg 21 0 A-D 0.004** 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 18 (56.3%) A-F 0.004** 31 9 29.0%) 13 (41.9%) 9 (29.0%)

E) MS 60 mg/NTX 0.01 mg 23 10 (43.5%) B-C O.001*** 18 3 (16.7%) 5 (27.8%) 10 (55.6%)

F) MS 60 mg NTX O.l mg 22 13 (59.1%) C-D .001 *** 23 7 (30.4%) 6 (26.1%) 10 (43.5%) C-E O.001*** C-F O.001 ***

ABDOMINAL PAIN A) PLACEBO 19 1 (5.3%) Treatment 0.441 1 0 0 1 (100.0%)

NOS B) MS 60 mg 25 2 (8.0%) 2 1 (50.0%) 1 (50.0%) 0

C) NTX O.Ol mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 1 (3.1%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

ABDOMINAL PAIN A) PLACEBO 19 0 Treatment 0.358 0 0 0 0

UPPER B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 22 1 (4.5%) 1 0 1 (100.0%) 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, = 0.01, or = 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of m

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

DYSPHAGIA A) PLACEBO 19 1 (5.3%) Treatment 0.547 1 0 0 1 (100.0%)

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 1 (3.1%) 1 0 0 1 (100.0%)

E) MS 60 mg NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

HICCUPS A) PLACEBO 19 0 Treatment 0.390 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX O.Ol mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 23 1 (4.3%) 1 0 1 (100.0%) 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

NAUSEA A) PLACEBO 19 2 (10.5%) Treatment 0.001** 2 1 (50.0%) 1 (50.0%) 0

B) MS 60 mg 25 10 (40.0%) A-B 0.029* To 7 (70.0%) 3 (30.0%) 0

C) NTX 0.01 mg 21 0 A-D 0.013* 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 14 (43.8%) A-F 0.014* 15 5 (33.3%) 7 (46.7%) 3 (20.0%)

E) MS 60 mg/NTX 0.01 mg 23 6 (26.1%) B-C 0.001** 6 2 (33.3%) 2 (33.3%) 2 (33.3%)

F) MS 60 mg/NTX O.l mg 22 10 (45.5%) C-D O.001*** 10 6 (60.0%) 4 40.0%) 0 C-E 0.011* C-F O.001 ***

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52C (Continued)

Adverse Events By Body System And

Intent-To-Treat Population, Male Patients

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [21

ADVERSE EVENTS NO. OF PATIENTS SOURCE [13 Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

SORE THROAT NOS A) PLACEBO 19 0 Treatment 0.629 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 1 (3.1%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg NTX O.l mg 22 0 0 0 0 0

VOMITING NOS A) PLACEBO 19 1 (5.3%) Treatment .001*** 1 0 0 1 (100.0%)

B) MS 60 mg 25 9 (36.0%) A-B 0.015* 9 3 (33.3%) 2 (22.2%) 4 (44.4%)

C) NTX 0.01 mg 21 0 A-D 0.010* 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 12 (37.5%) A-E 0.020* 13 2 (15.4%) 6 (46.2%) 5 (38.5%)

E) MS 60 mg/NTX 0.01 mg 23 8 (34.8%) A-F 0.001** 11 1 (9.1%) 2 (18.2%) 8 (72.7%)

F) MS 60 mg/NTX O.l mg 22 11 (50.0%) B-C 0.002** 12 1 (8.3%) 1 (8.3%) 10 (83.3%) C-D 0.001** C-E 0.002** C-F O.001 ***

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [2]

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

ALL EVENTS A) PLACEBO 19 3 (15.8%) Treatment 0.280 3 1 (33.3%) 2 (66.7%) 0

B) MS 60 mg 25 5 (20.0%) A-E 0.047* 5 2 (40.0%) 2 (40.0%) 1 (20.0%)

C) NTX 0.01 mg 21 1 (4.8%) B-E 0.023* 2 0 1 (50.0%) 1 (50.0%)

D) MS 60 mg/NTX 0.001 mg 32 4 (12.5%) 4 3 (75.0%) 1 (25.0%) 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 22 3 (13.6%) 3 2 (66.6%) 1 (33.3%) 0

ASTHENIA A) PLACEBO 19 0 Treatment 0.013* 0 0 0 0

B) MS 60 mg 25 3 (12.0%) B-D 0.044* 3 1 (33.3%) 2 (66.7%) 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

FEELING ABNORMAL A) PLACEBO 19 0 Treatment 0.451 0 0 0 0

B) MS 60 mg 25 1 (4.0%) 1 0 0 1 (100.0%)

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l g 22 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <-= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [2]

FEELING HOT A) PLACEBO 19 0 Treatment 0.600 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 1 (4.8%) 1 0 0 1 (100.0%)

D) MS 60 mg/NTX 0.001 mg 32 1 (3.1%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0

PAIN NOS A) PLACEBO 19 0 Treatment 0.624 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg NTX 0.001 mg 32 1 (3.1%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 1 (4.5%) 1 0 1 1 (100.0%) 0

PYREXIA A) PLACEBO 19 1 (5.3%) Treatment 0.839 1 1 (100.0%) 0 0

B) MS 60 mg 25 1 (4.0) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 1 (3.1%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 22 1 (4.5%) 1 1 (100.0%) 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [21

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

RIGORS A) PLACEBO 19 2 (10.5%) Treatment 0.264 2 0 2 (100.0%) 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 1 (4.58%) 1 0 1 (100.0%) 0

D) MS 60 mg NTX 0.001 mg 32 1 (3.1%) 1 0 1 (100.0%) 0

E) MS 60 mg NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0

WEAKNESS A) PLACEBO 19 0 Treatment 0.358 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX O.Ol mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg NTX 0.1 mg 22 1 (4.5%) 1 1 (100.0%) 0 0

INFECTIONS AND INFESTATIONS

ALL EVENTS A) PLACEBO 19 4 (21.1%) Treatment 0.654 6 4 (66.7%) 1 (16.7%) 1 (16.7%)

B) MS 60 mg 25 2 (8.0%) 2 0 0 2 (100.0%)

C) NTX 0.01 mg 21 2 (9.5%) 2 0 2 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 32 2 (6.3%) 2 0 0 2 (100.0%)

E) MS 60 mg/NTX 0.01 mg 23 2 (8.7%) 3 0 0 3 (100.0%)

F) MS 60 mg NTX O.l mg 22 2 (9.1%) 2 0 1 (50.0%) 1 (50.0%)

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of m

ADVERSE EVENTS NO. OF PATIENTS SOURCE [11 Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

CELLULITIS A) PLACEBO 19 0 Treatment 0.358 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 1 (4.5%) 1 0 0 1 (100.0%)

DRY SOCKET NOS A) PLACEBO 19 1 (5.3%) Treatment 0.848 1 0 1 (100.0%) 0

B) MS 60 mg 25 1 (4.0%) 1 0 0 1 (100.0%)

C) NTX 0.01 mg 21 1 (4.8%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 32 2 (6.3%) 2 0 0 2 (100.0%)

E) MS 60 mg/NTX 0.01 mg 23 2 (8.7%) 2 0 0 2 (100.0%)

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

NASOPHARYNGITIS A) PLACEBO 19 0 Treatment 0.451 0 0 0 0

B) MS 60 mg 25 1 (4.0%) 1 0 0 1 (100.0%)

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/ΝTX O.l mg 22 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [21

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

ORAL INFECTION NEC A) PLACEBO 19 0 Treatment 0.390 0 0 0

B) MS 60 mg 25 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0

E) MS 60 mg NTX 0.01 mg 23 1 (4.3%) 1 0 0 (100.0%)

F) MS 60 mg/NTX O.l mg 22 0 0 0 0

PHARYNGITIS NOS A) PLACEBO 19 2 (10.5%) Treatment 0.093 4 3 (75.0%) 0 1 (25.0%)

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 1 (4.8%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg . 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0

TOOTH INFECTION A) PLACEBO 19 0 Treatment 0.358 0 0

B) MS 60 mg 25 0 0 0

C) NTX 0.01 mg 21 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0

F) MS 60 mg/NTX O.l mg 22 1 (4.5%) 1 0 (100.0%)

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [2]

ADVERSE EVENTS NO. OF PATIENTS ^■ SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

UPPER RESPIRATORY TRACT INFECTION NOS

A) PLACEBO 19 1 (5.3%) Treatment 0.258 1 1 (100.0%) 0

B) MS 60 mg 25 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0

INJURY AND POISONING ALL EVENTS A) PLACEBO 19 1 (5.3%) Treatment 0.258 1 0 1 (100.0%) 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mgNTX O.l mg 22 0 0 0 0 0

HYPOTHERMIA A) PLACEBO 19 1 (5.3%) Treatment 0.258 1 0 1 (100.0%) 0

B) MS 60 mg 25 0 0 0 0 0

C) ΝTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/ΝTX O.l mg 22 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

* ** ***. p. VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of

ADVERSE EVENTS NO. OF PATIENTS SOURCE [11 Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

INVESTIGATIONS ALL EVENTS A) PLACEBO 19 0 Treatment 0.390 0 0

B) MS 60 mg 25 0 0 0

C) NTX 0.01 mg 21 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 1 (4.3%) 1 1 (100.0%)

F) MS 60 mg/NTX O.l mg 22 0 0 0

HAEMATURIA PRESENT A) PLACEBO 19 0 Treatment 0.390 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 23 1 (4.3%) 1 1 (100.0%) 0 0

F) MS 60 mg/ΝTX O.l mg 22 0 0 0 0 0

ΝΝECTΓVE TISSUE AND BONE DISORDERS

ALL EVENTS A) PLACEBO 19 0 Treatment 0.090 0 0

B) MS 60 mg 25 2 (8.0%) 2 0 (100.0%)

C) NTX 0.01 mg 21 0 0 0

D) MS 60 mg NTX 0.001 mg 32 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG = 'SUSPECT' OR 'PROBABLE'

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52C (Continued)

Adverse Events By Body System And

Intent-To-Treat Population, Male Patients

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [21

ADVERSE EVENTS NO. OF PATIENTS SOURCE [11 Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

NECK STIFFNESS A) PLACEBO 19 0 Treatment 0.451 0 0 0 0

B) MS 60 mg 25 1 (4.0%) 1 0 1 (100.0%) 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

SENSATION OF HEAVINESS

A) PLACEBO 19 0 Treatment 0.451 0 0 0 0

B) MS 60 mg 25 1 (4-0) 1 0 1 (100.0%) 0

C) NTX O.Ol mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg NTX 0.1 mg 22 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

NERVOUS SYSTEM

DISORDERS

ALL EVENTS A) PLACEBO 19 6 (31.6%) Treatment 0.005** 6 3 (50.0%) 3 (50.0%) 0

B) MS 60 mg 25 13 (52.0%) A-D 0.032* 15 5 (33.3%) 10 (66.7%) 0

C) NTX 0.01 mg 21 4 (19.0%) A-F 0.019* 4 2 (50.0%) 1 (25.0%)) 1 (25.0%)

D) MS 60 mg/NTX 0.001 mg 32 20 (62.5%) B-C 0.021* 26 12 (46.2%) 12 (46.2%) 2 (7.7%)

E) MS 60 mg/NTX 0.01 mg 23 14 (60.9%) C-D 0.001** 21 11 (52.4%) 7 (33.3%) 3 (14.3%)

F) MS 60 mg/NTX O.l mg 22 15 (68.2%) C-E 0.004** 21 9 (42.9%) 10 (47.6%) 2 (9.5%) C-F 0.001**

DIZZINESS A) PLACEBO 19 1 (5.3%) Treatment 0.008** 1 0 1 (100.0%) 0

(EXC VERTIGO) B) MS 60 mg 25 3 (12.0%) A-D 0.046* 3 1 (33.3%) 2 (66.7%) 0

C) NTX 0.01 mg 21 0 A-E 0.020* 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 9 (28.1%) A-F 0.032* 10 4 (40.0%) 5 (50.0%) 1 (10.0%)

E) MS 60 mg/NTX 0.01 mg 23 8 (34.8%) C-D 0.007** 9 5 (55.6%) 4 (44.4%) 0

F) MS 60 mg/NTX O.l mg 22 7 (31.8%) C-E 0.002** 9 4 (44.4%) 4 (44.4%) 1 (11.1%) C-F 0.004**

HEADACHE NOS A) PLACEBO 19 3 (15.8%) Treatment 0.444 3 2 (66.7%) 1 (33.3%) 0

B) MS 60 mg 25 6 (24.0%) 7 2 (28.6%) 5 (71.4%) 0

C) NTX 0.01 mg 21 3 (14.3%) 3 1 (33.3%) 1 (33.3%) 1 (33.3%)

D) MS 60 mg/NTX 0.001 mg 32 6 (18.8%) 7 1 (14.3%) 5 (71.4%) 1 (14.3%)

E) MS 60 mg/NTX 0.01 mg 23 2 (8.7%) 2 1 (50.0%) 0 1 (50.0%)

F) MS 60 mg/NTX O.l mg 22 7 (31.8%) 7 4 (57.1%) 3 (42.9%) 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [2]

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

HYPERTONIA A) PLACEBO 19 0 Treatment 0.390 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX O.Ol mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 1 (4.3%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

HYPOAESTHESIA A) PLACEBO 19 0 Treatment 0.390 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX O.Ol mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 23 1 (4.3%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

MIGRAINE NOS A) PLACEBO 19 0 Treatment 0.390 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 1 (4.3%) 1 0 0 1 (100.0%)

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of PI

ADVERSE EVENTS NO. OF PATIENTS .SOURCE [1] Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

MUSCLE SPASTICITY A) PLACEBO 19 0 Treatment 0.451 0 0 0 0

B) MS 60 mg 25 1 (4.0%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

PARAESTHESIA

CIRCUMORAL A) PLACEBO 19 0 Treatment 0.629 0 0 0

B) MS 60 mg 25 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 1 (3.1%) 1 1 (100.0%) 0

E) MS 60 mg/NTX O.Ol mg 23 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0

PARAESTHESIA NEC A) PLACEBO 19 2 (10.5%) Treatment 0.510 2 1 (50.0%) 1 (50.0%) 0

B) MS 60 mg 25 0 _* 0 0 0 0

C) NTX 0.01 mg 21 1 (4.8%) 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 32 2 (6.3%) 2 2 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 23 1 (4.3%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [2]

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

SOMMOLENCE A) PLACEBO 19 0 Treatment 0.209 0 0 0 0

B) MS 60 mg 25 3 (12.0%) C-F 0.040* 4 1 (25.0%) 3 (75.0%) 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg NTX 0.001 mg 32 5 (15.6%) 6 4 (66.7%) 2 (33.3%) 0

E) MS 60 mg/NTX 0.01 mg 23 3 (13.0%) 3 1 (33.3%) 2 (66.7%) 0

F) MS 60 mg/NTX O.l mg 22 4 (18.2%) 4 1 (25.0%) 3 (75.0%) 0

SYNCOPE A) PLACEBO 19 0 Treatment 0.390 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 1 (4.3%) 1 0 0 1 (100.0%)

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

TENSION HEADACHES A) PLACEBO 19 0 Treatment 0.358 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 1 (4.5%) 1 0 0 1 (100.0%)

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [21

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W EVENT Mild Moderate Severe

TREMOR NEC A) PLACEBO 19 0 Treatment 0.062 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX O.Ol mg 21 0 0 0 0 0

D) MS 60 mg NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 23 2 (8.7%) 2 1 (50.0%) 1 (50.0%) 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

PSYCHIATRIC DISORDERS

ALL EVENTS A) PLACEBO 19 1 ((5.3%) Treatment 0.593 1 0 1 (100.0%) 0

B) MS 60 mg 25 2 (8.0%) 2 1 (50.0%) 1 (50.0%) 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 2 (6.3%) 2 0 2 (100.0%) 0

E) MS 60 mg/NTX 0.01 mg 23 1 (4.3%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX O.l mg 22 3 (13.6%) 3 1 (33.3%) 1 (33.3%) 1 (33.3%)

DISORIENTATION A) PLACEBO 19 0 Treatment 0.390 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 23 1 (4.3%) 1 . 1 (100.0%) 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [21

DISSOCIATION A) PLACEBO 19 0 Treatment 0.358 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX O.Ol mg 21 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 1 (4.5%) 1 0 0 1 1 (100.0%)

EUPHORIC MOOD A) PLACEBO 19 0 Treatment 0.400 0 0 0 0

B) MS 60 mg 25 1 (4.0%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 1 (3.1%) 1 0 1 (100.0%) 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 2 (9.1%) 2 1 (50.0%) 1 (50.0%) 0

NERVOUSNESS A) PLACEBO 19 1 (5.3%) Treatment 0.711 1 0 1 (100.0%) 0

B) MS 60 mg 25 1 (4.0%) 1 0 1 (100.0%) 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 1 (3.1%) 1 0 1 (100.0%) 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [2]

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

RENAL AND URINARY DISORDERS

ALL EVENTS A) PLACEBO 19 0 Treatment 0.551 0 0 0 0

B) MS 60 mg 25 1 (4.0%) 1 1 (100. 0%) 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 1 (4.3%) 1 0 1 (100.0%) 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

URINARY RETENTION A) PLACEBO 19 0 Treatment 0.551 0 0 0 0

B) MS 60 mg 25 1 (4.0%) 1 1 (100. 0%) 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 1 (4.3%) 1 0 1 (100.0%) 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

REPRODUCTIVE SYSTEM AND BREAST DISORDERS

ALL EVENTS A) PLACEBO 19 0 Treatment 0.390 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 1 (4.3%) 2 0 1 (50.0%) 1 (50.0%)

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [21

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1J Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

PROSTATIC

DISORDER NOS A) PLACEBO 19 0 Treatment 0.390 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 23 1 (4.3%) 1 0 1 (100.0%) 0

F) MS 60 mg/ΝTX 0.1 mg 22 0 0 0 0 0

TESTICULAR

DISORDER NOS A) PLACEBO 19 0 Treatment 0.390 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) ΝTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/ΝTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg ΝTX 0.01 mg 23 1 (4.3%) 1 0 0 1 (100.0%)

F) MS 60 mg/ΝTX O.l mg 22 0 0 0 0 0

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

ALL EVENTS A) PLACEBO 19 0 Treatment 0.643 0 0 • 0 0

B) MS 60 mg 25 1 (4.0%) 1 1 (100.0%) 0 0

C) ΝTX O.Ol mg 21 1 (4.8%) 1 1 (100.0%) 0 0

D) MS 60 mg/ΝTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/ΝTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 1 (4.5%) 1 1 (100.0%) 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [2]

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

EPISTAXIS A) PLACEBO 19 0 Treatment 0.325 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.0 l mg 21 1 (4.8%) 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

NECK TIGHTNESS A) PLACEBO 19 0 Treatment 0.358 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 1 (4.5%) 1 1 (100.0%) 0 0

RHINITIS NOS A) PLACEBO 19 0 Treatment 0.451 0 0 0 0

B) MS 60 mg 25 1 (4.0%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events (COSTART ENGLISH) TREATMENT PAΉENTS W/EVENT Mild Moderate Severe

SKIN & SUBCUTANEOUS TISSUE DISORDERS ALL EVENTS A) PLACEBO 19 0 Treatment 0.122 0 0 0 0

B) MS 60 mg 25 2 (8.0%) D-E 0.014* 2 2 (100.0%) 0 0

C) NTX Q.01 mg 21 1 (4.8%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 4 (17.4%) 5 2 (40.0%) 3 (60.0%) 0

F) MS 60 mg/NTX O.l mg 22 2 (9.1%) 2 0 1 (50.0%) 1 (50.0%)

