Inhibiting the development of tolerance to and/or dependence on an addictive substance

Abstract

Nontoxic substances that block the N-methyl-D-aspartate (NMDA) receptor, e.g., a morphinan such as dextromethorphan or dextrorphan, or that block a major intracellular consequence of NMDA-receptor activation, e.g., a ganglioside such as GM 1 or GT 1b , a phenothiazine such as trifluoperazine or a naphthalenesulfonamide such as N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, inhibit the development of tolerance to and/or dependence on addictive drugs, e.g., narcotic analgesics such as morphine, codeine, etc.

1. A composition comprising an addictive substance and at least one nontoxic substance that blocks the N-methyl-D-aspartate receptor or a major intracellular consequence of N-methyl-D-aspartate receptor activation, the addictive substance being selected from the group consisting of alfentanyl, alphaprodine, anileridine, bezitramide, codeine, dihydrocodeine, diphenoxylate, ethylmorphine, fentanyl, heroin, hydrocodone, hydromorphone, isomethadone, levomethorphan, levorphanol, metazocine, methadone, metopon, morphine, opium extracts, opium fluid extracts, powdered opium, granulated opium, raw opium, tincture of opium, oxycodone, oxymorphone, pethidine, phenazocine, piminodine, racemethorphan, racemorphan and pharmaceutically acceptable salts thereof. 
     
     
       2. The composition of  claim 1  in sustained release dosage form. 
     
     
       3. A formulated pharmaceutical composition comprising an addictive substance and at least one nontoxic synthetic substance that provides an improved effect for the addictive substance if used alone and that blocks the N- methyl - D - aspartate receptor and consists essentially of a morphinan or blocks a major intracellular consequence of N - methyl - D - aspartate receptor activation, the addictive substance being selected from the group consisting of alfentanyl, alphaprodine, anileridine, bezitramide, codeine, dihydrocodeine, diphenoxylate, ethylmorphine, fentanyl, heroin, hydrocodone, hydromorphone, isomethadone, levomethorphan, levorphanol, metazocine, methadone, metopon, morphine, opium extracts, opium fluid extracts, powdered opium, granulated opium, raw opium, tincture of opium, oxycodone, oxymorphone, pethidine, phenazocine, piminodine, racemethorphan, racemorphan and pharmaceutically acceptable salts thereof.   
     
     
       4. A formulated pharmaceutical composition comprising an addictive substance and a non- toxic synthetic substance, the addictive substance being selected from the group consisting of alfentanyl, codeine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, isomethadone, levorphanol, methadone, morphine, oxycodone, oxymorphone, pethidine, and pharmaceutically acceptable salts thereof, the non - toxic synthetic substance providing an improved effect for the addictive substance if used alone and being selected from the group consisting of dextromethorphan, dextrorphan, and pharmaceutically acceptable salts thereof.   
     
     
       5. A formulated pharmaceutical composition comprising an addictive substance and a non- toxic synthetic substance, the addictive substance being selected from the group consisting of alfentanyl, codeine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, isomethadone, levorphanol, morphine, oxycodone, oxymorphone, pethidine, and pharmaceutically acceptable salts thereof, the non - toxic synthetic substance being a blocker of the N - methyl - D - aspartate receptor and consisting essentially of morphinans, and providing an improved effect for the addictive substance if used alone.   
     
     
       6. A composition according to claims  3 ,  4  or  5  wherein the addictive substance is selected from the group consisting of alfentanyl, codeine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, isomethadone, methadone, morphine, oxycodone, oxymorphone, pethidine, and pharmaceutically acceptable salts thereof. 
     
     
       7. A composition according to claims  3 ,  4  or  5  wherein the addictive substance is selected from the group consisting of alfentanyl, codeine, dihydrocodeine, fentanyl, isomethadone, methadone, pethidine, and pharmaceutically acceptable salts thereof. 
     
     
       8. A composition according to claims  3 ,  4  or  5  wherein the addictive substance is selected from the group consisting of codeine, methadone, and pharmaceutically acceptable salts thereof. 
     
     
       9. A composition according to claims  3 ,  4  or  5  wherein the addictive substance includes morphine or a pharmaceutically acceptable salt thereof. 
     
     
       10. A composition according to claims  3 ,  4  or  5  wherein the addictive substance includes oxycodone or a pharmaceutically acceptable salt thereof. 
     
     
       11. A composition according to claims  3 ,  4  or  5  wherein the addictive substance includes hydrocodone or a pharmaceutically acceptable salt thereof. 
     
     
       12. A composition according to claims  3 ,  4  or  5  wherein the addictive substance includes oxymorphone or a pharmaceutically acceptable salt thereof. 
     
     
       13. A composition according to  claim 3 ,  4  or  5  wherein the addictive substance includes hydromorphone or a pharmaceutically acceptable salt thereof. 
     
     
       14. A composition according to claims  3 ,  4  or  5 , in oral dosage form. 
     
     
       15. A composition according to claims  3 ,  4  or  5 , in sustained release dosage form. 
     
     
       16. A composition according to claims,  3 ,  4  or  5 , in oral dosage and sustained release dosage form. 
     
     
       17. A formulated pharmaceutical composition comprising an addictive substance and at least one nontoxic synthetic substance that blocks the N- methyl - D - aspartate receptor or a major intracellular consequence of N - methyl - D - aspartate receptor activation, selected from pyrroloquinoline quinone and cis -   4   -( phosphonomethyl )-   2   - piperidinecarboxylic acid, the addictive substance being selected from the group consisting of alfentanyl, alphaprodine, anileridine, bezitramide, codeine, dihydrocodeine, diphenoxylate, ethylmorphine, fentanyl, heroin, hydrocodone, hydromorphone, isomethadone, levomethorphan, levorphanol, metazocine, methadone, metopon, morphine, opium extracts, opium fluid extracts, powdered opium, granulated opium, raw opium, tincture of opium, oxycodone, oxymorphone, pethidine, phenazocine, piminodine, racemethorphan, racemorphan, racemorphan and pharmaceutically acceptable salts thereof.