WO1998050075A1

WO1998050075A1 - Cox-2 inhibitors in combination with nmda-blockers for treating pain

Info

Publication number: WO1998050075A1
Application number: PCT/US1998/009252
Authority: WO
Inventors: Frank S. Caruso
Original assignee: Algos Pharmaceutical Corporation
Priority date: 1997-05-07
Filing date: 1998-05-06
Publication date: 1998-11-12
Also published as: AU7472798A

Abstract

The analgesic effectiveness of a cyclooxygenase-2 inhibitor is significantly enhanced by administering a cyclooxygenase-2 inhibitor with a nontoxic NMDA receptor antagonist and/or a nontoxic substance that blocks at least one major intracellular consequence of NMDA receptor activation.

Description

COX-2 INHIBITORS IN COMBINATION WITH NMDA-BLOCKERS FOR TREATING PAIN

BACKGROUND OF THE INVENTION

This invention relates to a method and composition for alleviating pain. More particularly, this invention is concerned with alleviating pain by administration of a cyclooxygenase-2 inhibitor (also referred to as a cyclooxygenase π, COX-2 or COX II inhibitor), together with a nontoxic antagonist, or blocker, for the N-methyl- D-aspartate (NMDA) receptor or nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation.

Non-steroidal antunflammatory drugs (NSAIDS) exert most of their antunflammatory, analgesic and antipyretic activity in addition to inhibiting hormone- induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Initially, only one form of cyclooxygenase was known, this corresponding to cyclooxygenase- 1 or the constitutive enzyme, as originally identified in bovine seminal vehicles. This enzyme has been cloned, sequenced and characterized from various sources including the sheep, the mouse and man. As prostaglandins have both physiological and pathological roles, cyclooxygenase- 1 is responsible for endogenous basal release of prostaglandins and is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. More recently, the gene for a second inducible form of cyclooxygenase, referred to as cyclooxygenase-2, has been cloned, sequenced and characterized initially from chicken, murine and human sources. Cyclooxygenase-2 is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. In contrast to cyclooxygenase- 1, cyclooxygenase-2, the inducible form, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Therefore, a selective inhibitor of cyclooxygenase-2 can have similar antunflammatory, analgesic and antipyretic properties to a conventional NSAID, and in addition would inhibit hormone- induced uterine contractions and have potential anti-cancer effects.

A number of cyclooxygenase-2 inhibitors are known. See, e.g., U.S. Patent Nos. 5,393,790, 5,409,944, 5,418,254, 5,420,343, 5,436,265, 5,474,995, 5,476,944, 5,486,534, 5,510,368, 5,521,213, 5,536,752, 5,547,975, 5,550,142, 5,552,422, 5,565,482, 5,576,339, 5,580,985, 5,585,504, 5,593,994 and 5,596,008. Cyclooxygenase-2 inhibitors exhibit a diminished ability to induce some of the mechanism-based side effects that occur with the use of NSAIDs. In particular, such inhibitors can have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a dkninished ability to induce asthma attacks in aspirin-sensitive aspirin-sensitive asthmatic subjects.

Heretofore, there has been no recognition or appreciation that the analgesic effectiveness of a cyclooxygenase-2 inhibitor can be appreciably potentiated, or enhanced, by administration of a cyclooxygenase-2 inhibitor prior to, with or following the administration of an analgesia-potentiating amount of a nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation.

SUMMARY OF THE INVENTION

In accordance with the present invention, a method of alleviating pain is provided with comprises administering to a mammal exhibiting pain (a) an analgesia-inducing amount of at least one cyclooxygenase-2 inhibitor and (b) an analgesia-potentiating amount of at least one analgesia-potentiator selected from the group consisting of nontoxic N-methyl-D-aspartate receptor antagonist and nontoxic substance that blocks a major intracellular consequence of N-methyl-D-aspartate receptor activation.