ERYTHEMA NEC A) PLACEBO 19 0 Treatment 0.451 0 0 0 0

B) MS 60 mg 25 1 (4.0%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

PHOTOSENSITΓVΠΎ A) PLACEBO 19 0 Treatment 0.390 0 0 0 0 REACΉON NOS

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg NTX 0.01 mg 23 1 (4.3%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [2]

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

PRURITUS NOS A) PLACEBO 19 0 Treatment 0.037* 0 0 0 0

B) MS 60 mg 25 0 D-E 0.035* 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 3 (13.0%) 3 0 3 (100.0%) 0

F) MS 60 mg/NTX O.l mg 22 1 (4.5%) 1 0 0 1 (100.0%)

SWEATING A) PLACEBO 19 0 Treatment 0.801 0 0 0 0

INCREASED B) MS 60 mg 25 1 (4.0%) 1 1 (100.0%) 0 0

C) NTX 0.01 mg 21 1 (4.8%) 1 0 1 (100.0%) 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 1 (4.3%) 1 1 (100.0%) 0 0

F) MS 60 mg/NTX O.l mg 22 1 (4.5%) 1 0 1 (100.0%) 0

_*-

VASCULAR DISORDERS

ALL EVENTS A) PLACEBO 19 1 (5.3%) Treatment 0.829 1 0 1 (100.0%) 0

B) MS 60 mg 25 3 (12.0%) 3 2 (66.7%) 1 (33.3%) 0

C) NTX 0.01 mg 21 1 (4.8%) 1 1 (100.0%) 0 0

D) MS 60 mg/NTX 0.001 mg 32 4 (12.5%) 4 3 (75.0%) 1 (25.0%) 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

No. SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of P]

ADVERSE EVENTS NO. OF PATIENTS SOURCE [1] Events

(COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

HOT FLUSHES NOS A) PLACEBO 19 0 Treatment 0.451 0 0 0 0

B) MS 60 mg 25 1 (4.0%) 1 0 1 (100.0%) 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0

E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0

HYPERTENSION NOS A) PLACEBO 19 0 Treatment 0.170 0 0 0 0

B) MS 60 mg 25 0 0 0 0 0

C) NTX 0.01 mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 3 (9.4%) 3 2 (66.7%) 1 (33.3%) 0

E) MS 60 mg/NTX 0.01 mg 23 1 (4.3%) 1 0 1 (100.0%) 0

F) MS 60 mg/NTX O.l mg 22 0 0 0 0 0

VASODILATATION A) PLACEBO 19 1 (5.3%) Treatment 0.979 1 0 1 (100.0%) 0

B) MS 60 mg 25 2 (8.0%) 2 2 (100.0%) 0 0

C) NTX 0.01 mg 21 1 (4.8%) 1 1 (100.0%) 0 0

D) MS 60 mg NTX 0.001 mg 32 1 (3.1%) 1 1 (100.0%) 0 0

E) MS 60 mg/NTX 0.01 mg 23 1 4.3%) 1 0 1 (100.0%) 0

F) MS 60 mg/NTX O.l mg 22 (4.5%) 1 0 1 (100.0%) 0

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52D

SELECTED ADVERSE EVENTS

SAFETY POPULATION, MALE PATIENTS

ADVERSE TOTAL NO. OF P-VALUE NUMBER SEVERITY [2]

EVENT NO. OF SUBJECTS [1] OF

(ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE EVENTS Mild Moderate < Severe

DIZZINESS A) PLACEBO 19 1 (5.3%) Treatment 0.008** 1 0 1 (100.0%) 0

(Exc. Vertigo) B) MS 60 mg 25 3 (12.0%) A-D 0.046* 3 1 (33.3%) 2 (66.7%) 0

C) NTX 0.01 mg 21 0 A-E 0.020* 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 9 (28.1%) A-F 0.032* 10 4 (40.0%) 5 (50.0%) 1 (10.0

E) MS 60 mg/NTX 0.01 mg 23 8 (34.8%) C-D 0.007** 9 5 (55.6%) 4 (44.4%) 0

F) MS 60 mg/NTX O.l mg 22 7 (31.8%) C-E 0.002** 9 4 (44.4%) 4 (44.4%) 1 (ll.l-⁰ C-F 0.004**

NAUSEA A) PLACEBO 19 2 (10.5%) Treatment 0.001** 2 1 (50.0%) 1 (50.0%) 0

B) MS 60 mg 25 10 (40.0%) A-B 0.029* 10 7 (70.0%) 3 (30.0%) 0

C) NTX O.Ol mg 21 0 A-D 0.013* 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 14 (43.8%) A-F 0.014* 15 5 (33.3%) 7 (46.7%) 3 (20.0

E) MS 60 mg/NTX 0.01 mg 23 6 (26.1%) B-C 0.001** 6 2 (33.3%) 2 (33.3%) 2 (33.3°/

F) MS 60 mg/NTX O.l mg 22 10 (45.5%) C-D O.001*** 10 6 (60.0%) 4 (40.0%) 0

C-E 0.011*

PAIRWISE COMPARISONS ONLY.

[21 THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*, **, ***: P-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

Table 52D (Continued)

SELECTED ADVERSE EVENTS

SAFETY POPULATION, MALE PATIENTS

ADVERSE TOTAL NO. OF P-VALUE NUMBER SEVERITY [2]

EVENT NO. OF SUBJECTS [1] OF (ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE EVENTS Mild Moderate Severe

SOMNOLENCE A) PLACEBO 19 0 Treatment 0.209 0 0 0 0

B) MS 60 mg 25 3 (12.0%) C-F 0.040* 4 1 (25.0%) 3 (75.0%) 0

C) NTX O.Ol mg 21 0 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 5 (15.6%) 6 4 (66.7%) 2 (33.3%) 0

E) MS 60 mg/NTX 0.01 mg 23 3 (13.0%) 3 1 (33.3%) 2 (66.7%) 0

F) MS 60 mg/NTX O.l mg 22 4 (18.2%) 4 1 (25.0%) 3 (75.0%) 0

VOMITING A) PLACEBO 19 1 (5.3%) Treatment O.001*** 1 0 0 1 (100.0 NOS B) MS 60 mg 25 9 (36.0%) A-B 0.015* 9 3 (33.3%) 2 (22.2%) 4 (44.4

C) NTX 0.01 mg 21 0 A-D 0.010* 0 0 0 0

D) MS 60 mg/NTX 0.001 mg 32 12 (37.5%) A-E 0.020* 13 2 (15.4%) 6 (46.2%) 5 (38.5

E) MS 60 mg/ΝTX 0.01 mg 23 8 (34.8%) A-F 0.001** 11 1 (9.1%) 2 (18.2%) 8 (72.7

F) MS 60 mg/ΝTX 0.1 mg 22 11 (50.0%) B-C 0.002** 12 1 (8.3%) 1 (8.3%) 10 (83.3

PAIRWISE COMPARISONS ONLY.

[2] THE DENOMMATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

*_j **₅ ***. p-VALUE <= 0.05, <= 0.01, or <= 0.001 RESPECTIVELY.

EXAMPLE 5

An additional clinical study, this one using hydrocodone with acetaminophen (instead of morphine) alone and in combination with naltrexone, was designed substantially the same as that described in Example 3, with the following differences:

(1) six treatment groups with four different doses of NTX (1.0 mg, 0.1 mg, 0.01 mg and 0.001 mg) in combination with hydrocodone 5 mg acetaminophen 500 mg versus hydrocodone 5 mg/acetaminophen 500 mg (HC/APAP) alone, and versus placebo alone in subjects with moderate to severe pain in a postsurgical dental pain clinical study; (2) the primary efficacy variable was the categorical sum of pain intensity difference scores through 4 hours (SPID-4); and (3) the secondary efficacy variables were: 4, 6 and 8 hour total pain relief scores (TOTPAR-4, TOTPAR-6 and TOTPAR- 8); categorical 6 and 8 hour sum of pain intensity difference scores (SPID-6 and SPID-8); categorical pain intensity difference (PID) scores through 8 hours; pain relief (PR) scores through 8 hours; peak categorical PID scores through 8 hours

(PEAKPID); peak pain relief score through 8 hours (TOTPAR); time to onset of analgesia (i.e., at least a one category improvement in the pain intensity score); time to onset of meaningful pain relief; time to taking backup medication; percent of patients taking backup medication; and patient overall evaluation of study drug. A total of 300 subjects were randomized; all 300 subjects were deemed evaluable (Table 53).

Table 53 Patients Enrollment and Evaluabilit

The demographic and baseline characteristics were summarized by treatment groups for all 300 randomized patients which were all evaluable (Table 54).

Demographic characteristics included age, race/ethnicity, sex, weight, height, medical history, teeth extracted (impacted and non-impacted), baseline pain intensity, and baseline visual analog scale.

Subjects ranged in age from 16 to 53 years; 19.0% were Caucasian and 63.0% were female. No adjustments in the analyses were made to take into account differences among treatment groups. These differences had little or no influence on pain assessments at baseline. The baseline pain intensity scores and visual analog scale scores were generally comparable across treatment groups (Tables 55 A and

55B).

Table 54

Baseline Characteristics

Safet Patients

TREATMENT BY SITE INTERACTIONS AS FACTORS. *, **, ***: P-VALUE < = 0.05, <= 0.01, OR < = 0.001 RESPECTIVELY

Table 54 (Continued)

Baseline Characteristics

Safet Patients

TREATMENT BY SITE MTERACTIONS AS FACTORS. *, **, ***: P-VALUE < = 0.05, <= 0.01, OR < = 0.001 RESPECTIVELY

Table 55A

Summary of Baseline Pain Intensity Scores Safet Patients

Table 55B

Summary of Baseline Visual Analog Scale (VAS) Scores

(Safety Patients)

[lj P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND

The TOTPAR results (4 hour, 6 hour, 8 hour) are summarized in Table 56 and the 4 hour TOTPAR scores are shown in Figure 30. The placebo treatment group had the lowest mean TOTPAR scores. All 5 of the active treatment groups with HC/APAP alone or in combination with NTX exhibited mean TOTPAR scores that were numerically higher than placebo. The mean TOTPAR score for the 0.001 mg NTX combination treatment was higher than that for the HC/APAP alone treatment, whereas the other NTX combination treatment means were comparable to or lower than that for the HC/APAP alone treatment (Figure 30).

Table 56

Efficacy Results Means and Standard Deviations for TOTPARs (Trapezoidal Method) (Safety Patients)

Table 56 (Continued)

Table 56 (Continued)

Efficacy Results ^■ Means and Standard Deviations for TOTPARs (Trapezoidal Method) Safet Patients

Table 57 summarizes the results of the 4, 6, and 8 hour SPID results (Figure 31). The 4 hour results are also represented in Figure 38 A. The placebo treatment group had the lowest mean 4 hour SPID scores. All 5 of the active treatment groups with HC/APAP alone or in combination with NTX exhibited improved profiles in mean SPID relative to placebo. The mean 4 hour SPED score for the 0.001 mg NTX combination treatment was higher than that for the HC/APAP alone treatment, whereas the other NTX combination treatments were comparable to or lower than that for the HC/APAP alone treatment (Figure 31 or 38 A).

Table 57

Efficacy Results - Means and Standard Deviations for the SPIDS (Safety Patients)

Summary of Pin Intensit Differences SPIDS)

MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED

LSD TEST

(MEANMG, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 57 (Continued)

Summar of Pin Intensity Differences (SPIDS)

MEANS GIVEN ARE LEAST SQUARE MEANS.

LSD TEST

Table 57 (Continued)

Summar of Pin Intensit Differences SPIDS)

MEANS GIVEN ARE LEAST SQUARE MEANS.

LSD TEST

Figure 32 is a visual presentation of the summary and analysis of time to onset of meaningful pain relief presented in Table 58 A. The median time to onset of meaningful pain relief was shortest in the 0.001 mg NTX (lowest-dose) combination treatment group. The placebo and the 0.01 mg NTX combination treatment groups had the lowest number of subjects who reached meaningful pain relief.

Figure 33 is a visual presentation of the summary and analysis of time to onset of analgesia presented in Table 58B. The median time to onset of analgesia was shortest in the 0.001 mg NTX and 0.1 mg NTX combination treatment groups. The placebo treatment group had the lower number of subjects who reached analgesia.

Table 58A

Efficacy Results — Results of Time to Onset of Relief Safet Patients

P-VALUES FOR TIME TO EVENT ARE FROM THE LOG RANK TEST.

P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM THE LIKELIHOOD RATIO CHI-SQUARE TEST.

Table 58B

Efficacy Results - Results of Analgesia

P-VALUES FOR TIME TO EVENT ARE FROM THE LOG RANK TEST.

P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM THE LIKELIHOOD - RATIO CHI-SQUARE TEST.

Table 59 summarizes the results of the time to remedication (see also Figure 34). The placebo and the 1.0 mg NTX combination treatment groups had the shortest median time to remedication and the 0.1 mg NTX and the 0.001 NTX combination treatment groups had the longest median time to remedication.

Table 60 summarizes the results of the percent of patients remedicating. The percentage of patients remedicating was comparable across all treatment groups, except that the 0.001 mg NTX combination group had a lower percentage of patients remedicating.

Table 59

Efficacy Results - Time to Rescue Medication

(Safety Patients)

NOTE: MEDIAN TIME AND ITS CONFIDENCE MTERVAL ARE ESTIMATED USMG KAPLAN-MEIER METHOD. LOG-RANK AND WILCOXON TESTS ARE USED TO TEST THE EQUALITY OF KAPLAN-MEIER SURVIVAL FUNCTIONS OVER DIFFERENT TREATMENT GROUPS.

Table 60

Efficacy Results Percent of Patients Remedicating Safet Patients

P-VALUES FOR TIME TO EVENT ARE FROM THE LOG RANK TEST.

Figure 35 is a visual presentation of the mean pain relief scores presented in Table 61. The mean pain relief score for the placebo treatment group was less than those for the active treatment groups (HC/APAP alone or in combination with NTX). There was separation between placebo and the active treatment groups from 1 hour to 5 hours of the 8 hour study period. Highest pain relief scores were observed for the 0.001 mg NTX combination group (Figure 35).

Table 61

Efficacy Results ^■ •Means and Standard Deviations for the Pain Relief Scores (Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAM RELIEF SCALE WAS: 0-NONE, 1=A LITTLE, 2=SOME, 3=A LOT, AND 4 - COMPLETE.

LSD TEST (MEANMG, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 61 (Continued) Efficacy Results - Means and Standard Deviations for the Pain Relief Scores Safety Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAM RELIEF SCALE WAS: 0=NONE, 1=A LITTLE, 2=SOME, 3=A LOT, AND 4 = COMPLETE.

Table 61 (Continued)

Efficacy Results • Means and Standard Deviations for the Pain Relief Scores (Safety Patients)

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 61 (Continued)

Efficacy Results ^■ Means and Standard Deviations for the Pain Relief Scores Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 61 (Continued)

Efficacy Results - Means and Standard Deviations for the Pain Relief Scores Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 61 (Continued) Efficacy Results - Means and Standard Deviations for the Pain Relief Scores

(Safet Patients)

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 61 (Continued) Efficacy Results - Means and Standard Deviations for the Pain Relief Scores Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAM RELIEF SCALE WAS: 0=NONE, 1=A LITTLE, 2-SOME, 3=A LOT, AND 4 = COMPLETE.

Table 61 (Continued)

Efficacy Results Means and Standard Deviations for the Pain Relief Scores Safet Patients)

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 61 (Continued)

Efficacy Results • Means and Standard Deviations for the Pain Relief Scores (Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 61 (Continued)

Efficacy Results ■ •Means and Standard Deviations for the Pain Relief Scores Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 61 (Continued) Efficacy Results — Means and Standard Deviations for the Pain Relief Scores

(Safety Patients)

MEANS GIVEN ARE LEAST SQUARE MEANS.

(Safety Patients)

MEANS GIVEN ARE LEAST SQUARE MEANS.

The mean categorical pain intensity difference (PID) scores are presented in Table 62 and Figure 36. The mean PID scores for placebo treatment groups decreased over the first 2 hours and then were generally flat, while the mean PFD scores first increase, then decreased over time for the active treatment groups (HC/APAP alone or in combination with NTX). The hourly mean scores for the HC/APAP alone and the HC/APAP NTX combination treatment groups were higher than the mean PID scores for the placebo group at each hourly assessment time from 1-8 hours. Highest pain relief as measured by mean PID scores was observed for the 0.001 NTX combination treatment group.

Table 62

Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients)

MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAM MTENSITY WAS: 0 = NONE, 1 = MILD, 2 = MODERATE, AND 3 - SEVERE.

LSD TEST

Table 62 (Continued)

Efficacy Results Means and Standard Deviations for the Categorical PID Scores Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAM MTENSITY WAS: 0 = NONE, 1 = MILD, 2 = MODERATE, AND 3 = SEVERE.

LSD TEST

Table 62 (Continued) Efficacy Results - Means and Standard Deviations for the Categorical PID Scores

(Safety Patients)

MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAM MTENSITY WAS: 0 = NONE, 1 - MILD, 2 = MODERATE, AND 3 = SEVERE.

LSD TEST

(Safety Patients)

MEANS GIVEN ARE LEAST SQUARE MEANS.

LSD TEST

Table 62 (Continued) Efficacy Results - Means and Standard Deviations for the Categorical PID Scores Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

LSD TEST

(MEANMG, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGMFICANT).

MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAM MTENSITY WAS: 0 = NONE, 1 = MELD, 2 = MODERATE, AND 3 = SEVERE.

LSD TEST

(Safety Patients)

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 62 (Continued)

Efficacy Results Means and Standard Deviations for the Categorical PED Scores Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAM MTENSITY WAS: 0 = NONE, 1 = MILD, 2 - MODERATE, AND 3 = SEVERE.

LSD TEST

Table 62 (Continued) Efficacy Results — Means and Standard Deviations for the Categorical PID Scores

(Safety Patients)

MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAM MTENSITY WAS: 0 = NONE, 1 = MILD, 2 = MODERATE, AND 3 = SEVERE;

LSD TEST

(Safety Patients)

MEANS GIVEN ARE LEAST SQUARE MEANS.

LSD TEST

Table 62 (Continued) Efficacy Results - Means and Standard Deviations for the Categorical PED Scores Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

LSD TEST

Table 62 (Continued)

Efficacy Results - Means and Standard Deviations for the Categorical PDD Scores Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

LSD TEST

Tables 63A and 63B present the mean peak (maximum) pain relief (MAXPAR) and mean peak pain intensity difference (PEAKPID) scores, respectively. The mean MAXPAR scores presented in Table 63A varied among treatment groups. The mean MAXPAR score was highest for the 0.001 mg NTX combination treatment group compared to all other groups. The mean scores for the other NTX combination treatment groups were generally comparable to the mean score for the HC/APAP alone treatment group, which in turn, was greater than the mean score for the placebo group. The mean PEAKPID scores presented in Table 63B varied among treatment groups, and were greater for the HC/APAP alone or HC/APAP - NTX combination treatment groups compared to the placebo group.

Compared to all other groups, the mean PEAKPID scores were highest for the 0.001 mg NTX combination treatment group.

Table 63A Efficacy Results - Means and Standard Deviations for the MAXPAR

(Safety Patients)

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 63B Efficacy Results - Means and Standard Deviation for the Categorical PEAKPID Safety Patients)

MEANS GIVEN ARE LEAST SQUARE MEANS.

