WO2014160077A1 - Compositions pour réduire la douleur comprenant un antagoniste opioïde du récepteur 4 de type toll, des énantiomères dextro associés, et leurs procédés d'utilisation - Google Patents

Compositions pour réduire la douleur comprenant un antagoniste opioïde du récepteur 4 de type toll, des énantiomères dextro associés, et leurs procédés d'utilisation Download PDF

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Publication number
WO2014160077A1
WO2014160077A1 PCT/US2014/025771 US2014025771W WO2014160077A1 WO 2014160077 A1 WO2014160077 A1 WO 2014160077A1 US 2014025771 W US2014025771 W US 2014025771W WO 2014160077 A1 WO2014160077 A1 WO 2014160077A1
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Prior art keywords
pain
pharmaceutically acceptable
naltrexone
composition
solvates
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PCT/US2014/025771
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English (en)
Inventor
Annette Channa Toledano
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Allodynic Therapeutics, Llc
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.)
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Publication date
Priority claimed from US13/799,287 external-priority patent/US20130310412A1/en
Priority claimed from US13/841,100 external-priority patent/US9205081B2/en
Priority claimed from US13/837,099 external-priority patent/US9095548B2/en
Priority claimed from US13/851,773 external-priority patent/US20150111917A9/en
Priority claimed from US13/851,267 external-priority patent/US20150111916A9/en
Application filed by Allodynic Therapeutics, Llc filed Critical Allodynic Therapeutics, Llc
Priority to EP14773349.7A priority Critical patent/EP2968293A4/fr
Priority to AU2014244152A priority patent/AU2014244152A1/en
Priority to JP2016501961A priority patent/JP2016512561A/ja
Priority to CA2942641A priority patent/CA2942641A1/fr
Publication of WO2014160077A1 publication Critical patent/WO2014160077A1/fr

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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

  • compositions comprising an opioid/TLR4 antagonist and dextro enantiomers thereof, compositions comprising combinations of an opioid/TLR4 antagonist and dextro enantiomers thereof with an alpha-2 adrenergic receptor agonist, acetyl-para-aminophenol (APAP), a cyclooxygenase (COX) inhibitor, and/or an alpha-2-delta ligand, particularly those that exhibit a synergistic effect for the treatment, prevention and reversal of pain.
  • APAP acetyl-para-aminophenol
  • COX cyclooxygenase
  • alpha-2-delta ligand particularly those that exhibit a synergistic effect for the treatment, prevention and reversal of pain.
  • This disclosure further relates to methods of treatment, prevention, and reversal of pain comprising administration of the compositions defined above.
  • This disclosure is a novel approach for the treatment of pain. It is directed to the treatment of neuropathic and nociceptive pain with an allodynic component. The components of the combination are directed to reducing neuropathic pain and the allodynic component associated with nociceptive pain. Specific combinations of drugs and the dosage needed to create that effect is the subject of the disclosure.
  • the opioid receptor antagonists exert their action in a site other than the opioid receptors. That site is the immune system receptor TLR4 located on glia cells.
  • composition comprising a compound that is an
  • the disclosure also provides synergistic compositions comprising an opioid/TLR4 antagonist, dextro enantiomeric mixtures thereof, or pharmaceutically acceptable salts thereof and an alpha-2 adrenergic receptor agonist, acetyl-para-aminophenol (APAP), a cyclooxygenase (COX) inhibitor, and/or an alpha-2-delta ligand.
  • the disclosure further provides a method of use of these synergistic compositions for the treatment, prevention, and reversal of pain, particularly neuropathic pain.
  • the disclosure provides a composition for treatment of pain in a mammal comprising a synergistic ratio of (a) an opioid/TLR4 antagonist, or pharmaceutically acceptable salts or solvates thereof and (b) a direct-acting alpha-2 adrenergic agonist, or pharmaceutically acceptable salts or solvates thereof.
  • the opioid/TLR4 antagonist is selected from a group consisting of naltrexone,
  • the opioid/TLR4 antagonist is naltrexone as well as pro drugs thereof or any enantiomeric and epimeric forms thereof, as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • the opioid/TLR4 antagonist is naltrexone in a sustained release formulation, as well as pro drugs thereof or any enantiomeric and epimeric forms thereof, as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • the opioid/TLR4 antagonist is (+)-naltrexone (dextro-naltrexone), as well as appropriate mixtures thereof, as well as pro drugs thereof, or pharmaceutically acceptable salts or solvates thereof. Dextro-naltrexone ((+)-naltrexone) blocks only the TLR-4 while not blocking the morphine receptors.
  • the direct-acting alpha 2 adrenergic agonist is selected from a group consisting of apraclonidine, brimonidine, clonidine, detomidine, dexmedetomidine, guanabenz, guanfacine, lofexidine, medetomidine, romifidine, tizanidine, tolonidine, xylazine and fadolmidine, or pharmaceutically acceptable salts or solvates of any thereof.
  • the direct-acting alpha-2 adrenergic agonist is clonidine, or pharmaceutically acceptable salts or solvates thereof.
  • the direct- acting alpha-2 adrenergic agonist is clonidine in a sustained release formulation, or pharmaceutically acceptable salts or solvates thereof.
  • the opioid/TLR4 antagonist is naltrexone, or
  • naltrexone and clonidine, or pharmaceutically acceptable salts or solvates of any thereof are in a weight to weight combination range which corresponds to a synergistic combination range of the order of 90:1 to 22.5:1 parts by weight.
  • the dose range of naltrexone, or pharmaceutically acceptable salts or solvates thereof is about 0.004 mg/kg- 0.71 mg/kg per day.
  • the dose range of clonidine, or pharmaceutically acceptable salts or solvates thereof is about 0.00018 mg/kg - 0.0086mg/kg per day.
  • the human dose range of naltrexone is 0.25 mg - 50 mg per day and the dose range of clonidine is 0.0125 mg - 0.6 mg, wherein said composition is formulated into a single fixed combination dosage form.
  • the human dose range of naltrexone is 0.25 mg - 15 mg per day and the dose range of clonidine is 0.0125 mg - 0.3 mg, wherein said composition is formulated into a single fixed combination dosage form.
  • the composition is administered once, twice, three or four times through the day.
  • the therapeutically effective dose of the pharmaceutical composition is administered systemically, including but are not limited to mucosal, nasal, oral, parenteral, gastrointestinal, topical or sublingual routes.
  • the combination is in a single dosage form, and said single dosage form is in the form of tablets, lozenges, troches, hard candies, liquid, powders, sprays, creams, salves and suppositories.
  • the composition is for treating, preventing and reversing pain.
  • the pain is back pain.
  • the pain is neuropathic pain.
  • the pain is migraine.
  • the pain is trigeminal neuralgia.
  • the pain is vulvodynia.
  • the pain is irritable bowel syndrome.
  • the pain is post herpetic neuralgia.
  • the pain is diabetic neuropathy.
  • the pain is nociceptive pain with an allodynic component.
  • the disclosure provides a composition for treatment of pain in a mammal comprising a synergistic ratio of (a) an opioid/TLR4 antagonist, or pharmaceutically acceptable salts or solvates thereof and (b) a acetyl-para-aminophenol, or pharmaceutically acceptable salts or solvates thereof.
  • the opioid/TLR4 antagonist is selected from a group consisting of naltrexone, norbinalto ⁇ himine, nalmefene, naloxone, nalorphine, methylnaltrexone, samidorphan, cyprodime, naltrindole, amentoflavone, naltriben, norbinaltorphimine, 6-6-naltrexol, metabolites and pro drugs thereof, including all enantiomeric and epimeric forms as well as the appropriate mixtures thereof, or
  • the opioid/TLR4 antagonist is naltrexone as well as pro drugs thereof or any enantiomeric and epimeric forms thereof, as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • the opioid/TLR4 antagonist is naltrexone in a sustained release formulation, as well as pro drugs thereof or any enantiomeric and epimeric forms thereof, as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • the opioid/TLR4 antagonist can be (+)-naltrexone (dextro- naltrexone), as well as appropriate mixtures thereof, as well as pro drugs thereof, or pharmaceutically acceptable salts or solvates thereof.
  • the acetyl-para- aminophenol or pharmaceutically acceptable salts or solvates thereof is the second compound.
  • the opioid/TLR4 antagonist is naltrexone, or pharmaceutically acceptable salts or solvates thereof, in a therapeutically effective amount and the acetyl-para-aminophenol is in therapeutically effective amount.
  • pharmaceutically acceptable salts or solvates of any thereof are in a weight to weight combination range which corresponds to a synergistic combination of 3:200 parts by weight.
  • the dose range of naltrexone, or pharmaceutically acceptable salts or solvates thereof is about 0.004 mg/kg-0.71 mg/kg and the dose range of acetyl-para- aminophenol, or pharmaceutically acceptable salts or solvates thereof, is about 5 mg/kg - 57mg/kg per day.
  • the human dose range of naltrexone is 0.25 mg - 50 mg per day and the dose range of acetyl-para-aminophenol is 325 mg - 4000 mg, wherein said composition is formulated into a single fixed combination dosage form.
  • the human dose range of naltrexone is 0.25 mg - 15 mg per day and the human the dose range of acetyl-para-aminophenol is 325 mg - 4000 mg, wherein said composition is formulated into a single fixed combination dosage form.
  • the composition is administered once, twice, three or four times through the day.
  • the therapeutically effective dose of the pharmaceutical composition is administered systemically, including but are not limited to mucosal, nasal, oral, parenteral, gastrointestinal, topical or sublingual routes.
  • the combination is in a single dosage form, and said single dosage form is in the form of tablets, lozenges, troches, hard candies, liquid, powders, sprays, creams, salves and suppositories.
  • the description provides a composition for treating, preventing and reversing pain.
  • the description provides a method of treating neuropathic pain, nociceptive pain, nociceptive pain with an allodynic component, migraine,
  • the description provides a composition for treatment of pain in a mammal comprising a synergistic ratio of an opioid/TLR4 antagonist, or pharmaceutically acceptable salts or solvates thereof and a cyclooxygenase (COX) inhibitor, or
  • the opioid/TLR4 antagonist is selected from a group consisting of naltrexone, norbinalto himine, nalmefene, naloxone, nalorphine, methylnaltrexone, samidorphan, cyprodime, naltrindole, amentoflavone, naltriben, ⁇ 3 ⁇ , ⁇ - ⁇ -naltrexol, metabolites and pro drugs thereof, including all enantiomeric and epimeric forms as well as the appropriate mixtures thereof, or
  • a composition comprising the formulation of claim 43, wherein, the opioid/TLR4 antagonist is naltrexone as well as pro drugs thereof or any enantiomeric and epimeric forms thereof, as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • the opioid/TLR4 antagonist is naltrexone in a sustained release formulation, as well as pro drugs thereof or any enantiomeric and epimeric forms thereof, as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • the opioid/TLR4 antagonist is (+)-naltrexone (dextro- naltrexone), as well as appropriate mixtures thereof, as well as pro drugs thereof, or pharmaceutically acceptable salts or solvates thereof.
  • the cyclooxygenase (COX) inhibitor is selected from a group consisting of aspirin diflunisal, salsalate. ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen. indomethacin, tolmetin, ,sulindac, etodolac, ketorolac, iclofenac, nabumetone. piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam.
  • the cyclooxygenase (COX) inhibitor is ibuprofen, or pharmaceutically acceptable salts or solvates thereof.
  • the opioid/TLR4 antagonist is naltrexone, or
  • the cyclooxygenase (COX) inhibitor is ibuprofen, or pharmaceutically acceptable salts or solvates thereof, in a therapeutically effective amount.
  • the naltrexone and ibuprofen, or pharmaceutically acceptable salts or solvates of any thereof are in a weight to weight combination range which corresponds to a synergistic combination of 1 :90 parts by weight.
  • the dose range of naltrexone, or pharmaceutically acceptable salts or solvates thereof is about 0.004 mg/kg-0.71 mg/kg and the dose range of ibuprofen, or pharmaceutically acceptable salts or solvates thereof, is about 3 mg/kg - 35mg/kg per day.
  • the human dose range of naltrexone is 0.25 mg - 50 mg per day and the dose range of ibuprofen is 200 mg - 2400 mg, wherein said composition is formulated into a single fixed combination dosage form.
  • the human dose range of naltrexone is 0.25 mg - 15 mg per day and the human the dose range of ibuprofen is 200 mg - 2400 mg, wherein said composition is formulated into a single fixed combination dosage form.
  • the composition is administered once, twice, three or four times through the day.
  • the therapeutically effective dose of the pharmaceutical composition is administered systemically, including but are not limited to mucosal, nasal, oral, parenteral, gastrointestinal, topical or sublingual routes.
  • the combination is in a single dosage form, and wherein, said single dosage form is in the form of tablets, lozenges, troches, hard candies, liquid, powders, sprays, creams, salves and suppositories.
  • the disclosure provides a composition for treating, preventing and reversing pain.
  • the disclosure provides a composition for treatment of pain in a mammal comprising a synergistic ratio of (a) an opioid/TLR4 antagonist, or pharmaceutically acceptable salts or solvates thereof and (b) an alpha-2-delta ligand, or pharmaceutically acceptable salts or solvates thereof.
  • the opioid/TLR4 antagonist is selected from a group consisting of naltrexone, norbinalto ⁇ himine, nalmefene, naloxone, nalorphine, methylnaltrexone, samidorphan, cyprodime, naltrindole, amentoflavone, naltriben, norbinaltorphimine, 6-alpha-naltrexol, 6-beta-naltrexol metabolites and pro drugs thereof, including all enantiomeric and epimeric forms as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • the opioid/TLR4 antagonist is naltrexone as well as pro drugs thereof or any enantiomeric and epimeric forms thereof, as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • the opioid/TLR4 antagonist is naltrexone in a sustained release formulation, as well as metabolites and pro drugs thereof or any enantiomeric and epimeric forms thereof, as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • the opioid/TLR4 antagonist is (+)- naltrexone (dextro-naltrexone), as well as appropriate mixtures thereof, as well as metabolites or pro drugs thereof, or pharmaceutically acceptable salts or solvates thereof.
  • the alpha-2-delta ligand is selected from Gabapentin or Pregabalin or pharmaceutically acceptable salts or solvates of any thereof.
  • the alpha-2-delta ligand inhibitor is Gabapentin, or
  • the alphas- delta ligand inhibitor is pregabalin, or pharmaceutically acceptable salts or solvates thereof.
  • the opioid/TLR4 antagonist is naltrexone, or pharmaceutically acceptable salts or solvates thereof, in a therapeutically effective amount and the alphas- delta inhibitor is Gabapentin or Pregabalin, or pharmaceutically acceptable salts or solvates thereof, in a therapeutically effective amount.
  • the opioid/TLR4 antagonist is dextro naltrexone, or pharmaceutically acceptable salts or solvates thereof, in a therapeutically effective amount and the alpha-2-delta inhibitor is Gabapentin or Pregabalin, or pharmaceutically acceptable salts or solvates thereof, in a therapeutically effective amount.
  • the naltrexone and alpha-2-delta ligand, or pharmaceutically acceptable salts or solvates of any thereof are in a weight to weight combination range which corresponds to a synergistic combination of 1 :30-1:125 parts by weight.
  • the dose range of naltrexone, or pharmaceutically acceptable salts or solvates thereof is about 0.004 mg/kg-0.71 mg/kg.
  • the human dose range of naltrexone is 0.25 mg - 50 mg per day.
  • the human dose range of naltrexone is 0.25 mg - 25 mg per day.
  • the human dose range of naltrexone is 0.25 mg - 15 mg per day.
  • the composition is formulated into a single fixed combination dosage form and wherein, the composition is administered once, twice, three or four times through the day.
  • the therapeutically effective dose of the composition is administered once, twice, three or four times through the day.
  • composition is administered systemically, including but are not limited to mucosal, nasal, oral, parenteral, gastrointestinal, topical or sublingual routes.
  • the combination is in a single dosage form, and wherein, said single dosage form is in the form of tablets, lozenges, troches, hard candies, liquid, powders, sprays, creams, salves and suppositories.
  • the disclosure provides a composition for treating, preventing and reversing pain.
  • the disclosure provides a method of treating neuropathic pain, nociceptive pain with an allodynic component, migraine, trigeminal neuralgia, vulvodynia, irritable bowel syndrome, post herpetic neuralgia, or diabetic neuropathy in a mammal in need thereof, comprising administering to the mammal in a therapeutically effective amount of a combination.
  • the disclosure provides a method for the treatment of pain in a mammal comprising administration to said mammal a therapeutically effective amount of a composition comprising an opioid/TLR4 antagonist, or a dextro enantiomer of the opioid/TLR4 antagonist or a racemic mixture thereof, or a pharmaceutically acceptable salt or solvate thereof.
