Combinations of opioid/tlr4 antagonists and acetaminophen for use in the treatment of emotional pain and insomnia

Abstract

Disclosed are compositions for the treatment of emotional pain, physical pain, and insomnia comprising a compound comprising an opioid antagonist that treats pain by blocking Toll-like receptor 4 (TLR4). Examples of opioid antagonist include naltrexone and naloxone, and their use in the treatment, prevention, and reversal of pain.

1 . A method for treating emotional pain, physical pain, and insomnia in a mammal in need thereof comprising administering to the mammal a composition of a pharmacologically active agent comprising of naltrexone, or a pharmaceutically acceptable salt or solvate thereof, wherein the naltrexone is administered to the mammal at a dose from about 0.25 mg to about 50 mg per day. 
     
     
         2 . The method of  claim 1 , wherein the naltrexone, or pharmaceutically acceptable salt or solvate thereof, is in a sustained release formulation. 
     
     
         3 . The method of  claim 1 , wherein, naltrexone or pharmaceutically acceptable salt or solvate thereof is (+)-naltrexone (dextro-naltrexone), 
     
     
         4 . The method of  claim 1 , wherein the naltrexone, or a pharmaceutically acceptable salt or solvate thereof, is administered to the mammal at a dose from about 0.25 mg to about 15 mg per day. 
     
     
         5 . The method of  claim 1 , wherein the naltrexone, or a pharmaceutically acceptable salt or solvate thereof, is administered to the mammal at a dose selected from the group consisting of about 1.5 mg per day, about 2.25 mg per day, about 3.25 mg per day, about 5 mg per day, about 9 mg per day, and about 15 mg per day. 
     
     
         6 .- 10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein the compound is administered once, twice, three or four times per day. 
     
     
         12 . The method of  claim 1 , wherein the compound is administered systemically, including but not limited to mucosal, nasal, oral, parenteral, gastrointestinal, topical or sublingual routes. 
     
     
         13 . The method of  claim 1 , wherein the naltrexone, or pharmaceutically acceptable salt or solvate thereof, is formulated into a single fixed dosage form. 
     
     
         14 . The method of  claim 13 , wherein the single dosage form is in the form of tablets, lozenges, troches, hard candies, or liquids. 
     
     
         15 . The method of  claim 1 , wherein the emotional pain is associated with an emotional disturbance with one or more signs or symptoms selected from the group consisting of abandonment, ambivalence, anger, anguish, betrayal, compulsion, confusion, deterioration, failure, fatigue, fear, grief, guilt, helplessness, hopelessness, horror, hurt feelings, inferiority, insomnia, irritation, loneliness, loss of meaning, lure of death, powerlessness, rejection, sadness, self-hate, shame, terror, and worthlessness; and wherein the physical pain is selected from the group consisting of neuropathic pain, nociceptive pain, nociceptive pain with an allodynic component, low back pain, migraine, inflammation, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, trigeminal neuralgia, vulvodynia, irritable bowel syndrome, post herpetic neuralgia, and diabetic neuropathy. 
     
     
         16 . The method of  claim 1 , wherein the mammal is also experiencing one or more substance abuse or addiction selected from drug abuse, drug addiction, alcohol abuse, and alcohol addiction. 
     
     
         17 .- 18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         20 . A method for treating emotional pain, physical pain, and insomnia in a mammal in need thereof comprising administering to the mammal a composition comprising pharmacologically active agents, wherein any pharmacologically active agents in the composition consist of a synergistic ratio of naltrexone, or pharmaceutically acceptable salts or solvates thereof, and acetaminophen, or pharmaceutically acceptable salts or solvates thereof, wherein the composition comprises a dose range of naltrexone of 0.25 mg-50 mg per day and a dose range of acetaminophen of 325 mg-4000 mg per day. 
     
     
         21 . The method of  claim 20 , wherein, the naltrexone, or pharmaceutically acceptable salts or solvates thereof is (+)-naltrexone (dextro-naltrexone). 
     
     
         22 . The method of  claim 20 , wherein the naltrexone, or pharmaceutically acceptable salt or solvate thereof, is in a sustained release formulation. 
     