LSD TEST

Table 64 presents the summary and analysis of global evaluations. The placebo treatment group had the highest number of subjects who had "poor" global evaluation scores. The 0.001 mg NTX combination treatment group had the highest number of subjects with a total of "excellent", "very good" and "good" global evaluation scores. The profiles of the global evaluation scores are based on subjects' evaluations.

Table 64

Efficacy Results - Patient Global Assessments

(Safety Patients)

OVERALL P-VALUE (AND ANY PAIRWISE RESULTS) FROM THE COCHRAN-MANTEL-HAENSZEL TEST FOR ROW MEAN SCORES.

The majority of adverse events reported were categorized as digestive (nausea or vomiting) or nervous system (dizziness or sedation) as further shown in Tables 65 A and 65B. Figure 37 represents a summary of exemplary adverse side effects that maybe attenuated according to methods and compositions of the invention.

Table 65A

Summary of Adverse Events by Body System . and Preferred Term

(Safety Patients)

Body System Total No. Of Total Severity

Adverse Events No. Of Subjects No. Of

Treatment Subj ects W/Event Events Mild Moderate Severe

ALL BODY SYSTEMS A) PLACEBO 50 14(28%) 14 (28%) 4 (8%) 8 (16%) 2 (4%)

B) HC/APAP 50 15(30%) 15 (30%) 3 (6%) 12 (24%) 0 (0%)

C) W/NTX 1 mg 50 23(46%) 23 (46%) 5 (10%) 13 (26%) 5 (10%)

D) W/NTX O.l mg 50 21(42%) 21 (42%) 6 (12%) 13 (26%) 2 (4%)

E) W/NTX 0.01 mg 50 21(42%) 21 (42%) 7 (14%) 12 (24%) 2 (4%)

F) W/NTX 0.001 mg 50 20(40%) 20 (40%) 3 (6%) 16 (32%) 1 (2%)

TOTAL 300 114(38%) 114 (38%)

EAR AND LABRYRINTH A) PLACEBO 50 0(0%)

DISORDERS B) HC/APAP 50 0(0%)

C) W/NTX 1 mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX 0.0 l mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

TINNITUS

1 (2%) 0 (0%) 1 (2%) 0 (0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTMG MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued)

Summary of Adverse Events by Body Systen L and Preferred Term

(Safety Patients)

Body System Total No. Of Total Severity

Adverse Events No. Of - Subjects No. Of

Treatment Subjects W/Event Events Mild Moderate Severe

EYE DISORDERS A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 1(2%) 1 i (2%) 0 (0%) 0 (0%) 1 (2%)

D) W/NTX O.l g 50 0(0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

VISION BLURRED A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 1(2%) 1 (2%) 0 (0%) 0 (0%) 1 (2%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

GASTROINTESTINAL A) PLACEBO 50 10(20%) 10 (20%) 3 (6%) 7 (14%) 0 (0%)

DISORDERS B) HC/APAP 50 14(28%) 14 (28%) 3 (6%) 11 (22%) 0 (0%)

C) W/NTX l mg 50 17(34%) 17 (34%) 4 (8%) 10 (20%) 3 (6%)

D) WNTX O.l mg 50 16(32%) 16 (32%) 3 (6%) 11 (22%) 2 (4%)

E) W/NTX O.Ol g 50 17(34%) 17 (34%) 6 (12%) 9 (18%) 2 (4%)

F) W/NTX 0.001 mg 50 18(36%) 18 (36%) 5 (10%) 12 (24%) 1 (2%)

TOTAL 300 92(31%)

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTMG MORE THAN ONE

EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued)

Summary of Adverse Events by Body System and Preferred Term (Safety Patients)

Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events Mild Moderate Severe

ABDOMINAL A) PLACEBO 50 0(0%)

DISTENSION B) HC/APAP 50 1(2%)

C) W/NTX l mg 50 0(0%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

ABDOMINAL PAIN NOS A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 0(0%)

D) W/NTX O.l mg 50 1(2%) 1 (2%) 0

E) W/NTX O.Ol mg 50 0(0%)

F) W NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

ABDOMINAL PAIN A) PLACEBO 50 0(0%)

UPPER B) HC/APAP 50 0(0%)

C) W NTX l mg 50 1(2%) 1 (2%) 0 %) 0 (0%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 1(2%) 1

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 2(1%)

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTMG MORE THAN ON EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued)

Summary of Adverse Events by Body System and Preferred Term (Safety Patients)

Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events Mild Moderate Severe

CONSTIPATION A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX 1 mg 50 0(0%)

D) W/NTX O.l mg 50 1(2%) ^■o) 0 (0%) 1 (2%) 0 (0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/ΝTX 0.001 mg 50 1(2%) 1 (2%) 0 (0%) 0 fw-

TOTAL 300 2(1%)

DIARRHEA NOS A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX 1 mg 50 1(2%)

D) W/NTX 0.1 mg 50 0(0%)

E) W/NTX 0.01 mg 50 0(0%)

F) W/NTX 0.001 mg 50 1(2%) 0 (0%) 0

TOTAL 300 2(1%)

DYSPEPSIA A) PLACEBO 50 1(2%) 1 (2%) 0

B) HC/APAP 50 0(0%)

W/NTX 1 mg 50 0(0%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX 0.01 mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

Table 65A (Continued)

Summary of Adverse Events by Body System and Preferred Term

(Safety Patients)

Body System Total No. Of Total Severity

Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events Mild Moderate Severe

FLATULENCE A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 2(1%) •

NAUSEA A) PLACEBO 50 9(18%) 9 (18%) 3 (6%) 6 (12%) 0 (0%)

B) HC/APAP 50 14(28%) 14 (28%) 3 (6%) 11 (22%) 0 (0%)

C) W/NTX l mg 50 17(34%) 17 (34%) 5 (10%) 9 (18%) 3 (6%)

D) W/NTX O.l mg 50 15(30%) 15 (30%) 6 (12%) 9 (18%) 0 (0%)

E) W/NTX O.Ol mg 50 12(24%) 12 (24%) 5 (10%) 6 (12%) 1 (2%)

F) W/NTX 0.001 mg 50 17(34%) 17 (34%) 4 (8%) 13 (26%) 0 (0%)

TOTAL 300 84(28%)

SORE THROAT NOS A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 0(0%)

D) W/ΝTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

Table 65A (Continued)

Summary of Adverse Events by Body System and Preferred Term

(Safety Patients) 1

Body System Total No. Of ' Total Severity

Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events Mild Moderate Severe

VOMITING NOS A) PLACEBO 50 3(6%) 3 (6%) 1 (2%) 2 (4%) _, 0 (0%)

B) HC/APAP 50 6(12%) 6 (12%) 1 (2%) 5 (10%) 0 (0%)

C) W/NTX l mg 50 4(8%) 4 (8%) 0 (0%) 4 (8%) 0 (0%)

D) W/NTX O.l mg 50 7(14%) 7 (14%) 2 (4%) 3 (6%) 2 (4%)

E) W/NTX O.Ol mg 50 8(16%) 8 (16%) 2 (4%) 5 (10%) 1 (2%)

F) W/NTX 0.001 mg 50 4(8%) 4 (8%) 0 (0%) 4 (8%) 0 (0%)

TOTAL 300 32(11%)

GENERAL DISORDERS AND ADMTN. SITE CONDITIONS

A) PLACEBO 50 0(0%)

B) HC/APAP 50 1(2%) 1 (2%) 1 (2%) 0 (0%) 0 (0%)

C) W/NTX l mg 50 1(2%) 1 (2%) 0 (0%) 0 (0%) . 1 (2%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

F) W/ΝTX 0.001 mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

TOTAL 300 4(1%)

APPLICATION SITE A) PLACEBO 50 0(0%)

BLEEDING B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 1(2%) 1 (2%) 0 (0%) 0 (0%) 1 (2%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

Table 65A (Continued)

Summary of Adverse Events by Body System and Preferred Term (Safety Patients)

Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events Mild Moderate Severe

FATIGUE A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 0(0%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 1(2%) 1 (2%) 0

TOTAL 300 1(<1%)

PYREXIA A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 0(0%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 1(2%) 1 (2%) 0

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

RIGORS A) PLACEBO 50 0(0%)

B) HC/APAP 50 1(2%) 1 (2%) 1 0 (0%) 0

C) W/NTX l mg 50 0(0%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

Table 65A (Continued)

Summary of Adverse Events by Body System and Preferred Term (Safety Patients)

Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events Mild Moderate Severe

INJURY AND POISONING A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 1(2%) 0 (0%) 0

D) W NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%) TOTAL 300 1(<1%)

ABRASION NOS A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 1(2%) 1 (2%) 1 (2%) 0 (0%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%) TOTAL 300 1(<1%)

INVESTIGATIONS A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 1(2%) 0 (0%) 0

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%) TOTAL 300 1(<1%)

Table 65A (Continued)

Summary of Adverse Events by Body System and Preferred Term (Safety Patients)

Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events Mild Moderate Severe

BLOOD PRESSURE A) PLACEBO 50 0(0%)

INCREASED B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 1(2%) 0 (0%) 0 (0%)

D) W/NTX O.l mg 50 0(0%)

E) W/ΝTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

MUSCULOSKELETAL, A) PLACEBO 50 0(0%)

CONNECT. TISSUE AND B) HC/APAP 50 0(0%)

BONE DISORDERS C) W/ΝTX l mg 50 0(0%)

D) W/NTX O.l mg 50 1(2%) 0 (0%) 0 (0%)

E) W/ΝTX O.Ol mg 50 0(0%)

F) W ΝTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

NECK PAIN A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 0(0%)

D) W/NTX O.l mg 50 1(2%) 0 (0%) 0 (0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

Table 65A (Continued)

Summary of Adverse Events by Body System i and Preferred Term

(Safety Patients)

Body System Total No. Of Total Severity

Adverse Events No. Of Subjects No, . Of

Treatment Subjects W Event Events ] vlild Moderate Severe

NERVOUS SYSTEM A) PLACEBO 50 6(12%) 6 (12%) 2 (4%) 2 (4%) 2 (4%)

DISORDERS B) HC/APAP 50 6(12%) 6 (12%) 2 (4%) 4 (8%) 0 (0%)

C) W/NTX l mg 50 8(16%) 8 (16%) 2 (4%) 5 (10%) 1 (2%)

D) W/NTX O.l mg 50 11(22%) 11 (22%) 6 (12%) 5 (10%) 0 (0%)

E) W/NTX O.Ol mg 50 4(8%) 4 (8%) 1 (2%) 2 (4%) 1 (2%)

F) W/NTX 0.001 mg 50 10(20%) 10 (20%) 2 (4%) 8 (16%) 0 (0%)

TOTAL 300 45(15%)

DIZZINESS EXC. A) PLACEBO 50 2(4%) 2 (4%) 1 (2%) 1 (2%) 0 (0%)

VERTIGO B) HC/APAP 50 2(4%) 2 (4%) 1 (2%) 1 (2%) 0 (0%)

C) W/NTX l mg 50 7(14%) 7 (14%) 3 (6%) 3 (6%) 1 (2%)

D) W/NTX O.l mg 50 6(12%) 6 (12%) 4 (8%) 2 (4%) 0 (0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 5(10%) 5 (10%) 2 (4%) 3 (6%) 0 (0%)

TOTAL 300 22(7%)

HEADACHE NOS A) PLACEBO 50 2(4%) 2 (4%) 0 (0%) 1 (2%) 1 (2%)

B) HC/APAP 50 1(2%) 1 (2%) 1 (2%) 0 (0%) 0 (0%)

C) W/NTX l mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

D) W/NTX O.l mg 50 1(2%) 1 (2%) 1 (2%) 0 (0%) 0 (0%)

E) W/NTX O.Ol mg 50 2(4%) 2 (4%) 1 (2%) 1 (2%) 0 (0%)

F) W ΝTX 0.001 mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

TOTAL 300 8(3%)

Table 65A (Continued) 1

Summary of Adverse Events by Body System and Preferred Term

(Safety Patients)

Body System Total No. Of Total Severity

Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events ] Mild Moderate Severe

MIGRAINE NOS A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 0(0%)

D) W/NTX O.l mg 50 0(0%)

E) W/ΝTX O.Ol g 50 1(2%) 1 (2%) 0 (0%) 0 (0%) 1 (2%)

F) W ΝTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

SEDATION A) PLACEBO 50 1(2%) 1 (2%) 1 (2%) 0 (0%) 0 (0%)

B) HC/APAP 50 2(4%) 2 (4%) 1 (2%) 1 (2%) 0 (0%)

C) W/ΝTX l mg 50 0(0%)

D) W/NTX O.l mg 50 2(4%) 2 (4%) 0 (0%) 2 (4%) 0 (0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/ΝTX 0.001 mg 50 3(6%) 3 (6%) 0 (0%) 3 (6%) 0 (0%)

TOTAL 300 8(3%)

SYNCOPE A) PLACEBO 50 1(2%) 1 (2%) 0 (0%) 0 (0%) 1 (2%)

B) HC/APAP 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

C) W ΝTX l mg 50 2(4%) 2 (4%) 0 (0%) 2 (4%) 0 (0%)

D) W/NTX O.l mg 50 2(4%) 2 (4%) 1 (2%) 1 (2%) 0 (0%)

E) W/ΝTX 0.0 l mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

F) W/NTX 0.001 mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

TOTAL 300 8(3%)

Table 65A (Continued)

Summary of Adverse Events by Body System and Preferred Term (Safety Patients)

Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events Mild Moderate Severe

TREMOR NEC A) PLACEBO 50 0(0%)

B) HC/APAP 50 1(2%) 0 (0%)

C) W/NTX 1 mg 50 0(0%)

D) W/NTX O.l mg 50 1(2%) 0 (0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 2(1%)

PHYCHIATRIC A) PLACEBO 50 0(0%) DISORDERS B) HC/APAP 50 1(2%) 1 { -'/o) 0 0

C) W/NTX 1 mg 50 2(4%) 2 ⁽Δ.°/~ 0 0

D) W/NTX O.l mg 50 0(0%)

E) W/NTX 0.01 mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 3(1%)

ANXIETY NEC A) PLACEBO 50 0(0%)

B) HC/APAP 50 1(2%) (0%) (0%)

C) W/NTX 1 mg 50 0(0%)

D) W/ΝTX O.l mg 50 0(0%)

E) W/NTX 0.01 mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

Table 65A (Continued)

Summary of Adverse Events by Body System and Preferred Term (Safety Patients)

Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events Mild Moderate Severe

CRYING A) PLACEBO 50 0(0%)

B) HC/APAP 50 1(2%) 1 (2%) 1 (2%) 0 (0%)

C) W/NTX l mg 50 0(0%)

D) W/NTX O.l mg 50 0(0%)

E) W/ΝTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

NERVOUSNESS A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/ΝTX l mg 50 2(4%) 2 (4%) 0 (0%)

D) W/NTX O.l mg 50 0(0%)

E) W ΝTX O.Ol mg 50 0(0%)

F) W/ΝTX 0.001 mg 50 0(0%)

TOTAL 300 2(1%) sNAL AND URINARY

SORDERS

0 (0%) 0 (0%)

TOTAL 300 1(<1%)

Table 65A (Continued)

Summary of Adverse Events by Body System and Preferred Term (Safety Patients)

Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events Mild Moderate Severe

DIFFICULTY TN A) PLACEBO ■50 0(0%)

MICTURITION B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 0(0%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 1(2%) 1 (2%) 0 (0%) 0 (0%)

F) W/ΝTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

RESPIRATORY, A) PLACEBO 50 0(0%)

THORACIC B) HC/APAP 50 1(2%) 0 (0%) (2%) 0 (0%)

AND MEDIASTlNAL C) W/NTX l mg 50 0(0%)

DISORDERS D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/ΝTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

RESPIRATORY A) PLACEBO 50 0(0%)

DISORDER NOS B) HC/APAP 50 1(2%) 0 (0%) 1 (2%) 0 (0%)

C) W/NTX l mg 50 0(0%)

D) W/ΝTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

Table 65A (Continued] 1

Summary of Adverse Events by Body System and Preferred Term

(Safety Patients)

Body System Total No. Of Total Severity

Adverse Events No. Of Subjects No. Of

Treatment Subj ects W/Event Events ] Mild Moderate Severe

SKIN AND A) PLACEBO 50 2(4%) 2 (4%) 1 (2%) 1 (2%) 0 (0%)

SUBCUTANEOUS TISSUE B) HC/APAP 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

DISORDERS C) W/ΝTX l mg 50 4(8%) 4 (8%) 0 (0%) 4 (8%) 0 (0%)

D) W/NTX O.l mg 50 4(8%) 4 (8%) 1 (2%) 3 (6%) 0 (0%)

E) W ΝTX O.Ol mg 50 4(8%) 4 (8%) 1 (2%) 3 (6%) 0 (0%)

F) W/NTX 0.001 mg 50 2(4%) 2 (4%) 0 (0%) 2 (4%) 0 (0%)

TOTAL 300 17(6%)

FACE OEDMA A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 0(0%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

PRURITUS ΝOS A) PLACEBO 50 2(4%) 2 (4%) 1 (2%) 1 (2%) 0 (0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 0(0%)

D) W/ΝTX O.l mg 50 2(4%) 2 (4%) 1 (2%) 1 (2%) 0 (0%)

E) W/NTX O.Ol mg 50 2(4%) 2 (4%) 1 (2%) 1 (2%) 0 (0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 6(2%)

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATEENTS REPORTMG MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued' >

Summary of Adverse Events by Body System and Preferred Term

(Safety Patients)

Body System Total No. Of Total Severity

Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events ] Mild Moderate Severe

SWEATING A) PLACEBO 50 0(0%)

INCREASED B) HC/APAP 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

C) W/NTX 1 mg 50 4(8%) 4 (8%) 0 (0%) 4 (8%) 0 (0%)

D) W/NTX O.l mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

E) W NTX 0.01 mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

F) W/NTX 0.001 mg 50 2(4%) 2 (4%) 0 (0%) 2 (4%) 0 . (0%)

TOTAL 300 9(3%)

URTICARIA NOS A) PLACEBO 50 0(0%) B) HC/APAP 50 0(0%) C) W/NTX 1 mg 50 0(0%)

D) W/NTX O.l mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

VASCULAR A) PLACEBO 50 1(2%) 1 (2%) 1 (2%) 0 (0%) 0 (0%)

DISORDERS B) HC/APAP 50 0(0%)

C) W/NTX 1 mg 50 4(8%) 4 (8%) 0 (0%) 3 (6%) 1 (2%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX 0.01 mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) 0 (0%)

F) W NTX 0.001 mg 50 1(2%) 1 (2%) 0 (0%) 1 (2%) Ό (0%)

TOTAL 300 7(2%)

Table 65A (Continued)

Summary of Adverse Events by Body System and Preferred Term (Safety Patients)

Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events Mild Moderate Severe

FLUSHING A) PLACEBO 50 1(2%) 0 (0%) 0 (0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 0(0%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 0(0%)

TOTAL 300 1(<1%)

HOT FLUSHES NOS A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 2(4%) 2 (4%) 0 (0%) 1 (2%)

D) W/NTX O.l mg 50 0(0%)

E) W/ΝTX O.Ol mg 50 0(0%)

F) W/ΝTX 0.001 mg 50 0(0%)

TOTAL 300 2(1%)

HYPERTENSION NOS A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 1(2%) 0 (0%) 0

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 1(2%) 0 (0%) 0

F) W NTX 0.001 mg 50 0(0%)

TOTAL 300 2(1%)

Table 65A (Continued)

Summary of Adverse Events by Body System and Preferred Term (Safety Patients)

Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events Mild Moderate Severe

PALLOR A) PLACEBO 50 0(0%)

