# US 2008/0188508 A1 · Methods and Therapies for Potentiating a Therapeutic Action of an Opioid Receptor Agonist and Inhibiting and/or Reversing Tolerance to Opioid Receptor Agonists > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2008/0188508 A1 - Document ID: US20080188508A1 - Status: Published application - Kind: A1 - Application number: 12/024,178 - Filed: 2008-02-01 - Published: 2008-08-07 - Earliest claimed: 2007-02-01 - Inventors: Khem Jhamandas; Tuan Trang - Web page: https://patentgrep.com/patent/US20080188508A1 ## CPC - A61K 31/415: 1,2-Diazoles - A61K 31/343: condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone - A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone - A61K 31/485: Morphinan derivatives, e.g. morphine, codeine - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Combination therapies of an opioid receptor agonist and a cannabinoid receptor antagonist in an amount effective to potentiate a therapeutic activity of the opioid receptor agonist and/or inhibit, delay, reduce and/or reverse tolerance to the opioid receptor agonist are provided. Also provided are methods for use of these combination therapies in potentiating a therapeutic activity of an opioid receptor agonist and/or inhibiting, delaying or reducing development of acute and/or chronic tolerance to opioid receptor agonists and treating conditions treatable by opioid receptor agonist therapy in a subject. In addition, a method for reversing opioid receptor agonist tolerance and/or restoring therapeutic effect of an opioid receptor agonist in a subject via administration of a cannabinoid receptor antagonist is provided. ## Claims ### Claim 1 A composition comprising an opioid receptor agonist in an amount effective to produce a therapeutic effect and a cannabinoid receptor antagonist in an amount effective to potentiate a therapeutic activity of an opioid receptor agonist and/or inhibit, delay, reduce and/or reverse tolerance to the opioid receptor agonist. ### Claim 2 (depends on 1) The composition of claim 1 wherein the opioid receptor agonist is an opioid. ### Claim 3 (depends on 1) The composition of claim 1 wherein the opioid receptor agonist is selected from the group consisting of morphine, oxycodone, oxymorphone, hydromorphone, mepridine, methadone, fentanyl, sufentanil, alfentanil, remifentanil, carfentanil, lofentanil, codeine, hydrocodone, levorphanol, tramadol, D-Pen2,D-Pen5-enkephalin (DPDPE), U50, 488H (trans-3,4-dichloro-N-methyl-N-[2-pyrrolindinyl]-cyclohexanyl)-benzeneacetamide, endorphins, dynorphins, enkephalins, diamorphine (heroin), dihydrocodeine, nicomorphine, levomethadyl acetate hydrochloride (LAAM), ketobemidone, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, pentazocine, phenazocine, buprenorphine, butorphanol, nalbufine or nalbuphine, tramadol, dezocine, etorphine, tilidine, loperamide, diphenoxylate, paregoric and nalorphine. ### Claim 4 (depends on 1) The composition of claim 1 wherein the cannabinoid receptor antagonist is selected from the group consisting of SR 141716, AM-251, LY320135, and SR 144528. ### Claim 5 (depends on 1) The composition of claim 1 wherein the opioid receptor agonist is morphine and the cannabinoid receptor antagonist is AM-251. ### Claim 6 (depends on 1) The composition of claim 1 wherein the opioid receptor agonist is morphine and the cannabinoid receptor antagonist is SR 141716. ### Claim 7 A method for potentiating a therapeutic activity of an opioid receptor agonist in a subject, the method comprising administering an opioid receptor agonist to the subject and administering a cannabinoid receptor antagonist to the subject in an amount effective to potentiate the therapeutic activity of the opioid receptor agonist and/or inhibit, delay, reduce and/or reverse tolerance to the opioid receptor agonist. ### Claim 8 (depends on 7) The method of claim 7 wherein the opioid receptor