Opioid agonist/opioid antagonist/acetaminophen combinations

Abstract

The invention is directed in part to oral dosage forms comprising a combination of an opioid agonist, acetaminophen and an orally active opioid antagonist, the opioid antagonist being included in a ratio to the opioid agonist to provide a combination product which is analgesically effective when the combination is administered orally, but which is aversive in a physically dependent subject. Preferably, the amount of opioid antagonist included in the combination product provides at least a mildly negative, “aversive” experience in physically dependent addicts (e.g., precipitated abstinence syndrome).

What is claimed is: 
     
         1 . An oral dosage form, comprising
 (A) an opioid agonist;   (B) acetaminophen, and   (C) an opioid antagonist, the ratio of opioid antagonist to opioid agonist to acetaminophen providing a combination product which is analgesically effective when the combination is administered orally, but which is aversive in physically dependent human subjects when administered at the same dose or at a higher dose than the usually prescribed dose of the opioid agonist.   
     
     
         2 . The oral dosage form of  claim 1 , wherein the amount of antagonist included in the oral dosage form causes an aversive experience in a physically dependent addict taking about 2-3 times the usually prescribed dose of the opioid. 
     
     
         3 . The oral dosage form of  claim 1 , wherein the opioid agonist is hydrocodone and the antagonist is naltrexone. 
     
     
         4 . The oral dosage form of  claim 3 , wherein the ratio of naltrexone to hydrocodone is from about 0.03:1 to about 0.27:1. 
     
     
         5 . The oral dosage form of  claim 3 , wherein the ratio of naltrexone to hydrocodone is from about 0.05:1 to about 0.20:1. 
     
     
         6 . The oral dosage form of  claim 1 , wherein the opioid agonist is selected from the group consisting of morphine, hydromorphine, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, dihydrocodeine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof. 
     
     
         7 . The oral dosage form of  claim 1 , further comprising an additional non-opioid drug selected from the group consisting of an NSAID, a COX-2 inhibitor, aspirin, an NMDA receptor antagonist, a drug that blocks a major intracellular consequence of NMDA-receptor activation, dimenhydrinate or a pharmaceutically acceptable salt thereof, an antitussive, an expectorant, a decongestant, an antihistamine and mixtures thereof. 
     
     
         8 . The oral dosage form of  claim 1 , further comprising one or more pharmaceutically acceptable inert excipients. 
     
     
         9 . The oral dosage form of  claim 6 , wherein said opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmephene, cyclazocine, levallorphan, and mixtures thereof. 
     
     
         10 . The oral dosage form of  claim 6 , wherein said opioid antagonist is naltrexone. 
     
     
         11 . The oral dosage form of  claim 1 , further comprising a sustained release carrier causes said opioid agonist to be released over a time period of about 8 to about 24 hours when orally administered to a human patient. 
     
     
         12 . The oral dosage form of  claim 1 , wherein said opioid antagonist is naltrexone and said opioid agonist is oxycodone, wherein the ratio of naltrexone to oxycodone is from about 0.037:1 to about 0.296:1. 
     
     
         13 . The oral dosage form of  claim 1 , wherein said opioid antagonist is naltrexone and said opioid agonist is codeine, wherein the ratio of naltrexone to codeine is from about 0.005:1 to about 0.044:1. 
     
     
         14 . The oral dosage form of  claim 1 , wherein said opioid antagonist is naltrexone and said opioid agonist is hydromorphone, wherein the ratio of naltrexone to hydromorphone is from about 0.148:1 to about 1.185:1. 
     
     
         15 . The oral dosage form of  claim 1 , wherein said opioid antagonist is naltrexone and said opioid agonist is levorphanol, wherein the ratio of naltrexone to levorphanol is from about 0.278:1 to about 2.222:1. 
     
     
         16 . The oral dosage form of  claim 1 , wherein said opioid antagonist is naltrexone and said opioid agonist is meperidine, wherein the ratio of naltrexone to meperidine is from about 0.0037:1 to about 0.0296:1. 
     
     
         17 . The oral dosage form of  claim 1 , wherein said opioid antagonist is naltrexone and said opioid agonist is methadone, wherein the ratio of naltrexone to methadone is from about 0.056:1 to about 0.444:1. 
     
     
         18 . The oral dosage form of  claim 1 , wherein said opioid antagonist is naltrexone and said opioid agonist is morphine, wherein the ratio of naltrexone to morphine is from about 0.018:1 to about 0.148:1. 
     
     
         19 . The oral dosage form of  claim 11 , wherein the sustained release carrier further causes said opioid antagonist to be released over a time period of about 8 to about 24 hours when orally administered to a human patient. 
     
     
         20 . The oral dosage form of  claim 19 , wherein the sustained release carrier further causes the acetaminophen to be released over a time period of about 8 to about 24 hours when orally administered to a human patient.