B) HC/APAP 50 0(0%)

C) W/NTX l mg 50 2(4%) 2 (4%) 0 (0%) 0 (0%)

D) W/NTX O.l mg 50 0(0%)

E) W/NTX O.Ol mg 50 0(0%)

F) W NTX 0.001 mg 50 1(2%) 1 (2%) 0 (0%) 1 0 (0%)

TOTAL 300 3(1%)

Table 65B

Summary of Adverse Events by Body System and Preferred Term

(Safety Patients)

Body System Total No. Of ' Total Severity

Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events Mild Moderate Severe

NAUSEA A) PLACEBO 50 9(18%) 9 (18%) 3 (6%) 6 (12%) 0 (0%)

B) HC/APAP 50 14(28%) 14 (28%) 3 (6%) 11 (22%) 0 (0%)

C) W/NTX 1 mg 50 17(34%) 17 (34%) 5 (10%) 9 (18%) 3 (6%)

D) W/NTX O.l mg 50 15(30%) 15 (30%) 6 (12%) 9 (18%) 0 (0%)

E) W ΝTX 0.01 mg 50 12(24%) 12 (24%) 5 (10%) 6 (12%) 1 (2%)

F) W/NTX 0.001 mg 50 17(34%) ^' 17 (34%) 4 (8%) 13 (26%) 0 (0%)

TOTAL 300 84(28%)

VOMITING NOS A) PLACEBO 50 3(6%) 3 (6%) 1 (2%) 2 (4%) 0 (0%)

B) HC/APAP 50 6(12%) 6 (12%) 1 (2%) 5 (10%) 0 (0%)

C) W/NTX 1 mg 50 4(8%) 4 (8%) 0 (0%) 4 (8%) 0 (0%)

D) W/NTX O.l mg 50 7(14%) 7 (14%) 2 (4%) 3 (6%) 2 (4%)

E) W/NTX 0.01 mg 50 8(16%) 8 (16%) 2 (4%) 5 (10%) 1 (2%)

F) W/NTX 0.001 mg 50 4(8%) 4 (8%) 0 (0%) 4 (8%) 0 (0%)

TOTAL 300 32(11%)

DIZZINESS EXC. A) PLACEBO 50 2(4%) 2 (4%) 1 (2%) 1 (2%) 0 (0%)

VERTIGO B) HC/APAP 50 2(4%) 2 (4%) 1 (2%) 1 (2%) 0 (0%)

C) W/NTX 1 mg 50 7(14%) 7 (14%) 3 (6%) 3 (6%) 1 (2%)

D) W/NTX O.l mg 50 6(12%) 6 (12%) 4 (8%) 2 (4%) 0 (0%)

E) W/ΝTX 0.01 mg 50 0(0%)

F) W/NTX 0.001 mg 50 5(10%) 5 (10%) 2 (4%) 3 (6%) 0 (0%)

TOTAL 300 22(7%)

Table 65B (Continued)

Continued: Summary of Adverse Events by Body System and Preferred Term (Safety Patients)

Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of

Treatment Subjects W/Event Events Mild Moderate Severe

SEDATION A) PLACEBO 50 1(2%) . 1 (2%) 1 (2%) 0 0

B) HC/APAP 50 2(4%) 2 (4%) 1 (2%) 1 (2%) 0

C) W/NTX l mg 50 0(0%)

D) W NTX O.l mg 50 2(4%) 2 (4%) 0 (0%) 2 0

E) W/NTX O.Ol mg 50 0(0%)

F) W/NTX 0.001 mg 50 3(6%) 3 (6%) 0 (0%) 3 0

TOTAL 300 8(3%)

EXAMPLE 6

An additional clinical study, this one using hydrocodone with acetaminophen (instead of morphine) alone and in combination with naltrexone, was designed substantially the same as that described in Example 2, with the following differences: (1) six treatment groups with four different doses of NTX (1.0 mg, 0.1 mg, 0.01 mg and 0.001 mg) in combination with hydrocodone 5 mg/acetaminophen 500 mg versus hydrocodone 5 mg/acetaminophen 500 mg (HC/APAP) alone, and versus placebo alone in subjects with moderate to severe pain in a postsurgical dental pain clinical study; (2) the primary efficacy variable was the categorical sum of pain intensity difference scores through 4 hours (SPED-4); and (3) the secondary efficacy variables were: 4, 6 and 8 hour total pain relief scores (TOTPAR-4, TOTPAR-6 and TOTPAR- 8); categorical 6 and 8 hour sum of pain intensity difference scores (SPID-6 and SPID-8); categorical pain intensity difference (PED) scores through 8 hours; pain relief (PR) scores through 8 hours; peak categorical PED scores through 8 hours (PEAKPID); peak pain relief score through 8 hours (TOTPAR); time to onset of analgesia (i.e., at least a one category improvement in the pain intensity score); time to onset of meaningful pain relief; time to taking backup medication; percent of patients taking backup medication; and patient overall evaluation of study drug.

The results for females and males separately are shown in the following tables and figures.

A total of 300 subjects were randomized; all 300 subjects were deemed evaluable as shown in Table 66. Table 61 shows the number of female and male subjects separately for each treatment group.

Table 66 Patient Enrollment and Evaluabilit

Table 61 Patient Characteristics (Safety Patients)

P-VALUE FROM A LIKELIHOOD RATIO CHI-SQUARE TEST. FOR RACE, NON-CAUCASIANS WERE COMBINED AS ONE CATEGORY FOR THE ANALYSIS.

The total pain relief scores (TOTPAR) results for 4, 6 and 8 hours are summarized in Tables 68A for females and 68B for males.

In females, all of the active treatment groups exhibited mean TOTPAR scores that were higher than the placebo group score. The HC/APAP alone treatment group had mean TOTPAR scores that were higher than the scores for the four NTX combination groups.

In males, all of the active treatment groups exhibited mean TOTPAR scores that were higher than the placebo group score. Both the 0.1 mg NTX and 0.001 mg

NTX combination treatment groups had higher mean TOTPAR scores than the HC/APAP alone group. The 0.001 mg NTX combination group had the highest mean

TOTPAR scores for the 4, 6 and 8 hours.

Table 68A Efficacy Results - Means and Standard Deviations for TOTPARs (Trapezoidal Method)

Female Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 68A (Continued) Efficacy Results - Means and Standard Deviations for TOTPARs (Trapezoidal Method)

Female Safety Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTE

LSD TEST (MEANMG, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGMFICANT).

Female Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 68B Efficacy Results - Means and Standard Deviations for TOTPARs (Trapezoidal Method)

Male Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 68B (Continued) Efficacy Results - Means and Standard Deviations for TOTPARs (Trapezoidal Method)

Male Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 68B (Continued)

Efficacy Results ^■ -Means and Standard Deviations for TOTPARs (Trapezoidal Method) Male Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

LSD TEST (MEANING, PALRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

The sum of pain intensity difference scores (SPED) results at 4, 6 and 8 hours are summarized in Tables 69A for females and 69B for males and the 4 hour SPID results are shown in Figures 38B for females and 38C for males. In females, all of the active treatment groups exhibited mean SPED scores that were higher than the placebo group score. The HC/APAP along group had the highest mean SPED scores throughout the 4, 6 and 8 hours. In males, all of the active treatment groups exhibited mean SPED scores that were higher than the placebo group score. Both the 0.1 mg NTX and the 0.001 mg NTX combination groups had higher mean SPED scores than the HC/APAP alone group. The 0.001 mg NTX combination group had the highest mean SPED scores for the 4, 6 and 8 hours.

Table 69A Efficacy Results - Means and Standard Deviations for the SPIDS (Trapezoidal Method)

Female Safety Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PATRWTSE RESULTS ARE FROM FISHER'S PROTECTE

Table 69A (Continued) Efficacy Results - Means and Standard Deviations for the SPIDS (Trapezoidal Method)

Female Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Female Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 69B

Efficacy Results ^■ • Means and Standard Deviations for the SPIDS (Trapezoidal Method) Male Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 69B (Continued)

Efficacy Results Means and Standard Deviations for the SPEDS (Trapezoidal Method) Male Safet Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 69B (Continued)

MEANS GIVEN ARE LEAST SQUARE MEANS.

Tables 70A for females and 70B for males summarize the results of the time to onset of analgesia. In females, the 0.1 mg NTX and the 0.001 mg NTX combination groups had the shortest median times to onset of analgesia. In males, the placebo, HC/APAP alone, and 0.001 mg NTX combination groups had the shortest median times to onset of analgesia. In females, the 0.1 mg NTX and the 0.001 mg NTX combination groups had the highest percentage of patients with analgesia. All active treatment groups had a higher percentage of patients with analgesia than the placebo group. In males, the 0.001 mg NTX combination group had the highest percentage of patients with analgesia.

Table 70A

Efficacy Results •Results of Time to Analyses and Percent of Patients with Events Safet Patients Female Patients

P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM THE LIKELfflQOD-RATIO CHI-SQUARE TEST. P-VALUES FOR TIME TO EVENT ARE FROM THE LONG RANK TEST.

Table 70A (Continued) Efficacy Results — Results of Time to Analyses and Percent of Patients with Events Safety Patients Female Patients

P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM THE LIKELIHOOD-RATIO CHI-SQUARE TEST. P-VALUES FOR TIME TO EVENT ARE FROM THE LONG RANK TEST.

labie tun Efficacy Results - Results of Time to Analyses and Percent of Patients with Events

(Safety Patients) Male Patients

Table 70B (Continued)

Efficacy Results ^■ •Results of Time to Analyses and Percent of Patients with Events Safet Patients Male Patients

Tables 71A for females and 71B for males summarize the results of the time to onset of meaningful pain relief. In females, the time to onset of relief was shortest in the 0.1 mg NTX and the 0.001 mg NTX combination groups. In males, the time to onset of relief was shortest in the HC/APAP alone, 0.1 mg NTX and the 0.001 mg NTX combination groups. In females, the 0.001 mg NTX combination group had the highest percentage of patients reporting relief. In males, the placebo group had the lowest percentage of patients reporting relief and the 0.001 mg NTX combination group had the highest percentage reporting relief.

Table 71A

Efficacy Results — Results of Time Onset of Meaningful Pain Relief

(Safety Patients Female Patients

P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM THE LIKELIHOOD-RATIO CHI-SQUARE TEST. P-VALUES FOR TIME TO EVENT ARE FROM THE LOG RANK TEST.

Table 71A (Continued)

Efficacy Results - Results of Time Onset of Meaningful Pain Relief

(Safet Patients) Female Patients

Table 7 IB

Efficacy Results -Results of Time Onset of Meaningful Pain Relief Safet Patients Male Patients

P-VALUES FOR TIME TO EVENT ARE FROM THE LOG RANK TEST.

Table 7 IB (Continued)

Tables 72 A for females and 72B for males summarize the results of the time to remedication (see also Figures 39A for females and 39B for males). In females, the placebo group had the shortest median time to remedication and the 0.1 mg NTX treatment group had the longest median time to remedication. In males, the placebo and 1.0 mg NTX combination groups had the shortest median times to remedication and the 0.001 mg NTX combination group had the longest median time to remedication.

Tables 73A for females and 73B for males summarize the results of the percent of patients remedicating. In females, the percentage of patients remedicating was comparable across all treatment groups. In males, the 0.1 mg NTX and the 0.001 mg NTX combination groups had the lowest percentages of patients remedicating.

Table 72A

Efficacy Results - Time to Rescue Medication

(Safet Patients) Female Patients

P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM FISHER'S EXACT TEST.

Table 72B

Efficacy Results - Time to Rescue Medication

(Safety Patients) Male Patients

P-VALUES FOR TIME TO EVENT ARE FROM THE LOG RANK TEST.

Table 73A

Efficacy Results Percent of Patients Remedicating

Intent-To-Treat Population, Female Patients

P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM FISHER'S EXACT TEST.

Table 73B

Efficacy Results Percent of Patients Remedicating

Intent-To-Treat Po ulation, Male Patients

P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM FISHER'S EXACT TEST.

Tables 74A for females and 74B for males summarize the results of the pain relief (PR) scores, and Tables 74C for females and 74D for males summarize the MAXPAR scores. In females, the placebo group had the lowest mean pain relief scores from 30 minutes to 5 hours. In males, the 0.001 mg NTX combination group had the highest mean pain relief scores from 15 minutes to 8 hours. In females, the 1.0 mg NTX and the 0.001 mg NTX combination groups had the highest mean peak relief scores. In males, the 0.001 mg NTX combination group had the highest mean peak relief scores.

Table 74A Efficacy Results - Means and Standard Deviations for the Pain Relief Scores (Safety Patients)

Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAM RELIEF SCALE WAS: 0 = NONE, 1 = A LITTLE, 2 = SOME, 3 = A LOT, AND 4 = COMPLETE.

Table 74A (Continued) Efficacy Results - Means and Standard Deviations for the Pain Relief Scores (Safety Patients)

Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAM RELIEF SCALE WAS: 0 = NONE, 1 - A LITTLE, 2 = SOME, 3 = A LOT, AND 4 = COMPLETE.

Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

LSD TEST (MEANMG, PAIRWISE P-VALUES ARE ONLY OBSERVED EF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAM RELIEF SCALE WAS: 0 = NONE, 1 = A LITTLE, 2 = SOME, 3 = A LOT, AND 4 - COMPLETE.

LSD TEST (MEANMG, PAIRWISE P-VALUES ARE ONXY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAM RELIEF SCALE WAS: 0 = NONE, 1 = A LITTLE, 2 - SOME, 3 = A LOT, AND 4 = COMPLETE.

Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAM RELIEF SCALE WAS : 0 = NONE, 1 = A LITTLE, 2 = SOME, 3 = A LOT, AND 4 = COMPLETE.

Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAM RELIEF SCALE WAS: 0 - NONE, 1 = A LITTLE, 2 = SOME, 3 = A LOT, AND 4 = COMPLETE.

Table 74B Efficacy Results - Means and Standard Deviations for the Pain Relief Scores (Safety Patients)

Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 74B (Continued) Efficacy Results - Means and Standard Deviations for the Pain Relief Scores (Safety Patients)

Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

LSD TEST (MEANMG, PAIRWISE P-VALUES ARE ONLY OBSERVED EF THE OVERALL TREATMENT EFFECT IS SIGMFICANT).

Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 74C Efficacy Results - Means and Standard Deviations for MAXPAR (Safety Patients)

Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table74D Efficacy Results - Means and Standard Deviations for MAXPAR (Safety Patients)

Male Patients

MEANS GIVEN ARE BEST SQUARE MEANS.

THE PAM RELIEF SCALE WAS 0=NONE, 1=A LITTLE, 2=SOME, 3=A LOT, AMD 4= COMPLETE.

Tables 75A for females and 75B for males summarize the results of the pain intensity difference (PED) scores. In females, the placebo group had the lowest mean PHD scores from 45 minutes to 8 hours. All active treatment groups had higher mean PED scores than the placebo group. In males, the placebo group had the lowest mean PED scores from 30 minutes to 8 hours. The 0.001 mg NTX combination group had the highest mean PDD scores from 15 minutes to 8 hours.

Tables 75C for females and 75D for males summarize the PEAKPTD scores. In females, the placebo group had the lowest PEAKPID score and the 1.0 mg NTX and the 0.001 mg NTX combination groups had the highest PEAKPID scores. In males, the 0.001 mg NTX combination group had the highest PEAKPID score.

Table 75A Efficacy Results - Means and Standard Deviations for the Categorical PDD Scores

(Safety Patients) Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 75A (Continued) Efficacy Results - Means and Standard Deviations for the Categorical PED Scores

(Safety Patients) Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

(Safety Patients) Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 75A (Continued) Efficacy Results - Means and Standard Deviations for the Categorical PID Scores

(Safety Patients) Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 75A (Continued) Efficacy Results - Means and Standard Deviations for the Categorical PHD Scores

(Safety Patients) Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 75A (Continued) Efficacy Results - Means and Standard Deviations for the Categorical PDD Scores

(Safety Patients) Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

(Safety Patients) Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

(Safety Patients) Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

(Safety Patients) Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

(Safety Patients) Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED DF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

(Safety Patients) Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

(Safety Patients) Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 75B Efficacy Results - Means and Standard Deviations for the Categorical PED Scores

(Safety Patients) Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAERWISE RESULTS ARE FROM FISHER'S PROTECTED

Table 75B (Continued) Efficacy Results - Means and Standard Deviations for the Categorical PDD Scores

(Safety Patients) Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

LSD TEST (MEANMG, PAIRWISE P-VALUES ARE ONLY OBSERVED DF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

(Safety Patients) Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 75B (Continued) Efficacy Results - Means and Standard Deviations for the Categorical PED Scores

(Safety Patients) Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

(Safety Patients) Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

(Safety Patients) Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

(Safety Patients) Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

(Safety Patients) Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

(Safety Patients) Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

(Safety Patients) Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

(Safety Patients) Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

(Safety Patients) Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Table 75C Efficacy Results - Means and Standard Deviations for PEAKPID (Safety Patients)

Female Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

LSD TEST (MEANMG, PAERWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGMFICANT).

Table 75D Efficacy Results - Means and Standard Deviations for PEAK PDD (Safety Patients)

Male Patients

MEANS GIVEN ARE LEAST SQUARE MEANS.

Tables 76A for females and 76B for males present the summary and analysis of global assessments. In females, the placebo group had the highest percentage of "poor" assessments. The 0.1 mg NTX and the 0.001 mg NTX combination groups had the highest percentage of "good" to "excellent" ratings. In males, the placebo group had the highest percentage of "poor" assessments. The 0.001 mg NTX combination group had the highest percentage of "good" to "excellent" ratings.

Table 76A Efficacy Results - Patient Global Assessments (Safety Patients)

Female Patients

Table 76B Efficacy Results - Patient Global Assessments (Safety Patients)

Male Patients

The majority of adverse side effects (adverse events) reported were categorized as digestive (nausea or vomiting) or nervous system (dizziness or somnolence) as further shown above in Tables 77 A for females and 77B for males.

In females, the placebo group had the lowest incidence of nausea and vomiting. The 0.01 mg NTX combination group had the lowest incidence of dizziness. The placebo, 1.0 mg NTX and the 0.01 mg NTX combination groups had the lowest incidence of sedation.

In males, the HC/APAP alone group had the lowest incidence of nausea. The

HC/APAP alone and the 1.0 mg NTX combination groups had the lowest incidence of vomiting. The placebo, HC/APAP alone, and 0.01 mg NTX combination groups had the lowest incidence of dizziness. The 1.0 mg NTX, 0.1 mg NTX and 0.01 mg NTX combination groups had the lowest incidence of sedation.

Figures 40A for females and 40B for males represent a summary of exemplary adverse side effects according to methods and compositions of the invention.