agonist is an opioid. ### Claim 9 (depends on 7) The method of claim 7 wherein the opioid receptor agonist is selected from the group consisting of morphine, oxycodone, oxymorphone, hydromorphone, mepridine, methadone, fentanyl, sufentanil, alfentanil, remifentanil, carfentanil, lofentanil, codeine, hydrocodone, levorphanol, tramadol, D-Pen2,D-Pen5-enkephalin (DPDPE), U50, 488H (trans-3,4-dichloro-N-methyl-N-[2-pyrrolindinyl]-cyclohexanyl)-benzeneacetamide, endorphins, dynorphins, enkephalins, diamorphine (heroin), dihydrocodeine, nicomorphine, levomethadyl acetate hydrochloride (LAAM), ketobemidone, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, pentazocine, phenazocine, buprenorphine, butorphanol, nalbufine or nalbuphine, tramadol, dezocine, etorphine, tilidine, loperamide, diphenoxylate, paregoric and nalorphine. ### Claim 10 (depends on 7) The method of claim 7 wherein the cannabinoid receptor antagonist is selected from the group consisting of SR 141716, AM-251, LY320135, and SR 144528. ### Claim 11 A method for inhibiting, delaying or reducing development of acute tolerance to a therapeutic effect of an opioid receptor agonist in a subject, the method comprising administering the opioid receptor agonist to the subject and administering a cannabinoid receptor antagonist to the subject. ### Claim 12 (depends on 11) The method of claim 11 wherein the opioid receptor agonist is an opioid. ### Claim 13 (depends on 11) The method of claim 11 wherein the opioid receptor agonist is selected from the group consisting of morphine, oxycodone, oxymorphone, hydromorphone, mepridine, methadone, fentanyl, sufentanil, alfentanil, remifentanil, carfentanil, lofentanil, codeine, hydrocodone, levorphanol, tramadol, D-Pen2,D-Pen5-enkephalin (DPDPE), U50, 488H (trans-3,4-dichloro-N-methyl-N-[2-pyrrolindinyl]-cyclohexanyl)-benzeneacetamide, endorphins, dynorphins, enkephalins, diamorphine (heroin), dihydrocodeine, nicomorphine, levomethadyl acetate hydrochloride (LAAM), ketobemidone, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, pentazocine, phenazocine, buprenorphine, butorphanol, nalbufine or nalbuphine, tramadol, dezocine, etorphine, tilidine, loperamide, diphenoxylate, paregoric and nalorphine. ### Claim 14 (depends on 11) The method of claim 11 wherein the cannabinoid receptor antagonist is selected from the group consisting of SR 141716, AM-251, LY320135, and SR 144528. ### Claim 15 A method for inhibiting, delaying or reducing development of chronic tolerance to a therapeutic effect of an opioid receptor agonist in a subject, the method comprising administering the opioid receptor agonist to the subject and administering a cannabinoid receptor antagonist to the subject. ### Claim 16 (depends on 15) The method of claim 15 wherein the opioid receptor agonist is an opioid. ### Claim 17 (depends on 15) The method of claim 15 wherein the opioid receptor agonist is selected from the group consisting of morphine, oxycodone, oxymorphone, hydromorphone, mepridine, methadone, fentanyl, sufentanil, alfentanil, remifentanil, carfentanil, lofentanil, codeine, hydrocodone, levorphanol, tramadol, D-Pen2,D-Pen5-enkephalin (DPDPE), U50, 488H (trans-3,4-dichloro-N-methyl-N-[2-pyrrolindinyl]-cyclohexanyl)-benzeneacetamide, endorphins, dynorphins, enkephalins, diamorphine (heroin), dihydrocodeine, nicomorphine, levomethadyl acetate hydrochloride (LAAM), ketobemidone, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, pentazocine, phenazocine, buprenorphine, butorphanol, nalbufine or nalbuphine, tramadol, dezocine, etorphine, tilidine, loperamide, diphenoxylate, paregoric and nalorphine. ### Claim 18 (depends on 15) The method of claim 15 wherein the cannabinoid receptor antagonist is selected from the group consisting of SR 141716, AM-251, LY320135, and SR 144528. ### Claim 19 A method for reversing tolerance to a therapeutic effect of an opioid