  • a method for the treatment of pain in a mammal comprising administration to said mammal a therapeutically effective amount of a composition predominantly comprising a dextro enantiomer of an opioid/TLR4 antagonist or a pharmaceutically acceptable salt or solvate thereof.
  • a method for the treatment of pain in a mammal comprising administration of a composition comprising a therapeutically effective amount of an opioid/TLR4 antagonist.
  • the opioid/TLR4 antagonist is selected from a group consisting of naltrexone, norbinaltorphimine, nalmefene, naloxone, nalorphine, methylnaltrexone, samidorphan, cyprodime, naltrindole, amentoflavone, naltriben, norbinaltorphimine, 6-beta- naltrexol, and 6-alpha-naltrexol, including all enantiomeric and epimeric forms as well as the appropriate mixtures thereof, as well as pro drugs or metabolites thereof or pharmaceutically acceptable salts or solvates of any thereof.
  • the method of treatment of pain in a mammal comprises administration to said mammal a pharmaceutical composition containing a therapeutically effective amount of naltrexone, naloxone or nalmefene, or a predominantly dextro enantiomeric mixture of naltrexone, naloxone or nalmefene, or a pharmaceutically acceptable salt or solvate of any thereof.
  • the method for treatment of pain in a mammal comprises administration to said mammal a pharmaceutical composition containing a therapeutically effective amount of naltrexone or a
  • the method for treatment of pain in a mammal comprises administration to said mammal a pharmaceutical composition containing a therapeutically effective amount of naloxone or a pharmaceutically acceptable salt or solvate thereof.
  • the method for treatment of pain in a mammal comprises administration to said mammal a pharmaceutical composition containing a therapeutically effective amount of nalmefene or a pharmaceutically acceptable salt or solvate thereof.
  • the method comprises administration to said mammal a pharmaceutical composition containing a therapeutically effective amount of predominantly dextro naltrexone mixture or a pharmaceutically acceptable salt or solvate thereof. In one embodiment the method comprises administration to said mammal a pharmaceutical composition containing a therapeutically effective amount of predominantly dextro naloxone mixture or a pharmaceutically acceptable salt or solvate thereof.
  • the method comprises administration to said mammal a pharmaceutical composition containing a therapeutically effective amount of predominantly dextro nalmefene mixture or a pharmaceutically acceptable salt or solvate thereof.
  • the amount of the opioid/TLR4 antagonist varies from about 0.004mg/kg to about 4.3mg/kg, preferably from about 0.004mg/kg to about 0.71mg/kg, and most preferably from about 0.004mg/kg to about 0.21 mg/kg.
  • the amount of naltrexone varies from about 0.004mg/kg to about 4.3mg/kg, preferably from about 0.004mg/kg to about 0.71mg/kg, and most preferably from about 0.004mg/kg to about 0.21 mg/kg.
  • the amount of dextro naltrexone varies from about 0.004mg/kg to about 4.3mg/kg, preferably from about 0.004mg/kg to about 0.71mg/kg, and most preferably from about 0.004mg/kg to about 0.21 mg/kg.
  • the disclosure provides a method for treatment of pain wherein the human dose range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof, varies from about 0.25mg - 50mg per day, preferably from about 0.25mg - 25 mg per day, most preferably from about 0.25 mg - 15 mg per day wherein said dose is formulated into a single dosage form.
  • the composition comprises greater than 50% to 60% dextro enantiomer.
  • the composition comprises greater than 60% dextro enantiomer.
  • the composition comprises greater than 70% dextro enantiomer.
  • the composition comprises greater than 80% dextro enantiomer.
  • the composition comprises greater than 90% dextro enantiomer.
  • the disclosure provides a method for treatment of pain wherein the single fixed dosage form is administered once, twice, three or four times through the day.
  • a therapeutically effective dose is administered systemically, via routes of mucosal, nasal, oral, parenteral, gastrointestinal, tropical or sublingual.
  • the composition is in a single dosage form, and said single dosage form is in the form of tablets, lozenges, troches, hard candies, liquid, powders, sprays, creams, salves and suppositories.
  • the disclosure provides a method for treatment of pain wherein the pharmaceutical composition is used for the treatment, prevention and reversal of neuropathic pain, back pain, chronic pain, diabetic neuropathic pain, trigeminal neuralgia pain, phantom limb pain, complex regional pain syndrome pain, post herpetic pain, causalgia pain, idiopathic pain, inflammatory pain, cancer pain,postoperative pain, fibromyalgia pain, headache pain, migraine pain, allodynia pain, vulvodynia pain, interstitial cystitis pain, irritable bowel syndrome (IBS), arthritic joint pain and tendinitis.
  • the disclosure provides a method in which the pharmaceutical composition is used for the treatment, prevention and reversal of nociceptive pain with an allodynic component.
  • Figure 1 is a graph of the various pain intensity scores over time in a patient suffering from lower back pain.
  • Figure 2 is a graph of the percent relief over time reported by the above patient suffering from lower back pain. .
  • Figure 3 is a graph of the various pain intensity scores over time in a patient suffering from pain associated with vulvodynia.
  • Figure 4 is a graph of the percent relief over time reported by the above patient suffering from pain associated with vulvodynia over time.
  • Figure 5 is a graph of the various pain intensity scores over time in a patient suffering from pain associated with trigeminal neuralgia.
  • Figure 6 is a graph of the percent relief reported by the above patient suffering from pain associated with trigeminal neuralgia over time.
  • Figure 7 is a graph of various IBS symptom intensity scores over time in a patient suffering from IBS.
  • Figure 8 is a graph of various headache parameter intensity scores over time in a patient suffering from migraine.
  • Figure 14 is a graph depicting the Open Phase Relief by Day compared with a baseline measurement.
  • Figure 15 is a graph demonstrating in the Oswestry Disability Index score of cervical pain over time comparing the ATNC05 group, Placebo Group, and Open-Label Phase group.
  • Figure 16 is a graph demonstrating the Oswestry Disability Index score of lumbar pain over time in the ATNC05 group, Placebo group, and Open-Label Phase group.
  • Figure 17 is a graph demonstrating the Pittsburgh Insomnia Rating Scale score over time comparing ATNC05, Placebo, and Open-Label Phase.
  • Figure 18 is a graph depicting the Roland-Morris Low Back Pain Disability Questionnaire (RMQ) scores over time comparing ATNC05, Placebo, and Open-Label Phase.
  • RMQ Roland-Morris Low Back Pain Disability Questionnaire
  • Figure 19 is a graph depicting change in pulse from baseline over time comparing ATNC05, Placebo, and Open-Label Phase.
  • Figure 20 is a graph depicting change in the systolic blood pressure (BP) from baseline over time comparing ATNC05, Placebo, and Open-Label Phase.
  • Figure 21 is a graph depicting change in the diastolic blood pressure (BP) from baseline over time comparing ATNC05, Placebo, and Open-Label Phase.
  • Figure 22 is a graph depicting the level of cervical pain and anxiety/irritability over time in a patient with cervical pain treated with naltrexone 2 mg twice daily.
  • Figure 23 is a graph depicting the level of pain and enjoyment of life over time for a patient with cervical pain treated with on naltrexone 12.5 mg per day.
  • Figure 25 is a graph depicting the response rates as measured by PGI-I during Week 3 during both the double-blind and open-label phases.
  • Figure 26 is a graph depicting the daily mean Average Pain Scores by day with standard error bars comparing ATNC05 and placebo groups. The Baseline Period Mean is shown on the chart as Day 0. Missing data were imputed by BOCF.
  • Figure 27 is a graph depicting the summary of pain severity scores by week for placebo in the Double-Blind phase. It shows the five pain severity measures. Missing data were imputed by BOCF.
  • Figure 28 is a graph depicting the summary of pain severity scores by week for ATNC05 in the Double-Blind phase. It shows the five pain severity measures . Missing data were imputed by BOCF.
  • Figure 29 is a graph depicting the summary of pain interference scores by week for placebo in the Double-Blind phase. It shows the nine interference measures. Missing data were imputed by BOCF.
  • Figure 30 is a graph depicting the summary of pain interference scores by week for ATNC05 in the Double-Blind phase. It shows the nine interference measures. Missing data were imputed by BOCF.
  • Figure 31 is a graph depicting the ODI score by week for each treatment group. For each subject, the score was taken for their primary area of back pain (cervical or lumbar, one per subject). Missing data in the double-blind period were imputed by BOCF.
  • Figure 32 is a graph depicting the average Roland-Morris score by week for each treatment group. Missing data in the double-blind period were imputed by BOCF
  • Figure 33 is a graph depicting the average PIRS-20 score by week for each treatment group. Missing data in the double-blind period were imputed by BOCF.
  • Figure 34 is a graph depicting the average length of time subjects were able to stand on one leg, in seconds.
  • Figure 35 is a graph depicting the weekly mean BPI-Severity for subjects during the open-label extension phase.
  • Figure 36 is a graph depicting the weekly mean BPI-Interference scores for subjects during the open-label extension phase.
  • Figure 37 is a graph depicting the mean number of doses of other pain medications taken per week per subject.
  • Figure 39 is a graph depicting the subjects' reported change in energy level during the treatment period.
  • Figure 40 is a graph depicting the subjects' reported change in activity level during the treatment period.
  • Figure 41 is a graph depicting the mean joint pain (for subjects who reported concomitant joint pain) during the back pain study.
  • Figure 42 is a graph depicting the long-term pain relief of participants surveyed after the back pain study as percentage of subjects with post-treatment follow-up and as a percentage of all subjects who received ATNC05.
  • TLR4 Toll-like receptor 4
  • PAMPs pathogen-associated molecular patterns
  • LPS lipopolysaccharide
  • Opioid agonists such as morphine act as TLR4 agonists
  • opioid antagonists such as naloxone and naltrexone were found to be TLR4 antagonists.
  • the disclosure provides combination therapies including opioid/TLR4 antagonists and any of the substances described in the sections below. In this section, dosage regimens for combinations of opioid/TLR4 antagonists and the substances described below are provided.
  • TLR4 Activation of TLR4 by opioid agonists such as morphine leads to downstream release of inflammatory modulators including TNF-a and inter leukin- 1. Constant low- level release of these modulators is thought to reduce the efficacy of opioid drug treatment with time and to be involved in both the development of tolerance to opioid analgesic drugs and in the emergence of side effects such as hyperalgesia and allodynia which can become problems following extended use of opioid drugs.
  • the disclosure relates to ⁇ -opioid receptor ligand as ligands of TLR4 as well and contemplates that allodynia is caused by activation of TLR4. Blockage of TLR4 accordingly will eliminate allodynia.
  • (+)-naloxone and (+)-naltrexone lack affinity for opioid receptors, they do not block the effects of opioid analgesic drugs, and so can be used to counteract the TLR4-mediated side effects of opioid agonists without affecting analgesia.
  • (+)- Naloxone was also found to be neuroprotective, and both (+)-naloxone and (+)-naltrexone are effective in their own right at treating symptoms of neuropathic pain in animal models.
  • Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. A dose of 50-300 mg once daily is recommended for most patients.
  • Naloxone is an opioid inverse agonist: it is a drug used to counter the effects of opiate overdose.
  • Low dose naltrexone describes the off label use of naltrexone at doses less than 15 mg per day for indications other than chemical dependency or intoxication.
  • low dose naltrexone exerts the opposite effect of naltrexone in full dose. While the full dose naltrexone blocks the opiate system, the low dose naltrexone promotes the production of endorphins by the mechanism of up regulation caused by partial opiate receptor blockage. The beneficial effect of naltrexone was attributed to the increase in endorphins. The beneficial effect of low dose naltrexone can be further explained by its antagonism of TLR4.
  • opioid receptor antagonists used in clinical or scientific practice which also can be used for the treatment of pain include but are not limited to the following: naloxone, nalmefene, norbinalto ⁇ himine, nalorphine, methylnaltrexone, samidorphan, cyprodime, naltrindole, amentoflavone, naltriben, norbinalto ⁇ himine, and the naltrexone metabolite 6- ⁇ - naltrexol.
  • TLRs can be activated not only by well-known "non-self molecular signals but also by endogenous signals (IL- ⁇ , TNFa, IL-6 and NO) produced during chronic neuropathic pain states.
  • IL- ⁇ endogenous signals
  • Fibronectin an endogenous TLR4 ligand that is produced in response to tissue injury, leads to an up regulation of the purinoceptor P2X4, which is expressed exclusively on microglia.
  • Blocking TLR4s with an opioid receptor antagonist solves the perplexing problem of neuropathic pain.
  • the disclosure includes findings from studies including a double-blind placebo-controlled clinical trial of 78 subjects treated with the opioid receptor naltrexone which proved the efficacy of this treatment for pain.
  • the package insert for full dose naltrexone reports single-digit incidence of nervousness, insomnia, and anxiety.
  • a study by Ploesser evaluating side effects of low dose naltrexone showed double digit incidence of nervousness, insomnia, and anxiety.
  • This disclosure contemplates the use of an alpha-2 adrenergic agonist in order to abate the adverse effects caused by the low dose opioid/TLR4 antagonist.
  • the direct-acting alpha-2 adrenergic agonist is selected from a group consisting of apraclonidine, brimonidine, clonidine, detomidine, dexmedetomidine, guanabenz, guanfacine, lofexidine, medetomidine, romifidine, tizanidine, tolonidine, xylazine and fadolmidine, or pharmaceutically acceptable salts or solvates of any thereof.
  • This disclosure provides an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvates thereof.
  • the opioid/TLR4 antagonist may be selected from a group consisting of (but not limited to) naltrexone, norbinaltorphimine, nalmefene, naloxone, nalorphine, methylnaltrexone, samidorphan, cyprodime, naltrindole, amentoflavone, naltriben, norbinaltorphimine, 6-6-naltrexol and metabolites thereof, including all enantiomeric and epimeric forms as well as the appropriate mixtures thereof, as well as pro drugs or metabolites thereof or pharmaceutically acceptable salts or solvates of any thereof.
  • the opioid/ TLR4 antagonist is (+)-naltrexone (dextro-naltrexone), as well as pro drugs thereof or any enantiomeric and epimeric forms thereof, as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • the dose range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof , or of any opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof when combined with any of the substances described below is about 0.001 to about 1.0 mg/kg, e.g. is about 0.004 mg/kg- about 0.71 mg/kg (e.g.
  • 0.004 mg/kg is about 0.004 mg/kg, 0.005mg/kg, 0.006 mg/kg, 0.007 mg/kg, 0.008 mg/kg, 0.009 mg/kg, 0.010 mg/kg, 0.011 mg/kg, 0.012 mg/kg, 0.013 mg/kg, 0.014 mg/kg, 0.015 mg/kg, 0.016 mg/kg, 0.017 mg/kg, 0.018 mg/kg, 0.019 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg, 0.10 mg/kg, 0.11 mg/kg, 0.12 mg/kg, 0.13 mg/kg, 0.14 mg/kg, 0.15 mg/kg, 0.16 mg/kg, 0.17 mg/kg, 0.18 mg/kg, 0.19 mg/kg, 0.20 mg/kg, 0.21 mg/kg, 0.22 mg/kg, 0.23 mg/kg, 0.
  • the dose range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof , or of any opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof when combined with any of the substances described below is administered in a range of about 0.001 to about 1.0 mg/kg, e.g. a range of about 0.004 mg/kg to about 0.71 mg/kg (e.g.
  • the range is about 0.004 to about 0.35 mg/kg, about 0.35 to about 0.71 mg/kg, about 0.004 to about 0.24 mg/kg, about 0.24 to about 0.47 mg/kg, about 0.47 to about 0.71 mg/kg, about 0.004 to about 0.18 mg/kg, about 0.18 to about 0.35 mg/kg, about 0.35 to about 0.53 mg/kg, about 0.53 to about 0.71 mg/kg, about 0.004 to about 0.07 mg/kg, 0.07 to about 0.14 mg/kg, about 0.14 to about 0.21 mg/kg, about 0.21 to about 0.28 mg/kg, 0.28 to about 0.35 mg/kg, about 0.35 to about 0.42 mg/kg, about 0.42 to about 0.49 mg/kg, about 0.49 to about 0.56 mg/kg, about 0.56 to about 0.63 mg/kg, about 0.63 to about 0.71 mg/kg, 0.004 to about 0.047 mg/kg, 0.024 to about 0.71 mg/kg, about 0.18 to about 0.53 mg/kg, or about 0.18 to about
  • the human dose range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof , or of any opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof is about 0.1 mg to about 100 mg per day, e.g. is about 0.25 mg to about 15 mg per day, about 0.25 mg to about 25 mg per day, or about 0.25 mg to about 50 mg per day (e.g.
