Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists

Abstract

This invention relates to a method of selectively enhancing the analgesic potency of morphine and other clinically used bimodally-acting opioid agonists and simultaneously attenuating development of physical dependence, tolerance and other undesirable side effects caused by the chronic administration of said bimodally-acting opioid agonists comprising the co-administration of a bimodally-acting opioid agonist which activates both inhibitory and excitatory opioid receptor-mediated functions of neurons in the nociceptive (pain) pathways of the nervous system and an opioid receptor antagonist which selectively inactivates excitatory opioid receptor-mediated side effects. This invention also relates to a method of using excitatory opioid receptor antagonists alone to block the undesirable excitatory side effects of endogenous bimodally-acting opioid agonists which may be markedly elevated during chronic pain. This invention further relates to a method of long-term treatment of previously detoxified opiate, cocaine and alcohol addicts utilizing said excitatory opioid receptor antagonists, either alone or in combination with low-dose methadone, to prevent protracted physical dependence, and to compositions comprising an excitatory opioid receptor antagonist of the invention and a bimodally-acting opioid agonist.

We claim: 
     
       1. A method for selectively enhancing the analgesic potency of a bimodally-acting opioid agonist and simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects associated with the administration of said bimodally-acting opioid agonist, comprising administering to a subject 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 the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of said bimodally-acting opioid agonist. 
     
     
       2. The method of claim 1 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. 
     
     
       3. The method of claim 1 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. 
     
     
       4. The method of claim 1 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. 
     
     
       5. The method of claim 2 wherein the excitatory opioid receptor antagonist is naltrexone. 
     
     
       6. The method of claim 3 wherein the bimodally-acting opioid agonist is morphine. 
     
     
       7. The method of claim 3 wherein the bimodally-acting opioid agonist is codeine. 
     
     
       8. The method of claim 1 wherein the mode of administration is selected from the group consisting of oral, sublingual, intramuscular, subcutaneous and intravenous. 
     
     
       9. The method of claim 1 wherein the opioid receptor antagonist is naltrexone, and is administered orally. 
     
     
       10. A method for treating a detoxified opiate, cocaine or alcohol addict so as to prevent protracted dependence thereon comprising administering to the detoxified addict over a long term an amount of an excitatory opioid receptor antagonist which does not block but instead enhances the analgesic effect of morphine and other bimodally-acting opioid agonists. 
     
     
       11. The method of claim 10 wherein the antagonist is administered in combination with a sub-analgesic amount of a long-lasting bimodally-acting opioid agonist. 
     
     
       12. The method of claim 11 wherein the opioid agonist is methadone. 
     
     
       13. The method of claim 10 wherein the excitatory opioid receptor antagonist is selected from the group consisting of naloxone, naltrexone, etorphine, dihydroetorphine, diprenorphine, and similarly acting opioid alkaloids and opioid peptides. 
     
     
       14. The method of claim 13 wherein the excitatory opioid receptor antagonist is naltrexone. 
     
     
       15. The method of claim 11 wherein the bimodally-acting opioid agonist is methadone and the excitatory opioid receptor antagonist is naltrexone. 
     
     
       16. 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 the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of said bimodally-acting opioid agonist. 
     
     
       17. The composition of claim 16 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. 
     
     
       18. The composition of claim 16 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. 
     
     
       19. The method of claim 1 wherein the bimodally-acting opioid agonist is morphine and the excitatory opioid receptor antagonist is naltrexone. 
     
     
       20. The method of claim 3 wherein the bimodally-acting opioid agonist is methadone. 
     
     
       21. The composition of claim 16 wherein the amount of the excitatory opioid receptor antagonist is at least 100-1000 fold less than the amount of the bimodally-acting opioid agonist. 
     
     
       22. The composition of claim 17 wherein the excitatory opioid receptor antagonist is naltrexone. 
     
     
       23. The composition of claim 18 wherein the bimodally-acting opioid agonist is morphine. 
     
     
       24. The composition of claim 18 wherein the bimodally-acting opioid agonist is methadone. 
     
     
       25. The composition of claim 16 wherein the bimodally-acting opioid agonist is morphine and the excitatory opioid receptor antagonist is naltrexone. 
     
     
       26. A method for treating pain in a subject comprising administering to said subject an analgesic or sub-analgesic amount of a bimodally-acting opioid agonist and an amount of an excitatory opioid receptor antagonist effective to enhance the analgesic potency of said bimodally-acting opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of said bimodally-acting opioid agonist. 
     
     
       27. The method of claim 26 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. 
     
     
       28. The method of claim 26 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. 
     
     
       29. The method of claim 26 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. 
     
     
       30. The method of claim 26 wherein the excitatory opioid receptor antagonist is naltrexone. 
     
     
       31. The method of claim 26 wherein the bimodally-acting opioid receptor agonist is morphine. 
     
     
       32. The method of claim 26 wherein the bimodally-acting opioid agonist is morphine and the excitatory opioid receptor antagonist is naltrexone.