receptor agonist or restoring a therapeutic effect of an opioid receptor agonist in a subject, the method comprising administering to the subject receiving opioid receptor agonist therapy a cannabinoid receptor antagonist. ### Claim 20 (depends on 19) The method of claim 19 wherein the cannabinoid receptor antagonist is selected from the group consisting of SR 141716, AM-251, LY320135, and SR 144528. ### Claim 21 A method for treating a subject suffering from a condition treatable with an opioid receptor agonist, the method comprising administering an opioid receptor agonist to the subject in an amount effective to produce a therapeutic effect and administering a cannabinoid receptor antagonist to the subject in an amount effective to potentiate a therapeutic activity of the opioid receptor agonist and/or inhibit, delay, reduce and/or reverse tolerance to the opioid receptor agonist. ### Claim 22 (depends on 21) The method of claim 21 wherein the opioid receptor agonist is an opioid. ### Claim 23 (depends on 21) The method of claim 21 wherein the opioid receptor agonist is selected from the group consisting of morphine, oxycodone, oxymorphone, hydromorphone, mepridine, methadone, fentanyl, sufentanil, alfentanil, remifentanil, carfentanil, lofentanil, codeine, hydrocodone, levorphanol, tramadol, D-Pen2,D-Pen5-enkephalin (DPDPE), U50, 488H (trans-3,4-dichloro-N-methyl-N-[2-pyrrolindinyl]-cyclohexanyl)-benzeneacetamide, endorphins, dynorphins, enkephalins, diamorphine (heroin), dihydrocodeine, nicomorphine, levomethadyl acetate hydrochloride (LAAM), ketobemidone, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, pentazocine, phenazocine, buprenorphine, butorphanol, nalbufine or nalbuphine, tramadol dezocine, etorphine, tilidine, loperamide, diphenoxylate, paregoric and nalorphine. ### Claim 24 (depends on 21) The method of claim 21 wherein the cannabinoid receptor antagonist is selected from the group consisting of SR 141716, AM-251, LY320135, and SR 144528. ### Claim 25 (depends on 21) The method of claim 21 wherein the subject is suffering from pain, coughing, diarrhea, pulmonary edema or addiction to an opioid receptor agonist. ### Claim 26 (depends on 25) The method of claim 25 wherein the pain is acute or chronic post-surgical pain, obstetrical pain, acute inflammatory pain, chronic inflammatory pain, pain associated with multiple sclerosis or cancer, pain associated with trauma, pain associated with migraines, neuropathic pain, central pain or a chronic pain syndrome of a non-malignant origin, or chronic back pain. ### Claim 27 (depends on 21) The method of claim 21 wherein the subject is treated for a condition treatable with an opioid receptor agonist without substantial undesirable side effects. ### Claim 28 A method for treating a subject suffering from a condition treatable with an opioid receptor agonist comprising administering to a subject receiving opioid receptor agonist therapy a cannabinoid receptor antagonist in an amount effective to potentiate a therapeutic activity of the opioid receptor agonist and/or inhibit, delay, reduce and/or reverse tolerance to the opioid receptor agonist. ### Claim 29 (depends on 28) The method of claim 28 wherein the cannabinoid receptor antagonist is selected from the group consisting of SR 141716, AM-251, LY320135, and SR 144528. ### Claim 30 (depends on 28) The method of claim 28 wherein the subject is suffering from pain, coughing, diarrhea, pulmonary edema or addiction to an opioid receptor agonist. ### Claim 31 (depends on 30) The method of claim 30 wherein the subject is suffering from acute or chronic post-surgical pain, obstetrical pain, acute inflammatory pain, chronic inflammatory pain, pain associated with multiple sclerosis or cancer, pain associated with trauma, pain associated with migraines, neuropathic pain, central pain or chronic pain syndrome of a non-malignant origin.