Further in accordance with this invention, a composition for alleviating pain is provided which comprises (a) an analgesia-inducing amount of at least one cyclooxygenase-2 inhibitor and (b) an analgesia-potentiating amount of at least one analgesia-potentiator selected from the group consisting of nontoxic N-methyl-D- aspartate receptor and nontoxic substance that blocks a major intracellular consequence of N-methyl-D-aspartate receptor activation. The method of the invention and the therapeutic composition therefor are applicable to the treatment of all varieties of pain. Thus, for a mammal in need of pain relief, an enhanced level of analgesia for an equivalent dosage of at least one cyclooxygenase-2 inhibitor, or an equivalent level of analgesia for a reduced dosage of at least one cyclooxygenase-2 inhibitor, can be achieved when at least one cyclooxygenase-2 inhibitor is administered prior to, with or following the administration of the analgesia-potentiator.

The expression "N-methyl-D-aspartate receptor" shall be understood to include all of the binding site subcategories associated with the NMDA receptor, e.g., the glycine-binding site, the phenylcyclidine (PCP)-binding site, etc., as well as the NMDA channel. Thus, the invention herein contemplates the use of nontoxic

substances that block an NMDA receptor binding site, e.g., dextromethorphan, or that block the NMDA channel, e.g., a source of magnesium such as magnesium sulfate. The term "nontoxic" as used herein shall be understood in a relative sense and is intended to designate any substance that has been approved by the United States Food and Drug Administration ("FDA") for administration to humans or, in keeping with established regulatory criteria and practice, is susceptible to approval by • the FDA for administration to humans. The term "nontoxic" is also used herein to distinguish the NMDA receptor antagonists, or blockers, that are useful in the practice of the present invention from NMDA receptor antagonists such as MK 801 (the compound 5-methyl-10,H-dihydro-SH-dibenze[a,d] cyclohepten-5,10-imine), CPP (the compound 3-[2-carboxypiperazin-4-yl] propyl-1-phosphonic acid) and PCP (the compound l-(l-phenylcyclohexyl)piperidine) whose toxicities effectively preclude their therapeutic use.

The terms "potentiate" and "potentiating" are used herein in their art- recognized sense, i.e., as referring to a significant increase in the level of pain- alleviating activity for the combination of cyclooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/or nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation compared with that which could have been expected based on the activities of the cyclooxygenase-2 inhibitor administered alone and nontoxic NMDA receptor antagonist and/or nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation administered alone.

The term "pain-alleviating" shall be understood herein to include the expressions "pain-suppressing" and "pain-inhibiting" as the invention is applicable to the alleviation of existing pain as well as the suppression or inhibition of pain which would otherwise ensue from an imminent pain-causing event.