  • the dose range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof , or of any opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof when combined with any of the substances described below is administered in a range of about 0.001 to about 1.0 mg per day, e.g. a range of about 0.25 mg to about 15 mg per day (e.g.
  • the range is about 0.25 to about 7.6 mg, about 7.6 to about 15 mg, about 0.25 to about 5.1 mg, about 5.1 to about 10.8 mg, about 10.8 to about 15 mg, about 0.25 to about 3.93 mg, about 3.93 to about 7.6 mg, about 7.6 to about 11.3 mg, about 11.3 to about 15 mg, about 0.25 to about 10 mg, 5.1 to about 15 mg, about 3.9 to about 11.3 mg, or about 3.9 to about 15 mg per day), about 0.25 to about 25 mg per day (e.g.
  • the range is about 0.25 to about 12.6 mg, about 12.6 to about 25 mg, about 0.25 to about 8.5 mg, about 8.5 to about 16.7 mg, about 16.7 to about 25 mg, about 0.25 to about 6.43 mg, about 6.43 to about 12.6 mg, about 12.6 to about 18.7 mg, about 18.7 to about 25 mg, about 0.25 to about 16.7 mg, 8.5 to about 25 mg, about 6.4 to about 18.8 mg, or about 6.4 to about 25 mg per day), or about 0.25 to about 50 mg per day (e.g.
  • the range is about 0.25 to about 25 mg, about 25 to about 50 mg, about 0.25 to about 16.8 mg, about 16.8 to about 33.4 mg, about 33.4 to about 50 mg, about 0.25 to about 12.6 mg, about 12.6 to about 25.1 mg, about 25.1 to about 37.5 mg, about 37.5 to about 50 mg, about 0.25 to about 33.4 mg, 16.8 to about 50 mg, about 12.6 to about 37.5 mg, or about 12.6 to about 50 mg per day).
  • This disclosure also provides a combination, comprising an opioid/TLR4 antagonist, and pharmaceutically acceptable salts or solvates of any thereof, and alpha-2 adrenergic agonist, and pharmaceutically acceptable salts or solvates of any thereof.
  • the alpha-2 adrenergic agonist can be selected from a group consisting of apraclonidine, brimonidine, clonidine, detomidine, dexmedetomidine, guanabenz, guanfacine, lofexidine, medetomidine, romifidine, tizanidine, tolonidine, xylazine and fadolmidine, or
  • the alpha-2 adrenergic agonist is clonidine.
  • Clonidine is a sympatholytic medication, classified as a direct-acting a-2 adrenergic agonist. It is an imidazoline derivative.
  • An alternative hypothesis that has been proposed is that clonidine acts centrally as an imidazoline-2 receptor agonist.
  • the imidazoline-2 receptor is an allosteric binding site of monoamine oxidase and is involved in pain modulation and neuroprotection.
  • Clonidine is used to treat medical conditions such as high blood pressure, ADHD, anxiety/panic disorder, and certain pain conditions.
  • the therapeutic doses most commonly employed have ranged from about 0.1 to about 1.0 mg, e.g.
  • Clonidine enhances the pain treatment effect of naltrexone by agonism of the imidazoline-2 receptor, while its sympatholytic properties are the cause of the abatement of naltrexone's adverse reactions.
  • the alpha-2 adrenergic agonist is a pharmaceutically acceptable salt or solvate thereof.
  • the direct-acting alpha-2 adrenergic agonist is in a sustained release formulation, or a pharmaceutically acceptable salt or solvate thereof.
  • the opioid/TLR4 antagonist is naltrexone or a pharmaceutically acceptable salt or solvate thereof, in a therapeutically effective amount and is combined with a direct-acting alpha-2 adrenergic agonist, or a pharmaceutically acceptable salt or solvate thereof, in a therapeutically effective amount.
  • the opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, and the alpha-2 adrenergic agonist, or a pharmaceutically acceptable salt or solvate thereof are in a weight to weight combination range which corresponds to a synergistic combination range of the order of about 100:1 to about 1:1 parts by weight, e.g. about 90:1 to about 22.5:1 parts by weight (e.g.
  • the weight to weight combination range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof, and the alpha-2 adrenergic agonist, or a pharmaceutically acceptable salt or solvate thereof are of the order of about 100:1 to about 1 :1 parts by weight, e.g. is about 90:1 to about 22.5:1 parts by weight (e.g. may range from about (e.g.
  • the dose range of the opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof is about 0.001 mg/kg to about 1 mg/kg, e.g. is about 0.004 mg/kg to about 0.71 mg/kg, as described herein.
  • the dose range of the alpha-2 adrenergic agonist, or a pharmaceutically acceptable salt or solvate thereof is about 0.0001 mg/kg to about 0.01 mg/kg per day, e.g. is about 0.00018 mg/kg - 0.0086mg/kg per day (e.g.
  • 0.0018 mg/kg is about 0.00018 mg/kg, 0.00019 mg/kg, 0.002 mg/kg, 0.0021 mg/kg, 0.0022 mg/kg, 0.0023 mg/kg, 0.0024 mg/kg, 0.0025 mg/kg, 0.0026 mg/kg, 0.0027 mg/kg, 0.0028 mg/kg, 0.0029 mg/kg, 0.003 mg/kg, 0.0031 mg/kg, 0.0032 mg/kg, 0.0033 mg/kg, 0.0034 mg/kg, 0.0035 mg/kg, 0.0036 mg/kg, 0.0037 mg/kg, 0.0038 mg/kg, 0.0039 mg/kg, 0.004 mg/kg, 0.0041 mg/kg, 0.0042 mg/kg, 0.0043 mg/kg, 0.0044 mg/kg, 0.0045 mg/kg, 0.0046 mg/kg, 0.0047 mg/kg, 0.0048 mg/kg, 0.0049 mg/kg, 0.005 mg/kg, 0.0051 mg/kg, 0.0052 mg/kg,
  • the dose range of the alpha-2 adrenergic agonist, or a pharmaceutically acceptable salt or solvate thereof is about 0.0001 mg/kg to about 0.01 mg/kg per day, e.g. may range from about 0.00018 mg/kg to 0.0086 mg/kg per day (e.g.
  • 0.0044 mg/kg may range from about 0.00018 to about 0.0044 mg/kg, about 0.0044 to about 0.0086 mg/kg, about 0.00018 to about 0.003 mg/kg, about 0.003 to about 0.006 mg/kg, about 0.006 to about 0.0086 mg/kg, about 0.00018 to about 0.003 mg/kg, about 0.003 to about 0.004 mg/kg, about 0.004 to about 0.006 mg/kg, about 0.006 to about 0.0086 mg/kg, about 0.00018 to about 0.0006 mg/kg, 0.003 to about 0.0086 mg/kg, about 0.003 to about 0.006 mg/kg, or about 0.003 to about 0.0086 mg/kg per day).
  • the human dose range of the opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof is about 0.1 mg to about 100 mg per day, e.g. is about 0.25 mg to about 50 mg per day, is about 0.25 mg to about 25 mg per day, or is about 0.25 mg - about 15 mg per day , as described above.
  • the human the dose range of the alpha-2 adrenergic agonist, or a pharmaceutically acceptable salt or solvate thereof is about 0.01 to about 1 mg per day, e.g. is about 0.0125 mg - about 0.6 mg (e.g.
  • the dose range of the alpha-2 adrenergic agonist, or a pharmaceutically acceptable salt or solvate thereof is about 0.0001 mg/kg to about 0.01 mg/kg per day, e.g. may range from about 0.0125 mg to about 0.6 mg per day (e.g.
  • 0.0125 mg to about 0.31 mg may range from about 0.0125 mg to about 0.31 mg, about 0.31 to about 0.6 mg, about 0.0125 mg to about 0.21 mg, about 0.21 to about 0.40 mg, about 0.40 to about 0.6 mg, about 0.0125 to about 0.16 mg, about 0.16 to about 0.31 mg, about 0.31 to about 0.45 mg, or about 0.45 to about 0.6 mg, about 0.0125 to about 0.45 mg, 0.16 to about 0.6 mg, about 0.16 to about 0.45 mg, or about 0.16 to about 0.6 mg per day).
  • the human the dose range of the alpha-2 adrenergic agonist, or a pharmaceutically acceptable salt or solvate thereof is about 0.01 to about 1.0 mg , e.g. is about 0.0125 mg to about 0.3 mg (e.g.
  • the dose range of the alpha-2 adrenergic agonist, or a pharmaceutically acceptable salt or solvate thereof is about 0.0001 mg/kg to about 0.01 mg/kg per day, e.g. may range from about 0.0125 mg to about 0.3 mg per day (e.g.
  • 0.0125 mg to about 0.16 mg may range from about 0.0125 mg to about 0.16 mg, about 0.16 to about 0.3 mg, about 0.0125 mg to about 0.11 mg, about 0.11 to about 0.20 mg, about 0.20 to about 0.3 mg, about 0.0125 to about 0.08 mg, about 0.08 to about 0.16 mg, about 0.16 to about 0.23 mg, or about 0.23 to about 0.3 mg, about 0.0125 to about 0.23 mg, 0.08 to about 0.3 mg, about 0.08 to about 0.23 mg, or about 0.08 to about 0.3 mg per day).
  • the human dose range of the opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof is about 0.1 to about 100 mg per day, e.g. is about 0.25 mg - about 50 mg per day, as described above, and the human the dose range of the alpha-2 adrenergic agonist, or a pharmaceutically acceptable salt or solvate thereof, is about 0.01 to about 1 mg, e.g. is about 0.0125 mg to about 0.6 mg or any of the ranges described herein (e.g.
  • the composition is administered once, twice, three or four times through the day.
  • the alpha-2 adrenergic agonist is clonidine, or a pharmaceutically acceptable salt or solvate thereof.
  • the direct-acting alpha-2 adrenergic agonist is clonidine in a sustained release formulation, or a pharmaceutically acceptable salt or solvate thereof.
  • the opioid/TLR4 antagonist is naltrexone or a pharmaceutically acceptable salt or solvate thereof, in a therapeutically effective amount and the direct-acting alpha-2 adrenergic agonist is clonidine, or a pharmaceutically acceptable salt or solvate thereof, in a therapeutically effective amount.
  • naltrexone, or a pharmaceutically acceptable salt or solvate thereof, and clonidine, or a pharmaceutically acceptable salt or solvate thereof are in a weight to weight combination range which corresponds to a synergistic combination range of the order of about 100:1 to about 1:1 parts by weight, e.g.
  • the weight to weight combination range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof, and clonidine, or a pharmaceutically acceptable salt or solvate thereof are of the order of about 100:1 to about 1:1 parts by weight, e.g. is about 90:1 to about 22.5:1 parts by weight (e.g. mayrange from about (e.g.
  • the naltrexone, or pharmaceutically acceptable salt or solvate thereof can be administered as explained above in the section entitled "Opioid/TLR4 Antagonists.
  • the dose range of clonidine, or a pharmaceutically acceptable salt or solvate thereof is about 0.0001 to about 0.01 mg/kg per day, e.g. is about 0.00018 mg/kg - about 0.0086mg/kg per day (e.g.
  • 0.0018 mg/kg is about 0.00018 mg/kg, 0.00019 mg/kg, 0.002 mg/kg, 0.0021 mg/kg, 0.0022 mg/kg, 0.0023 mg/kg, 0.0024 mg/kg, 0.0025 mg/kg, 0.0026 mg/kg, 0.0027 mg/kg, 0.0028 mg/kg, 0.0029 mg/kg, 0.003 mg/kg, 0.0031 mg/kg, 0.0032 mg/kg, 0.0033 mg/kg, 0.0034 mg/kg, 0.0035 mg/kg, 0.0036 mg/kg, 0.0037 mg/kg, 0.0038 mg/kg, 0.0039 mg/kg, 0.004 mg/kg, 0.0041 mg/kg, 0.0042 mg/kg, 0.0043 mg/kg, 0.0044 mg/kg, 0.0045 mg/kg, 0.0046 mg/kg, 0.0047 mg/kg, 0.0048 mg/kg, 0.0049 mg/kg, 0.005 mg/kg, 0.0051 mg/kg, 0.0052 mg/kg,
  • the dose range of clonidine, or a pharmaceutically acceptable salt or solvate thereof is about 0.0001 mg/kg to about 0.01 mg/kg per day, e.g. may range from about 0.00018 mg/kg to 0.0086mg/kg per day (e.g.
  • 0.004 mg/kg may range from about 0.00018 to about 0.004 mg/kg, about 0.004 to about 0.0086 mg/kg, about 0.00018 to about 0.003 mg/kg, about 0.003 to about 0.006 mg/kg, about 0.006 to about 0.0086 mg/kg, about 0.00018 to about 0.003 mg/kg, about 0.003 to about 0.4 mg/kg, about 0.004 to about 0.006 mg/kg, or about 0.006 to about 0.0086 mg/kg, about 0.00018 to about 0.0006 mg/kg, 0.003 to about 0.0086 mg/kg, about 0.003 to about 0.006 mg/kg, or about 0.003to about 0.0086 mg/kg per day).
  • the human dose range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof is about 0.1 to about 100 mg per day, e.g. about 0.25 mg - about 50 mg per day, about 0.25 mg - about 25 mg per day, or about 0.25 mg - about 15 mg per day, as described above.
  • the human the dose range of clonidine, or a pharmaceutically acceptable salt or solvate thereof is about 0.01 to about 1.0 mg, e.g. is about 0.0125 mg to about 0.6 mg per day (e.g.
  • the human the dose range of clonidine, or a pharmaceutically acceptable salt or solvate thereof is about 0.01 to about 1.0 mg, e.g. is about 0.0125 mg to about 0.6 mg (e.g.
  • the human the dose range of clonidine, or a pharmaceutically acceptable salt or solvate thereof is about 0.01 to about 1.0 mg, e.g. is about 0.0125 mg to about 0.3 mg (e.g.
  • the dose range of clonidine, or a pharmaceutically acceptable salt or solvate thereof is about 0.0001 mg/kg to about 0.01 mg per day, e.g. may range from about 0.0125 to about 0.3 mg (e.g.
  • 0.0125 mg to about 0.16 mg may range from about 0.0125 mg to about 0.16 mg, about 0.16 to about 0.3 mg, about 0.0125 mg to about 0.11 mg, about 0.11 to about 0.20 mg, about 0.20 to about 0.3 mg, about 0.0125 to about 0.08 mg, about 0.08 to about 0.16 mg, about 0.16 to about 0.22 mg, or about 0.22 to about 0.3 mg, about 0.0125 to about 0.22 mg, 0.08 to about 0.3 mg, about 0.08 to about 0.22 mg, or about 0.08 to about 0.3 mg per day).
  • the human dose range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof is about 0.1 to about 100 mg per day, e.g. is about 0.25 mg - about 50 mg per day, as described above, and the human the dose range of clonidine, or a pharmaceutically acceptable salt or solvate thereof, is about 0.01 to about 1.0 mg, e.g. is about 0.0125 mg to about 0.6 mg (e.g. may be any of the dose ranges listed above, e.g.
  • this disclosure teaches using the direct-action alpha-2 adrenergic receptor agonist clonidine to abate the adverse effects caused by the low dose opioid/TLR4 antagonist naltrexone.
  • Acetyl-para-aminophenol enhances the pain relief action of the opioid/TLR4 antagonist naltrexone.
  • a specific synergistic dose range of the combination is herein presented.
  • acetyl-para- aminophenol can also be used in the management of more severe pain such as post-surgical pain and providing palliative care in advanced cancer patients. Though acetyl-para- aminophenol is used to treat inflammatory pain, it is not generally classified as an NSAID because it exhibits only weak anti-inflammatory activity.
  • Acetyl-para-aminophenol enhances the pain treatment effect of naltrexone by affecting nociceptive pain.
  • This disclosure provides a combination, comprising an opioid/TLR4 antagonist and acetyl-para-aminophenol, and pharmaceutically acceptable salts or solvate of any thereof.
  • Another embodiment is a combination, comprising an opioid/TLR4 antagonist and acetyl-para-aminophenol.
  • Another embodiment is a combination, comprising an opioid/TLR4 antagonist and acetyl-para-aminophenol, the opioid /TLR4 antagonist is naltrexone as well as pro drugs and all enantiomeric and epimeric forms including, but not limited to, (+)-naltrexone (dextro-naltrexone), as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • Another embodiment is a combination, comprising an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, and acetyl-para- aminophenol, or a pharmaceutically acceptable salt or solvate thereof.
