US2005181974A1PendingUtilityA1

Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists

67
Priority: Sep 21, 1992Filed: Aug 24, 2004Published: Aug 18, 2005
Est. expirySep 21, 2012(expired)· nominal 20-yr term from priority
Inventors:Stanley M. CrainKe-Fei Shen
A61K 31/485G01N 2500/10G01N 33/9486A61K 38/33A61K 31/00G01N 33/94
67
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Claims

Abstract

This invention relates to a method for selectively enhancing the analgesic potency of a bimodally-acting opioid agonist such as morphine and simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects associated with the administration of the bimodally-acting opioid agonist. The method of the present invention comprises administering to a subject an analgesic or sub-analgesic amount of a bimodally-acting opioid agonist such as morphine and an amount of an excitatory opioid receptor antagonist such as naltrexone or nalmefene effective to enhance the analgesic potency of the bimodally-acting opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the bimodally-acting opioid agonist.

Claims

exact text as granted — not AI-modified
1 - 29 . (canceled)  
     
     
         30 . A method for selectively enhancing the analgesic potency of a bimodally-acting opioid agonist and simultaneously attenuating tolerance associated with the administration of said bimodally-acting opioid agonist, comprising administering to a subject a composition comprising an analgesic or sub-analgesic amount of said bimodally-acting opioid agonist and an amount of an excitatory opioid receptor antagonist effective to enhance the analgesic potency of said bimodally-acting opioid agonist and attenuate tolerance associated with said bimodally-acting opioid agonist.  
     
     
         31 . The method of  claim 30 , wherein the excitatory opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, etorphine, diprenorphine, dihydroetorphine, and similarly acting opioid alkaloids and opioid peptides.  
     
     
         32 . The method of  claim 30 , wherein the bimodally-acting opioid agonist is selected from the group consisting of morphine, codeine, fentanyl analogs, pentazocine, buprenorphine, methadone, enkephalins, dynorphins, endorphins and similarly acting opioid alkaloids and opioid peptides.  
     
     
         33 . The method of  claim 30 , wherein the amount of the excitatory opioid receptor antagonist administered is at least 100-1000 fold less than the amount of the bimodally-acting opioid agonist administered.  
     
     
         34 . The method of  claim 31 , wherein the excitatory opioid receptor antagonist is naltrexone.  
     
     
         35 . The method of  claim 32 , wherein the bimodally-acting opioid agonist is morphine.  
     
     
         36 . The method of  claim 30 , wherein the bimodally-acting opioid agonist is morphine and the excitatory opioid receptor antagonist is naltrexone.  
     
     
         37 . The method of  claim 30 , wherein the mode of administration is selected from the group consisting of oral, sublingual, intramuscular, subcutaneous and intravenous.  
     
     
         38 . A method for treating pain in a subject comprising administering to said subject a composition comprising an analgesic or sub-analgesic amount of a bimodally-acting opioid agonist and an amount of an excitatory opioid receptor antagonist effective to enhance the analgesic potency of said bimodally-acting opioid agonist and attenuate tolerance associated with said bimodally-acting opioid agonist.  
     
     
         39 . The method of  claim 38 , wherein the bimodally-acting opioid agonist is selected from the group consisting of morphine, codeine, fentanyl analogs, pentazocine, methadone, buprenorphine, enkephalins, dynorphins, endorphins and similarly acting opioid alkaloids and opioid peptides.  
     
     
         40 . The method of  claim 38 , wherein the excitatory opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, etorphine, diprenorphine and dihydroetorphine, and similarly acting opioid alkaloids and opioid peptides.  
     
     
         41 . The method of  claim 38 , wherein amount of the excitatory opioid receptor antagonist administered is at least 100-1000 fold less than the amount of the bimodally-acting opioid agonist administered.  
     
     
         42 . The method of  claim 40 , wherein the excitatory opioid receptor antagonist is naltrexone.  
     
     
         43 . The method of  claim 39 , wherein the bimodally-acting opioid receptor agonist is morphine.  
     
     
         44 . The method of  claim 30 , wherein the bimodally-acting opioid agonist is a mu opioid receptor agonist.  
     
     
         45 . The method of  claim 30 , wherein the bimodally-acting opioid agonist is a delta opioid receptor agonist.  
     
     
         46 . The method of  claim 30 , wherein the bimodally-acting opioid agonist is a kappa opioid receptor agonist.  
     
     
         47 . The method of  claim 31 , wherein the excitatory opioid receptor antagonist is naloxone.  
     
     
         48 . The method of  claim 37 , wherein the mode of administration is oral administration.  
     
     
         49 . The method of  claim 30 , wherein the bimodally-acting opioid agonist is a mu opioid receptor agonist and the excitatory opioid receptor antagonist is naloxone.  
     
     
         50 . The method of  claim 30 , wherein the bimodally-acting opioid agonist is a mu opioid receptor agonist and the excitatory opioid receptor antagonist is naltrexone.  
     
     
         51 . The method of  claim 30 , wherein the amount of the excitatory opioid receptor antagonist administered is 1,000-10,000,000 fold less than the amount of the bimodally-acting opioid agonist administered.  
     