The expression "analgesia-inducing amount" as applied to the cyclooxygenase-2 inhibitor employed in the therapeutic method and composition of this invention shall be understood to mean an amount of cyclooxygenase-2 inhibitor which when administered by itself or in combination with the nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation provides significant analgesic activity.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Any of the cyclooxygenase-2 inhibitors heretofore used to alleviate pain can be used herein. Specific cyclooxygenase-2 inhibitors that can be used in this invention are disclosed in aforementioned U.S. Patent Nos. 5,393,790, 5,409,944, 5,418,254, 5,420,343, 5,436,265, 5,474,995, 5,476,944, 5,486,534, 5,510,368, 5,521,213, 5,536,752, 5,547,975, 5,550,142, 5,552,422, 5,565,482, 5,576,339, 5,580,985, 5,585,504, 5,593,994 and 5,596,008, the contents of which are incorporated by reference herein. More particularly, the useful cyclooxygenase-2 inhibitors include the substituted spiro compounds of U.S. Patent No. 5,393,790, e.g. , 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene, 4-[6-(4- fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide, 6-(4-fluorophenyl)-7-[4- (methylsulfonyl)phenyl]spiro[3.4]oct-6-ene, and the like; the sulfonamides of U.S. Patent No. 5,409,944, e.g., 5-methanesulfonamido-6-(2-thienylthio)-l-indanone, 5- methanesulfonamido-6-(2-(4-methyl-l ,3-diazinylthio))-l-indanone, 5- methanesulfonamido-6-(2-thiazolylthio)-l-indanone, and the like; the 2, 3 -substituted cyclopentadienyl compounds of U.S. Patent No. 5,418,254, e.g., l-methylsulfonyl-4- [l,l-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl]benzene, 4-[4-(4- fluorophenyl)-l , l-dimethylcyclopenta-2,4-dien-3-yl]benzenesulfonamide, 1- methylsulfonyl-4-{4-(4-trifluoromethylphenyl)-l-trifluoromethylcyclopenta-2,4-dien-3- yl]benzene, and the like; the aromatic cycloethers of U.S. Patent No. 5,420,343, e.g., methyl 3,5-bis(l,l-dimethylethyl)benzoate, 3,5-bis(lJ-dimethylethyl) benzenemethanol, l,3-bis(l,l-dimethylethyl)-5-(2-chloroethyl)benzene, and the like; the 1-aroyl acids of U.S. Patent No. 5,436,265, e.g. , l-(2,4,6-trichlorobenzoyl)-5- methoxy-2-methyl-3-indolyl acetic acid, l-(2,6-dichlorobenzoyl)-5-methoxy-2-methyl- 3-indolyl acetic acid and the like; the phenyl heterocycles of U.S. Patent Nos. 5,474,995, 5,536,752 and 5,550,142, e.g., 3-(4-(aminosulfonyl)phenyl)-2-(4- fluorophenyl)thiophene, 2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2- cyclopentenone, 4-(4-methylsulfonyl)phenyl)-5-(4-fluorophenyl)isothiazole, and the like; the cyclic phenolic thioether derivatives of U.S. Patent No. 5,476,944, e.g., 3,5- bis(l J-dimethylethyl)benzenethiol, trans-2-[[3 ,5-bis(l , l-dimethylethyl)henyl] hiojcyclohexanol, 3-,6-dioxabicyclo-[3J.0]hexane, and the like; the 3,4-substituted pyrazoles of U.S. Patent No. 5,486,534, e.g., 4-(4-fluorophenyl)-l-methyl-3-[4- (methylsulfonyl)phenyl]-5-trifluoromethyl)pyrazole, l-benzyl-4-(4-fluorophenyl)-3-[4- (methylsulfonyl)phenyl]-5-(trifluoromethyl)pyrazole, l-allyl-4(4-fluorophenyl)-3-[4- methylsulfonyl)phenyl]-5-(trifluoromethyl)-lH-pyrazole, and the like; the N-benzyl-3- indoleacetic acids of U.S. Patent No. 5,510,368, e.g. , 2-(5-bromo-l-(4-bromobenzyl)- 2-methyl-lH-indol-3-yl)propionic acid, (S)-( +)-2-(5-bromo-l-(4-bromophenyl)-2- methyl-lH-indol-3-yl)acetyl acid, (R)-(-)-2-(5-bromo-l-(4-bromobenzyl)-2-methyl-lH- indol-3-yl)propionic acid, and the like; the diaryl bicyclic heterocyclics of U.S. Patent No. 5,521,213, e.g., 3-(4-(methylsulfonyl)phenyl)-2-phenylbenzo[b]furan, 3-(4- (methanesulfonyl)phenyl)-2-phenylbenzo[b]thioρhene, 2-(4-fluorophenyl)-3-(4- aminosulfonyl)phenyl)-4H-thieno[2,3-c]furan-6-one, and