Compositions and methods for treating opiate intolerance

Abstract

Provided are compositions comprising an opiate analgesic and an active compound containing the R isomer of N-methylnalorphine in a pharmaceutically acceptable carrier. Also provided are methods of treating opiate intolerance by administration of an active compound containing R N-methylnalorphine or a pharmaceutically acceptable salt thereof. The active compound may administered either acutely or chronically to subjects receiving opiate treatment. Further provided are methods of inducing analgesia by administering to a subject an opiate analgesic concurrently with an active compound containing R N-methylnalorphine or a pharmaceutically acceptable salt thereof.

We claim:  
     
         1 . A method of treating opiate intolerance in a subject in need of such treatment, comprising administering to the subject a treatment effective amount of R N-methylnalorphine or a pharmaceutically acceptable salt thereof.  
     
     
         2 . The method according to  claim 1 , wherein the opiate intolerance comprises a condition selected from the group consisting of nausea, vomiting, constipation, hypotension, bradycardia, puritus, and combinations thereof.  
     
     
         3 . The method according to  claim 1 , wherein the subject is one in which opiates provide medically useful analgesia.  
     
     
         4 . The method according to  claim 1 , wherein the subject is selected from the group consisting of human and canine subjects.  
     
     
         5 . The method according to  claim 1 , wherein the subject is a human subject.  
     
     
         6 . The method according to  claim 1 , wherein the R N-methylnalorphine or a pharmaceutically acceptable salt thereof is administered by a route selected from the group consisting of oral, subcutaneous, intradermal, intramuscular, intravenous, rectal, dermal, buccal, and sublingual administration, and combinations thereof.  
     
     
         7 . The method according to  claim 1 , wherein the R N-methylnalorphine or a pharmaceutically acceptable salt thereof is administered by a route selected from the group consisting of intramuscular, subcutaneous, and intravenous administration, and combinations thereof.  
     
     
         8 . The method according to  claim 1 , wherein the R N-methylnalorphine or a pharmaceutically acceptable salt thereof is administered by a patient-controlled injection device.  
     
     
         9 . The method according to  claim 1 , wherein the R N-methylnalorphine or a pharmaceutically acceptable salt thereof is administered in a dose of about 0.11 to about 20 mg/kg/day.  
     
     
         10 . The method according to  claim 5 , wherein the R N-methylnalorphine or a pharmaceutically acceptable salt thereof is administered in a dose of about 70 to about 1400 mg/day.  
     
     
         11 . The method according to  claim 1 , further comprising concurrently administering an anti-emetic compound that does not treat opiate intolerance.  
     
     
         12 . The method according to  claim 11 , wherein the R N-methylnalorphine or a pharmaceutically acceptable salt thereof and the anti-emetic compound are included in the same composition.  
     
     
         13 . The method according to  claim 1 , wherein said administering step is a chronically administering step.  
     
     
         14 . A method of inducing analgesia in a subject in need of such treatment, comprising administering to the subject an opiate analgesic in an amount effective to induce analgesia in the subject concurrently with R N-methylnalorphine or a pharmaceutically acceptable salt thereof in an amount effective to treat opiate intolerance.  
     
     
         15 . The method according to  claim 14 , wherein the analgesia is not substantially reduced in the subject by the concurrently administered R N-methylnalorphine or a pharmaceutically acceptable salt thereof.  
     
     
         16 . The method according to  claim 14 , wherein the opiate intolerance comprises a condition selected from the group consisting of nausea, vomiting, constipation, hypotension, bradycardia, puritus, and combinations thereof.  
     
     
         17 . The method according to  claim 14 , wherein the subject is selected from the group consisting of human and canine subjects.  
     
     
         18 . The method according to  claim 14 , wherein the subject is a human subject.  
     
     
         19 . The method according to  claim 14 , wherein the R N-methylnalorphine or a pharmaceutically acceptable salt thereof is administered by a route selected from the group consisting of intramuscular, subcutaneous, and intravenous administration, and combinations thereof.  
     
     
         20 . The method according to  claim 14 , wherein the R N-methylnalorphine or a pharmaceutically acceptable salt thereof is administered by a patient-controlled injection device.  
     
     
         21 . The method according to  claim 14 , wherein the R N-methylnalorphine or a pharmaceutically acceptable salt thereof is administered in a dose of about 0.11 to about 20 mg/kg/day.  
     
     
         22 . The method according to  claim 14 , further comprising concurrently administering an anti-emetic compound that does not treat opiate intolerance.  
     
     
         23 . The method according to  claim 14 , wherein said administering step is a chronically administering step.  
     
     
         24 . The method according to  claim 14 , wherein the opiate analgesic and the R N-methylnalorphine or a pharmaceutically acceptable salt thereof are included together in the same composition.  
     
     
         25 . A composition, comprising, in combination in a pharmaceutically acceptable carrier, an opiate analgesic in an amount effective to induce analgesia in a subject and R N-methylnalorphine or a pharmaceutically acceptable salt thereof in an amount effective to treat opiate intolerance.  
     
     
         26 . The composition of  claim 25  further comprising an anti-emetic compound.  
     
     
         27 . The composition of  claim 26 , wherein said anti-emetic compound comprises a serotonin receptor antagonist.  
     
     
         28 . The composition of  claim 25 , wherein said opiate analgesic is selected from the group consisting of morphine, fentanyl, sufentanyl, alfentanyl, remifentanyl, and combinations thereof.  
     
     
         29 . The composition of  claim 25 , wherein said composition is in a form selected from the group consisting of a tablet, a capsule, a suppository, and an injectable solution.  
     
     
         30 . A patient-controlled injection device comprising the composition of  claim 25 .  
     
     
         31 . A patient-controlled device comprising a composition comprising, in a pharmaceutically acceptable carrier, R N-methylnalorphine or a pharmaceutically acceptable salt thereof in an amount effective to treat opiate intolerance.  
     
     
         32 . A composition, comprising, in combination in a pharmaceutically acceptable carrier, an anti-emetic compound in an amount effective to treat emesis in a subject and R N-methylnalorphine or a pharmaceutically acceptable salt thereof in an amount effective to treat opiate intolerance.