  • Another embodiment is a combination, comprising an opioid/TLR4 antagonist and acetyl-para-aminophenol in a weight to weight combination range which corresponds to a synergistic combination range of the order of 3:200 parts by weight.
  • the dose range of an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof may be about 0.001 mg/kg to about 1.0 mg/kg per day, e.g. about 0.004 mg/kg-0.71 mg/kg per day, as described above, in combination with acetyl-para- aminophenol, or a pharmaceutically acceptable salt or solvate thereof, at about 1 mg/kg - about 100 mg/kg per day, e.g. about 5mg/kg - about 57mg/kg per day (e.g.
  • the dose range of acetyl-para-aminophenol, or a pharmaceutically acceptable salt or solvate thereof is about 1 mg/kg to about 100 mg/kg per day, e.g. may range from about 5 mg/kg to about 57 mg/kg per day (e.g. may range from about (e.g.
  • the weight of about 31 mg/kg may range from about 5 to about 31 mg/kg, about 31 to about 57 mg/kg, about 5 to about 22 mg/kg, about 22 to about 40 mg/kg, about 40 to about 57 mg/kg, about 5 to about 18 mg/kg, about 18 to about 31 mg/kg, about 31 to about 44 mg/kg, about 44 to about 57 mg/kg, about 5 to about 44 mg/kg, 22 to about 57 mg/kg, about 18 to about 44 mg/kg about 31 to about 57 mg/kg, or about 18 to about 57 mg/kg per day).
  • Another embodiment is a combination, wherein the human dose range of an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, is about 0.1 mg to about 100 mg per day, e.g. is about 0.25 mg - about 50 mg per day, about 0.25 mg - about 25 mg per day, or about 0.25 to about 15 mg per day, as described above, and the dose range of acetyl-para-aminophenol, or a pharmaceutically acceptable salt or solvate thereof, is about 100 to about 10,000 mg, e.g. is about 324 mg - 4000 mg (e.g. is about 324 mg, 325 mg, 326 mg, 327 mg, 328 mg,.
  • the combination may also comprise an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, at a dosage range of about 0.1 mg to about 100 mg per day, e.g. about 0.25 mg - about 50 mg per day, as described above, and acetyl-para-aminophenol or a pharmaceutically acceptable salt or solvate thereof, at a dosage range of about 100 mg to about 10,000 mg, e.g. about 324 mg - about 4000mg (e.g. is about 324 mg, 325 mg, 326 mg, 327 mg, 328 mg,.
  • the dose range of acetyl-para-aminophenol, or a pharmaceutically acceptable salt or solvate thereof is about 100 mg to about 10,000 mg, e.g. about 324 mg - about 4000mg (e.g.
  • the method may range from about 324 to about 2162 mg, about 2162 to about 4000 mg, about 324 to about 1550 mg, about 1550 to about 2776 mg, about 2776 to about 4000 mg, about 324 to about 1240 mg, about 1240 to about 2162 mg, about 2160 to about 3080 mg, about 3080 to about 4000 mg, about 324 to about 3081 mg, 1550 to about 4000 mg, about 1240 to about 3080 mg about 2160 to about 4000 mg, or about 1240 to about 4000 mg per day).
  • Another embodiment is a combination, comprising an opioid antagonist and acetyl-para-aminophenol, the opioid /TLR4 antagonist is naltrexone in a sustained release formulation, as well as pro drugs thereof or any enantiomeric and epimeric forms thereof, as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • Another embodiment is a combination, comprising an opioid antagonist and acetyl-para-aminophenol, the opioid /TLR4 antagonist is (+)-naltrexone (dextro-naltrexone), as well as pro drugs thereof or any enantiomeric and epimeric forms thereof, as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • Another embodiment is a combination, comprising naltrexone, or a pharmaceutically acceptable salt or solvate thereof, and acetyl-para-aminophenol, or a pharmaceutically acceptable salt or solvate thereof.
  • Another embodiment is a combination, comprising naltrexone and acetyl-para-aminophenol in a weight to weight combination range which corresponds to a synergistic combination range of the order of 3:200 parts by weight.
  • naltrexone or a pharmaceutically acceptable salt or solvate thereof, may be about 0.001 mg/kg to about 1.0 mg/kg, e.g. about 0.004 mg/kg-0.71 mg/kg, as described above, per day in combination with acetyl-para-aminophenol, or a
  • pharmaceutically acceptable salt or solvate thereof at about 1 mg/kg to about 100 mg/kg per day, e.g. is about 5mg/kg to about about 57mg/kg per day (e.g. may range from about (e.g. may range from about 5 to about 31 mg/kg, about 31 to about 57 mg/kg, about 5 to about 22 mg/kg, about 22 to about 40 mg/kg, about 40 to about 57 mg/kg, about 5 to about 18 mg/kg, about 18 to about 31 mg/kg, about 31 to about 44 mg/kg, about 44 to about 57 mg/kg, about 5 to about 44 mg/kg, 22 to about 57 mg/kg, about 18 to about 44 mg/kg about 31 to about 57 mg/kg, or about 18 to about 57 mg/kg per day; e.g.
  • mg/kg may be about 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 21 mg/kg, 22 mg/kg, 23 mg/kg, 24 mg/kg, 25 mg/kg, 26 mg/kg, 27 mg/kg, 28 mg/kg, 29 mg/kg, 30 mg/kg, 31 mg/kg, 32 mg/kg, 33 mg/kg, 34 mg/kg, 35 mg/kg, 36 mg/kg, 37 mg/kg, 38 mg/kg, 39 mg/kg, 40 mg/kg, 41 mg/kg, 42 mg/kg, 43 mg/kg, 43 mg/kg, 44 mg/kg, 45 mg/kg, 46 mg/kg, 47 mg/kg, 48 mg/kg, 49 mg/kg, 50 mg/kg, 51 mg/kg, 52 mg/kg, 53 mg/
  • Another embodiment is a combination, wherein the human dose range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof, is about 0.1 to about 100 mg per day, e.g. is about 0.25 mg - about 50 mg per day, about 0.25 mg - about 25 mg per day, or about 0.25 mg - about 15 mg, as described above, per day and the dose range of acetyl-para-aminophenol, or a pharmaceutically acceptable salt or solvate thereof, is about 100 mg to about 10,000 mg, e.g. is about 324 mg to about 4000 mg (e.g.
  • the method may range from about 324 to about 2162 mg, about 2162 to about 4000 mg, about 324 to about 1550 mg, about 1550 to about 2776 mg, about 2776 to about 4000 mg, about 324 to about 1240 mg, about 1243 to about 2162 mg, about 2160 to about 3080 mg, about 3081 to about 4000 mg, about 324 to about 3080 mg, 1550 to about 4000 mg, about 1240 to about 30801 mg about 2160 to about 4000 mg, or about 1240 to about 4000 mg per day, e.g. is about 324 mg, 325 mg, 326 mg, 327 mg, 328 mg,.
  • the combination may also comprise naltrexone, or a pharmaceutically acceptable salt or solvate thereof, at a dosage range of about 0.1 mg to about 100 mg per day, e.g. is about 0.25 mg - about 50 mg per day, as described above, and acetyl-para-aminophenol or a pharmaceutically acceptable salt or solvate thereof, at a dosage range of about 100 mg to about 10000 mg, e.g. is about 324 mg to about 4000mg (e.g.
  • ⁇ may range from about 324 to about 2162 mg, about 2162 to about 4000 mg, about 324 to about 1550 mg, about 1550 to about 2776 mg, about 2776 to about 4000 mg, about 324 to about 1243 mg, about 1243 to about 2162 mg, about 2162 to about 3081 mg, about 3081 to about 4000 mg, about 324 to about 3081 mg, 1550 to about 4000 mg, about 1243 to about 3081 mg about 2162 to about 4000 mg, or about 1243 to about 4000 mg per day; e.g. is about 324 mg, 325 mg, 326 mg, 327 mg, 328 mg,.
  • Described herein is a method of treating neuropathic, nociceptive and migraine pain in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a combination comprising an opioid/TLR4 antagonist and acetyl-para-aminophenol, or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating neuropathic, nociceptive and migraine pain in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a combination comprising naltrexone and acetyl-para-aminophenol, or a pharmaceutically acceptable salt or solvate thereof.
  • NSAIDs nonsteroidal anti- inflammatory drugs
  • COX cyclooxygenase
  • COX-1 cyclooxygenase-1
  • COX-2 cyclooxygenase-2
  • COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid.
  • Prostaglandins act as messenger molecules in the process of inflammation. This mechanism of action was elucidated by John Vane (1927-2004), who received a Nobel Prize for his work.
  • NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present.
  • Nonsteroidal anti- inflammatory drug can be classified based on their chemical structure or mechanism of action. Older NSAIDs were known long before their mechanism of action was elucidated and were for this reason classified by chemical structure or origin. Newer substances are more often classified by mechanism of action.
  • NSAIDs can be selected from groups consisting of
  • Salicylates Aspirin, Difiunisal, Salsalate
  • Propionic acid derivatives Ibuprofen
  • Sulphonanilides, Nimesulide, LOX (lipooxygenase); and COX 5-LOX/COX inhibitors Licofelone, Lysine, clonixinate. Natural: Hyperforin, Figwort, Calcitriol(Vitamin D).
  • Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) it is used primarily for fever, pain, dysmenorrhea and inflammatory diseases such as rheumatoid arthritis; it is also used for pericarditis. Ibuprofen is a 'core' medicine in the World Health Organization's Model List of Essential Medicines necessary to meet the minimum medical needs of a basic healthcare system.
  • NSAID nonsteroidal anti-inflammatory drug
  • Ibuprofen enhances the pain treatment effect of naltrexone by inhibiting the enzyme cyclooxygenase (COX), which converts arachidonic acid to prostaglandin H2 (PGH2).
  • COX cyclooxygenase
  • PGH2 in turn, is converted by other enzymes to several other prostaglandins, which are mediators of pain, inflammation, and fever.
  • the disclosure teaches use of a combination of an opioid/TLR4 antagonist and a cyclooxygenase inhibitor, particularly ibuprofen, for its action on nociception and its anti- inflammatory action. The disclosure teaches that the combination is synergy as far as the effect on pain treatment.
  • One embodiment taught by this disclosure is a combination, comprising an opioid/TLR4 antagonist and a cyclooxygenase inhibitor wherein, a cyclooxygenase inhibitor is selected from a group consisting of aspirin, diclofenac, difluinsal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, zomepirac, and their pharmaceutically acceptable salts or solvates or pharmaceutically acceptable salts or solvates of any thereof.
  • a cyclooxygenase inhibitor is selected from a group consisting of aspirin, diclofenac, difluin
  • Another embodiment is a combination, comprising an opioid antagonist and a cyclooxygenase inhibitor, the opioid /TLR4 antagonist is naltrexone as well as pro drugs and all enantiomeric and epimeric forms, specifically, (+)-naltrexone (dextro-naltrexone), as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • Another embodiment is a combination, comprising an opioid antagonist and a cyclooxygenase inhibitor, the opioid /TLR4 antagonist is naltrexone in a sustained release formulation, as well as pro drugs thereof or any enantiomeric and epimeric forms thereof, as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • Another embodiment is a combination, comprising an opioid antagonist and a cyclooxygenase inhibitor, the opioid /TLR4 antagonist is (+)-naltrexone (dextro-naltrexone), as well as pro drugs thereof or any enantiomeric and epimeric forms thereof, as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • opioid /TLR4 antagonist is (+)-naltrexone (dextro-naltrexone), as well as pro drugs thereof or any enantiomeric and epimeric forms thereof, as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • Another embodiment is a combination, comprising an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, and a COX inhibitor, or a pharmaceutically acceptable salt or solvate thereof.
  • Another embodiment is a combination, comprising an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, and a COX inhibitor, or a pharmaceutically acceptable salt or solvate thereof, in a weight to weight combination range which corresponds to a synergistic combination range of the order of 90:1 parts by weight.
  • Another embodiment is a combination, comprising the dose range of an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, is about O.OOlmg/kg to about 1.0 mg/kg per day, e.g. is about 0.004 mg/kg-0.71 mg/kg per day, as described above, and the COX inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is about 1 mg/kg to about 50 mg/kg per day, e.g. is about 3 mg/kg - 35mg/kg per day (e.g.
  • mg/kg about 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 21 mg/kg, 22 mg/kg, 23 mg/kg, 24 mg/kg, 25 mg/kg, 26 mg/kg, 27 mg/kg, 28 mg/kg, 29 mg/kg, 30 mg/kg, 31 mg/kg, 32 mg/kg, 33 mg/kg, 34 mg/kg or 35 mg/kg).
  • the COX inhibitor, or a pharmaceutically acceptable salt or solvate thereof can be administered in a range of a about 1 mg/kg to about 50 mg/kg per day, e.g. may be administered at a range of about 3 mg/kg to about 35 mg/kg per day (e.g.
  • Another embodiment is a combination, comprising the human dose range of an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, of about 0.1 mg to about 100 mg, e.g. is about 0.25 mg - 50 mg, about 0.25 mg - about 25 mg, or about 0.25 mg - about 15 mg, as described above, per day in combination with a COX inhibitor, or a pharmaceutically acceptable salt or solvate thereof, at a dosage range of about 100 mg to about 5000 mg per day, e.g. is about 200 mg - about 2400 mg per day (e.g.
  • Another embodiment is a combination, comprising the human dose range of an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, of about 0.1 mg to about 100 mg, e.g. is about 0.25 mg - 50 mg, as described above, per day and the human the dose range of a COX 2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is about 100 to about 5000 mg, e.g. is about 200 mg - about 2400 mg (e.g.
  • composition is formulated into a single fixed combination dosage form.
  • a combination comprising naltrexone, or a pharmaceutically acceptable salt or solvate thereof, and ibuprofen, or a pharmaceutically acceptable salt or solvate thereof.
  • a combination comprising naltrexone and ibuprofen in a weight to weight combination range which corresponds to a synergistic combination range of the order of 90:1 parts by weight.
  • Another embodiment is a combination, comprising the dose range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof, at about 0.001 mg/kg to about 1.0 mg/kg per day, e.g. at about 0.004 mg/kg-0.71 mg/kg per day, as described above, with ibuprofen, or a pharmaceutically acceptable salt or solvate thereof, at a dosage range of about 1 mg/kg to about 50 mg/kg per day, e.g. at about 3 mg/kg to about 35mg/kg per day (e.g. in any of the ranges described herein; e.g.
  • mg/kg about 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 21 mg/kg, 22 mg/kg, 23 mg/kg, 24 mg/kg, 25 mg/kg, 26 mg/kg, 27 mg/kg, 28 mg/kg, 29 mg/kg, 30 mg/kg, 31 mg/kg, 32 mg/kg, 33 mg/kg, 34 mg/kg or 35 mg/kg).
  • Another embodiment is a combination, comprising the human dose range of naltrexone, at about 0.1 to about 100 mg, e.g. at about 0.25 mg - about 50 mg, about 0.25 mg - about 25 mg, or about 0.25 mg - about 15 mg, as described above, in combination with ibuprofen, or a pharmaceutically acceptable salt or solvate thereof, at a dosage range of about 100 mg to about 5000 mg per day, e.g. about 200 mg to about 2400 mg per day (e.g.
  • Another embodiment is a combination, comprising the human dose range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof, is about 0.1 mg to about 100 mg, e.g. is about 0.25 mg - 50 mg, as described above, and the human the dose range of ibuprofen, or a pharmaceutically acceptable salt or solvate thereof, is about 100 mg to about 5000 mg, e.g. is about 200 mg - 2400 mg (e.g.
  • composition is about 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, or 2400 mg), wherein said composition is formulated into a single fixed combination dosage form.
  • An alpha-2-delta ligand including, but not limited to, Gabapentin and pregabalin or a pharmaceutically acceptable salt any thereof, enhances the pain relief action of the opioid/TLR4 antagonists including, but not limited to, naltrexone.
  • a specific synergistic dose range of the combination is herein presented.
  • Voltage-dependent calcium channels alpha-2-delta -1 and alpha-2-delta -2 subunits are the binding site of the two anticonvulsant drugs, gabapentin (Neurontin) and pregabalin (Lyrica), that also find use in treating chronic neuropathic pain.
  • Gabapentin (Neurontin) is a pharmaceutical drug, specifically a GABA analog. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain. Gabapentin provides significant pain relief in about a third of people who take it for fibromyalgia or chronic neuropathic pain.
  • Pregabalin is an anticonvulsant drug used for neuropathic pain.
  • pregabalin is effective at treating chronic pain in disorders such as fibromyalgia.
  • Gabapentin and Pregabalin enhance the pain treatment effect of naltrexone by treating pain via another pathway, by binding Voltage-dependent calcium channels alpha-2-delta.