Table 77A

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Female Patients

BODY SYSTEM TOTAL NO. OF NO. . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

ALL BODY SYSTEMS A) PLACEBO 28 11 (39%)

B) HC/APAP 34 13 (38%)

C) W/NTX 1 31 18 (58%)

D) W/NTX O.l mg 35 14 (40%)

E) W/NTX 0.01 mg 31 15 (48%)

F) W/NTX 0.001 30 15 (50%)

TOTAL 189 86 (46%)

GASTROINTESTINAL A) PLACEBO 28 8 (29%)

DISORDERS B) HC/APAP 34 13 (38%)

C) W/ΝTX 1 31 15 (48%)

D) W/NTX O.l mg 35 12 (34%)

E) W/NTX 0.01 mg 31 13 (42%)

F) W/NTX 0.001 30 15 (50%)

TOTAL 189 76 (40%)

Abdominal Distension A) PLACEBO 28 0 (0%)

B) HC/APAP 34 1 (3%)

C) W/ΝTX 1 31 0 (0%)

D) W/NTX O.l mg 35 0 (0%)

E) W/ΝTX 0.01 mg 31 0 (0%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Table 77A (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Female Patients

BODY SYSTEM TOTAL NO. OF NO. . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Abdominal Pain Nos A) PLACEBO 28 0 (0%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 1 (3%)

E) W/NTX O.Ol mg 31 0 (0%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Abdominal Pain Upper A) PLACEBO 28 0 (0%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 1 (3%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Constipation A) PLACEBO 28 0 (0%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 1 (3%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W/ΝTX 0.001 30 1 (3%)

TOTAL 189 2 (1%)

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATENTS REPORTMG MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77A (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Female Patients

BODY SYSTEM TOTAL NO. OF NO. . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Diarrhea Nos A) PLACEBO 28 0 (0%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 1 (3%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W/NTX 0.001 30 1 (3%)

TOTAL 189 2 (1%)

Dyspepsia A) PLACEBO 28 1 (4%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W/ΝTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Flatulence A) PLACEBO 28 0 (0%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 1 (3%)

D) W/NTX O.l mg 35 0 (0%)

E) W/ΝTX 0.01 mg 31 1 (3%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 2 (1%)

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTMG MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77A (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Female Patients

BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Nausea A) PLACEBO 28 7 (25%)

B) HC/APAP 34 13 (38%)

C) W/NTX 1 31 15 (48%)

D) W NTX O.l mg 35 12 (34%)

E) W/NTX 0.01 mg 31 10 (32%)

F) W/NTX 0.001 30 14 (47%)

TOTAL 189 71 (38%)

Vomiting Nos A) PLACEBO 28 2 (7%)

B) HC/APAP 34 6 (18%)

C) W/NTX 1 31 4 (13%)

D) W/NTX O.l mg 35 5 (14%)

E) W/NTX O.Ol mg 31 7 (23%)

F) W/NTX 0.001 30 3 (10%)

TOTAL 189 27 (14%)

GENERAL DISORDERS AND

ADMTN. SITE CONDITIONS A) PLACEBO 28 0 (0%)

B) HC/APAP 34 1 (3%)

C) W/NTX 1 31 1 (3%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 1 (3%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 3 (2%)

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATENTS REPORTMG MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77A (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Female Patients

BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Application Site Bleeding A) PLACEBO 28 0 (0%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 1 (3%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W NTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Pyrexia A) PLACEBO 28 0 (0%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 1 (3%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Rigors A) PLACEBO 28 0 (0%)

B) HC/APAP 34 1 (3%)

C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W/ΝTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Table 77A (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Female Patients

BODY SYSTEM TOTAL NO. OF NO . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

NERVOUS SYSTEM A) PLACEBO 28 4 (14%)

DISORDERS B) HC/APAP ^' 34 5 (15%)

C) W/NTX 1 31 4 (13%)

D) W/NTX O.l mg 35 7 (20%)

E) W/NTX 0.01 mg 31 4 (13%)

F) W/NTX 0.001 30 6 (20%)

TOTAL 189 30 (16%)

Dizziness exc. Vertigo A) PLACEBO 28 2 (7%)

B) HC/APAP 34 2 (6%)

C) W/NTX 1 31 4 (13%)

D) W/NTX O.l mg 35 5 (14%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W/ΝTX 0.001 30 4 (13%)

TOTAL 189 17 (9%)

Headache Nos A) PLACEBO 28 1 (4%)

B) HC/APAP 34 1 (3%)

C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 2 (6%)

F) W/ΝTX 0.001 30 0 (0%)

TOTAL 189 4 (2%)

Table 77A (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Female Patients

BODY SYSTEM TOTAL NO. OF NO, . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Migraine Nos A) PLACEBO 28 0 (0%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 1 (3%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Sedation A) PLACEBO 28 0 (0%)

B) HC/APAP 34 1 (3%)

C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 2 (6%)

E) W NTX 0.01 mg 31 0 (0%)

F) W/NTX 0.001 30 1 (3%)

TOTAL 189 4 (2%)

Syncope A) PLACEBO 28 1 (4%)

B) HC/APAP 34 1 (3%)

C) W/NTX 1 31 1 (3%)

D) W/NTX O.l mg 35 1 (3%)

E) W/NTX 0.01 mg 31 1 (3%)

F) W/NTX 0.001 30 1 (3%)

TOTAL 189 6 (3%)

Table 77A (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Female Patients

BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Tremor Nee A) PLACEBO 28 0 (0%)

B) HC/APAP 34 1 (3%)

C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

PSYCHIATRIC A) PLACEBO 28 0 (0%)

DISORDERS B) HC/APAP 34 1 (3%)

C) W/NTX 1 31 1 (3%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 2 (1%)

Anxiety Nee A) PLACEBO 28 0 (0%)

B) HC/APAP 34 1 (3%)

C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Table 77A (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Female Patients

BODY SYSTEM TOTAL NO. OF NO . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Crying A) PLACEBO 28 0 (0%)

B) HC/APAP 34 1 (3%)

C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W/ΝTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Nervousness A) PLACEBO 28 0 (0%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 1 (3%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W/ΝTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

RESPIRATORY, THORACIC A) PLACEBO 28 0 (0%)

AND MEDIASTINAL B) HC/APAP 34 1 (3%)

DISORDERS C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Table 77A (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Female Patients

BODY SYSTEM TOTAL NO. OF NO, . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Respiratory Disorder Nos A) PLACEBO 28 0 (0%)

B) HC/APAP 34 1 (3%)

C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

SKIN AND A) PLACEBO 28 1 (4%)

SUBCUTANEOUS TISSUE B) HC/APAP 34 1 (3%)

DISORDERS C) W/NTX 1 31 3 (10%)

D) W/NTX O.l mg 35 2 (6%)

E) W/NTX 0.01 mg 31 3 (10%)

F) W/NTX 0.001 30 1 (3%)

TOTAL 189 11 (6%)

Face Oedma A) PLACEBO 28 0 (0%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 0 (0%)

D) W/ΝTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 1 (3%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Table 77A (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Female Patients

BODY SYSTEM TOTAL NO. OF NO . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Pruritus Nos A) PLACEBO 28 1 (4%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 1 (3%)

E) W/NTX O.Ol mg 31 2 (6%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 4 (2%)

Sweating Increased A) PLACEBO 28 0 (0%)

Urticaria Nos A) PLACEBO 28 0 (0%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 1 (3%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Table 77A (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Female Patients

BODY SYSTEM TOTAL NO. OF NO. . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Vascular Disorders A) PLACEBO 28 1 (4%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 2 (6%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX 0.01 mg 31 0 (0%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 3 (2%)

Flushing A) PLACEBO 28 1 (4%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 0 (0%)

D) W/NTX O.l mg 35 0 (0%)

E) W NTX 0.01 mg 31 0 (0%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Hot Flushes Nos A) PLACEBO 28 0 (0%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 1 (3%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX O.Ol mg 31 0 (0%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Table 77A (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Female Patients

BODY SYSTEM TOTAL NO. OF NO. . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Hypertension Nos A) PLACEBO 28 0 (0%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 1 (3%)

D) W/NTX O.l mg 35 0 (0%)

E) W/NTX O.Ol mg 31 0 (0%)

F) W/NTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Pallor A) PLACEBO 28 0 (0%)

B) HC/APAP 34 0 (0%)

C) W/NTX 1 31 1 (3%)

D) W/NTX O.l mg 35 0 (0%)

E) W/ΝTX 0.01 mg 31 0 (0%)

F) W/ΝTX 0.001 30 0 (0%)

TOTAL 189 1 (1%)

Table 77B

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Male Patients

BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

ALL BODY SYSTEMS A) PLACEBO 22 3 (14%)

B) HC/APAP 16 2 (13%)

C) W/NTX 1 19 5 (26%)

D) W/NTX O.l mg 15 7 (47%)

E) W/NTX 0.01 mg 19 6 (32%)

F) W/ΝTX 0.001 20 5 (25%)

TOTAL 111 28 (25%)

EAR AND LABRYRTNTH A) PLACEBO 22 0 (0%)

DISORDERS B) HC/APAP 16 0 (0%)

C) W/ΝTX 1 19 1 (5%)

D) W/ΝTX O.l mg 15 0 (0%)

E) W/NTX O.Ol mg 19 0 (0%)

F) W/NTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

Tinnitus A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 1 (5%)

D) W/NTX O.l mg 15 0 (0%)

E) W/NTX 0.01 mg 19 0 (0%)

F) W/ΝTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

Table 77B (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Male Patients

BODY SYSTEM TOTAL NO. OF NO . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

EYE DISORDERS A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 1 (5%)

D) W/NTX O.l mg 15 0 (0%)

E) W ΝTX 0.01 mg 19 0 (0%)

F) W/NTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

Vision Blurred A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 1 (5%)

D) W/ΝTX O.l mg 15 0 (0%)

E) W/ΝTX 0.01 mg 19 0 (0%)

F) W/ΝTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

GASTROINTESTINAL A) PLACEBO 22 2 (9%)

DISORDERS B) HC/APAP 16 1 (6%)

C) W/NTX 1 19 2 (11%)

D) W/ΝTX O.l mg 15 4 (27%)

E) W/NTX O.Ol mg 19 4 (21%)

F) W/NTX 0.001 20 3 (15%)

TOTAL 111 16 (14%)

Table 77B (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Male Patients

BODY SYSTEM TOTAL NO. OF NO . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Abdominal Pain Upper A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 0 (0%)

D) W/NTX O.l mg 15 0 (0%)

E) W/NTX 0.01 mg 19 1 (5%)

F) W/NTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

Nausea A) PLACEBO 22 2 (9%)

B) HC/APAP 16 1 (6%)

C) W/NTX 1 19 2 (11%)

D) W/NTX O.l mg 15 3 (20%)

E) W/NTX 0.01 mg 19 2 (11%)

F) W/NTX 0.001 20 3 (15%)

TOTAL 111 13 (12%)

Sore Throat Nos. A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 0 (0%)

D) W/NTX O.l mg 15 0 (0%)

E) W/NTX 0.01 mg 19 1 (5%)

F) W/NTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

Table 77B (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Male Patients

BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Vomiting Nos A) PLACEBO 22 1 (5%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 0 (0%)

D) W/NTX O.l mg 15 2 (13%)

E) W/NTX 0.01 mg 19 1 (5%)

F) W/NTX 0.001 20 1 (5%)

TOTAL 111 5 (5%)

GENERAL DISORDERS AND

ADMIN. SITE CONDITIONS A) PLACEBO 22 0 (0%)

Fatigue A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/ΝTX 1 19 0 (0%)

D) W/ΝTX O.l mg 15 0 (0%)

E) W/NTX 0.01 mg 19 0 (0%)

F) W/NTX 0.001 20 1 (5%)

TOTAL 111 1 (1%)

Table 77B (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Male Patients

BODY SYSTEM TOTAL NO. OF NO . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

INJURY AND POISONING A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 1 (5%)

D) W/NTX O.l mg 15 0 (0%)

E) W/NTX 0.01 mg 19 0 (0%)

F) W/NTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

Abrasion Nos A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 1 (5%)

D) W/ΝTX O.l mg 15 0 (0%)

E) W/ΝTX 0.01 mg 19 0 (0%)

F) W/NTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

INVESTIGATIONS A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/ΝTX 1 19 1 (5%)

D) W/NTX O.l mg 15 0 (0%)

E) W/NTX 0.01 mg 19 0 (0%)

F) W/NTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

Table 77B (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Male Patients

BODY SYSTEM TOTAL NO. OF NO, . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Blood Pressure Increased A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 1 (5%)

D) W/NTX O.l mg 15 0 (0%)

E) W/NTX 0.01 mg 19 0 (0%)

F) W/NTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

MUSCULOSKELETAL A) PLACEBO 22 0 (0%)

CONNECT TISSUE AND B) HC/APAP 16 0 (0%)

BONE DISORDERS C) W/NTX 1 19 0 (0%)

D) W/NTX O.l mg 15 1 (7%)

E) W NTX O.Ol g 19 0 (0%)

F) W/NTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

Neck Pain A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 0 (0%)

D) W/NTX O.l mg 15 1 (7%)

E) W/NTX 0.01 mg 19 0 (0%)

F) W/NTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

Table 77B (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Male Patients

BODY SYSTEM TOTAL NO. OF NO . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

NERVOUS SYSTEM A) PLACEBO 22 2 (9%)

DISORDERS B) HC/APAP 16 1 (6%)

C) W/NTX 1 19 4 (21%)

D) W/NTX O.l mg 15 4 (27%)

E) W/NTX 0.01 mg 19 0 (0%)

F) W/NTX 0.001 20 4 (20%)

TOTAL 111 15 (14%)

Dizziness exc. Vertigo A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 3 (16%)

D) W/NTX O.l mg 15 1 (7%)

E) W/NTX 0.01 mg 19 0 (0%)

F) W/NTX 0.001 20 1 (5%)

TOTAL 111 5 (5%)

Headache Nos A) PLACEBO 22 1 (5%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 1 (5%)

D) W/NTX O.l mg 15 1 (7%)

E) W/NTX 0.01 mg 19 0 (0%)

F) W/NTX 0.001 20 1 (5%)

TOTAL 111 4 (4%)

Table 77B (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Male Patients

BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Sedation A) PLACEBO 22 1 (5%)

B) HC/APAP 16 1 (6%)

C) W/NTX 1 19 0 (0%)

D) W/NTX O.l mg 15 0 (0%)

E) W/NTX O.Ol mg 19 0 (0%)

F) W/NTX 0.001 20 2 (10%)

TOTAL 111 4 (4%)

Syncope A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 1 (5%)

D) W/NTX O.l mg 15 1 (7%)

E) W/NTX 0.01 mg 19 0 (0%)

F) W/NTX 0.001 20 0 (0%)

TOTAL 111 2 (2%)

Tremor Nee A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 0 (0%)

D) W/NTX O.l mg 15 1 (7%)

E) W/NTX 0.01 mg 19 0 (0%)

F) W/ΝTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

Table 77B (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Male Patients

BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

PSYCHIATRIC A) PLACEBO 22 0 (0%)

DISORDERS B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 1 (5%)

D) W/NTX O.l mg 15 0 (0%)

E) W/NTX 0.01 mg 19 0 (0%)

F) W/NTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

Nervousness A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 1 (5%)

D) W/ΝTX O.l mg 15 0 (0%)

E) W/NTX 0.01 mg 19 0 (0%)

F) W/NTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

RENAL AND URINARY A) PLACEBO 22 0 (0%)

DISORDERS B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 0 (0%)

D) W/NTX O.l mg 15 0 (0%)

E) W/ΝTX 0.01 mg 19 1 (5%)

F) W/NTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

Table 77B (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Male Patients

BODY SYSTEM TOTAL NO. OF NO. . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Difficulty in Micturition A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 0 (0%)

D) W/NTX O.l mg 15 0 (0%)

E) W/NTX 0.01 mg 19 1 (5%) _

F) W ΝTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

SKTN AND A) PLACEBO 22 1 (5%)

SUBCUTANEOUS TISSUE B) HC/APAP 16 0 (0%)

DISORDERS C) W/ΝTX 1 19 1 (5%)

D) W/NTX O.l mg 15 2 (13%)

E) W/NTX 0.01 mg 19 1 (5%)

F) W/ΝTX 0.001 20 1 (5%)

TOTAL 111 6 (5%)

Pruritus Nos A) PLACEBO 22 1 (5%)

B) HC/APAP 16 0 (0%)

C) W/ΝTX 1 19 0 (0%)

Table 77B (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Male Patients

BODY SYSTEM TOTAL NO. OF NO. . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Sweating Increased A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 1 (5%)

D) W/NTX O.l mg 15 1 (7%)

E) W/NTX 0.01 mg 19 1 (5%)

F) W/NTX 0.001 20 1 (5%)

TOTAL 111 4 (4%)

VASCULAR DISORDERS A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 2 (11%)

D) W/NTX O.l mg 15 0 (0%)

E) W/NTX 0.01 mg 19 1 (5%)

F) W/ΝTX 0.001 20 1 (5%)

TOTAL 111 4 (4%)

Hot Flushes Nos A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

Table 77B (Continued)

Summary Of Adverse Events By Body System And Preferred Term

Safety Patients, Male Patients

BODY SYSTEM TOTAL NO. OF NO . OF SUBJECTS

ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT

(COSTART ENGLISH)

Hypertension Nos A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 0 (0%)

D) W/NTX 0.1 mg 15 0 (0%)

E) W/NTX 0.01 mg 19 1 (5%)

F) W/NTX 0.001 20 0 (0%)

TOTAL 111 1 (1%)

Pallor A) PLACEBO 22 0 (0%)

B) HC/APAP 16 0 (0%)

C) W/NTX 1 19 1 (5%)

D) W/ΝTX O.l mg 15 0 (0%)

E) W/NTX 0.01 mg 19 0 (0%)

F) W/NTX 0.001 20 1 (5%)

TOTAL 111 2 (2%)

EXAMPLE 7

An additional dose ranging clinical study with morphine sulfate (MS or morphine) alone or in combination with low doses of naltrexone hydrochloride (NTX or naltrexone) was designed substantially the same as that described in Example 1, with the following differences: (1) seven treatment groups (not 5) with three different doses of MS (30 mg, 60 mg and 90 mg) alone or in combination with 0.1 mg NTX versus placebo alone, in subjects with moderate to severe pain in a postsurgical dental pain clinical study; (2) each group was 30 patients (not 40) for a total of 210 males only (not 200 females and males); (3) subjects had three or four third molars, including at least one mandibular partial or complete bony impaction (not 2 or more impacted third molars); (4) time to onset of analgesia (not time to onset of meaningful and perceptible pain relief or time to onset of meaningful pain relief) was measured; (5) the primary efficacy variable was SPID measured through 4 hours (not TOTPAR and SPED measured through 8 hours); (6) the secondary efficacy variables included: 4, 6 and 8 hour Total Pain Relief Scores (TOTPAR-4, TOTPAR-6, and TOTPAR-8); MAXPAR scores; pain relief (PR) scores; 6 and 8 hour Sum of Pain Intensity Difference Scores (SPID-6 and SPDD-8); categorical PDD scores (pain intensity differences on the categorical scale); PEAKPID scores; VAS-PDD scores (pain intensity differences on the visual analog scale); PEAK- V AS-SPED scores; VAS- SPED-4, -6 and -8 scores; (7) additional exclusion criteria were patients with known history of severe hepatic or renal impairment; and (8) for adverse events, body systems and preferred terms were from the MedDRA (not the COSTART) dictionary.

A total of 210 male subjects were randomized; among them all 210 subjects were deemed evaluable (Table 78). Table 78 Anal sis Po ulations

The demographic and baseline characteristics were summarized by treatment groups for all 210 randomized patients which were all evaluable (Table 79).

Subjects ranged in age from 16 to 49 years; 62.9% were Caucasian and all were male. No adjustments in the analyses were made to take into account differences among treatment groups. These differences had little or no influence on pain assessments at baseline. The baseline pain intensity scores and visual analog scale scores were generally comparable across treatment groups (Tables 80 A and

80B).

raoie /y

Baseline Demographic Characteristics

Primary Efficacy Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE FOR AGE, HEIGHT, AND WEIGHT AND FROM CHI-SQUARE TEST FORRACE/ETHMC ORIGIN.

Table 80A

Baseline Pain Intensity Scores (Categorical)

Primary Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE FOR AGE, HEIGHT, AND WEIGHT AND FROM CHI-SQUAR TEST FOR RACE/ETHMC ORIGIN.