     
         23 . The method of  claim 20 , wherein the naltrexone, or a pharmaceutically acceptable salt or solvate thereof, is administered to the mammal at about 0.25 mg to 15 mg per day, and wherein the acetaminophen, or a pharmaceutically acceptable salt or solvate thereof, is administered to the mammal at between about 325 mg to 2000 mg per day. 
     
     
         24 . The method of  claim 20 , wherein the acetaminophen or pharmaceutically acceptable salt or solvate thereof is administered to the mammal at about 325 mg per day, and wherein the naltrexone or pharmaceutically acceptable salt or solvate thereof is administered to the mammal at a dose selected from the group consisting of about 1.5 mg per unit dose, about 2.25 mg per day, about 3.25 mg per day, and about 5 mg per day. 
     
     
         25 .- 27 . (canceled) 
     
     
         28 . The method of  claim 20 , wherein the naltrexone or pharmaceutically acceptable salt or solvate thereof is administered to the mammal at about 9 mg per day, and wherein the acetaminophen or pharmaceutically acceptable salt or solvate thereof is administered to the mammal at about 1300 mg per day. 
     
     
         29 . The method of  claim 20 , wherein the naltrexone or pharmaceutically acceptable salt or solvate thereof is administered to the mammal at about 15 mg per day, and wherein the acetaminophen or pharmaceutically acceptable salt or solvate thereof is administered to the mammal at about 2000 mg per day. 
     
     
         30 . The method of  claim 20 , wherein the combination is administered once, twice, three or four times per day. 
     
     
         31 . The method of  claim 20 , wherein the combination is administered systemically, including but not limited to mucosal, nasal, oral, parenteral, gastrointestinal, topical or sublingual routes. 
     
     
         32 . The method of  claim 20 , wherein the naltrexone, or pharmaceutically acceptable salt or solvate thereof, and the acetaminophen, or pharmaceutically acceptable salt or solvate thereof are formulated into a single fixed combination dosage form. 
     
     
         33 . The method of  claim 32 , wherein the single fixed combination dosage form is in the form of tablets, lozenges, troches, hard candies, or liquids. 
     
     
         34 . The method of  claim 20 , wherein the emotional pain is associated with an emotional disturbance with one or more signs or symptoms selected from the group consisting of abandonment, ambivalence, anger, anguish, betrayal, compulsion, confusion, deterioration, failure, fatigue, fear, grief, guilt, helplessness, hopelessness, horror, hurt feelings, inferiority, insomnia, irritation, loneliness, loss of meaning, lure of death, powerlessness, rejection, sadness, self-hate, shame, terror, and worthlessness; and wherein the physical pain is selected from the group consisting of neuropathic pain, nociceptive pain, nociceptive pain with an allodynic component, migraine, inflammation, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, trigeminal neuralgia, vulvodynia, irritable bowel syndrome, post herpetic neuralgia and diabetic neuropathy. 
     
     
         35 . The method of  claim 20 , wherein the mammal is also experiencing one or more substance abuse or addiction selected from drug abuse, drug addiction, alcohol abuse, and alcohol addiction. 
     
     
         36 .- 37 . (canceled) 
     
     
         38 . The method of  claim 20 , wherein the mammal is a human. 
     
     
         39 . A method for treating physical pain in a mammal in need thereof comprising administering to the mammal a combination of:
 (a) a first compound comprising naltrexone, or a pharmaceutically acceptable salt or solvate thereof, wherein the naltrexone or pharmaceutically acceptable salt or solvate thereof is administered to the mammal at about 1.5 mg per day, or about 2.25 mg per day, or about 3.25 mg per day, or about 5 mg per day; and   (b) a second compound comprising acetyl-para-aminophenol, or a pharmaceutically acceptable salt or solvate thereof, wherein the acetyl-para-aminophenol or pharmaceutically acceptable salt or solvate thereof is administered to the mammal at about 325 mg per day.   
     
     
         40 . The method of  claim 39 , wherein the physical pain is selected from the group consisting of neuropathic pain, nociceptive pain, nociceptive pain with an allodynic component, low back pain, migraine, inflammation, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, trigeminal neuralgia, vulvodynia, irritable bowel syndrome, post herpetic neuralgia, and diabetic neuropathy.