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EP1280529A2 - Nouvelles compositions et methodes destinees a ameliorer la puissance ou reduire les effets secondaires indesirables d'agonistes opioides - Google Patents

Nouvelles compositions et methodes destinees a ameliorer la puissance ou reduire les effets secondaires indesirables d'agonistes opioides

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Publication number
EP1280529A2
EP1280529A2 EP01933110A EP01933110A EP1280529A2 EP 1280529 A2 EP1280529 A2 EP 1280529A2 EP 01933110 A EP01933110 A EP 01933110A EP 01933110 A EP01933110 A EP 01933110A EP 1280529 A2 EP1280529 A2 EP 1280529A2
Authority
EP
European Patent Office
Prior art keywords
agonist
ntx
opioid
dose
analgesic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01933110A
Other languages
German (de)
English (en)
Inventor
Barry Sherman
Mary Remien
Remi Barbier
Kathleen Dumas
Grant Schoenhard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Albert Einstein College of Medicine
Pain Therapeutics Inc
Original Assignee
Albert Einstein College of Medicine
Pain Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2000/012493 external-priority patent/WO2000067739A2/fr
Application filed by Albert Einstein College of Medicine, Pain Therapeutics Inc filed Critical Albert Einstein College of Medicine
Publication of EP1280529A2 publication Critical patent/EP1280529A2/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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.
  • 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.
  • opioid agonists such as heroin or morphine.
  • 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
  • Naltrexone 17-(cyclopropylmethyl)-4,5-epoxy-3 , 14-dihydroxy-morphinan-6-one
  • 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
  • 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.
  • 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.
  • opioid agonists such as morphine
  • other actions of opioid agonists such, as morphine 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).
  • 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 e.g., U.S. Patent No. 5,512,578 reissued as RE 36,457
  • an opioid antagonist such as naloxone or naltrexone
  • 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 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.
  • 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.
  • 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.
  • 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)].
  • Miaskowski and Levine summarize data from human studies on sex-related differences in responses to opioid analgesics, particularly kappa opioids.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • opioid antagonists such as naltrexone
  • 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.
  • a non-kappa opioid receptor agonist preferably a mu opioid receptor agonist
  • 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.
  • opioid receptor agonist preferably a non- kappa opioid receptor agonist, most preferably a mu opioid receptor agonist
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 NTX
  • morphine and high dose 1.0 mg
  • 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 ( ⁇ ); 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.
  • PID pain intensity difference
  • 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.
  • SPUD pain intensity difference
  • Figures 10A and 10B show the time to onset of meaningful pain relief results
  • 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.
  • placebo 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.
  • placebo 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.
  • NTX naltrexone
  • morphine and mid- dose 0.1 mg
  • morphine and high-dose 1.0 mg
  • 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.
  • placebo 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.
  • NTX naltrexone
  • morphine and mid-dose 0.1 mg
  • morphine and high-dose 1.0 mg
  • 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 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)
  • 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
  • NTX 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)
  • 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)
  • 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.
  • SPED pain intensity difference
  • Figures 24A and 24B show the time to onset of meaningful pain relief results
  • 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
  • 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.
  • PID pain intensity difference
  • Figures 29A for women 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
  • NTX naltrexone
  • C HC/APAP and 0.1 mg NTX
  • D HC/APAP and 0.01 mg NTX
  • E HC/APAP and 0.001 mg NTX
  • 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
  • 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).
  • placebo A
  • B HC/APAP
  • C HC/APAP and 1.0 mg naltrexone
  • D HC/APAP and 0.1 mg NTX
  • E HC/APAP and 0.01 mg NTX
  • F HC/APAP and 0.001 mg NTX
  • 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).
  • placebo A
  • B HC/APAP
  • C HC/APAP and 1.0 mg naltrexone
  • D HC/APAP and 0.1 mg NTX
  • E HC/APAP and 0.01 mg NTX
  • F HC/APAP and 0.001 mg NTX
  • 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).
  • placebo A
  • B HC/APAP
  • C HC/APAP and 1.0 mg naltrexone
  • D HC/APAP and 0.1 mg NTX
  • E HC/APAP and 0.01 mg NTX
  • F HC/APAP and 0.001 mg NTX
  • 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 NTX
  • HC/APAP 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 NTX
  • HC/APAP 0.1 mg NTX
  • HC/APAP 1.0 mg NTX.