Table 80B

Baseline Pain Intensity Scores (VAS)

Primar Efficacy Po ulation

[1] FOR AGE, HEIGHT, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR GENDER, RACE/ETHMC ORIGIN, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

[2] BLACK, ASIAN, HISPAMC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

[3] 4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

The sum of pain relief (total pain relief or TOTPAR) scores (4 hour, 6 hour, 8 hour) are summarized in Table 81 and the mean 4 hour scores are shown in Figure 41. The placebo treatment group had the lowest mean TOTPAR scores. All 6 of the active treatment groups with 30 mg, 60 mg or 90 mg MS alone or in combination with 0.1 mg NTX exhibited mean TOTPAR scores that were numerically higher than placebo. The mean TOTPAR score for the 90 mg MS/0.1 mg NTX combination treatment was the highest among all treatment groups.

The mean TOTPAR scores for the 30 mg, 60 mg and 90 mg MS alone treatment groups were comparable. In contrast, the mean TOTPAR scores for the 30 mg MS/0.1 mg NTX, 60 mg MS/0.1 mg NTX and 90 mg/MS 0.1 mg NTX combination treatment groups demonstrated a dose response as shown in Table 81 and Figure 41.

Table 81

Sum of Pain Relief Scores (TOTPAR)

Primar Efficacy Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 81 (Continued)

Sum of Pain Relief Scores (TOTPAR)

Primar Efficacy Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 81 (Continued)

Sum of Pain Relief Scores (TOTPAR)

Primar Efficacy Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 82 summarizes the 4, 6, and 8 hour sum of pain intensity difference (SPDD) scores. The mean 4 hour results are also represented in Figure 42. The placebo treatment group had the lowest mean 4 hour SPED scores. All 6 of the active treatment groups with 30 mg, 60 mg or 90 mg MS alone or in combination with 0.1 mg NTX exhibited improved profiles in mean SPDD relative to placebo. The mean 4 hour SPDD score for the 90 mg MS/0.1 mg NTX combination treatment was the highest among all treatment groups.

The mean SPDD scores for the 30 mg, 60 mg and 90 mg MS alone treatment groups were comparable. In contrast the mean SPDD scores for the 30 mg MS/0.1 mg NTX, 60 mg MS/0.1 mg NTX and 90 mg MS/0.1 mg NTX combination treatment groups demonstrated a dose response as shown in Table 82 and Figure 42.

Table 82

Sum of Pain Intensity Difference Scores (SPDD)

Primary Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 82 (Continued)

Sum of Pain Intensity Difference Scores (SP D)

Primar Efficac Population

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 82 (Continued)

Sum of Pain Intensity Difference Scores (SPDD)

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Figure 43 is a visual presentation of the summary and analysis of time to onset of analgesia presented in Table 83. The median time to onset of analgesia was shortest in the 90 mg MS/0.1 mg NTX combination treatment group.

Table 83

Time to Onset of Analgesia

Note: median time and its confidence interval are estimated using aplan-meier method. Log-rank and wilcoxon tests are used to test the equality of Kaplan-Meier survival functions over different treatment groups.

Table 84 summarizes the results of the time to remedication (see also Figure 44). The placebo group had the shortest median time to remedication and the 90 mg MS/0.1 mg NTX combination treatment group had the longest median time to remedication.

Table 84

Time to Re-Medication

Primary Efficacy Po ulation

NOTE: MEDIAN TIME AND ITS CONFIDENCE INTERVAL ARE ESTIMATED USING KAPLAN-MEER METHOD. LOG-RANK AN WECOXON TESTS ARE USED TO TEST THE EQUALITY OF KAPLAN-MEER SURVIVAL FUNCTIONS OVER DEFERENT TREATMENT GROUPS.

The summary and analysis of percent of subjects who took rescue medication up to 4, 8 and 24 hours are presented in Table 85. More than 70% of subjects at 4 hours in the 90 mg MS/0.1 mg NTX combination group and more than 60% of subjects in the same combination group at 8 hours did not require rescue medication.

Table 85

Time to Re-Medicated

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM CHI-SQUARE TEST.

Table 85 (Continued)

Time to Re-Medicated

Primary Efficacy Po ulation

NOTE: P-VALUES ARE FROM CHI-SQUARE TEST.

Table 85 (Continued)

Time to Re-Medicated

Primary Efficac Po ulation

NOTE: P-VALUES ARE FROM CHI-SQUARE TEST.

Figure 45 is a visual presentation of the mean pain relief scores presented in Table 86. The mean pain relief score for the placebo treatment was less than those for the active treatment groups (30 mg, 60 mg, 90 mg MS alone or in combination with 0.1 mg NTX) which improved over time. There was separation between the placebo and the active treatment groups that continued throughout the 8 hour study period. Highest pain relief scores were observed for the 90 mg MS/0.1 mg NTX combination group (Figure 45).

Table 86

Pain Relief (PR) Score

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE

Table 86 (Continued)

Pain Relief (PR) Score

Primary Efficacy Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE

Table 86 (Continued)

Pain Relief (PR) Score

Primary Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE

Table 86 (Continued)

Pain Relief (PR) Score

Primar Efficacy Population

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE

Table 86 (Continued)

Pain Relief (PR) Score

Primary Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE

Table 86 (Continued)

Pain Relief (PR) Score

Primar Efficacy Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE

Table 86 (Continued)

Pain Relief (PR) Score

Primary Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE

Table 86 (Continued)

Pain Relief (PR) Score

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE

Table 86 (Continued)

Pain Relief (PR) Score

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE

Table 86 (Continued)

Pain Relief (PR) Score

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE

Table 86 (Continued)

Pain Relief (PR) Score

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE

The mean categorical pain intensity difference (PED) scores are presented in Table 87 and Figure 46. The mean PDD scores for the placebo treatment group was generally flat while the mean PDD scores generally improved over time for the active treatment groups (30 mg MS, 60 mg MS and 90 mg MS alone or in combination with 0.1 mg NTX). The mean scores for the morphine alone and morphine/naltrexone combination treatment groups were higher than the mean PDD scores for the placebo group at each hourly assessment time from 1-8 hours. Highest pain relief as measured by PDD scores was observed for the 90 mg MS/0.1 mg NTX combination treatment group.

Table 87

Pain Intensity Difference Score (Categorical)

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued)

Pain Intensity Difference Score (Categorical)

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued)

Pain Intensity Difference Score (Categorical)

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued)

Pain Intensity Difference Score (Categorical)

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued)

Pain Intensity Difference Score (Categorical)

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued)

Pain Intensity Difference Score (Categorical)

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued)

Pain Intensity Difference Score (Categorical)

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued)

Pain Intensity Difference Score (Categorical)

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued)

Pain Intensity Difference Score (Categorical)

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued)

Pain Intensity Difference Score (Categorical)

Primary Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued)

Pain Intensity Difference Score (Categorical)

Primary Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Tables 88A and 88B present the mean maximum pain relief (MAXPAR) and mean peak pain intensity difference (PEAKPID) scores. The mean MAXPAR scores presented in Table 88A varied among treatment groups. The mean MAXPAR score was highest for the 90 mg MS/0.1 mg NTX combination treatment group compared to all other groups. The mean scores for all 6 active treatment groups were greater than the mean score for the placebo group. The mean PEAKPID scores presented in Table 88B varied among treatment groups, and were greater for all 6 active treatment groups compared to the placebo group. Compared to all other groups, the mean PEAKPID scores were highest for the 90 mg MS/0.1 mg NTX combination treatment group.

Table 88A

Maximum Pain Relief Score (MAXPAR)

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 88B

Pain Intensity Difference Score (Categorical)

Primar Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 89 presents the summary and analysis of global evaluations (see also Figure 47). The placebo treatment group had the highest number of subjects who had "poor" global evaluation scores. The 90 mg MS/0.1 mg NTX combmation treatment group had the highest number of subjects with a total of "excellent", "very good" and "good" global evaluation scores. The profiles of the global evaluation scores are based on subjects' evaluations.

Table 89

Global Evaluation of Study Medication

Primary Efficac Po ulation

NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE

The majority of adverse events reported were categorized as digestive (nausea or vomiting) or nervous system (dizziness or somnolence) as further shown in Table 90. Figure 48 represents a summary of exemplary adverse side effects that may be attenuated according to methods and compositions of the invention.

Table 90

Adverse Events Primary Efficacy Population

Total No. Of P-Value Total < Severity

Body System No. Of Patients Source No. Of

Adverse Events Treatment Patients W/Event Events

ALL BODY SYSTEMS PLACEBO 31 9 (29.0%) TRT O.001*** 21 9 (42.9%) 7 (33.3%) 5 (23.8%)

ALL EVENTS MS30 30 20 (66.7%) A-B 0.003** 57 21 (36.8%) 25 (43.9%) 11 (19.3%)

MS60 30 27 (90.0%) A-C .001*** 83 44 (53.0%) 27 (32.5%) 12 (14.5%)

MS90 30 28 (93.3%) A-D O.001*** 108 47 (43.5%) 39 (36.1%) 22 (20.4%)

MS30/NTX.1 31 17 (54.8%) A-E 0.039* 34 14 (41.2%) 17 (50.0%) 3 (8.8%)

MS60 NTX.1 30 24 (80.0%) A-F .001*** 80 31 (38.8%) 35 (43.8%) 14 (17.5%)

MS90/NTX.1 28 24 (85.7%) A-G O.001*** 79 39 (49.4%) 26 (32.9%) 14 (17.7%) 100 B-C 0.028* B-D 0.010**

C-E 0.002** D-E O.001*** E-F 0.036* E-G 0.010*

CARDIAC DISORDERS PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

ALL EVENTS MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30 NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 1 (3.0%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

NOTE:P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAJN EFFECT AND SIGNIFICANT (P<= 0.05)

PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

Body System No. Of Patients Source No. Of Mild Moderate Severe Adverse Events Treatment Patients W/Event Events

CHEST PRESSURE PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

SENSATION MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

EAR AND LABYRINTH PLACEBO 31 0 (0.0%) TRT 0.552 0 0 0 0

DISORDERS MS30 30 0 (0.0%) 0 0 0 0

ALL EVENTS MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 1 (3.2%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS60/NTX.1 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

SENSATION OF PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

PRESSURE IN EAR MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

ΝOTE:P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

Body System No. Of Patients Source No. Of

Mild Moderate Severe Adverse Events Treatment Patients W/Event Events

TINNITUS PLACEBO 31 0 (0.0%) TRT 0.446 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30NTX.1 31 1 (3.2%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS60/ΝTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

EYE DISORDERS PLACEBO 31 2 (6.5%) TRT 0.175 2 1 (50.0%) 1 (50.0%) 0 (0.0%)

ALL EVENTS MS30 30 6 (20.0%) A-C 0.033* 6 3 (50.0%) 3 (50.0%) . 0 (0.0%)

MS60 30 8 (26.7%) A-D 0.017* 8 5 (62.5%) 1 (12.5%) 2 (25.0%)

MS90 30 9 (30.0%) A-G 0.048* 11 8 (72.7%) 2 (18.2%) 1 (9.1%)

MS30/NTX.1 31 3 (9.7%) D-E 0.046* 3 2 (66.7%) 1 (33.3%) 0 (0.0%)

MS60/NTX.1 30 7 (23.3%) 7 2 (28.6%) 5 (71.4%) 0 (0.0%)

MS90/NTX.1 28 7 (25.0%) 9 6 (66.7%) 3 (33.3%) 0 (0.0%)

BLOODSHOT EYE PLACEBO 31 2 (6.5%) TRT 0.175 2 1 (50.0%) 1 (50.0%) 0 (0.0%)

MS30 30 6 (20.0%) A-C 0.033* 6 3 (50.0%) 3 (50.0%) 0 (0.0%)

MS60 30 8 (26.7%) A-D 0.017* 8 5 (62.5%) 1 (12.5%) 2 (25.0%)

MS90 30 9 (30.0%) A-G 0.048* 9 7 (77.8%) 1 (11.1%) 1 (11.1%)

MS30/ΝTX.1 31 3 (9.7%) D-E 0.046* 3 2 (66.7%) 1 (33.3%) 0 (0.0%)

MS60/NTX.1 30 7 (23.3%) 7 2 (28.6%) 5 (71.4%) 0 (0.0%)

MS90/ΝTX.1 28 7 (25.0%) 7 5 (71.4%) 2 (28.6%) 0 (0.0%)

NOTE:P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

Body System No. Of Patients Source No. Of Mild Moderate S < evere Adverse Events Treatment Patients W/Event Events

EYE IRRITATION PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS30/ΝTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

EYE PATN PLACEBO 31 0 (0.0%) TRT 0.366 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 1 (3.6%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MIOSIS PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS30 NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

PHOTOPHOBIA PLACEBO 31 0 (0.0%) TRT 0.366 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/ΝTX.1 28 1 (3.6%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

GASTROINTESTINAL DISORDERS

ALL EVENTS PLACEBO 31 2 (6.5%) TRT O.001*** 3 2 (66.7%) 0 (0.0%) 1 (33.3%)

MS30 30 10 (33.3%) A-B 0.008** 14 4 (28.6%) 5 (35.7%) 5 (35.7%)

MS60 30 15 (50.0%) A-C O.001*** 29 12 (41.4%) 8 (27.6%) 9 (31.0%)

MS90 30 19 (63.3%) A-D O.001*** 42 11 (26.2%) 18 (42.9%) 13 (31.0%)

MS30/NTX.1 31 7 (22.6%) A-F O.001*** 8 3 (37.5%) 4 (50.0%) 1 (12.5%)

MS60/NTX.1 30 16 (53.3%) A-G O.001*** 33 7 (21.2.%) 15 (45.5%) 11 (33.3%)

MS90/NTX.1 28 18 (64.3%) B-D 0.020* 32 9 (28.1%) 11 (34.4%) 12 (37.5%) B-G 0.018*

C-E 0.026* D-E 0.001** E-F 0.013* E-G 0.001**

NOTE:P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAJN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

ABDOMINAL PATN NOS PLACEBO 31 0 (0.0%) TRT 0.059 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 2 (6.7%) 2 0 (0.0%) 1 (50.0%) 1 (50.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

ABDOMINAL PAIN PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

LOWER MS30 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

ABDOMINAL PAIN PLACEBO 31 0 (0.0%) TRT 0.366 0 0 0 0

UPPER MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 1 (3.6%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

DRY MOUTH PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/ΝTX.1 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

DRY THROAT PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

DYSPEPSIA PLACEBO 31 0 (0.0%) TRT 0.176 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 2 (6.7%) 2 1 (50.0%) 1 (50.0%) 0 (0.0%)

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 1 (3.6%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

DYSPHAGIA PLACEBO 31 0 (0.0%) TRT 0.669 0 0 0

MS30 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/ΝTX.1 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

HICCUPS PLACEBO 31 0 (0.0%) TRT 0.506 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS90/ΝTX.1 28 1 (3.6%) 1 0 (0.0%) 0 (0.0%) 1 (100.0%)

MOUTH PLACEBO 31 0 (0.0%) TRT 0.366 0 0 0 0

HEMORRHAGE MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 1 (3.6%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

ΝOTE:P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAJRWISE COMPARISONS ARE PRESENTED.

SI , H/lOSfl/13d 0SΪS8/Ϊ0 OΛV Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

SORE THROAT NOS PLACEBO 31 0 (0.0%) TRT 0.809 0 0 0 0

MS30 30 1 (3.3%) 1 0 (0.0%) 0 (0.0%) K ;ιoo.o%)

MS60 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS30/NTX.1 31 1 (3.2%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

VOMITING NOS PLACEBO 31 1 (3.2%) TRT O.OOl*** 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS30 30 4 (13.3%) A-C O.OOl*** 4 0 (0.0%) 2 (50.0%) 2 (50.0%)

MS60 30 12 (40.0%) A-D O.001*** 12 2 (16.7%) 3 (25.0%) 7 (58.3%)

MS90 30 15 (50.0%) A-F O.001*** 16 2 (12.5%) 5 (31.3%) 9 (56.3%)

MS30/NTX.1 31 1 (3.2%) A-G O.001*** 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS60/NTX.1 30 13 (43.3%) B-C 0.020* 13 2 (15.4%) 3 (23.1%) 8 (61.5%)

MS90/NTX.1 28 13 (46.4%) B-D 0.002** 13 2 (15.4%) 2 (15.4%) 9 (69.2%) B-F 0.010** B-G 0.006** C-E O.001*** D-E .001*** E-F O.001*** E-G .001***

ΝOTE.P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued)

Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

Body System No. Of Patients Source No. Of Mild Moderate Severe

Adverse Events Treatment Patients W/Event Events

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

ALL EVENTS PLACEBO 31 1 (3.2%) TRT 0.739 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS30 30 5 (16.7%) 6 1 (16.7%) 4 (66.7%) 1 (16.7%)

MS60 30 4 (13.3%) 4 1 (25.0%) 3 (75.0%) 0 (0.0%)

MS90 30 4 (13.3%) 9 2 (22.2%) 5 (55.6%) 2 (22.2%)

MS30/NTX.1 31 4 (12.9%) 4 2 (50.0%) 2 (50.0%) 0 (0.0%)

MS60/NTX.1 30 5 (16.7%) 6 3 (50.0%) 3 (50.0%) 0 (0.0%)

MS90/NTX.1 28 3 (10.7%) 3 1 (33.3%) 2 (66.7%) 0 (0.0%)

ENERGY PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

INCREASED MS30 30 0 (0.0%) 0 0 0 0

MS60 30 1 (3.3%) 1 0 (0.0%) 1 (0.0%) 0 (0.0%)

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

FATIGUE PLACEBO 31 0 (0.0%) TRT 0.312 0 0 0 0

MS30 30 1 (3.3%) A-D 0.035* 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS60 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS90 30 4 (13.3%) 5 0 (0.0%) 4 (80.0%) 1 (20.0%)

MS30/NTX.1 31 2 (6.5%) 2 0 (0.0%) 2 (100.0%) 0 (0.0%)

MS60/NTX.1 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS90/NTX.1 28 1 (3.6%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

NOTE.P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

FEELING HOT PLACEBO 31 1 (3.2%) TRT 0.835 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS30 30 2 (6.7%) 2 1 (50.0%) 0 (0.0%) 1 (50.0%)

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 2 (6.7%) 2 2 (100.0%) 0 (0.0%) 0 (0.0%)

MS30/NTX.1 31 1 (3.2%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS60/NTX.1 30 2 (6.7%) 2 1 (50.0%) 1 (50.0%) 0 (0.0%)

MS90/NTX.1 28 1 (3.6%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

FEELING JITTERY PLACEBO 31 0 (0.0%) TRT 0.538 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

NECK SWELLING PLACEBO 31 0 (0.0%) TRT 0.366 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/ΝTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 1 (3.6%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

PYREXIA PLACEBO 31 0 (0.0%) TRT 0.538 0 0 0 0

MS30 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 1 (3.3%) 1 0 (0.0%) 0 (0.0%) 1 (100.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

SHIVERING PLACEBO 31 0 (0.0%) TRT 0.679 0 0 0 0

MS30 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) .0 0 0 0

MS30/NTX.1 31 1 (3.2%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS60/NTX.1 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90/ΝTX.1 28 0 (0.0%) 0 0 0 0

WEAKNESS PLACEBO 31 0 (0.0%) TRT 0.802 0 0 0

MS30 30 1 (3.3%) 1 (0.0%) 1 (100.0%) 0 (0.0%)

MS60 30 1 (3.3%) 1 (0.0%) 1 (100.0%) 0 (0.0%)