  • the disclosure first teaches the use of an opioid/TLR4 antagonist in combination with an alpha-2-delta ligand for their action on neuropathic pain.
  • the disclosure also teaches the use of naltrexone, in combination with an alpha-2-delta ligand such as Gabapentin or Pregabalin, for their action on neuropathic pain.
  • the disclosure teaches that the combination is synergistic as far as the effect on pain.
  • Another embodiment is a combination, comprising an opioid/TLR4 antagonist and an alpha-2-delta ligand.
  • the alpha-2-delta ligand inhibitor may be any alpha-2-delta ligand inhibitor including, but not limited to, Gabapentin or Pregabalin or pharmaceutically acceptable salts or solvates of any thereof.
  • Another embodiment is a combination, comprising an opioid antagonist and an alpha-2-delta ligand, the opioid /TLR4 antagonist is naltrexone as well as pro drugs and all enantiomeric and epimeric forms, specifically, (+)-naltrexone (dextro-naltrexone), as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • Another embodiment is a combination, comprising an opioid antagonist and an alpha-2-delta ligand, the opioid /TLR4 antagonist is naltrexone in a sustained release formulation, as well as pro drugs thereof or any enantiomeric and epimeric forms thereof, as well as the appropriate mixtures thereof, or pharmaceutically acceptable salts or solvates of any thereof.
  • Another embodiment is a combination, comprising an opioid/TLR4 antagonist and Gabapentin in a weight to weight combination range which corresponds to a synergistic combination range of the order of about 1 :50 to about 1 : 125 parts by weight (e.g. about 1 :50, 1 :60, 1 :70, 1 :80, 1 :90, 1 :100, 1 :110, 1 : 120 or 1 :125).
  • Another embodiment is a combination, comprising an opioid/TLR4 antagonist and Pregabalin in a weight to weight combination range which corresponds to a synergistic combination range of the order of order of about 1 : 10 to about 1 :100 parts by weight, e.g.
  • Another embodiment is a combination, comprising the dose range of an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, is about 0.001 mg/kg to about 1.0 mg/kg per day, e.g. is about 0.004 mg/kg-0.71 mg/kg per day, as described above, with Gabapentin, or a pharmaceutically acceptable salt or solvate thereof, at a dosage range of about 0.1 mg/kg to about 100 mg/kg per day, e.g. about 1.3 mg/kg to about 26mg/kg per day (e.g.
  • mg/kg about 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 21 mg/kg, 22 mg/kg, 23 mg/kg, 24 mg/kg, 25 mg/kg or 26 mg/kg).
  • Another embodiment is a combination, comprising the dose range of an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, is about 0.001 mg/kg to about 1.0 mg/kg per day, e.g. about 0.004 mg/kg- about 0.71 mg/kg per day, as described above, with Pregabalin, or a pharmaceutically acceptable salt or solvate thereof, at a dosage range of about 0.1 mg/kg to about 10 mg/kg per day, e.g. about 2 mg/kg to about 4 mg/kg per day (e.g.
  • ⁇ may range from about 2 to about 3 mg/kg, about 3 to about 4 mg/kg, about 2 to about 2.6 mg/kg, about 2.6 to about 3.3 mg/kg, about 3.3 to about 4 mg/kg, about 2 to about 2.5 mg/kg, about 2.5 to about 3 mg/kg, about 3 to about 3.5 mg/kg, about 3.5 to about 4 mg/kg, about 2 to about 3.5 mg/kg, about 2.6 to about 4 mg/kg, about 2.5 to about 3.5 mg/kg about 3 to about 4 mg/kg, or about 2.5 to about 4 mg/kg per day; e.g.
  • Another embodiment is a combination, comprising an alpha-2-delta ligand with an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, wherein the opioid/TLR4 antagonist is at a dosage range of about 0.1 mg to about 100 mg, e.g. about 0.25 mg to about 50 mg , about 0.25 mg - about 25 mg, or a "low" dose of about 0.25 mg - about 15 mg per day, as described above.
  • Another embodiment is a combination, comprising an alpha-2-delta ligand with an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, wherein the opioid/TLR4 antagonist is at a dosage range of about 0.1 mg to about 100 mg, e.g. about 0.25 mg - about 50 mg about 0.25 mg - about 25 mg, or a "low" dose of about 0.25 mg - about 15 mg per day, as described above, and the alpha-2-delta ligand is
  • Another embodiment is a combination, comprising an alpha-2-delta ligand with an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, wherein the opioid/TLR4 antagonist is at a dosage range of about 0.1 mg to about 100 mg , e.g. about 0.25 mg - about 50 mg, about 0.25 mg - about 25 mg, or a "low" dose of about 0.25 mg - about 15 mg per day, as described above, and the alpha-2-delta ligand is
  • Another embodiment is a combination, comprising the human dose range of an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, is about 0.1 mg to about 100 mg, e.g. is about 0.25 mg - about 50 mg, as described above, and the human the dose range of Gabapentin, or a pharmaceutically acceptable salt or solvate thereof, is about 10 mg to about 5000 mg per day, e.g. is about 100 mg to about 1800 mg per day (e.g.
  • 950 mg may range from about 100 to about 950 mg, about 950 to about 1800 mg, about 100 to about 670 mg, about 670 to about 1230 mg, about 1230 to about 1800 mg, about 100 to about 520 mg, about 520 to about 950 mg, about 950 to about 1375 mg, about 1375 to about 1800 mg, about 100 to about 1375 mg, about 670 to about 1800 mg, about 525 to about 1375 mg about 950 to about 1800 mg, or about 525 to about 1800 mg per day; e.g.
  • composition is about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg orl800 mg), wherein said composition is formulated into a single fixed combination dosage form.
  • Another embodiment is a combination, comprising the human dose range of an opioid/TLR4 antagonist, or a pharmaceutically acceptable salt or solvate thereof, is about 0.1 mg to about 100 mg, e.g. is about 0.25 mg - about 50 mg per day, as described above, and the human dose range of pregabalin, or a pharmaceutically acceptable salt or solvate thereof, is about 10 to about 1000 mg per day; e.g.
  • composition is about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg or 300 mg), wherein said composition is formulated into a single fixed combination dosage form.
  • Another embodiment is a combination, comprising naltrexone and
  • Gabapentin in a weight to weight combination range which corresponds to a synergistic combination range of the order of about 1 : 10 to about 1 :500 parts by weight, e.g. about 1 :50- about 1 :125 parts by weight (e.g. about 1 :50, 1 :60, 1 :70, 1 :80, 1 :90, 1 :100, 1 : 110, 1 :120 or 1 : 125).
  • Another embodiment is a combination, comprising naltrexone and Pregabalin in a weight to weight combination range which corresponds to a synergistic combination range of the order of about 1 : 1 to about 1 : 100 parts by weight, e.g. about 1 :30- about 1 :50 parts by weight (e.g. about 1 :30, 1 :40, or 1 :50).
  • Another embodiment is a combination, comprising the dose range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof, at a dosage range of about 0.001 mg/kg to about 1.0 mg/kg per day, e.g. about 0.004 mg/kg- about 0.71 mg/kg per day, about 0.25 mg - about 50 mg, about 0.25 mg - about 25 mg, or a "low" dose of about 0.25 mg - about 15 mg, as described above, per day with Gabapentin, or a pharmaceutically acceptable salt or solvate thereof, at a dosage range of about 0.1 mg/kg to about 100 mg/kg per day, e.g.
  • about 1.3 mg/kg - about 26mg/kg per day (e.g. may range from about 1.3 to about 13.6 mg/kg, about 13.6 to about 26 mg/kg, about 1.3 to about 9.5 mg/kg, about 9.5 to about 17.8 mg/kg, about 17.8 to about 26 mg/kg, about 1.3 to about 7.4 mg/kg, about 7.4 to about 13.6 mg/kg, about 13.6 to about 19.8 mg/kg, about 19.8 to about 26 mg/kg, about 1.3 to about 19.8 mg/kg, about 9.5 to about 26 mg/kg, about 7.4 to about 19.8 mg/kg about 13.6 to about 26 mg/kg, or about 7.4 to about 26 mg/kg per day; e.g.
  • mg/kg about 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 21 mg/kg, 22 mg/kg, 23 mg/kg, 24 mg/kg, 25 mg/kg or 26 mg/kg).
  • Another embodiment is a combination, comprising the dose range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof, at a dosage range of about O.OOlmg/kg to about 1.0 mg/kg per day, e.g. about 0.004 mg/kg- about 0.71 mg/kg per day, about 0.25 mg - about 50 mg, about 0.25 mg - about 25 mg, or a "low" dose of about 0.25 mg - about 15 mg, as described above, per day with Pregabalin, or a pharmaceutically acceptable salt or solvate thereof, at a dosage range of about 0.2 mg/kg to about 10 mg/kg per day, e.g. about 2 mg/kg - about 4 mg/kg per day (e.g.
  • ⁇ may range from about 2 to about 3 mg/kg, about 3 to about 4 mg/kg, about 2 to about 2.7 mg/kg, about 2.7 to about 3 mg/kg, about 3 to about 4 mg/kg, about 2 to about 2.5 mg/kg, about 2.5 to about 3 mg/kg, about 3 to about 3.5 mg/kg, about 3.5 to about 4 mg/kg, about 2 to about 3.5 mg/kg, about 2.7 to about 4 mg/kg, about 2.5 to about 3.5 mg/kg about 3 to about 4 mg/kg, or about 2.5 to about 4 mg/kg per day; e.g.
  • the combination with the opioid/TLR4 antagonist may also include
  • the combination with the opioid/TLR4 antagonist may also include Pregabalin, or a pharmaceutically acceptable salt or solvate thereof, at a dosage range of about 10 mg to about 1000 mg per day, e.g. about 150 mg to about 300 mg per day (e.g., is in a range from about e.g.
  • One embodiment is a combination, comprising the human dose range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof, of about 0.1 mg to about 100 mg per day, e.g. about 0.25 mg - about 50 mg per day, as described above, and the human the dose range of Gabapentin, or a pharmaceutically acceptable salt or solvate thereof, of about 10 mg to about 5000 mg, e.g. about 100 mg to about 1800 mg (e.g.
  • 950 mg may range from about 100 to about 950 mg, about 950 to about 1800 mg, about 100 to about 670 mg, about 670 to about 1230 mg, about 1230 to about 1800 mg, about 100 to about 525 mg, about 525 to about 950 mg, about 950 to about 1375 mg, about 1375 to about 1800 mg, about 100 to about 1375 mg, about 670 to about 1800 mg, about 525 to about 1375 mg about 950 to about 1800 mg, or about 525 to about 1800 mg per day; e.g.
  • composition is about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg orl800 mg), wherein said composition is formulated into a single fixed combination dosage form.
  • Another embodiment is a combination, comprising the human dose range of naltrexone, or a pharmaceutically acceptable salt or solvate thereof, of about 0.1 mg to about 100 mg, e.g. about 0.25 mg - about 50 mg per day, as described above, and the human the dose range of pregabalin, or a pharmaceutically acceptable salt or solvate thereof at about 1 mg to about 500 mg per day, e.g. about 50 mg to about 300 mg per day (e.g.
  • ⁇ may range from about 50 to about 175 mg, about 175 to about 300 mg, about 50 to about 133 mg, about 216 to about 300 mg, about 216 to about 300 mg, about 50 to about 112 mg, about 112 to about 175 mg, about 175 to about 237 mg, about 237 to about 300 mg, about 50 to about 237 mg, about 133to about 300 mg, about 112 to about 237 mg about 175 to about 300 mg, or about 112 to about 300 mg per day; e.g.
  • composition is about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg or 300 mg), wherein said composition is formulated into a single fixed combination dosage form.
  • Another embodiment comprises administering the combination of an opioid/TLR4 antagonist and an alpha-2-delta ligand once, twice, three or four times through the day.
  • Another embodiment comprising the therapeutically effective dose of the pharmaceutical composition of an opioid/TLR4 antagonist and an alpha-2-delta ligand is administered systemically by such routes including but are not limited to mucosal, nasal, oral, parenteral, gastrointestinal, topical or sublingual routes.
  • Another embodiment comprising, said combination of an opioid/TLR4 antagonist and an alpha-2-delta ligand is in a single dosage form, and said single dosage form is in the form of tablets, lozenges, troches, hard candies, liquid, powders, sprays, creams, salves and suppositories.
  • the pharmaceutical composition comprising the combination of an opioid/TLR4 antagonist and an alpha-2-delta ligand may be used for the treatment, prevention and reversal of neuropathic pain, back pain, chronic pain, diabetic neuropathic pain, trigeminal neuralgia pain, phantom limb pain, complex regional pain syndrome pain, acute herpetic pain, post herpetic pain, causalgia pain, idiopathic pain, inflammatory pain, cancer pain, postoperative pain, fibromyalgia pain, headache pain, migraine pain, allodynia pain, vulvodynia pain, interstitial cystitis pain, irritable bowel syndrome (IBS), arthritic joint pain and tendinitis.
  • IBS irritable bowel syndrome
  • Another embodiment is a method of treating neuropathic and nociceptive pain with an allodynic component and migraine in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a combination comprising an opioid/TLR4 antagonist and an alpha-2-delta ligand, or pharmaceutically acceptable salts or solvates of any thereof.
  • Another embodiment is a method of treating neuropathic and nociceptive pain with an allodynic component and migraine in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a combination comprising naltrexone and Gabapentin or Pregabalin, or pharmaceutically acceptable salts or solvates of any thereof.
  • Pain can be classified as either acute or chronic. Acute pain can be caused by damage to tissue and generally has a sudden onset and a limited duration. Chronic pain tends to last longer than acute pain and is usually associated with a long-term illness. It is usually more resistant to treatment, and can be the defining characteristic of a disease (such as fibromyalgia). It can be the result of damaged tissue, but more often is attributed to nerve damage. Pain can also be classified by the kind of damage that causes it. Nociceptive pain is pain caused by tissue damage, while neuropathic pain is pain caused by nerve damage. Nociceptive pain may be further divided into three different sub-categories: visceral, deep somatic, and superficial somatic pain.
  • pain examples include but are not limited to: acute pain, chronic pain, muscle pain, joint pain, chest pain, neck pain, shoulder pain, hip pain, abdominal pain, carpal tunnel syndrome, knee pain, back pain, myofascial pain syndrome, fibromyalgia, arthritic pain, headache, migraine headache, Piriformis syndrome, whiplash, chronic muscle pain, nociceptive pain, visceral pain, deep somatic pain, superficial somatic pain, neuropathic pain, central pain syndrome, complex regional pain syndrome, diabetic peripheral neuropathy, pain associated with shingles, postherpetic neuralgia, neuralgia, trigeminal neuralgia, sciatica pain, arachnoiditis (spinal pain), central pain syndrome, phantom limb pain, phantom body pain, neuropathy, compartment syndrome, acute herpetic pain, post herpetic pain, causalgia pain, idiopathic pain, inflammatory pain, cancer pain, postoperative pain, vulvodynia pain, interstitial cyst
  • Allodynia is a clinical feature of many painful conditions, including but not limited to: back pain, chronic pain, neuropathic pain, diabetic neuropathic pain, trigeminal neuralgia pain, phantom limb pain, complex regional pain syndrome pain, acute herpetic pain, post herpetic pain, causalgia pain, idiopathic pain, inflammatory pain, cancer pain, postoperative pain, fibromyalgia pain, headache pain, migraine pain, vulvodynia pain, interstitial cystitis pain, irritable bowel syndrome (IBS), arthritic joint pain and tendinitis. It becomes apparent that allodynia plays a role in every kind of pain.
  • IBS irritable bowel syndrome
  • compositions and methods of use therefore described in this application may be used to prevent, reduce, or eliminate any type of pain, including those types of pain that have an allodynic component.
  • the prevention, reduction, or elimination of pain may be measured in many ways, including (but not limited to): percent relief of pain, decrease in relative severity of the pain, decrease in frequency of breakout pain, reduction in the duration of pain, reduction in the level of pain, reduction in the frequency of night pain, reduction in the patient's Oswestry disability index level, reduction in the patient's Pittsburgh Insomnia scale rating, a decrease in insomnia, a decrease in disability, a decrease in the patient's score on the Roland-Morris low back pain and disability questionnaire, an increase in amount of time patient can stand, an increase in amount of time patient can stand on one leg, an increase in the patient's quality of life, an increase in the patient's energy levels, or an increase in the patient's activity levels.
  • the term "pharmaceutical composition” refers to a preparation of one or more of the components described herein, or physiologically acceptable salts or prodrugs thereof, with other chemical components such as physiologically suitable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • prodrug refers a precursor compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the active compound.