     
         52 . The method of  claim 30 , wherein the amount of the excitatory opioid receptor antagonist administered is 10,000-1,000,000 fold less than the amount of the bimodally-acting opioid agonist administered.  
     
     
         53 . The method of  claim 30 , wherein the bimodally-acting opioid agonist is a mu opioid receptor agonist, the excitatory opioid receptor antagonist is naltrexone, and the bimodally-acting opioid agonist and the excitatory opioid receptor antagonist are administered orally.  
     
     
         54 . The method of  claim 53 , wherein the amount of the excitatory opioid receptor antagonist administered is 1,000-10,000,000 fold less than the amount of the bimodally-acting opioid agonist administered.  
     
     
         55 . The method of  claim 30 , wherein the bimodally-acting opioid agonist is a mu opioid receptor agonist, the excitatory opioid receptor antagonist is naloxone, and the bimodally-acting opioid agonist and the excitatory opioid receptor antagonist are administered intramuscularly, subcutaneously or intravenously.  
     
     
         56 . The method of  claim 55 , wherein the amount of the excitatory opioid receptor antagonist administered is 1,000-10,000,000 fold less than the amount of the bimodally-acting opioid agonist administered.  
     
     
         57 . The method of  claim 30  wherein the amount of the excitatory opioid receptor antagonist is 100-1000 fold less than the amount of the bimodally-acting opioid agonist administered.  
     
     
         58 . The method of  claim 30  wherein the amount of the bimodally-acting opioid agonist administered is an analgesic amount.  
     
     
         59 . The method of  claim 30  wherein the amount of the bimodally-acting opioid agonist administered is a sub-analgesic amount.  
     
     
         60 . The method of  claim 38 , wherein the bimodally-acting opioid agonist is a mu opioid receptor agonist.  
     
     
         61 . The method of  claim 38 , wherein the bimodally-acting opioid agonist is a delta opioid receptor agonist.  
     
     
         62 . The method of  claim 38 , wherein the bimodally-acting opioid agonist is a kappa opioid receptor agonist.  
     
     
         63 . The method of  claim 40 , wherein the excitatory opioid receptor antagonist is naloxone.  
     
     
         64 . The method of  claim 38 , wherein the mode of administration is selected from the group consisting of oral, sublingual, intramuscular, subcutaneous and intravenous.  
     
     
         65 . The method of  claim 64 , wherein the mode of administration is oral administration.  
     
     
         66 . The method of  claim 38 , wherein the bimodally-acting opioid agonist is a mu opioid receptor agonist and the excitatory opioid receptor antagonist is naloxone.  
     
     
         67 . The method of  claim 38 , wherein the bimodally-acting opioid agonist is a mu opioid receptor agonist and the excitatory opioid receptor antagonist is naltrexone.  
     
     
         68 . The method of  claim 38 , wherein the amount of the excitatory opioid receptor antagonist administered is 1,000-10,000,000 fold less than the amount of the bimodally-acting opioid agonist administered.  
     
     
         69 . The method of  claim 38 , wherein the amount of the excitatory opioid receptor antagonist administered is 10,000-1,000,000 fold less than the amount of the bimodally-acting opioid agonist administered.  
     
     
         70 . The method of  claim 38 , wherein the bimodally-acting opioid agonist is a mu opioid receptor agonist, the excitatory opioid receptor antagonist is naltrexone, the bimodally-acting opioid agonist and the excitatory opioid receptor antagonist are administered orally, and the amount of the bimodally-acting opioid agonist is an analgesic amount.  
     
     
         71 . The method of  claim 70 , wherein the amount of the excitatory opioid receptor antagonist administered is 1,000-10,000,000 fold less than the amount of the bimodally-acting opioid agonist administered.  
     
     
         72 . The method of  claim 38 , wherein the bimodally-acting opioid agonist is a mu opioid receptor agonist, the excitatory opioid receptor antagonist is naloxone, the bimodally-acting opioid agonist and the excitatory opioid receptor antagonist are administered intramuscularly, subcutaneously or intravenously, and the amount of the bimodally-acting opioid agonist is an analgesic amount.  
     
     
         73 . The method of  claim 72 , wherein the amount of the excitatory opioid receptor antagonist administered is 1,000-10,000,000 fold less than the amount of the bimodally-acting opioid agonist administered.  
     
     
         74 . The method of  claim 38  wherein the amount of the excitatory opioid receptor antagonist is 100-1000 fold less than the amount of the bimodally-acting opioid agonist administered.  
     
     
         75 . The method of  claim 38  wherein the amount of the bimodally-acting opioid agonist administered is an analgesic amount.  
     
     
         76 . The method of  claim 38  wherein the amount of the bimodally-acting opioid agonist administered is a sub-analgesic amount.  
     
     
         77 . The method of  claim 30  wherein the bimodally-acting opioid agonist is chronically administered.  
     
     
         78 . The method of  claim 38  wherein the bimodally-acting opioid agonist is chronically administered.

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