  • Figures 39A and 39B show the time to remedication (rescue medication) up to
  • Example 6 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);
  • 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
  • Example 7 placebo; morphine (30 mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 mg); mo ⁇ hine (60 mg) and NTX (0.1 mg); morphine (90 mg); mo ⁇ hine (90 mg) and NTX
  • 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; mo ⁇ hine (30 mg); mo ⁇ hine (30 mg) and NTX (0.1 mg); mo ⁇ hine (60 mg); mo ⁇ hine (60 mg) and
  • 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; mo ⁇ hine (30 mg); mo ⁇ hine (30 mg) and NTX (0.1 mg); mo ⁇ hine (60 mg); mo ⁇ hine (60 mg) and NTX (0.1 mg); mo ⁇ hine (90 mg); mo ⁇ hine (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 mo ⁇ hine 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 mo ⁇ hine 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 mo ⁇ hine 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).
  • 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 su ⁇ rising results from clinical trials that the analgesic potency effects of opioid agonists can be dissociated from their adverse effects in humans.
  • 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.
  • 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.
  • 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 mo ⁇ hine 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
  • 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.
  • 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.
  • a non- kappa opioid receptor agonist preferably a mu opioid receptor agonist
  • opioid receptor antagonist e.g., in number and/or severity
  • 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.
  • a non-kappa opioid receptor agonist preferably a mu opioid receptor agonist
  • the adverse side effects are attenuated.
  • 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.
  • responder human subjects e.g., women
  • 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.
  • compositions and methods of the invention useful for human subjects e.g., patients
  • 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 mo ⁇ hine and its metabolite mo ⁇ hine-6- glucuronide and the antagonist naltrexone and its metabolite and opioid peptides, including enkephalins, dyno ⁇ hins and endo ⁇ hins.
  • 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.
  • opiate refers to drugs derived from opium or related analogs.
  • 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.
  • 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.
  • 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.
  • opioid receptor agonist 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, apomo ⁇ hine, apocodeine, benzylmo ⁇ hine, bezitramide, bupreno ⁇ hine, buto ⁇ hanol, clonitazene, codeine, cyclazocine, cyclo ⁇ hen, cypreno ⁇ hine, desomo ⁇ hine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromo ⁇ hine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmo ⁇ hine, etonitazene, fentanyl, heroin, hydrocodone, hydroxymethylm
  • Preferred opioid agonists for human use are mo ⁇ hine, hydrocodone, oxycodone, codeine, fentanyl (and its relatives), hydromo ⁇ hone, meperidine, methadone, oxymo ⁇ hone, propoxyphene or tramadol, or mixtures thereof.
  • Particularly preferred opioid agonists include mo ⁇ hine, 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.
  • APD action potential duration
  • DRG dorsal root ganglion
  • 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 ⁇ M concentrations (i.e., inhibitory effects).
  • a “non-kappa opioid receptor agonist” or “mo ⁇ hine-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 buto ⁇ hanol.
  • Such agonists include, for example, mo ⁇ hine, hydrocodone, oxycodone, codeine, hydromo ⁇ hone, levo ⁇ hanol, meperidine, fentanyl, (and its relatives), oxymo ⁇ hone, propoxyphene, methadone or tramadol.
  • a preferred non-kappa opioid agonist is a mu opioid receptor agonist.
  • 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 mo ⁇ hine, 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 buto ⁇ hanol.
  • analgesic activity such as mo ⁇ hine, hydrocodone, and oxycodone
  • 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 buto ⁇ hanol.
  • Selective delta opioid receptor agonists include those described by U.S. Patent Nos.
  • 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 buto ⁇ henal.
  • Selective mu-delta opioid receptor agonists include those described by U.S. Patent No. 5,389,645 hereby inco ⁇ orated by reference in its entirety [e.g., tyrosyldiamine amide opioid agonists such as U.S. Patent No. 6,054,557 hereby inco ⁇ orated by reference in its entirety; U.S. Patent No. 5,872,097 hereby inco ⁇ orated by reference in its entirety; U.S. Patent Nos. 6,568,908, 5,681,830,
  • 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 buto ⁇ henol.
  • Selective kappa opioid agonists include those described by: U.S. Patent No. 4,923,863 hereby inco ⁇ orated by reference in its entirety [e.g., mo ⁇ holine derivatives]; U.S. Patent No. 6,110,947 hereby inco ⁇ orated by reference in its entirety [e.g., pyrrolidinyl hydroxamic acid compounds]; U.S. Patent No.