  • excipient refers to an inert or inactive substance added to a pharmaceutical composition to further facilitate administration of a compound.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • compositions of the present disclosure comprise an opioid/TLR4 antagonist, dextro enantiomer thereof, pro-drugs, salts, or solvates thereof and may also include one or more additive drugs (e.g., additional active ingredients), such as, but not limited to those listed above that may be suitable for combination therapy.
  • additive drugs e.g., additional active ingredients
  • compositions of the present disclosure comprises an opioid/TLR4 antagonist or pharmaceutically acceptable salts thereof.
  • Another pharmaceutical composition of the present disclosure comprises a dextro-enantiomer of an opioid/TLR4 antagonist or the pharmaceutically acceptable salt thereof.
  • the disclosure also provides synergistic compositions comprising an opioid/TLR4 antagonist, dextro enantiomeric mixtures thereof, or pharmaceutically acceptable salts thereof and an alpha-2 adrenergic receptor agonist, acetyl-para-aminophenol (APAP), a cyclooxygenase (COX) inhibitor, and/or an alpha-2-delta ligand.
  • the pharmaceutical compositions of the present disclosure also comprise an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with an alpha-2 adrenergic receptor agonist.
  • compositions of the present disclosure may also comprise an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with an acetyl-para-aminophenol (APAP).
  • APAP acetyl-para-aminophenol
  • the pharmaceutical compositions of the present disclosure also comprise an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with a cyclooxygenase (COX) inhibitor.
  • COX cyclooxygenase
  • pharmaceutical compositions of the present disclosure also comprise an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with an alpha-2-delta ligand.
  • Synergy occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.
  • a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds when administered alone.
  • Synergy can be in terms of lower cytotoxicity, increased decrease in pain, or some other beneficial effect of the combination compared with the individual components.
  • synergy can encompass the reduction of side effects associated with one or more of the substances in the combination because one or more of the substances can be used at a lower dose while still maintaining or enhancing pharmaceutical effectiveness.
  • compositions of the present disclosure may comprise an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with an alpha-2 adrenergic receptor agonist and acetyl-para-aminophenol (APAP); an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with an alpha-2 adrenergic receptor agonist and a cyclooxygenase (COX) inhibitor; or an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with an alpha-2 adrenergic receptor agonist and an alpha-2-delta ligand.
  • APAP acetyl-para-aminophenol
  • COX cyclooxygenase
  • compositions of the present disclosure may also comprise an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with acetyl-para-aminophenol (APAP) and a cyclooxygenase (COX) inhibitor, or it may comprise an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with acetyl-para-aminophenol (APAP) and an alpha-2-delta ligand.
  • APAP acetyl-para-aminophenol
  • COX cyclooxygenase
  • compositions of the present disclosure may also comprise an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with a cyclooxygenase (COX) inhibitor and an alpha-2-delta ligand.
  • COX cyclooxygenase
  • compositions of the present disclosure may also comprise an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with a cyclooxygenase (COX) inhibitor in combination with acetyl-para-aminophenol (APAP) and an alpha-2-delta ligand.
  • COX cyclooxygenase
  • APAP acetyl-para-aminophenol
  • alpha-2-delta ligand an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with a cyclooxygenase (COX) inhibitor in combination with acetyl-para-aminophenol (APAP) and an alpha-2-delta ligand.
  • COX cyclooxygenase
  • APAP acetyl-para-aminophenol
  • compositions of the present disclosure may comprise an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with an alpha-2 adrenergic receptor agonist, acetyl- para-aminophenol (APAP), and a cyclooxygenase (COX) inhibitor. It may also comprise an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with an alpha-2 adrenergic receptor agonist, a cyclooxygenase (COX) inhibitor, and an alpha-2-delta ligand.
  • an opioid/TLR4 antagonist dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with an alpha-2 adrenergic receptor agonist, a cyclooxygenase (COX) inhibitor, and an alpha-2-delta ligand.
  • the pharmaceutical composition may comprise an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with an alpha-2 adrenergic receptor agonist, acetyl- para-aminophenol (APAP), and an alpha-2-delta ligand.
  • opioid/TLR4 antagonist dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with an alpha-2 adrenergic receptor agonist, acetyl- para-aminophenol (APAP), and an alpha-2-delta ligand.
  • APAP acetyl- para-aminophenol
  • the pharmaceutical composition may also comprise an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with an alpha-2 adrenergic receptor agonist, acetyl-para-aminophenol (APAP), an alpha-2 adrenergic receptor agonist, and a cyclooxygenase (COX) inhibitor.
  • an opioid/TLR4 antagonist dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof in combination with an alpha-2 adrenergic receptor agonist, acetyl-para-aminophenol (APAP), an alpha-2 adrenergic receptor agonist, and a cyclooxygenase (COX) inhibitor.
  • APAP acetyl-para-aminophenol
  • COX cyclooxygenase
  • the term “combination” refers to two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such combination of therapeutic agents may be in the form of a single pill, capsule, or intravenous solution. However, the term “combination” also encompasses the situation when the two or more therapeutic agents are in separate pills, capsules, or intravenous solutions. Likewise, the term “combination therapy” refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, or in separate containers (e.g., capsules) for each active ingredient.
  • administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times.
  • the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • the dosage form can be prepared by various conventional mixing, comminution and fabrication techniques readily apparent to those skilled in the chemistry of drug formulations.
  • the method of treating a disease according to the invention can comprise (i) administration of the opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or pharmaceutically acceptable salts thereof and (ii) administration of one or more of: an alpha-2 adrenergic receptor agonist, acetyl-para-aminophenol (APAP), and an alpha-2- delta ligand, or any pharmaceutically acceptable salts thereof simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g. in daily or intermittently dosages corresponding to the amounts described herein.
  • APAP acetyl-para-aminophenol
  • any pharmaceutically acceptable salts thereof simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g. in daily or intermittently dosages corresponding to the amounts described herein.
  • the individual combination partners of the combination of the invention can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • administering also encompasses the use of a pro-drug of a combination partner that convert in vivo to the combination partner as such.
  • the instant invention is therefore to be understood as embracing all such regimens of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • Frequency of dosage can vary depending on the compound used and the particular condition to be treated or prevented. In general, the use of the minimum dosage that is sufficient to provide effective therapy is preferred. Patients can generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those of ordinary skill in the art. Different dosage regimens may be used to treat any of the disease states referenced herein. In some embodiments, a daily dosage, such as any of the exemplary dosages described herein, is administered once, twice, three times, or four times a day for three, four, five, six, seven, eight, nine, or ten days.
  • the compounds described herein may be used on the order of about 10 times per day to about once per six months (e.g., about 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 times per day to about 31 , 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 times per month).
  • dosing frequencies are once per day, once per week, once per two weeks, once per three weeks, and once per month.
  • a shorter treatment time e.g., up to five days
  • a longer treatment time e.g., ten or more days, or weeks, or a month, or longer
  • the dosing regimen may change over time depending on the condition being treated and the patient's response to the treatment.
  • the disclosure provides a composition comprising a compound that is an opioid/TLR4 antagonist, dextro enantiomeric mixture thereof, or a pharmaceutically acceptable salt thereof and its use for the treatment, prevention, and reversal of pain.
  • the disclosure also provides synergistic compositions comprising an opioid/TLR4 antagonist, dextro enantiomeric mixtures thereof, or pharmaceutically acceptable salts thereof and an alpha-2 adrenergic receptor agonist, acetyl-para-aminophenol (APAP), a cyclooxygenase (COX) inhibitor, and/or an alpha-2-delta ligand.
  • the disclosure further provides a method of use of these synergistic compositions for the treatment, prevention, and reversal of pain, particularly neuropathic pain.
  • compositions of the present disclosure may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, grinding, pulverizing, dragee-making, levigating, emulsifying, encapsulating, entrapping or by lyophilizing processes.
  • compositions for use in accordance with the present disclosure thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the term "administration" or any variation thereof as used herein is meant any way of administration.
  • the one or more opioid/TLR4 antagonists, dextro enantiomers thereof, pro-drugs, salts, or solvates thereof may be administered alone.
  • the one or more opioid/TLR4 antagonists, dextro enantiomers thereof, pro-drugs, salts, or solvates thereof and at least one additional drug may be administered in one therapeutic dosage form or in two or more separate therapeutic dosages such as in separate capsules, tablets or injections. In the case of the two or more separate therapeutic dosages, the administration may be such that the periods between the administrations vary or are determined by the practitioner.
  • the second drug and any other additional drugs may be administered within the therapeutic response time of the first drug.
  • the second drug and any other additional drugs may be also administered after the therapeutic response time of the first drug.
  • the one or more of opioid/TLR4 antagonists, dextro enantiomers thereof, pro-drugs, salts, or solvates thereof and at least one additional drug which may be administered either at the same time, or separately, or sequentially, according to the disclosure, do not represent a mere aggregate of known agents, but a new combination with the valuable property that the effectiveness of the treatment is achieved at a much lower dosage of said at least one additional drug.
  • compositions of the present disclosure may be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with any other therapeutic agent. Administration can be systemic or local.
  • Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, or capsules that may be used to administer the compositions of the disclosure.
  • Methods of administration include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally (including by suppository or enema), by inhalation, or topically to the cars, nose, eyes, or skin.
  • administration is left to the discretion of the practitioner, and will depend in part upon the site of the medical condition and the severity of thereof.
  • composition of the disclosure may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants for example DMSO, or polyethylene glycol are generally known in the art.
  • composition can be formulated readily by combining the active components with any pharmaceutically acceptable carriers known in the art.
  • carriers may facilitate the manufacture of such as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
  • Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydro xypropylmethyl-cellulose, sodium carbomethylcellulose, and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • compositions which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active components may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active NSAID doses.
  • stabilizers may be added.
  • compositions for parenteral administration include aqueous solutions of the active preparation in a water-soluble form. Additionally, suspensions of the active preparation may be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl, cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds, to allow for the preparation of highly concentrated solutions.
  • the composition may be in a powder form for constitution before use with a suitable vehicle, e.g., sterile, pyrogen- free water.
  • a suitable vehicle e.g., sterile, pyrogen- free water.
  • the exact formulation, route of administration and dosage may be chosen by the physician familiar with the patient's condition. (See for example Fingl, et al., 1975, in "The Pharmacological Basis of
  • dosing can also be a single administration of a slow release composition, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved.
  • dosing can also be a single administration of a slow release composition, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved.
  • Example 1 A Pharmaceutical Composition Comprising Naltrexone and Clonidine and Clinical Trials Thereof
  • Naltrexone and clonidine were evaluated alone and in combination on a human subject with the purpose of finding whether or not a combination of the two compounds offers synergistic advantage.
  • Two aspects were evaluated for synergy: one aspect was pain treatment effect comparing the amounts used weight to weight, and the other aspect was an assessment of synergy of side effects.
  • naltrexone 4.5mg was given in the morning.
  • the clonidine dose was divided into two doses, a dose of O. lmg in the morning and a dose of 0.2mg at bedtime.
  • the morning/daytime combination of naltrexone/clonidine 2.25mg/ 0.025 mg respectively was given in the morning, and the night/bedtime combination of naltrexone/clonidine of 2.25 mg/ 0.05mg and 2.25mg/0.1mg respectively was given at night.
  • the pain treatment effect of naltrexone and clonidine was evaluated after one hour post-dose. Side effects were assessed over the next 24 hours.
  • naltrexone and clonidine administered alone were compared to the combination combined amounts.
  • WAV weight to weight
  • Naltrexone and clonidine were administered at fixed dose ratios of 90:1, 45:1 and 22.5 :1 to a human subject afflicted with neuropathic back pain.
  • Table 1 illustrates the naltrexone/clonidine ratios that exhibit weight to weight
  • the 90:1 combination represents a 2-fold lower dose of naltrexone and 4-fold lower dose of clonidine when administered alone.
  • the 45:1 combination represents a 2-fold lower dose of naltrexone and 2-fold lower dose of clonidine when administered alone.
  • Table 1 Naltrexone/Clonidine Ratios And Weight to Weight (WAV) Synergy
  • the 22.5:1 ratio represents a 2-fold lower dose of naltrexone and the same dose of clonidine when administered alone.
  • the fixed dose ratio of 90:1, 45:1 and 22.5 :1 demonstrated weight to weight synergy with neuropathic back pain completely blocked by the doses of 2.25 mg/ 0.025mg, 2.25mg/0.05mg and 2.25mg/0.1mg of naltrexone/clonidine respectively.
  • Table 2 demonstrates the side effect synergy of the naltrexone/clonidine combination: alertness and anxiety from naltrexone are counteracted by the somnolence and calmness caused by clonidine.
  • Naltrexone administered by itself at a 4.5mg dosage carries a high incidence of alertness, insomnia and anxiety which deters compliance.
  • Clonidine administered by itself at a .3mg dosage at bedtime causes excessive somnolence that carries over through the next day.
  • the 90:1 ratio is a suitable synergistic ratio for morning/daytime contemplated administration. It embodies a lower adjusted total weight to weight dose of 2.625 mg compared to 4.5mg of naltrexone and clonidine alone. Furthermore, it offers balance between the side effects: alertness and anxiety from naltrexone are counteracted by calmness from clonidine.
  • the 45 :1 ratio is a suitable synergistic ratio for night/bedtime contemplated use. It embodies a lower adjusted total weight to weight dose of 2.35mg compare to 4.5mg of naltrexone and clonidine alone. This ratio provides additional sedation for more restorative night sleep.
  • the 22.5:1 ratio is a synergistic ratio for night/bedtime use as it provides additional sedative effect.
  • combination dosage ratio range is between 90:1 and 22.5:1. This dosage ratio range exhibits synergy of weight to weight proportion and of side effect profile.
  • LBP leg weakness and pain. Additionally, she had a lifelong history of migraine headaches averaging two headache-days a week with an average intensity of 5 on a scale of 10, where 10 is intolerable pain. Prior to entering the double blind clinical trial, she had used duloxetine, topiramate, and non-steroidal anti-inflammatory drugs (NSAIDs) on a regular basis, all of which were discontinued upon entering the trial.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Her baseline average back pain score the week before receiving study drug was 6.5 on a scale of 10, and her headache pain level was rated as 10. Eight minutes after the first dose combination of naltrexone/clonidine 2.25mg/0.025mg she reported that her headache had begun to resolve. After one hour her migraine pain had resolved to 0; her LBP had become 5 for a 60% improvement by her own report. After six hours, her LBP had fully resolved to a score of 0 out of 10.
  • Vulvodynia is a chronic pain syndrome that affects the vulvar area and often occurs without an identifiable cause or visible pathology.
  • a 55 year old female with a six year history of vulvodynia presented with constant pain and sensitivity in the vulva which interfered with her daily living and prevented her from having sexual intercourse.
  • Table 4 tabulates the various pain intensity scores over time and percent relief for the example of Vulvodynia.
  • the drawing in Figure 3 is a graph of the various pain intensity scores over time in the case of Vulvodynia pain.
  • the drawing in Figure 4 is a graph of the percent relief reported by the case of Vulvodynia pain over time. This case study demonstrates complete reversal of vulvodynia pain starting after the first dose of ATNC05. The effect was maintained throughout the 30-day treatment period. The patient reported increased energy level, improvement of sleep quality, and resolution of headaches.
  • Trigeminal neuralgia also known as suicide disease, is a neuropathic disorder characterized by episodes of intense pain in the face, originating from the trigeminal nerve. It has been described as among the most painful conditions known to centuries. This case study is of a 40 year old male with a three month history of trigeminal neuralgia. The patient had a gradual onset of pain in the right side of his face that started six weeks after a root canal. The pain involved the right check, upper jaw and the upper front teeth. The pain was constant and described as burning, stinging and aching. It was aggravated by eating, brushing teeth, flossing, chewing and talking. The subject's pain level on average was 5, but it would peak to 9.
  • a double-blind, placebo-controlled, randomized, proof-of-concept clinical trial was conducted in order to determine the efficacy and safety of a combination of low dose naltrexone and low dose clonidine (code-named ATNC05) for the treatment of symptoms of back pain.
  • the studies were conducted under the regulatory oversight of the Food and Drug Administration (FDA) and the Independent Institutional Review Board (presently known as Shulman IRB). The subjects were screened to verify the diagnosis of chronic back pain (longer than three months).
  • BPI Baseline Period Brief Pan Inventory
  • SD Severity Scores - Mean
  • BPI Baseline Period Brief Pan Inventory
  • SD Interference Scores - Mean
  • Table 9 shows 23 subjects out of 78 who entered the study for back pain had concomitant migraine or tension headache. This finding represents a higher incidence of headaches than found in the general population. Similarly, table 10 shows 30 out of 78subjects had joint pain, most of which was associated with tendinitis rather than arthritic pain.