MS90 30 1 (3.3%) 1 (0.0%) 1 (100.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0

MS60/NTX.1 30 1 (3.3%) 1 (0.0%) 1 (100.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

Body System No. Of Patients Source No. Of Mild Moderate Severe Adverse Events Treatment Patients W Event Events

INVESTIGATIONS PLACEBO 31 0 (0.0%) TRT 0.363 0 0 0 0

ALL EVENTS MS30 30 2 (6.7%) 2 2 (100.0%) 0 (0.0%) 0 (0.0%)

MS60 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 1 (3.2%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

BLOOD PRESSURE PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

INCREASED MS30 30 0 (0.0%) 0 0 0 0

MS60 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90 30 0 (0.0%) 0 0 0 0

MS30/ΝTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

BODY PLACEBO 31 0 (0.0%) TRT .059 0 0 0 0

TEMPERATURE MS30 30 2 (6.7%) 2 2 (100.0%) 0 (0.0%) 0 (0.0%)

INCREASED MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

NOTE.P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MATN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

HEART RATE PLACEBO 31 0 (0.0%) TRT 0.446 0 0 0 0

INCREASED MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 1 (3.2%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

JSCULOSKELETAI . CONNECTIVE TISSUE AND BONE DISORDERS

ALL EVENTS PLACEBO 31 1 (3.2%) TRT 0.679 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 1 (3.3%) 2 0 (0.0%) 2 (100.0%) 0 (0.0%)

MS90 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90 NTX.1 28 0 (0.0%) 0 0 0 0

JOINT RANGE OF PLACEBO 31 1 (3.2%) TRT 0.446 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MOTION MS30 30 0 (0.0%) 0 0 0 0

DECREASED MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30 NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

ΝOTE.P-NALUE ARE FROM CHI-SQUARE TEST. P-NALUES FOR TREATMENT MATN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued)

Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

Body System No. Of Patients Source No. Of ^" Mild Moderate Severe

Adverse Events Treatment Patients W/Event Events

MUSCLE SPASMS PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90 NTX.1 28 0 (0.0%) 0 0 0 0

MYALGIA PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 1 (3.3%) 2 0 (0.0%) 2 (100.0%) 0 (0.0%)

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

NERVOUS SYSTEM DISORDERS

ALL EVENTS PLACEBO 31 7 (22.6%) TRT O.001*** 14 5 (35.7%) 5 (35.7%) 4 (28.6%)

MS30 30 15 (50.0%) A-B 0.026* 23 8 (34.8%) 11 (47.8%) 4 (17.4%)

MS60 30 21 (70.0%) A-C O.001*** 29 16 (55.2%) 12 (41.4%) 1 (3.4%)

MS90 30 19 (63.3%) A-D O.001*** 31 17 (54.8%) 9 (29.0%) 5 (16.1%)

MS30/NTX.1 31 11 (35.5%) A-F 0.048* 15 7 (46.7%) 6 (40.0%) 2 (13.3%)

MS60/NTX.1 30 14 (46.7%) A-G .001*** 25 13 (52.0%) 9 (36.0%) 3 (12.0%)

MS90/NTX.1 28 19 (67.9%) C-E 0.007** 28 18 (64.3%) 8 (28.6%) 2 (7.1%) D-E 0.030* E-G 0.013*

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

DIZZINESS (EXC PLACEBO 31 1 (3.2%) TRT 0.007** 1 0 (0.0%) 0 (0.0%) 1 (100.0%)

VERTIGO) MS30 30 9 (30.0%) A-B 0.005** 10 5 (50.0%) 3 (30.0%) 2 (20.0%)

MS60 30 11 (36.7%) A-C 0.001** 12 7 (58.3%) 5 (41.7%) 0 (0.0%)

MS90 30 13 (43.3%) A-D .001*** 14 9 (64.3%) 4 (28.6%) 1 (7.1%)

MS30/NTX.1 31 7 (22.6%) A-E 0.023* 8 3 (37.5%) 4 (50.0%) 1 (12.5%)

MS60/NTX.1 30 12 (40.0%) A-F O.001*** 12 7 (58.3%) 4 (33.3%) 1 (8.3%)

MS90/NTX.1 28 12 (42.9%) A-G .001*** 14 8 (57.1%) 4 (28.6%) 2 (14.3%)

HEADACHE NOS PLACEBO 31 7 (22.6%) TRT 0.810 9 4 (44.4%) 2 (22.2%) 3 (33.3%)

MS30 30 8 (26.7%) 8 1 (12.5%) 5 (62.5%) 2 (25.0%)

MS60 30 8 (26.7%) 10 6 (60.0%) 4 (40.0%) 0 (0.0%)

MS90 30 6 (20.0%) 6 5 (83.3%) 1 (16.7%) 0 (0.0%)

MS30 NTX.1 31 4 (12.9%) 4 3 (75.0%) 1 (25.0%) 0 (0.0%)

MS60/NTX.1 30 5 (16.7%) 5 2 (40.0%) 2 (40.0%) 1 (20.0%)

MS90/NTX.1 28 7 (25.0%) 7 6 (85.7%) 1 (14.3%) 0 (0.0%)

HYPERAESTHESIA PLACEBO 31 1 (3.2%) TRT 0.446 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

Table 90 (Continued)

Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

Body System No. Of - Patients Source No. Of Mild Moderate Severe

Adverse Events Treatment Patients W/Event Events

HYPOAESTHESIA PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

PARAESTHESIA PLACEBO 31 0 (0.0%) TRT 0.506 0 0 0 0

NEC MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90/NTX.1 28 1 (3.6%) 2 2 (100. 0%) 0 (0.0%) 0 (0.0%)

SOMNOLENCE PLACEBO 31 1 (3.2%) TRT 0.174 1 0 (0. 0%) 1 (100.0%) 0 (0.0%)

MS30 30 4 (13.3%) A-C 0.020* 5 2 (40. 0%) 3 (60.0%) 0 (0.0%)

MS60 30 7 (23.3%) A-D 0.020* 7 3 (42.9%) 3 (42.9%) 1 (14.3%)

MS90 30 7 (23.3%) 7 2 (28.6%) 4 (57.1%) 1 (14.3%)

MS30/NTX.1 31 2 (6.5%) 2 0 (0. 0%) 1 (50.0%) 1 (50.0%)

MS60/NTX.1 30 4 (13.3%) 5 1 (20.0%) 3 (60.0%) 1 (20.0%)

MS90/NTX.1 28 5 (17.9%) 5 2 (40. 0%) 3 (60.0%) 0 (0.0%)

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

SYNCOPE PLACEBO 31 1 (3.2%) TRT 0.368 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 2 (6.7%) 2 0 (0.0%) 0 (0.0%) 2 (100.0%)

MS30/NTX.1 31 1 (3.2%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

TENSION PLACEBO 31 1 (3.2%) TRT 0.446 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

HEADACHES MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

TREMOR NEC PLACEBO 31 0 (0.0%) TRT 0.186 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 2 (6.7%) 2 1 (50.0%) 0 (0.0%) 1 (50.0%)

MS30/ΝTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

ΝOTE.P- VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

PSYCHIATRIC DISORDERS ALL EVENTS PLACEBO 31 0 (0.0%) TRT 0.554 0 0 0 0

MS30 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS60 30 T (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90 30 2 (6.7%) 2 2 (100.0%) 0 (0.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

ANXIETY NEC PLACEBO 31 0 (0.0%) TRT 0.538 0 0 0 0

MS30 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS60 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60 NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

EUPHORIC MOOD PLACEBO 31 0 (0.0%) TRT 0.59 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 2 (6.7%) 2 2 (100.0%) 0 (0.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

NERVOUSNESS PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

RENAL AND URINARY DISORDERS

ALL EVENTS PLACEBO 31 0 (0.0%) TRT 0.506 0 0 0

MS30 30 0 (0.0%) 0 0 0

MS60 30 0 (0.0%) 0 0 0

MS90 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 1 (3.6%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

DIFFICULTY IN PLACEBO 31 0 (0.0%) TRT 0.506 0 0 0 0

MICTURITION MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 1 (3.6%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

ALL EVENTS PLACEBO 31 0 (0.0%) TRT 0.802 0 0 0 0

MS30 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS60 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS30 NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

CHEST TIGHTNESS PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

MS30 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/ΝTX.1 28 0 (0.0%) 0 0 0 0

DYSPNOEA NOS PLACEBO 31 0 (0.0%) TRT 0.538 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

THROAT PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

TIGHTNESS MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/ΝTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 1 (3.3%) 1 0 (0.0)% 1 (100.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

SKIN & SUBCUTANEOUS TISSUE DISORDERS

ALL EVENTS PLACEBO 31 0 (0.0%) TRT 0.213 0 0 0 0

MS30 30 3 (10.0%) A-C 0.018* 3 2 (66.7%) 0 (0.0%) 1 (33.3%)

MS60 30 5 (16.7%) A-D 0.009** 7 6 (85.7%) 1 (14.3%) 0 (0.0%)

MS90 30 6 (20.0%) A-G 0.029* 7 5 (71.4%) 1 (14.3%) 1 (14.3%)

MS30/NTX.1 31 2 (6.5%) 2 0 (0.0%) 2 (100.0%) 0 (0.0%)

MS60/NTX.1 30 3 (10.0%) 5 5 (100.0%) 0 (0.0%) 0 (0.0%)

MS90/NTX.1 28 4 (14.3%) 4 2 (50.0%) 2 (50.0%) 0 (0.0%)

CLAMMINESS PLACEBO 31 0 (0.0%) TRT 0.538 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 1 (3.3%) 1 0 (0.0%) 0 (0.0%) 1 (100.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

DERMATITIS NOS PLACEBO 31 0 (0.0%) TRT 0.357 0 0 0 0

MS30 30 1 (3.3%) 1 0 (0.0%) 0 (0.0%) 1 (100.0%)

MS60 30 2 (6.7%) 2 2 (100.0%) 0 (0.0%) 0 (0.0%)

MS90 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90 NTX.1 28 0 (0.0%) 0 0 0 0

ECCHYMOSIS PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

MS30 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

PHOTOSENSITΓVΠΎ PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

REACTION NOS MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/ΝTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

NOTE.P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MALN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

PRURITUS NOS PLACEBO 31 0 (0.0%) TRT 0.785 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 1 (3.3%) 2 2 (100.0%) 0 (0.0%) 0 (0.0%)

MS90 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 1 (3.3%) 2 2 (100.0%) 0 (0.0%) 0 (0.0%)

MS90/NTX.1 28 1 (3.6%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

RASH MACULAR PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 0 (0.0%) 0 0 0 0

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 1 (3.3%) 2 2 (100.0%) 0 (0.0%) 0 (0.0%)

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

SWEATING PLACEBO 31 0 (0.0%) TRT 0.286 0 0 0 0

INCREASED MS30 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS60 30 3 (10.0%) 3 2 (66.7%) 1 (33.3%) 0 (0.0%)

MS90 30 3 (10.0%) 3 2 (66.7%) 1 (33.3%) 0 (0.0%)

MS30/NTX.1 31 2 (6.5%) 2 0 (0.0%) 2 (100.0%) 0 (0.0%)

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 3 (10.7%) 3 2 (66.7%) 1 (33.3%) 0 (0.0%)

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

Body System No. Of Patients Source No. Of

Mild Moderate Severe Adverse Events Treatment Patients W/Event Events

VASCULAR DISORDERS ALL EVENTS PLACEBO 31 0 (0.0%) TRT 0.199 0 0 0 0

MS30 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS60 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90 30 3 (10.0%) 3 1 (33.3%) 2 (66.7%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 2 (7.1%) 2 2 (100.0%) 0 (0.0%) 0 (0.0%)

FLUSHING PLACEBO 31 0 (0.0%) TRT 0.785 0 0 0

MS30 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS60 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS90 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 1 (3.6%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

HOT FLUSHES NOS PLACEBO 31 0 (0.0%) TRT 0.506 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 1 (3.3%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 1 (3.6%) 1 1 (100.0%) 0 (0.0%) 0 (0.0%)

NOTE: P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population

Total No. Of P-Value Total Severity

HYPOTENSION NOS PLACEBO 31 0 (0.0%) TRT 0.420 0 0 0 0

MS30 30 0 (0.0%) 0 0 0 0

MS60 30 0 (0.0%) 0 0 0 0

MS90 30 1 (3.3%) 1 0 (0.0%) 1 (100.0%) 0 (0.0%)

MS30/NTX.1 31 0 (0.0%) 0 0 0 0

MS60/NTX.1 30 0 (0.0%) 0 0 0 0

MS90/NTX.1 28 0 (0.0%) 0 0 0 0

NOTE.P- VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

EXAMPLE 8

In addition to the clinical studies described in Examples 1-7, several small pilot clinical studies were done with varying results.

One pilot study involved the co-administration of oral naltrexone and intrathecal morphine in patients with refractory chronic pain. This pilot study was performed to preliminarily evaluate and compare the analgesic effectiveness of intrathecal morphine and alone and in combmation with two different doses of oral naltrexone in patients with chronic refractory pain. The 15 subject study had three treatment groups: a) morphine + placebo (5 patients); b) morphine + naltrexone 0.1 mg (3 patients); c) morphine + naltrexone 0.01 mg (7 patients). In this pilot study, all

15 patients had an indwelling intrathecal catheter and were currently receiving intrathecal morphine for refractory chronic pain. Each subject took one capsule of oral study medication every 12 hours for seven days. Subjects completed pain and side effect assessments before dosing and at 30 minutes, 1, 2, 3, 4, 5, 6, 7 and 8 hour after receiving the first dose of oral study medication. Subjects then completed assessments three times each day for the remaining six days of treatment, with a follow-up visit on the eighth day.

The efficacy and safety evaluations included: pain evaluation questionnaires (VAS), side effect scoring sheets, global efficacy evaluations (VAS), and adverse event assessments.

The mean pain intensity difference (PID) scores are shown by day and time in Tables 91 and 92, and Figures 49 and 50. Generally, the 0.1 mg NTX combination treatment group showed the highest mean PID scores.

The mean daily global assessment of pain scores are shown for days 2-8 in Table 93 and Figure 51. Particularly, for days 2-4, the 0.1 mg NTX combination treatment group showed the best (lowest mean) global assessment scores.

Table 92 Mean Dail Global Assessment Scores

In another pilot study, very low doses (e.g., 1 mg, 5 mg) of morphine in combination with naltrexone (0.01 mg or 0.001 mg) were admimstered for moderate to severe pain in patients following dental surgery. This pilot study was performed to investigate the analgesic efficacy (onset, peak, duration, and total effect) of 60 mg morphine alone, two different doses (0.01 mg or 0.001 mg) of naltrexone in combmation with two different low doses (1 mg, 5 mg) of morphine, and placebo.

The 50 subject study was designed with six treatment groups: a) placebo (5 patients); b) morphine 60 mg (5 patients); c) morphine 1.0 mg and naltrexone 0.01 mg (10 patients); d) morphine 1.0 mg and naltrexone 0.001 mg (10 patients); e) morphine

5.0 mg and naltrexone 0.01 mg (10 patients); and f) morphine 5.0 mg and naltrexone 0.001 mg (10 patients). In this pilot study in the treatment of moderate to severe pain following extraction of 3 or 4 full or partial bony impacted third molars, a single oral dose of one of the treatments was administered when the patient was suffering moderate to severe postoperative pain. The observation period for efficacy was 8 hours post treatment and for safety was 24 hours post treatment.

The efficacy and safety evaluations included pain intensity, pain relief, global pain evaluation, evaluation of time to meaningful pain relief (stopwatch), visual analog scale (VAS), and adverse event assessment. This pilot study did not reveal any efficacy differences in the active treatment groups as compared with placebo.

In another pilot study of 25 subjects, the analgesic effects of morphine (5 mg, i.v.) in the presence of varying doses of an opioid antagomst (i.v. naloxone; 5 mg, 0.5 mg, 0.05 mg) as compared with morphine alone and placebo in healthy volunteers using the cold pain test. Treatments were admimstered by 15 min i.v. infusion:

The cold pain test was performed pre-dose and at 20 minutes, 1 hr 20 in, 2 hr 20 in, 4 hr 20 min, and 6 hr 20 min post-dose on each of the five dosing occasions. In the test, a subject's hand is immersed in cold water usually over the range of 1 to 3°C. The initial sensation of cold is replace by a deep burning discomfort in the hand. It is thought that this is mediated by nociceptors in veins. The discomfort gradually builds to a plateau over 90 seconds or so and then either stays the same or decreases slightly.

The test statistic for each cold pain test was the cumulative area under the curve of the visual analogue scale-time profile from 0-120 seconds (AUC_cpr) calculated automatically by the cold pain test software. AUC_cpr values from the cold pain test were listed and plotted for each subject and treatment.

Minimum AUC_cpt and the time to achieve minimum AUC_cpt was determined for each subject and treatment/dose level. This pilot study did not reveal any efficacy differences in the active treatment groups as compared with placebo.

EXAMPLE 9

A study of tramadol alone and in combmation with naltrexone is described in Example 10 of U.S. Application Serial No. 09/566,071, filed May 5, 2000 and 09/756,331, filed January 8, 2001, as well as of PCT/USOO/12493 [WO/00 67739] filed May 5, 2000, the entire disclosures of which are hereby incorporated by reference. A summary of exemplary study results follows.

In this study in human subjects with pain, tramadol hydrochloride (tramadol) was administered alone or in combination with various amounts (doses) of an opioid antagonist, naltrexone. h this study, one objective was to determine whether an opioid antagonist such as naltrexone hydrochloride (hereafter referred to in this example as naltrexone or NTX) enhanced the analgesic properties of tramadol hydrochloride (hereafter referred to in this example as tramadol or T) in human subjects/patients with pain following dental surgery. An additional objective was to evaluate whether an opioid antagonist such as NTX attenuated (e.g., reduced, blocked or prevented) tramadol's adverse side effects in humans.

Human subjects were randomized into one of the following five treatment groups:

Group 1 : T (50 mg) with NTX (1 mg)

Group 2: T (50 mg) with NTX (0.1 mg) Group 3 : T (50 mg) with NTX (0.01 mg)

Group 4: T (50 mg) with Placebo

Group 5: Placebo with Placebo

All subjects with moderate to severe pain received one dose of study medication. Subjects received two capsules to take by mouth, one tramadol or placebo, the other naltrexone or placebo.

A pain assessment was performed pre-treatment. Following the dental surgery, the subject's pain level was assessed by a trained observer. The subject reported the initial pain intensity by both (1) verbalizing one pain category (0 = none, 1 = mild, 2 = moderate or 3 = severe), and (2) using a Visual Analog Scale (VAS) of 0 -100 mm where 0 = no pain and 100 = worst pain imaginable, by placing a single slash on the scale. A pain assessment was also performed post-treatment. The efficacy and safety evaluations included pain intensity, pain relief, global pain evaluation, evaluation of time to meaningful pain relief (stop watch), visual scale analog (VAS), and adverse event assessments. For the data analysis, certain pain parameters were computed as generally described above. The placebo treatment group had the lowest mean 4-hour Total Pain Relief scores. All 4 of the active treatment groups exhibited mean 4-hour Total Pain Relief scores that were numerically higher than placebo. The combination treatments had a reverse dose-response relation in the mean 4-hour Total Pain Relief scores, i.e., the highest dose of NTX had the lowest mean 4-hour Total Pain Relief scores and the lowest dose of NTX had the highest mean 4-hour Total Pain Relief scores. The mean

4-hour Total Pain Relief scores for the 0.01-mg NTX and 0.1-mg NTX combination treatments were higher than that for the T alone treatment, whereas the 1.0-mg NTX combination treatment mean was lower than that for the T alone treatment.