  • 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 buto ⁇ hanol.
  • Selective sigma opioid agonists include those described by: U.S. Patent Nos. 5,656,633 and 5,556,857, both inco ⁇ orated by reference (e.g., carbostyril derivatives).
  • 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 include: naltrexone, naloxone nalmefene, naloxone methiodide, nalo ⁇ hine, naloxonazine, nalide, nalmexone, nalbuphine, nalo ⁇ hine dinicotinate, naltrindole (NTI), naltrindole isothiocyanate,
  • NTH naltriben
  • NB naltriben
  • b-FNA b-funaltrexamine
  • BNTX cyprodime
  • ICI-174,864, LYl 17413, MR2266 or an opioid antagonist having the same pentacyclic nucleus as nalmefene, naltrexone, nalo ⁇ hine, nalbuphine, thebaine, levallo ⁇ han, oxymo ⁇ hone, buto ⁇ hanol, bupreno ⁇ hine, levo ⁇ hanol, 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.
  • APD action potential duration
  • 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.
  • 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.
  • opioid agonists or opioid antagonists may be provided in the form of free bases or pharmaceutically acceptable acid addition salts.
  • 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.
  • 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.
  • 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.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and others known
  • 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 pu ⁇ ose.
  • the salt may include an amine-based (primary, secondary, tertiary or quaternary amine) counter ion, an alkali metal cation, or a metal cation.
  • amine-based (primary, secondary, tertiary or quaternary amine) counter ion an alkali metal cation, or a metal cation.
  • suitable salts are found in texts such as Remington's Pharmaceutical Sciences, 18 th Ed. (Alfonso R. Gennaro, ed.; Mack Publishing
  • An "adverse side effect" of an opioid agonist is a side effect in humans, typically associated with opioid analgesics such as mo ⁇ hine, 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.
  • opioid agonists may produce certain adverse side effects.
  • side effects that have been recognized for products containing mo ⁇ hine 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.
  • PDR Physician Desk Reference
  • opioid agonists as follows: mo ⁇ hine: 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
  • Co-administer 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.
  • 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).
  • an additional active pharmaceutical ingredient may be co-administered with the opioid agonist and opioid antagonist.
  • active pharmaceutical ingredients include acetaminophen as shown herein, steroidal drugs or non-steroidal anti-inflammatory drugs (NSA ⁇ DS) such as ibuprofen, COX-1 and/or COX-2 inhibitors such as aspirin, rofecoxib (marketed as VIOXX®), and celcoxib (marketed as CELEBREXTM).
  • NSA ⁇ DS non-steroidal anti-inflammatory drugs
  • COX-1 and/or COX-2 inhibitors such as aspirin, rofecoxib (marketed as VIOXX®), and celcoxib (marketed as CELEBREXTM).
  • “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.
  • 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.
  • 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.
  • active material e.g., non-kappa opioid receptor agonist and/or opioid antagonist and/or other active pharmaceutical ingredient
  • 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.
  • 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
  • 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
  • hydromo ⁇ hone e.g., DILAUDID® from Knoll
  • levo ⁇ hanol e.g., LEVO-DROMORAN® from ICN Pharmaceuticals
  • meperidine e.g., DEMEROL® from Sanofi Pharmaceuticals
  • methadone e.g., METHADOSE® from Mallinckrodt
  • DOLOPHINE® HCl from Roxane Laboratories
  • mo ⁇ hine e.g., KADIAN® from Faulding Laboratories; MS
  • 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
  • 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).
  • 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), hydromo ⁇ hone (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).