  • Non-Hispanic 3 (30) 4 (30.7) 7 (30.4)
  • Table 11 presents the daily improvement of pain scores of study drug vs. placebo measured on a scale of 0-10, with 10 being most severe during the blinded study drug period.
  • Table 11 Daily Improvement of Pain Scores of Study Drug vs. Placebo by Day subjects ATNC05 (n Placebo ATNC05
  • Pain intensity scores of study drug vs. placebo, as reported daily by the subjects for Worst Pain, Least Pain, Average Pain, Right-Now Pain, and Night Pain during the previous 24-hours are summarized in the following 5 tables and graphs.
  • the data and graphs show consistent treatment impact on all pain intensity measures. Improvement begins starting the first day.
  • the study drug impact increases as time progresses showing approximately a 5 point (on a scale of 0-10 with 10 being most severe) improvement compared to baseline by the end of the study.
  • the Study Drug group exhibited resolution of pain.
  • Table 12 tabulates the worst pain intensity scores over time for the study drug group versus placebo group in the clinical trial subjects.
  • the drawing in Figure 9 is a graph of the treatment impact on worst pain by day of study drug group versus placebo group in the clinical trial subjects.
  • Table 13 tabulates the least pain intensity scores over time for the study drug group versus placebo group in the clinical trial subjects.
  • the drawing in Figure 10 is a graph of the treatment impact on least pain by day of study drug group versus placebo group in the clinical trial subjects.
  • Table 14 tabulates the average pain intensity scores over time for the study drug group versus placebo group in the clinical trial subjects.
  • the drawing in Figure 11 is a graph of the treatment impact on average pain by day of study drug group versus placebo group in the clinical trial subjects.
  • Table 15 tabulates the right now pain intensity scores over time for the study drug group versus placebo group in the clinical trial subjects.
  • the drawing in Figure 12 is a graph of the treatment impact on right now pain by day of study drug group versus placebo group in the clinical trial subjects.
  • Table 16 tabulates the night pain intensity scores over time for the study drug group versus placebo group in the clinical trial subjects.
  • the drawing in Figure 13 is a graph of the treatment impact on night pain by day of study drug group versus placebo group in the clinical trial subjects.
  • Table 14 Average Pain Scores (Scale: 0-10) By Treatment Group
  • Figure 14 shows an average 4.5 point drop in pain score during the Open
  • the Oswestry Disability Index is considered the gold standard for assessing the disability level of back pain for those, who suffer back pain, to assess their disability level.
  • the drawing in Figure 15 shows the change in the Oswestry Disability Index of the cervical pain over time in the study drug group versus the placebo group.
  • the drawing in Figure 16 shows the change in the Oswestry Disability Index of the lumbar pain over time in the study drug group versus the placebo group.
  • the Pittsburgh Insomnia Rating Scale (PIRS) was developed by the University of Pittsburgh's Western Psychiatric Institute and Clinic to assess insomnia. The Total Score is a sum of all nineteen responses to questions on the questionnaire with possible values of zero to sixty. Higher scores indicate greater degree of insomnia.
  • the drawing in Figure 17 shows the change in the Pittsburgh Insomnia Rating Scale over time in the study drug group versus the placebo group.
  • the Study Drug treatment group showed statistically significant improvement over the placebo group in PIRS 20 Total Score at Week 1 and at Week 3.
  • the drawing in Figure 18 graphs average the Roland-Morris Low Back Pain and Disability Questionnaire (RMQ) scores for the Study Drug Group and Placebo at Baseline, Week 1 , and Week 3.
  • the Roland-Morris Questionnaire is a self-administered disability measure in which greater levels of disability are reflected by higher numbers on a 24-point scale.
  • the RMQ has been shown to yield reliable measurements, which are valid for inferring the level of disability, and to be sensitive to change over time for groups of patients with lower back pain.
  • Example 2 A Pharmaceutical Composition Comprising Qpioid7TLR4 Antagonists and Acetyl-Para-Aminophenol (APAP) for use in treatment of Pain.
  • APAP Acetyl-Para-Aminophenol
  • Naltrexone and acetyl-para-aminophenol were evaluated alone and in combination on a human subject with the purpose of finding whether or not a combination of the two compounds offers a synergistic advantage for the pain treatment effect comparing the amounts used weight to weight.
  • the components of the combination were administered to a subject as follows, the naltrexone dose administered by itself was 4.5mg and the acetyl-para-aminophenol dose administered by itself was lOOOmg, The naltrexone/acetyl-para-aminophenol combination dose was 2.25mg/325 respectively.
  • the pain treatment effect of naltrexone and acetyl-para- aminophenol was evaluated two hours post-dose.
  • naltrexone and acetyl-para- aminophenol administered alone were compared to the combination combined amounts.
  • WAV weight to weight
  • an adjustment for the higher potency of naltrexone was made based on the dose of each compound given by itself.
  • Naltrexone and acetyl-para-aminophenol were administered at fixed dose ratios of 3 :200 to a human subject afflicted with neuropathic back pain.
  • Table 18 illustrates the naltrexone/acetyl-para-aminophenol ratio that exhibit weight to weight (WAV) synergy in a human subject.
  • the 3:200 combinations represent a 2- fold lower dose of naltrexone and 3-fold lower dose of acetyl-para-aminophenol when administered together.
  • the disclosure teaches that the optimal contemplated naltrexone, or a pharmaceutically acceptable salt or solvate thereof, to acetyl-para-aminophenol, combination dosage ratio range is 3:200, and this dosage ratio exhibits synergy of weight to weight proportion.
  • Example 3 A Pharmaceutical Composition Comprising Opioid/TLR4 Antagonists and a cvclo oxygenase (COX) inhibitor for use in treatment of Pain.
  • COX cvclo oxygenase
  • Naltrexone and ibuprofen were evaluated alone and in combination on a human subject with the purpose of finding whether or not a combination of the two compounds offers a synergistic advantage for the pain treatment effect comparing the amounts used weight to weight.
  • the components of the combination were administered to a subject as follows: the naltrexone dose administered alone was 4.5mg, and the ibuprofen dose administered alone was 800mg. The dose of the naltrexone/ibuprofen combination was 2.25mg/200, respectively. The pain treatment effect was evaluated one hour post-dose. [00259] To determine synergy, the amounts of naltrexone and ibuprofen administered alone were compared to the combination combined amounts. For proper weight to weight (WAV) comparison between naltrexone and ibuprofen an adjustment for the higher potency of naltrexone was made based on the dose of each compound given by itself.
  • WAV weight to weight
  • Table 19 illustrates the naltrexone/ibuprofen ratio that exhibit weight to weight
  • the 1 :90 combinations represent a 2-fold lower dose of naltrexone and 4-fold lower dose of ibuprofen when administered together.
  • the disclosure teaches that the optimal contemplated naltrexone to ibuprofen combination dosage ratio is 1 :90. This dosage ratio exhibits synergy of weight to weight proportion.
  • Example 4 A Pharmaceutical Composition Comprising Opioid7TLR4 Antagonists and an Alpha 2 Delta Ligand for use in treatment of Pain.
  • Naltrexone and Gabapentin or Pregabalin were evaluated alone and in combination on a human subject with the purpose of finding whether or not a combination of the two compounds offers a synergistic advantage for the pain treatment effect comparing the amounts used weight to weight.
  • the components of the combination were administered to a subject as follows: the naltrexone dose administered alone was 4.5mg, and the Gabapentin and pregabalin dose administered alone was 1800mg and 300mg respectively.
  • the dose of the naltrexone/ Gabapentin combination was 2.25mg/300 respectively and the naltrexone/pregabalin combination was 2.25mg/150 respectively, the pain treatment effect was evaluated one hour post-dose.
  • naltrexone and Gabapentin or pregabalin administered alone were compared to the combination combined amounts.
  • WAV weight to weight
  • an adjustment for the higher potency of naltrexone was made based on the dose of each compound given by itself.
  • Naltrexone and Gabapentin were administered at fixed dose ratios of 1 :50- 1 : 125 to a human subject afflicted with neuropathic back pain.
  • the 1 : 125 combinations represent a 2-fold lower dose of naltrexone and a 6-fold lower dose of Gabapentin
  • Table 20 illustrates the naltrexone/Gabapentin ratio that exhibit weight to weight (WAV) synergy in a human subject.
  • the 1 :50 combinations represent a 2-fold lower dose of naltrexone and 18 fold lower dose of Gabapentin.
  • the 1 :125 combinations represent a 2-fold lower dose of naltrexone and 6-fold lower dose of Gabapentin.
  • Table 21 illustrates the naltrexone/pregabalin ratio that exhibit weight to weight (WAV) synergy in a human subject.
  • the 1 :30 combinations represent a 2-fold lower dose of naltrexone and 4 fold lower dose of pregabalin when administered together.
  • the 1 :50 combinations represent a 2-fold lower dose of naltrexone and 2.4 fold lower dose of Pregalbin when administered together.
  • Example 5 A Pharmaceutical Composition Comprising Opioid7TLR4 Antagonists and Dextro Enantiomers Thereof for use in treatment of Pain.
  • Table 22 tabulates the change of the pulse from baseline by visit of the study drug group and the placebo group.
  • Table 19 graphs the change in the pulse from baseline of the study drug group versus the placebo group.
  • Table 23 tabulates the change of the systolic blood pressure (BP) from baseline by visit of the study drug group and the placebo group.
  • the drawing in Figure 20 graphs the change in the systolic blood pressure (BP) from baseline of the study drug group versus the placebo group.
  • Table 24 tabulates the change of the diastolic blood pressure (BP) from baseline by visit of the study drug group and the placebo group.
  • the drawing in Figure 21 graphs the change in the diastolic blood pressure (BP) from baseline of the study drug group versus the placebo group.
  • the data shows that there were no clinically significant changes in pulse, systolic blood pressure and diastolic blood pressure over a three to four week treatment, either during treatment period or Open Phase (OP).
  • BP diastolic blood pressure
  • a human subject used naltrexone in a low dose of 2 mg twice daily for cervical pain. The subject experienced a significant relief of his pain however he discontinued using the drug after 2 weeks because he was unable to tolerate the side effects that included anxiety and irritability.
  • Table 25 tabulates the change of pain and side effects for this patient (on).
  • the drawing in Figure 22 graphs the change of pain and side effects over the same period.
  • Table 25 and Figure 22 show naltrexone's effect on pain and side effects.
  • the pain treatment effect of naltrexone continued for a few days after discontinuation.
  • the side effects resolved within one day of treatment discontinuation.
  • ATNC05 is the code name for the investigational product discussed in this application. It consists of capsules containing naltrexone 2.25 mg and clonidine 0.025 mg to be administered orally for neuropathic lower back pain as 1 to 2 capsules taken twice daily.
  • Naltrexone was approved for opioid addiction in 1984 and for alcohol dependence in 1995. A dose of 50 mg once daily is recommended for most patients.
  • Clonidine a direct acting alpha 2 adrenergic agonist and an imidazoline receptor agonist, was approved for hypertension in 1974 and in an extended release form for the treatment of attention deficit hyperactivity disorder in 2009. The therapeutic doses most commonly employed for clonidine have ranged from 0.2 mg to 0.6 mg per day given in divided doses.
  • ATNC05 represents a low dose of naltrexone and clonidine.
  • the dose of naltrexone is 9% of the recommended dose for the approved indication
  • the dose of clonidine is 8% (0.05 mg/0.6 mg) of the upper range of the common therapeutic dose for the approved indications.
  • a higher dose of ATNC05 was needed.
  • the doses of naltrexone and clonidine are 18% and 16% of the approved doses, respectively.
  • Dextro -naltrexone (+)-naltrexone) blocks only the TLR-4 while not blocking the morphine receptors. Therefore, the side effects arising from blocking of the morphine receptors by the racemic naltrexone (a mix of (-)-naltrexone and (+)-naltrexone), which are caused by (-)-naltrexone, are eliminated by use of (+)-naltrexone.
  • BOCF Baseline Observation Carried Forward
  • BOCF Placebo 34 5.50 4.59 -0.91 (0.36) 0.00000
  • BOCF ATNC05 44 5.55 1.86 -3.69 (0.34)
  • Pain Severity score one to four hours after the initial dose (on average, two hours). The change from the baseline period mean was compared. For the placebo group, pain was reduced by 1.96. For the ATNC05 arm, pain was reduced by 3.88. The treatment effect size is 1.92 ⁇ 1.488 (99% confidence interval), which is significant, with p ⁇ 0.00001 (Figure 24, Table 28).
  • Table 28 Mean change from base line to Post-Initial Dose in Right Now Pain Intensity
  • ATNC05 causes immediate significant relief of neuropathic back pain.
  • other treatments for neuropathic lower back pain take weeks to provide relief.
  • Figure 25 shows the response rates as measured by PGI-I during Week 3 during both the double-blind and open-label phases.
  • the sections on the x-axis indicate ranges of improvement.
  • the columns in the charts are a histogram of the number of subjects with a mean PGI-I in Week 3 in each range.
  • the lines indicate the cumulative distribution of the subjects; it shows the percentage of subjects whose score is in that range or one greater.
  • Table 29 shows the response rates across study phases. The percent indicates the percentage of subjects reporting improvement of the threshold or greater.
  • ATNC05 subjects had a high improvement in PGI-I. 7 out of 10 of ATNC05 subjects reported 90% or greater improvement, 8 out of 10 subjects reported 70% or greater improvement, and nearly 9 out of 10 subjects reported of 50% or greater improvement during Week 3 of the double-blind phase. Subjects showed even stronger improvement in the Open- Label phase, where nearly 9 out of 10 subjects reported 70% or greater improvement, and 95.7% of subjects reported improvement of 50% or greater. By comparison, 2 out of 10 placebo subjects reported 70% or greater improvement, consistent with the placebo effect size observed in other studies.
  • Table 30 shows the daily self -reported mean Average Pain Scores for subjects starting on Study Day 2 during the Double-Blind phase (Average Pain is measured over the previous 24 hours, and taking this measure on Day 1 would have included time in the Baseline Period; Day 1 data were discussed earlier).
  • the p-value column shows the result of a Student's t-test comparing the Placebo Treatment Effect and the ATNC05 Treatment Effect. Please note that data were not imputed by BOCF during the taper-off periods (days 22-24).
  • Figure 26 shows the daily mean Average Pain Scores by day with standard error bars.
  • the Baseline Period Mean is shown on the chart as Day 0.
  • Table 31 shows the mean weekly pain scores for each of the five back pain severity measures. For each pain measurement and period, the p-value is based on a Student's t-test comparing the groups' mean change in the score from the Baseline Period Mean for that score. For all groups in all time-frames, ATNC05 subjects had significantly greater improvement than the placebo subjects. In the main treatment period (Week 1, Week 2, and Week 3), the improvement has a p-value of ⁇ 0.00001.
  • Figure 27 shows the summary of weekly pain severity scores in graphical form for subjects in the placebo treatment group. It shows the five severity measures for each week of the treatment period.
  • Figure 28 shows the same summary graph for subjects receiving ATNC05. As illustrated, placebo group subjects do not show a strong trend of improvement, while the ATNC05 subjects show a strong downward trend in all the pain severity measures.
  • Table 30 Mean Average Pain Scores of ATNC05 and Placebo by Day (BOCF)
  • Table 32 shows the mean weekly pain scores for each of the nine back pain interference measures. For each pain measurement and period, the p-value is based on a Student's t-test comparing the groups' mean change in the score from the Baseline Period Mean for that score.
  • Figure 29 shows the summary of weekly pain interference scores in graphical form for subjects in the placebo treatment group.
  • Figure 30 shows the same summary graph for subjects receiving ATNC05. As illustrated, placebo group subjects do not show a strong trend of improvement, while the ATNC05 subjects show a strong downward trend in all the pain interference measures.
  • Table 32 Summary of Back Pain Interference Measures by Week (BOCF)
  • Oswestry Disability Index is a 10 item questionnaire which measures permanent functional disability caused by back pain. It was measured during each office visit, and is measured on a scale of 0 to 100.
  • Figure 31 shows the average ODI score for each treatment group during the
  • the Roland-Morris Low Back Pain and Disability Questionnaire is a 24 item questionnaire which asks the subjects to choose statements about back pain which apply to them.
  • the statements cover a variety of impairments caused by back pain. It was measured during each office visit, and is measured on a scale of 0 to 24 (where each statement the subject agrees with increases the score by one).
  • Figure 32 shows the average Roland-Morris score for each treatment group during the Baseline Period, and at the Week 1 and Week 3 visits.