The placebo treatment had the lowest mean 4-hour Sum of Pain Intensity Differences scores. All 4 of the active treatment groups exhibited improved profiles in mean 4-hour Sum of Pain Intensity Differences relative to placebo. The mean 4- hour Sum of Pain Intensity Differences scores for the 0.01-mg NTX and 0.1-mg NTX combination treatments were higher than that for the T alone treatment, whereas the 1.0-mg NTX combmation treatment was lower than that for the T alone treatment. The patterns of the 6-hour and 8-hour Sum of Pain Intensity Differences scores were similar to those at 4 hours.

The 4, 6, and 8 hour Visual Analog Scale Sum of Pain Intensity Differences results were as follows. The placebo treatment had the lowest mean 4-hour VAS-Sum of Pain Intensity Differences. The 4 active treatment groups exhibited mean VAS- Sum of Pain Intensity Differences scores that were higher than that for the placebo.

The mean 4-hour VAS-Sum of Pain Intensity Differences for the 3 NTX combination treatments was higher than that for T alone. The profiles of 6-hour and 8-hour VAS- Sum of Pain Intensity Differences scores were similar to those at 4 hours.

The placebo treatment had the lowest number of subjects who reached meaningful pain relief. In addition, all the combination treatment groups had higher numbers of subjects reaching meaningful pain relief than did the group that received T alone. Whereas the hourly pain relief scores for the placebo treatment were generally flat, those for the active treatment groups were generally improving over time. There was separation between the placebo and the active treatment groups that continued throughout the 8-hour study period. The majority of adverse events reported were categorized as gastrointestinal disorders (nausea or vomiting) or nervous system disorders (dizziness, headache or sedation).

The results from this clinical study using tramadol alone and in combination with naltrexone were analyzed by gender. The results for females and males with respect to pain intensity difference (PID) scores are shown in Tables 93 A and 93B and in Figures 52A and 52B.

Table 93A

Pain Intensity Difference (PID) Scores

Intent-to-Treat Po ulation, Female Patients

PATN INTENSITY SCORE: 0=NONE, 1-MILD, 2=MODERATE, 3=SEVERE. THE PAIN INTENSITY DIFFERENCE (PID) AT EACH

TIME POINT IS CALCULATED AS THE DIFFERENCE BETWEEN THE PATN INTENSITY SCORE AT HOUR 0 AND THE SCORE AT

OBSERVATION TIME.

[1] P-VALUES COMPARING ALL 5 TREATMENT GROUPS AND PAIRWISE COMPARISONS ARE DETERMINED USING ANOVA.

*SIGNIFICANCE IS AT 0.05 NOMINAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSING VALUES.

Table 93A (Continued)

Pain Intensity Difference (PID) Scores

Intent-to-Treat Po ulation, Female Patients

PAM MTENSITY SCORE: 0=NONE, 1-MILD, 2=MODERATE, 3=SEVERE. THE PAM MTENSITY DIFFERENCE (PID) AT EACH

TIME POMT IS CALCULATED AS THE DIFFERENCE BETWEEN THE PAM MTENSITY SCORE AT HOUR 0 AND THE SCORE AT

OBSERVATION TIME.

[1] P-VALUES COMPARING ALL 5 TREATMENT GROUPS AND PAIRWISE COMPARISONS ARE DETERMINED USMG ANOVA.

*SIGNIFICANCE IS AT 0.05 NOMMAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSMG VALUES.

Table 93A (Continued)

Pain Intensity Difference (PID) Scores

Intent-to-Treat Po ulation, Female Patients

PAM MTENSITY SCORE: 0=NONE, 1-MILD, 2=MODERATE, 3=SEVERE. THE PAM MTENSITY DIFFERENCE (PID) AT EACH TIME POMT IS CALCULATED AS THE DIFFERENCE BETWEEN THE PAM MTENSITY SCORE AT HOUR 0 AND THE SCORE AT OBSERVATION TIME. [1] P-VALUES COMPARING ALL 5 TREATMENT GROUPS AND PAIRWISE COMPARISONS ARE DETERMMED USMG ANOVA.

*SIGNΓFICANCE IS AT 0.05 NOMMAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSMG VALUES.

Table 93A (Continued)

Pain Intensity Difference (PID) Scores

Intent-to-Treat Po ulation Female Patients

PAM MTENSITY SCORE: 0=NONE, 1-MILD, 2=MODERATE, 3=SEVERE. THE PAJN MTENSITY DIFFERENCE (PID) AT EACH

TPME POMT IS CALCULATED AS THE DIFFERENCE BETWEEN THE PAM INTENSITY SCORE AT HOUR 0 AND THE SCORE AT

OBSERVATION TIME.

[1] P-VALUES COMPARMG ALL 5 TREATMENT GROUPS AND PAIRWISE COMPARISONS ARE DETERMINED USMG ANOVA.

*SIGNLFICANCE IS AT 0.05 NOMMAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSMG VALUES.

Table 93A (Continued)

Pain Intensity Difference (PK)) Scores

Intent-to-Treat Po ulation, Female Patients

OBSERVATION TIME.

*SIGNTFICANCE IS AT 0.05 NOMMAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSMG VALUES.

OBSERVATION TIME.

^♦SIGNIFICANCE IS AT 0.05 NOMMAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSMG VALUES.

Table 93B (Continued)

Pain Intensity Difference (PID) Scores

Intent-to-Treat Po ulation, Male Patients

OBSERVATION TIME.

*SIGNIFICANCE IS AT 0.05 NOMMAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSMG VALUES.

Table 93B (Continued)

Pain Intensity Difference (PHD) Scores

Intent-to-Treat Po ulation, Male Patients

PAM MTENSITY SCORE: 0=NONE, 1-MILD, 2=MODERATE, 3=SEVERE. THE PAM MTENSITY DIFFERENCE (PHD) AT EACH

OBSERVATION TIME.

*SIGNTFICANCE IS AT 0.05 NOMMAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSMG VALUES.

Table 93B (Continued)

Pain Intensity Difference (PID) Scores

Intent-to-Treat Po ulation, Male Patients

OBSERVATION TIME.

[1] P-VALUES COMPARMG ALL 5 TREATMENT GROUPS AND PAIRWISE COMPARISONS ARE DETERMMED USMG ANOVA.

*SIGNTFICANCE IS AT 0.05 NOMMAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSMG VALUES.

Table 93B (Continued)

Pain Intensity Difference (PID) Scores

Intent-to-Treat Po ulation, Male Patients

OBSERVATION TIME.

*SIGNIFICANCE IS AT 0.05 NOMMAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSMG VALUES.

Claims

WHAT IS CLAIMED IS:

1. A method for enhancing the potency of an opioid agonist in a human subject comprising administering to the human subject an analgesic or subanalgesic amount of the agonist and an amount of an opioid antagonist effective to enhance the analgesic potency of the agonist without attenuating an adverse side effect of the agonist.

2. A method according to claim 1 wherein the opioid agonist is morphine, hydrocodone, oxycodone, or tramadol.

3. A method according to claim 1 wherein the opioid agonist is morphine.

4. A method according to claim 1 wherein the opioid antagonist is naltrexone, naloxone, or nalmefene.

5. A method according to claim 1 wherein the opioid antagonist is naltrexone.

6. A method according to claim 1 wherein the opioid antagonist is nalmefene.

7. A method according to claim 1 wherein the administration is oral, sublingual, intramuscular, subcutaneous, intravenous, transmucosal or transdermal.

8. A method according to claim 1 wherein the administration is oral.

9. A method according to claim 1 wherein the human subject is male.

10. A method according to claim 1 wherein the human subject is female.

11. A method for attenuating an adverse side effect associated with administration of an opioid agonist to a human subject comprising administering to the human subject an analgesic or subanalgesic amount of the agonist and an amount of an opioid antagonist effective to attenuate the adverse side effect while maintaining analgesic potency of the agonist.

12. A method according to claim 11 wherein the adverse side effect is nausea, vomiting, dizziness, headache, sedation or pruritus.

13. A method according to claim 11 wherein the opioid agonist is morphine, hydrocodone, oxycodone or tramadol.

14. A method according to claim 11 wherein the opioid agonist is morphine.

15. A method according to claim 11 wherein the opioid antagonist naltrexone, naloxone, or nalmefene.

16. A method according to claim 11 wherein the opioid antagonist is naltrexone.

17. A method according to claim 11 wherein the opioid antagonist is nalmefene.

18. A method according to claim 11 wherein the administration is oral, sublingual, intramuscular, subcutaneous, intravenous, transmucosal or transdermal.

19. A method according to claim 11 wherein the administration is oral.

20. A method according to claim 11 wherein the analgesic potency of the agonist is maintained without increasing or decreasing the cumulative daily dose of the agonist relative to the antagonist.

21. A method according to claim 11 wherein the human subject is female.

22. A method according to claim 11 wherein the human subject is male.

23. A method for treating pain in a human subject comprising administering to the human subject an analgesic or subanalgesic amount of the agonist and an amount of an opioid antagonist effective to enhance the analgesic potency of the agonist without attenuating an adverse side effect of the agonist.

24. A method according to claim 23 wherein the opioid antagonist is morphine.

25. A method according to claim 23 wherein the opioid antagonist is naltrexone, naloxone, or nalmefene.

26. A method according to claim 23 wherein the opioid antagonist is naltrexone.

27. A method according to claim 23 wherein the opioid antagonist is nalmefene.

28. A method according to claim 23 wherein the administration is oral, sublingual, intramuscular, subcutaneous, intravenous, transmucosal or transdermal.

29. A method according to claim 23 wherein the administration is oral.

30. A method according to claim 23 wherein the human subject is male.

31. A method according to claim 23 wherein the human subject is female.

32. A method for treating pain with an opioid agonist and attenuating an adverse side effect of the agonist in a human subject comprising administering to the human subject an analgesic amount of the agonist and an amount of an opioid antagonist effective to attenuate the adverse side effect while maintaining analgesic potency of the agonist.

33. A method according to claim 32 wherein the opioid agonist is morphine, hydrocodone, oxycodone or tramadol.

34. The method according to claim 32 wherein the opioid agonist is morphine.

35. A method according to claim 32 wherein the opioid antagomst is naltrexone, naloxone, or nalmefene.

36. A method according to claim 32 wherein the opioid antagonist is naltrexone.

37. A method according to claim 32 wherein the opioid antagonist is nalmefene.

38. A method according to claim 32 wherein the administration is oral, sublingual, intramuscular, subcutaneous, intravenous, transmucosal or transdermal.

39. A method according to claim 32 wherein the administration is oral.

40. A method according to claim 32 wherein the analgesic potency of the agonist is maintained without increasing or decreasing the cumulative daily dose of the agonist relative to the antagonist.

41. A method according to claim 32 wherein the human subject is female.

42. A method according to claim 32 wherein the human subject is male.

43. A composition comprising an analgesic or subanalgesic amount of the agonist and an amount of an opioid antagonist effective to enhance the analgesic potency of the agonist without attenuating an adverse side effect of the agonist.

44. A composition according to claim 43 wherein the opioid agonist is morphine, hydrocodone, oxycodone, or tramadol.

45. A composition according to claim 43 wherein the opioid agonist if morphine.

46. A composition according to claim 43 wherein the opioid antagonist is naltrexone, naloxone, or nalmefene.

47. A composition according to claim 43 wherein the opioid antagonist is naltrexone.

48. A composition according to claim 43 wherein the opioid antagonist of nalmefene.

49. A composition according to claim 43 wherein the administration is oral, sublingual, intramuscular, subcutaneous, intravenous, transmucosal or transdermal.

50. A composition according to claim 43 wherein the administration is oral.

51. A composition comprising an analgesic amount of the agonist and an amount of an opioid antagonist effective to attenuate the adverse side effect while maintaining analgesic potency of the agonist.

52. A composition according to claim 51 wherein the opioid agonist is morphine, hydrocodone, oxycodone, or tramadol.

53. A composition according to claim 51 wherein the opioid agonist is morphine.

54. A composition according to claim 51 wherein the opioid antagonist is naltrexone, naloxone, or nalmefene.

55. A composition according to claim 51 wherein the opioid antagonist is naltrexone.

56. A composition according to claim 51 wherein the opioid antagonist is nalmefene.

57. A composition according to claim 51 wherein the administration is oral, sublingual, intramuscular, subcutaneous, intravenous, transmucosal or transdermal.

58. A composition according to claim 51 wherein the administration is oral.

59. A composition according to claim 51 wherein the analgesic potency of the agonist is maintained without increasing or decreasing the cumulative daily dose of the agonist relative to the antagonist.

60. A method providing or enhancing pain relief in men comprising administering to a man a hypo-analgesic dose of a non-kappa opioid receptor agonist and a dose of an opioid antagonist that in combination provides or enhances pain relief.

61. A method according to claim 60 wherein the non-kappa opioid receptor agonist is a mu opioid receptor agonist.

62. A method according to claim 60 wherein the hypo-analgesic dose of the agonist is a non-analgesic dose or an anti-analgesic dose in men and an analgesic dose in women.

63. A method according to claim 60 wherein the dose of the antagonist prolongs the time to remedication.

64. A method according to claim 60 wherein the dose of the antagonist enhances the global evaluation of pain relief.

65. A method according to claim 60 wherein the agonist is morphine.

66. A method according to claim 60 wherein the antagonist is naltrexone.

67. A method according to claim 60 wherein the pain relief is measured by the men using a categorical scale or a visual analog scale.

68. A composition for providing or enhancing pain relief in men comprising a hypo-analgesic amount of a non-kappa opioid receptor agonist and an amount of an opioid antagonist that in combination provides or enhances pain relief.

69. A composition according to claim 68 wherein the non-kappa opioid receptor agonist is a mu opioid receptor agonist.

70. A composition according to claim 68 wherein the hypo-analgesic amount of the agonist is a non-analgesic dose or an anti-analgesic amount in men and an analgesic dose in women.

71. A composition according to claim 68 wherein the dose of the antagonist prolongs the time to remedication.

72. A composition according to claim 68 wherein the dose of the antagomst enhances the global evaluation of pain relief.

73. A composition according to claim 68 wherein the agonist is morphine.

74. A composition according to claim 68 wherein the antagonist is naltrexone.

75. A composition according to claim 68 wherein the pain relief produced by the composition is measured by the men using a categorical scale or a visual analog scale.

76. A method of enhancing pain relief in women comprising administering to a woman an analgesic dose of a non-kappa opioid receptor agonist and a dose of opioid antagonist that in combination provides pain relief comparable to that of the agonist alone but with attenuation of one or more adverse side effects of the agonist.

77. A method according to claim 76 wherein the non-kappa opioid receptor agonist is a mu opioid receptor agonist.

78. A method according to claim 76 wherein the dose of the agonist is an analgesic dose in women and a hypo-analgesic dose in men.

79. A method according to claim 76 wherein the dose of the antagonist prolongs the time to remedication.

80. A method according to claim 76 wherein the dose of the antagonist enhances the global evaluation of pain relief.

81. A method according to claim 76 wherein the agonist is morphine.

82. A method according to claim 76 wherein the antagonist is naltrexone.

83. A method according to claim 76 wherein the pain relief is measured by the women using a categorical scale or a visual analog scale.

84. A composition for enhancing pain relief in women comprising an analgesic amount of a non-kappa opioid receptor agonist and an amount of an opioid antagonist that in combination provides pain relief comparable to that of the agomst alone but with attenuation of one or more adverse side effects of the agonist.

85. A composition according to claim 84 wherein the non-kappa opioid receptor agonist is a mu opioid receptor agonist.

86. A composition according to claim 84 wherein the amount of the agonist is an analgesic amount in women and a hypo-analgesic amount in men.

87. A composition according to claim 84 wherein the amount of the antagonist prolongs the time to remedication.

88. A composition according to claim 84 wherein the dose of the antagonist enhances the global evaluation of pain relief.

89. A composition according to claim 84 wherein the agonist is morphine.

90. A composition according to claim 84 wherein the antagonist is naltrexone.

91. A composition according to claim 84 wherein the pain relief produced by the composition is measured by the women using a categorical scale or a visual analog scale.

92. A composition for treating pain in women, comprising:

(a) morphine in a dose range of about 0.1 mg to about 300 mg; and;

(b) naltrexone in a dose range of about 0.0001 mg to about 1.0 mg.

93. A composition according to claim 92 wherein:

(a) morphine is about 15 mg, 30 mg, 60 mg or 90 mg; and (b) naltrexone is about 0.001 mg, 0.01 mg, 0.1 mg or 1.0 mg.

94. A composition for treating pain in men, comprising:

(a) morphine in a dose range of about 0.1 mg to about 300 mg; and

(b) naltrexone in a dose range of about 0.0001 mg to about 1 mg.

95. A composition according to claim 94 wherein:

(a) morphine is about 15 mg, 30 mg, 60 mg or 90 mg; and

(b) naltrexone is about 0.001 mg, 0.01 mg, 0.1 mg or 1.0 mg.

96. A composition for treating pain in men, comprising:

(a) hydrocodone; (b) acetaminophen; and

(c) an amount of naltrexone sufficient to enhance analgesia associated with (a) or (b) above.

97. A composition according to claim 96, wherein the amount of the hydrocodone is about 5 mg.

98. A composition according to claim 96, wherein the amount of the acetominophen is about 500 mg.

99. A composition according to claim 96, wherein the amount of the naltrexone is about 0.001 mg.

100. A composition for treating pain in women, comprising: (a) hydrocodone;

(b) acetaminophen; and

(c) an amount of naltrexone sufficient to attenuate an adverse side effect associated with (a) or (b) above.

101. A composition according to claim 100, wherein the amount of the hydrocodone is about 5 mg.

102. A composition according to claim 100, wherein the amount of the acetominophen is about 500 mg.

103. A method for providing analgesia in a human subject administered a non-analgesic amount of an opioid agonist comprising concurrently administering with the agonist, an amount of opioid antagonist effective to provide analgesia.

104. A method according to claim 103 wherein the human subject is a man.

105. A method according to claim 104 wherein the opioid agonist is morphine.

106. A method according to claim 103 wherein the human subject is a woman.

107. A method according to claim 106 wherein the opioid agonist is tramadol.

108. A method of converting a hypo-analgesic dose of an opioid agonist into an analgesic dose of the agonist comprising administering to a human subject a combination of the hypo-analgesic dose of the agonist and an amount of an opioid antagonist sufficient to provide analgesia.

109. A method according to claim 108 wherein the opioid agonist is moφhine, hydrocodone, oxycodone, or tramadol.

110. A method according to claim 108 wherein the opioid agonist is morphine.

111. A method according to claim 108 wherein the opioid antagonist is naltrexone, naloxone, or nalmefene.

112. A method according to claim 108 wherein the opioid antagonist is naltrexone.

113. A method according to claim 108 wherein the opioid antagonist is nalmefene.

114. A method according to claim 108 wherein the administration is oral, sublingual, intramuscular, subcutaneous, intravenous, transmucosal or transdermal.

115. A method according to claim 108 wherein the administration is oral.

116. A method according to claim 108 wherein the human subj ect is male.

117. A method according to claim 108 wherein the human subject is female.

118. A method according to claim 108 wherein the hypo-analgesic dose of the agonist is a non-analgesic dose or an anti-analgesic dose in men and an analgesic dose in women.

119. A method according to claim 108 wherein the dose of the antagonist prolongs the time to remedication.

120. A method according to claim 108 wherein the analgesia is measured by a pain relief score or a pain intensity difference score using a categorical scale or a visual analog scale.