  • hydrocodone e.g., HYDROPHANE® from Halsey
  • hydromo ⁇ hone e.g., DILAUDID® from Knoll
  • meperidine e.g., DEMEROL® from Sanofi
  • methadone e.g., DOLOPHINE® from Roxane
  • oxycodone e.g., HYCOMLNE® from Knoll; RO
  • the compounds may be combined with a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
  • 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), bupreno ⁇ hine (e.g., BUPRENEX® from Reckitt & Colman Pharmaceuticals), buto ⁇ hanol (e.g., STADOL® from Apothecon), dezocine (e.g., DALGAN® from Astrazeneca), fentanyl, hydromo ⁇ hone (e.g., DILAUDID-HP® from Knoll), levallo ⁇ han (e.g., LORFAN® from Roche), levo ⁇ hanol (e.g., LEVO-DROMORAN® from ICN), meperidine (e.g., DEMEROL® from Sanofi), methadone (e.g., DOLOPHINE® HCl from Roxane), mo ⁇ hine (e.g, ASTRAMORPH® from Astrazeneca; DURAMORPH® and INFUMORPH® from
  • oxymo ⁇ hone e.g., NUMORPHAN® from Endo
  • nalbu ⁇ hine e.g., NUBAIN® from Endo Pharmaceutical
  • pentazocine TALWLN® from Abbott
  • 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.
  • 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
  • oxymo ⁇ hone e.g., NUMORPHAN® from Endo
  • 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.
  • 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.
  • 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.
  • 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.
  • opioid agonists such as mo ⁇ hine, hydrocodone, or tramadol
  • naltrexone an opioid antagonist
  • 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 mo ⁇ hine, hydrocodone or tramadol are strikingly different in women and men.
  • 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 mo ⁇ hine.
  • subjects had two or more impacted third molars requiring extraction, wherein at least one extracted tooth was a partial or full bony mandibular impaction.
  • 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 mo ⁇ hine 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 mo ⁇ hine.
  • naltrexone 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).
  • PID pain intensity differences
  • 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.
  • the PID score in the female subjects decreased below 0, indicating that the subjects experienced increased pain.
  • naltrexone 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.
  • 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 mo ⁇ hine individually.
  • the combination of naltrexone and mo ⁇ hine at certain times and at certain concentrations caused a decrease in analgesia as compared with mo ⁇ hine alone.
  • the lowest dose of naltrexone (0.001 mg) administered in combination with mo ⁇ hine decreased the PLD score produced in the presence of mo ⁇ hine from a peak of about
  • naltrexone having maximal effect in females when administered with 60 mg mo ⁇ hine is about 0.01 mg.
  • naltrexone at doses of 0.01 mg and 0.1 mg each potentiated the analgesia associated with mo ⁇ hine (60 mg).
  • naltrexone decreased the analgesia associated with mo ⁇ hine.
  • the lowest dose of naltrexone (0.001 mg) increased analgesia in the presence of 60 mg mo ⁇ hine.
  • 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.
  • naltrexone in combination with mo ⁇ hine produced more analgesia than did mo ⁇ hine alone.
  • the effect of naltrexone was dose-dependent with the highest doses (1.0 mg) having the greatest effect.
  • Gender-based opioid compositions according to the invention may have therapeutic advantages.
  • females can exhibit significant analgesic responses to an opioid agonist such as mo ⁇ hine, and at certain doses, an opioid antagonist such as naltrexone can potentiate the analgesia induced by mo ⁇ hine.
  • an opioid antagonist such as naltrexone
  • effective doses of an opioid agonist such as mo ⁇ hine may have undesirable adverse side effects, including nausea, vomiting, other gastrointestinal symptoms, and other serious side effects such as respiratory depression.
  • an opioid antagonist such as naltrexone by itself may increase pain in females experiencing pain.
  • compositions are provided for use in females comprising low concentrations of opioid agonists including, by way of example only, mo ⁇ hine 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.
  • opioid agonists including, by way of example only, mo ⁇ hine or oxycodone
  • naltrexone that are sufficiently low to avoid producing undesirable adverse side effects themselves.
  • compositions are provided for use in males comprising concentrations of mo ⁇ hine 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 mo ⁇ hine.
  • an opioid antagonist such as naltrexone can substantially potentiate or enhance the effects of an opioid agonist such as mo ⁇ hine, it is now possible to reduce the dose of an opioid agonist such as mo ⁇ hine 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.
  • 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, inco ⁇ orated 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 inco ⁇ orated by reference herein.
  • compositions were compendial in the USP/NF, when there was an existing monograph.
  • NTX naltrexone HCl
  • 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.
  • preblended inactive components were 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.
  • naltrexone HCl e.g., 0.03% w/w/, 0.003 % w/w, and 0.0003% w/w
  • naltrexone HCl e.g., 0.03% w/w/, 0.003 % w/w, and 0.0003% w/w
  • 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 mo ⁇ hine were prepared from commercially obtained tablets (Roxane), which contained 15 mg mo ⁇ hine sulfate pentahydrate and various inactive components.
