Combination Analgesic Employing Opioid and Neutral Antagonist

Abstract

Methods of utilizing an opioid agonist in a mammalian subject in a manner that inhibits peripheral effects of the opioid agonist are described. The methods comprise administering the opioid agonist in an amount sufficient to confer analgesia the subject and co-administering a neutral opioid antagonist or pharmaceutically acceptable isomorph or pharmaceutically acceptable salt thereof in an amount sufficient to substantially inhibit peripheral effects and insufficient to block substantial central effects of the opioid agonist in the subject.

1 . A method of utilizing an opioid agonist in a mammalian subject in a manner that inhibits peripheral effects of the opioid agonist, the method comprising:
 administering the opioid agonist in an amount sufficient to confer analgesia the subject;   co-administering a neutral opioid antagonist in an amount sufficient to substantially inhibit peripheral effects and insufficient to block substantial central effects of the opioid agonist in the subject.   
     
     
         2 . A method according to  claim 1 , wherein the opioid agonist is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, noroxycodone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine and tramadol. 
     
     
         3 . A method according to  claim 2 , wherein the opioid agonist is hydrocodone. 
     
     
         4 . A method according to  claim 2 , wherein the opioid agonist is morphine. 
     
     
         5 . A method according to  claim 1 , wherein the neutral opioid antagonist is selected from the group consisting of 6β-naltrexol, 6β-naltrexamide, 6β-naloxol, 6α-naltrexol, 6α-naloxol, 6α-naltrexamine, 6β-naltrexamine, 6-deoxynaltrexone, and 6α-naltrexamide, pharmaceutically acceptable physical isomorphs thereof, and pharmaceutically acceptable salts thereof. 
     
     
         6 . A method according to  claim 5 , wherein the neutral opioid antagonist is 6β-naltrexol in a dosage of approximately 0.0008-0.3 mg per kg of body weight of the subject. 
     
     
         7 . A method according to  claim 6 , wherein the 6β-naltrexol is co-administered orally in a dosage of approximately 0.01-0.3 mg per kg of body weight of the subject. 
     
     
         8 . A method according to  claim 5 , wherein the neutral opioid antagonist is 6β-naltrexamide in a dosage of approximately 0.002-0.8 mg per kg of body weight of the subject. 
     
     
         9 . A method according to  claim 1 , wherein co-administering the neutral opioid antagonist comprises administering the neutral opioid antagonist as a unit dosage. 
     
     
         10 . A method according to  claim 9 , wherein the unit dosage is administered in a manner selected from the group consisting of orally, perorally, intragastrically, sublingually, by suppository, intravenously and a combinations thereof. 
     
     
         11 . A method according to  claim 9 , wherein the unit dosage is provided as a single co-formulated unit dosage. 
     
     
         12 . A method according to  claim 11 , further comprising sequentially administering multiple single co-formulated unit dosages. 
     
     
         13 . A method according to  claim 9 , wherein the unit dosage is a slow-release formulation. 
     
     
         14 . A method of utilizing an opioid agonist in a mammalian subject in a manner that inhibits peripheral effects of the opioid agonist, the method comprising administering a unit dosage of an analgesic composition, wherein the unit dosage comprises:
 the opioid agonist in an amount sufficient to confer analgesia in a mammalian subject; and   a neutral opioid antagonist or pharmaceutically acceptable salt thereof in an amount sufficient to substantially inhibit peripheral effects and insufficient to block substantial central effects of the opioid agonist in the subject.   
     
     
         15 . A method according to  claim 14 , wherein the opioid agonist is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, noroxycodone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine and tramadol. 
     
     
         16 . A method according to  claim 15 , wherein the opioid agonist is hydrocodone. 
     
     
         17 . A method according to  claim 15 , wherein the opioid agonist is morphine. 
     
     
         18 . A method according to  claim 14 , wherein the neutral opioid antagonist is selected from the group consisting of 6β-naltrexol, 6β-naltrexamide, 6β-naloxol, 6α-naltrexol, 6α-naloxol, 6α-naltrexamine, 6β-naltrexamine, 6-deoxynaltrexone, and 6α-naltrexamide, pharmaceutically acceptable physical isomorphs thereof, and pharmaceutically acceptable salts thereof. 
     
     
         19 . A method according to  claim 18 , wherein the neutral opioid antagonist is 6β-naltrexol in a dosage of approximately 0.0008-0.3 mg per kg of body weight of the subject. 
     
     
         20 . A method according to  claim 18 , wherein the neutral opioid antagonist is 6β-naltrexamide in a dosage of approximately 0.002-0.8 mg per kg of body weight of the subject. 
     
     
         21 . A method according to  claim 14 , wherein the unit dosage is administered in a manner selected from the group consisting of orally, perorally, intragastrically, sublingually, by suppository, intravenously and a combinations thereof. 
     
     
         22 . A method according to  claim 21 , wherein the unit dosage is administered orally, and wherein the unit dosage comprises 6β-naltrexol in a dosage of approximately 0.01-0.3 mg per kg of body weight of the subject. 
     
     
         23 . A method according to  claim 14 , wherein the unit dosage is a slow-release formulation.