Analgesic combination of opioid analgesic and cyclooxygenase-2 inhibitor

Abstract

The invention relates to the use of a combination of an opioid analgesic together with a COX-2 inhibitor.

1 . A pharmaceutical composition comprising a combination of a COX-2 inhibitor in an amount sufficient to render a therapeutic effect together with an opioid analgesic, except for combinations of the COX-2 inhibitor with an anti-tussive dose of hydrocodone or codeine. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein such that an analgesic effect is attained which is at least about 5 times greater than that obtained with the dose of opioid analgesic alone. 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein the dose of opioid analgesic would be subtherapeutic if administered without the COX-2 inhibitor. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the opioid analgesic and COX-2 inhibitor are administered orally, via implant, parenterally, sublingually, rectally, topically, or via inhalation. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the opioid analgesic is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, salts thereof, complexes thereof; and mixtures of any of the foregoing. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein said opioid analgesic is selected from the group consisting of mu-agonists, kappa-agonists, mixed mu-agonists/antagonists, mu-antagonist combinations, salts thereof, complexes thereof, and mixtures thereof. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , which is selected from the group consisting of a tablet; a multiparticulate formulation for oral administration; a solution, suspension or elixer for oral administration; an injectable formulation; an implantable device; a topical preparation; a suppository; a buccal tablet; or an inhalation formulation. 
     
     
         8 . The pharmaceutical composition according to  claim 1 , which is a solid oral dosage form formulated as a tablet or a capsule. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , comprising a therapeutically effective or sub-therapeutic amount of an opioid analgesic selected from the group consisting of morphine, methadone, meperidine, levorphanol, codeine, hydrocodone, dihydrocodeine, hydromorphone, oxycodone, oxymorphone, salts thereof, and mixtures of any of the foregoing. 
     
     
         10 . The pharmaceutical composition according to  claim 1 , wherein said COX-2 inhibitor is selected from the group consisting of celecoxib (SC-58635), DUP-697, flosulide (CGP-28238), meloxicam, Vioxx (L 745,337), 6-methoxy-2 naphthylacetic acid (6-MNA), MK-966, nabumetone, nimesulide, NS-398, SC-5766, SC-58215, T-614, and mixtures thereof. 
     
     
         11 . The pharmaceutical composition according to  claim 1 , comprising a COX-2 inhibitor in an amount sufficient to render a therapeutic effect together with a dose of hydrocodone which is analgetic if administered without the COX-2 inhibitor. 
     
     
         12 . The pharmaceutical composition according to  claim 11 , wherein the dose of hydrocodone is preferably from about 15 to about 2000 mg. 
     
     
         13 . The pharmaceutical composition according to  claim 1 , comprising a COX-2 inhibitor in an amount sufficient to render a therapeutic effect together with a dose of codeine which is analgetic if administered without the COX-2 inhibitor. 
     
     
         14 . The pharmaceutical composition according to  claim 13 , wherein the dose of codeine is from about 30 to about 400 mg. 
     
     
         15 . The pharmaceutical composition according to  claim 1 , comprising an opioid analgesic selected from the group consisting morphine, methadone, meperidine, levorphanol, hydromorphone, oxycodone, hydrocodone, and codeine, together with a COX-2 inhibitor selected from the group consisting of celecoxib, flosulide, meloxicam, nabumetone, nimesulide, T614 and MK 966, in the ratios set forth in Table I. 
     
     
         16 . The pharmaceutical composition according to  claim 1 , wherein the dose of COX-2 inhibitor synergistically potentiates the effect of the opioid analgesic, but the dose of opioid analgesic does not appear to significantly potentiate the effect of the COX-2 inhibitor. 
     
     
         17 . The pharmaceutical composition according to  claim 8 , wherein the oral solid dosage form includes a sustained release carrier which causes the sustained release of the COX-2 inhibitor, the opioid analgesic, or both the opioid analgesic and the COX-2 inhibitor, when the dosage form contacts gastrointestinal fluid. 
     
     
         18 . A method of effectively treating pain in humans or other mammals, comprising administering to the patient a therapeutically effective amount of a COX-2 inhibitor together with a dose of an opioid analgesic. 
     
     
         19 . The method of  claim 18 , wherein the combination provides an analgesic effect which is at least about 5 times greater than that obtained with the dose of opioid analgesic alone. 
     
     
         20 . The method of  claim 18 , wherein the dose of the COX-2 inhibitor and the opioid analgesic are administered orally. 
     
     
         21 . The method of  claim 18 , wherein the dose of the COX-2 inhibitor and the opioid analgesic are administered in a single oral dosage form. 
     
     
         22 . The method of  claim 18 , wherein the dose of opioid analgesic would be sub-therapeutic if administered without the dose of COX-2 inhibitor. 
     
     
         23 . The method of  claim 18 , wherein the dose of opioid analgesic is effective to provide analgesia alone, but the dose of opioid provides at least a five-fold greater analgesic effect than typically obtained with that dose of opioid alone. 
     
     
         24 . The use of a pharmaceutical combination of a COX-2 inhibitor together with an opioid analgesic to provide effective pain management in humans. 
     
     
         25 . The use of a COX-2 inhibitor in the manufacture of a pharmaceutical preparation containing a COX-2 inhibitor and an opioid analgesic for the treatment of pain. 
     
     
         26 . The use of an opioid analgesic in the manufacture of a pharmaceutical preparation containing a COX-2 inhibitor and an opioid analgesic for the treatment of pain. 
     
     
         27 . The method of  claim 18 , wherein the COX-2 inhibitor is administered before, simultaneously with, or after administration of the opioid analgesic, such that the dosing interval of the COX-2 inhibitor overlaps with the dosing interval of the opioid analgesic. 
     
     
         28 . A method of reducing the amount of opioid required to treat a patient affected with pain comprising co-administering with said opioid analgesic an effective amount of a COX-2 inhibitor, to augment the analgesia attributable to said opioid analgesic during at least a portion of the dosage interval of said opioid analgesic. 
     
     
         29 . A method of reducing the amount of a COX-2 inhibitor required to treat a patient affected with pain, comprising co-administering with said COX-2 inhibitor an effective amount of an opioid analgesic, to augment the analgesia attributable to said COX-2 inhibitor during at least a portion of the dosage interval of said COX-2 inhibitor.