  • Roxane commercially obtained tablets
  • a 60 mg mo ⁇ hine sulfate strength capsule was made by mixing (e.g., microcrystalline cellulose and magnesium stearate) to form a blend, and this blend and four mo ⁇ hine 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.
  • 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 mo ⁇ hine-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.
  • 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.
  • NTX naltrexone
  • 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:
  • subjects able to remain at the study site for the entire eight-hour study period 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
  • 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;
  • 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;
  • 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.
  • 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;
  • SPLD-8 8-Hour Sum of Pain Intensity Difference Scores
  • 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.
  • TOTPAR-8 total pain relief score
  • SPLD-8 sum of pain intensity differences
  • MAXPAR maximum pain relief score
  • PEAKPID peak pain intensity difference
  • 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.
  • 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.
  • ITT intent-to-treat
  • Demographic and baseline characteristics were summarized with descriptive statistics (for continuous variables) or frequencies (for categorical variables).
  • ANOVA 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.
  • the sample size was estimated from historical data and from practical considerations rather than from calculation of expected measured differences.
  • 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).
  • 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
  • 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).
  • PALN INTENSITY DIFFERENCE PAIN INTENSITY AT BASELINE - PAIN INTENSITY AT CURRENT TIME.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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 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.
  • Figure 8 represents a summary of exemplary adverse side effects attenuated according to methods and compositions of the invention.
  • PLACEBO 40 0 TRT 0.512 0 0 0 0 0
  • PLACEBO 40 0 TRT 0.009** 0 0 0 0 0
  • Rhinitis A PLACEBO 40 1 ( 2.5%) TRT 0.196 1 1 (100.0%) 0 0
  • 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.
  • VAS Visual Analog Scale
  • Placebo 10 (55.6%) 8 (44.4%) 1.000 0.527 0.527 0.343 0.749
  • VAS Baseline Visual Analog Scale
  • the TOTPAR results (4 hour, 6 hour, 8 hour) are summa ⁇ ze ⁇ 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.
  • 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.
  • 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
  • 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.
  • the placebo treatment had the lowest mean 6 and 8 hour SPTD scores.
  • 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.
  • PAIN INTENSITY DIFFERENCE PATN INTENSITY AT BASELINE - PAJN INTENSITY AT CURRENT TIME.
  • PAIN INTENSITY DIFFERENCE PAIN INTENSITY AT BASELINE - PAJN INTENSITY AT CURRENT TIME.
  • PAIN INTENSITY DIFFERENCE PAIN INTENSITY AT BASELINE - PAIN INTENSITY AT CURRENT TIME.
  • PALN INTENSITY DIFFERENCE PAIN INTENSITY AT BASELINE - PAJN INTENSITY AT CURRENT TIME.
  • 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.
  • the median time to onset of meaningful pain relief was shortest in the 0.01 mg NTX (low-dose) combination treatment group.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • N/D 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.
  • 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.
  • 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.
  • the highest PID scores were most often observed for the high dose (1.0 mg NTX) combination group .

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Abstract

L'invention concerne d'une manière générale de nouvelles compositions et méthodes faisant intervenir un agoniste opioïde et un antagoniste opioïde pour obtenir un dosage différentiel d'un sujet humain de manière à soit améliorer la puissance analgésique sans atténuer un effet secondaire indésirable de l'agoniste, soit autrement maintenir la puissance analgésique de l'agoniste tout en atténuant un effet secondaire indésirable de l'agoniste. L'invention concerne également de nouvelles compositions opioïdes et méthodes de dosage basées sur le sexe chez l'homme et la femme.
EP01933110A 2000-05-05 2001-05-04 Nouvelles compositions et methodes destinees a ameliorer la puissance ou reduire les effets secondaires indesirables d'agonistes opioides Withdrawn EP1280529A2 (fr)

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WOPCT/US00/12493 2000-05-05
PCT/US2000/012493 WO2000067739A2 (fr) 1999-05-06 2000-05-05 Compositions et procedes permettant d'ameliorer la puissance analgesique du tramadol et d'attenuer ses effets secondaires negatifs
US202227P 2000-05-05
US202268P 2000-05-05
US566071 2000-05-05
US24448200P 2000-10-30 2000-10-30
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US75633101A 2001-01-08 2001-01-08
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