  • the Open-Label results are shown for Week 1 and Week 3. Double-Blind period were imputed by BOCF when needed.
  • placebo subjects scored a mean of 15.75
  • ATNC05 subjects scored a mean of 14.18.
  • the Placebo subjects scored a mean of 14.98, a change of 0.77.
  • the ATNC05 subjects had a Week 3 mean of 3.85, a change of 10.33 points from their baseline period.
  • subjects scored a mean of 1.89 points.
  • the difference between the placebo and ATNC05 groups was statistically significant, with p-values of ⁇ 0.00001.
  • the Pittsburgh Insomnia Scale (PIRS-20) is a 20 item questionnaire which measures the difficulty subjects have with sleeping due to pain. It was measured during each office visit and is measured on a sale of 0 to 60.
  • Figure 33 shows the average PIRS-20 score for each treatment group during the Baseline Period, and at the Week 1 and Week 3 visits.
  • the Open-Label results are shown for Week 1 and Week 3. Double-Blind period were imputed by BOCF when needed.
  • placebo subjects scored a mean of 36.05, while ATNC05 subjects scored a mean of 34.81.
  • the Placebo subjects scored a mean of 30.57, a change of 5.48.
  • the ATNC05 subjects had a Week 3 mean of 12.88, a change of 21.93 points from their baseline period.
  • subjects scored a mean of 6.96 points.
  • the difference between the placebo and ATNC05 groups was statistically significant, with p- values of 0.00010 and ⁇ 0.00001 , respectively.
  • Figure 34 shows the average length of time these subjects were able to stand on one leg, in seconds.
  • both groups have a similar ability to stand on one leg.
  • the placebo group never exceeds 5 seconds of standing on one leg, by the end of the first week, ATNC05 subjects are able to stand on one leg for over 24 seconds on average.
  • subjects are able to stand on one leg for over 59 seconds on average.
  • Figure 35 and Figure 36 show the weekly mean BPI-Severity and BPI-
  • ATNC05 took fewer doses of other pain medications than placebo subjects throughout the treatment period.
  • Week 3 ATNC05 subjects took a mean of 0.5 doses, a reduction from baseline of 4.16 doses, while placebo subjects took 2.87 doses, a reduction from baseline of 0.95 doses.
  • Table 33 shows both the total number of doses taken and the number per subject as a table.
  • Figure 37 shows the mean number of doses taken per week. This indicates that ATNC05 relieved the subjects' symptoms, so they did not need to take other pain medications.
  • Table 34 shows the results of post-study questionnaires, collected by in-person and telephone interviews with subjects after the treatment period. 60 or more days after treatment ended. Of 58 patients who completed a treatment with ATNC05, 32 were available for this follow up. These data were collected outside of the original protocol. Responders analysis was done as a percentage of patients who had the post-study follow-up and as a percentage of all ATNC05 treated patients. Reversal is defined as 70% or more improvement in the Patient Global Impression of Improvement (PGI-I).
  • PKI-I Patient Global Impression of Improvement
  • Post-study data gathering was not part of the original protocol and was collected on an ad hoc basis.
  • a conservative estimate, taking post-study responders as a percentage of all subjects who ever completed a course ATNC05 (N 58), gives a response rate of 43% who were 70% or more improved 60 days or more after they finished their three- week treatment with ATNC05.
  • ATNC05 The components of ATNC05 have separately been demonstrated to be safe in decades of clinical use, and it may be concluded from this study that they are safe in combination.
  • Naltrexone and clonidine are present in ATNC05 in a low dose of less than 10% of their approved doses for other indications.
  • the mean dose of ATNC05 was 2.18 capsules per day in the double-blind phase, and 2.13 capsules per day when the taper-off period is included. Information on doses taken in the study is found on pages 128-131 of the Clinical Study Report. Dose-dependent adverse effects are therefore less pronounced in ATNC05.
  • ATNC05 is a product which consists of a low dose of two approved medications. It has a low adverse events profile and the preliminary data show it to be well- tolerated.
  • Table 35 shows the effect size for ATNC05 compared to two other recently studied medications approved for neuropathic pain: Cymbalta (duloxetine) and Lyrica (pregabalin). The data are taken from reviewer's analyses from statistical reviews published by the Center for Drug Evaluation and Research.
  • the open-label extension phase of the ATNC05 Back Pain Study during which all subjects received ATNC05, the subjects showed a mean improvement of 4.6 points at the primary endpoint (Week 3).
  • the open-label extension phase consisted of subjects who were non-responders in the Double-Blind phase (most subjects in the extension phase received placebo during the Double-Blind phase); 27 subjects began the open- label extension phase and 22 subjects were evaluated for the primary end point. Of the subjects who left the open-label extension phase, two left due to adverse effects, while three were lost to follow up. When compared to the improvement experienced by the placebo group, the effect size of ATNC05 becomes 3.7 points, over six times more than the mean for Lyrica and Cymbalta.
  • ATNC05 was tested for subjects with moderate chronic pain (4 points to 8 points on an 11-point scale).
  • NSAIDs treatments for moderate neuropathic pain are NSAIDs, APAP, alpha-2-delta ligands, and serotonin and norepinephrine reuptake inhibitors.
  • ATNC05 is more effective than NSAIDs and has fewer adverse effects.
  • APAP alpha-2-delta ligands
  • serotonin and norepinephrine reuptake inhibitors ATNC05 has fewer negative impacts compared to opioids used for moderate pain.
  • Opioids are one option, but they carry a significant risk of misuse, abuse, overdose and death (FDA Works to Reduce Risk of Opioid Pain Relievers, 2012).
  • ATNC05 has the potential to greatly reduce the risks linked to narcotic medication used in chronic neuropathic lower back pain.
  • Chronic neuropathic back pain is a serious condition, and is one of the leading causes of disability in the world, as measured by the WHO.
  • the treatment effect size of ATNC05 is 4.5 times larger than recently approved treatments for neuropathic pain (duloxetine and pregabalin).
  • ATNC05 has the potential to greatly reduce the risks linked to narcotic medication used in chronic neuropathic lower back pain because of the lack of effective non-narcotic treatment options.
  • ATNC05 shows reversal and a "cure" in at least 43% of the subjects in the Phase II trial, showing 70% or more improvement of their back pain more than two months after the end of their three- week treatment course with ATNC05.
  • TLR-4 antagonism has a relationship to the pathophysiology of chronic neuropathic back pain and has the ability to "switch off the cycle that perpetuates the chronicity of neuropathic pain.
  • ATNC05 has the potential to revolutionize the treatment of neuropathic lower back pain, and alleviate the suffering and economic impact.
  • ATNC05 has the potential to be a game-changer for the treatment of back pain and may eliminate the need for lengthy and costly treatments with marginal benefit, such as physical therapy and chiropractic treatment. Additionally, ATNC05 will most likely reduce the prevalence of spinal surgical procedures.
  • ATNC05 represents an inexpensive treatment option for three primary reasons. First, it is administered at home and does not have to be administered by a medical professional. Second, ATNC05 provides substantial relief after a short course of treatment, and this relief endures even after ceasing treatment. Third, even if needed to be taken for a long term, the components of ATNC05 are available generically, so when ATNC05 is commercialized, the prices will need to be competitive with compounding variations.
  • ATNC05 chronic neuropathic back pain is a serious condition
  • ATNC05 is superior in efficacy and safety profile to current treatments (e.g., APAP, NSAIDs, alpha-2-delta ligands, and antidepressants) and begins to work within hours of the initial dose, rather than taking several weeks to reach an effect
  • current treatments e.g., APAP, NSAIDs, alpha-2-delta ligands, and antidepressants
  • TLR-4 antagonism which "switches off the underlying cause of neuropathic pain
  • ATNC05 will be an inexpensive treatment option, since its components are generically available, significantly reducing the direct and indirect costs of chronic neuropathic back pain, and e) will greatly reduce the need for opioids for chronic neuropathic back pain of moderate severity.
  • the study was a 78-subject double-blind placebo -controlled randomized proof-of- concept clinical trial. Following a one-week Baseline period, subjects were administered ATNC05 or placebo for three weeks. The study had an open-label extension phase for back pain non-responders in the double -blind phase, during which all subjects received ATNC05 with no comparator.
  • the Clinical Study Report for this trial was submitted to FDA on July 7, 2013 and is available upon request. Because this was a proof-of-concept study, data on concomitant migraine were collected.
  • Table 42 Migraine Day Incidence Data from Daily Questionnaire, Expressed As Monthly (Four- Week) Frequency
  • MIDAS Migraine Disability Assessment Test
  • the MIDAS was used on the most severe migraine subjects.
  • the reliability of the MIDAS is supported by the fact that, for the baseline period, the frequency of migraine reported on the daily questionnaire (15.38 migraine days per month) and the frequency reported by MIDAS (15.28 migraine days per month) differ by only 0.1 days for ATNC05 subjects.
  • the memory bias of the subjects is practically non-existent. The applicant believes that the data represent true and compelling findings.
  • ATNC05 showed an effect size of 10.56 fewer migraine days per month.
  • ATNC05 migraine subjects had a 92% completion rate, with only one migraine subject discontinuing the study early (on day 15 of the 21 -day treatment period) due to lack of sexual interest.
  • ATNC05 produced fewer side effects than topiramate. In the topiramate studies, the completion rate was between 55% and 75%. ATNC05 had a 92% completion rate for migraine subjects, which indicates that ATNC05 is well-tolerated and effective compared to topiramate. Onabotulinumtoxin A has to be administered by a trained professional. By contrast, ATNC05 is administered orally at home. The components of ATNC05 are available generically, so ATNC05 represents an inexpensive treatment option.
  • ATNC05 The efficacy of ATNC05 on neuropathic back pain is shown in Table 45.
  • ATNC05 showed an effect size of 2.78 points (on an 11-point scale) in Week 3 of the treatment period.
  • Table 45 Summary of Results from Phase II Study For Neuropathic Back Pain
  • ATNC05 provides a large effect size of 10.56 fewer migraine days per month, compared to 1.7-3.7 for topiramate, and 2.0 for Onabotulinumtoxin A. ATNC05 is tolerated much better than topiramate, as evidenced by the low dropout rate. ATNC05 has a quick onset of action, starting immediately (1-2 hours) after the first dose and persisting throughout the treatment period. The components of ATNC05 are available generically, so ATNC05 represents an inexpensive treatment option.
  • This analysis is based on the subset of migraine subjects in the back pain study.
  • Figure 41 shows the mean joint pain (for subjects who reported concomitant joint pain) during the back pain study. Subjects on ATNC05 reported significant reductions in joint pain; subjects reported no joint pain at all during the third week of the Open-Label phase.
  • Table 46 shows the results of post-study questionnaires, collected from the daily questionnaire forms and telephone interviews. For this analysis, a subject is classified as having responded to the treatment if they report 70% or more improvement in the Patient Global Impression of Improvement (PGI-I).
  • PKI-I Patient Global Impression of Improvement
  • Figure 39 shows the subjects' reported change in energy level during the treatment period.
  • the percentage is the percentage of questionnaires with the response in each group (i.e., the percentage of subject-days reporting the given energy level).
  • Subjects on ATNC05 reported increased levels of energy on 70% of subject days, compared to 10% for subjects in the placebo treatment group.
  • Figure 40 shows the subjects' reported change in activity level during the treatment period.
  • the percentage is the percentage of questionnaires with the response in each group (i.e., the percentage of subject-days reporting the given energy level).
  • Subjects on ATNC05 reported an increase in activity of 68% of subject-days during the Double-Blind phase and of 75% during the Open-Label phase, compared to 35% for subjects in the placebo treatment group.
  • ATNC05 subjects reported a mean percentage increase in activity level of more than 50%, while subjects on the placebo reported an increase of 16.78%.

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Abstract

Cette invention concerne l'utilisation d'une composition comprenant des antagonistes opioïdes/du récepteur 4 de type Toll (TLR4) (des antagonistes opioïdes qui traitent la douleur par le blocage du récepteur 4 de type Toll (TLR4)) et des énantiomères dextro de ceux-ci pour le traitement de la douleur. Des exemples d'antagonistes opioïdes et leurs énantiomères dextro comprennent naltréxone, naloxone et nalméfène, et des sels pharmaceutiquement acceptables de ceux-ci, des compositions pharmaceutiques associées et leurs utilisations dans le traitement de la douleur, en particulier la douleur neuropathique. L'invention concerne également des compositions pour le traitement de la douleur comprenant des antagonistes opioïdes/du récepteur 4 de type Toll (TLR4), des énantiomères dextro de ceux-ci ou un sel pharmaceutiquement acceptable de ceux-ci, et au moins un d'un antagoniste du récepteur alpha-2 adrénergique, de l'acétyle-para-aminophénol (APAP), d'un inhibiteur de cyclooxygénase (COX) et d'un ligand alpha-2-delta qui améliore l'effet de traitement de la douleur du premier composé.
PCT/US2014/025771 2013-03-13 2014-03-13 Compositions pour réduire la douleur comprenant un antagoniste opioïde du récepteur 4 de type toll, des énantiomères dextro associés, et leurs procédés d'utilisation WO2014160077A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP14773349.7A EP2968293A4 (fr) 2013-03-13 2014-03-13 Compositions pour réduire la douleur comprenant un antagoniste opioïde du récepteur 4 de type toll, des énantiomères dextro associés, et leurs procédés d'utilisation
AU2014244152A AU2014244152A1 (en) 2013-03-13 2014-03-13 Compositions to reduce pain comprising an opioid/toll-like receptor 4 antagonist, dextro enantiomers thereof, and methods of use therefor
JP2016501961A JP2016512561A (ja) 2013-03-13 2014-03-13 オピオイド／トール様受容体４アンタゴニスト、そのデキストロエナンチオマーを含む、痛みを軽減するための組成物、及びそのための使用方法
CA2942641A CA2942641A1 (fr) 2013-03-13 2014-03-13 Compositions pour reduire la douleur comprenant un antagoniste opioide du recepteur 4 de type toll, des enantiomeres dextro associes, et leurs procedes d'utilisation

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US13/799,287 2013-03-13
US13/799,287 US20130310412A1 (en) 2010-06-28 2013-03-13 Combinations of an Opioid/TLR4 Antagonist and a Direct-Acting Alpha-2 Adrenergic Agonist for Use in the Treatment of Pain
US13/841,100 US9205081B2 (en) 2010-04-29 2013-03-15 Combinations of opiod/TLR4 antagonist and a cyclooxygenase (COX) inhibitor for use in the treatment of pain
US13/837,099 US9095548B2 (en) 2010-04-29 2013-03-15 Combinations of opioid/TLR4 antagonists and acetyl-para-aminophenol (APAP) for use in the treatment of pain
US13/837,099 2013-03-15
US13/841,100 2013-03-15
US13/851,773 US20150111917A9 (en) 2010-04-29 2013-03-27 Combinations of an Opioid/TLR4 Antagonist and an Alpha-2-Delta Ligand for Use in the Treatment of Pain
US13/851,773 2013-03-27
US13/851,267 US20150111916A9 (en) 2010-04-29 2013-03-27 Treatment of pain using a composition of opioid/Toll-like receptor 4 antagonists and dextro enantiomers thereof
US13/851,267 2013-03-27

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WO2016105449A1 (fr) * 2014-12-22 2016-06-30 Seth Lederman Composés destinés à être utilisés en tant qu'agents thérapeutiques contre la douleur
JP2020143111A (ja) * 2015-08-31 2020-09-10 リージェンツ オブ ザ ユニバーシティ オブ ミネソタ オピオイド受容体調節因子及びその使用
US11058680B2 (en) 2016-10-31 2021-07-13 Allodynie Therapeutics, LLC Combinations of opioid/TLR4 antagonists and acetaminophen for use in the treatment of emotional pain and insomnia

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EP3511320A4 (fr) * 2016-09-09 2020-04-15 Takeda Pharmaceutical Company Limited Composé cyclique

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Cited By (4)

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WO2016105449A1 (fr) * 2014-12-22 2016-06-30 Seth Lederman Composés destinés à être utilisés en tant qu'agents thérapeutiques contre la douleur
JP2020143111A (ja) * 2015-08-31 2020-09-10 リージェンツ オブ ザ ユニバーシティ オブ ミネソタ オピオイド受容体調節因子及びその使用
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US11058680B2 (en) 2016-10-31 2021-07-13 Allodynie Therapeutics, LLC Combinations of opioid/TLR4 antagonists and acetaminophen for use in the treatment of emotional pain and insomnia

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JP2016512561A (ja) 2016-04-28
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CA2942641A1 (fr) 2014-10-02
EP2968293A1 (fr) 2016-01-20

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