the like; the benzopyranopyrazolyl derivatives of U.S. Patent No. 5,547,975, e.g. , 4-[l,4-dihydro- 3-(trifluoromeώyl)-[l]benzopyrano[4,3-c]pyrazol-l-yl]benzenesulfonamide, methyl[l- [4-(aminosulfonyl)phenyl] - 1 ,4-dihydro-[ ljbenzopyrano [4 , 3-c]pyrazol-3-yl] carboxylate, 4-[3-(trifluoromethyl)-lH-benzofuro[3 ,2-c]pyrazol-l-yl] benzenesulfonamide, and the like; the aryl substituted 5,5 fused aromatic nitrogen compounds of U.S. Patent No. 5,552,422, e.g., 5-(4-methylsulfonyl)phenyl)-6- phenylimidazo[2, l-b]thiazole, 2-methyl-5-(methylsulfonyl)phenyl)-6- phenylimidazo [2 , 1 -b] thiazole , 3 -methyl-5-(4-methylsulfonyl)phenyl)-6- phenylimidazo[2,l-b]thiazole, and the like; the heteroarylpyranopyrazolyl derivatives of U.S. Patent No. .5,565,482, e.g., 4-[l,5-dihydro-6-fluoro-7-methoxy-3- (trifluoromethyl)-[2]benzothiopyrano[4,3-c]pyrazol, 4-[l,4-dihydro-3-(trifluoromethyl)- [l]benzopyrano-[4,3-c]pyrazol-l-yl]benzenesulfonamide, 1 ,5-dihydro-6-fluoro-7- memoxy-l-[(4-meώylsulfonyl)phenyl]-3-(trifluoromemyl)-[2]beιιzothiopyrano-[4,3- c]pyrazol-l-yl]benzenesulfonamide, and the like; the pyridyl substituted cyclopentadienes of U.S. Patent No. 5,576,339, e.g., l-methylsulfonyl-4-[l,l- dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl]benzene, 4-[4-(4-fluoropyhenyl)- l,l-dimethylcyclopenta-2,4-dien-3-yl]benzenesulfonamide, and the like; the substituted pyrazoles of U.S. Patent No. 5,580,985, e.g., l-ethyl-4-(4-fiuorophenyl)-3-[4- (methylsulfonyl)phenyl]-5-(trifluoromethyl)-lH-pyrazole, 3-amino-4,4,4-trifluoro-2(4- fluorophenyl)-l-[4-(methylthio)phenyl]-2-buten-l-one, l-benzyl-4-(4-fluorophenyl)-3- [4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)pyrazole, and the like; the lactones of U.S. Patent No. 5,585,504, e.g., 3-phenyl-4-(4-methylsulfonyl)phenyl-2-(5H)- furanone, 3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, and the like; the ortho substituted phenyl compounds of U.S. Patent No. 5,593,994, e.g., 2- [(4-methylthio)phenyl]-l-biphenyl,l-_lcyclohexene-2-(4'-methylsulfonylphenyl) benzene, 3-(4'-methylsulfonylphenyl)-4-phenylphenol, and the like; and the 3,4-diaryl substituted pyridines of U.S. Patent No. 5,596,008, e.g. , 5-(4-fluorophenyl)-2- methoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine, 2-ethoxy-5-(4- fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine, 5-(4- fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6- (trifluoromethyl)pyridine, and the like. Among the nontoxic substances that block the NMDA receptor and as such are useful for enhancing the analgesic activity of a cyclooxygenase-2 inhibitor in accordance with this invention are dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) and its metabolite dextrorphan ((+)-3-hydroxy-N- methylmorphinan), their mixtures and their pharmaceutically acceptable salts. Other useful nontoxic substances that block the NMDA receptor include amantadine (1- aminoadamantine), memantine (3,5-dimethylaminoadamantone), pyrroloquinoline quinone and cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid. Of the nontoxic NMDA receptor antagonists, dextromethorphan in the form of its hydrobromide salt is preferred for use herein due to its ready availability and its established use in over- the-counter medications where it functions as a cough suppressant. While dextrorphan and its pharmaceutically acceptable salts will also provide excellent results, it is not known to be in commercial manufacture at this time. In addition to, or in place of, a blocker for the NMDA receptor, at least one nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation can also be used. Activation of the NMDA receptor, a subtype of excitatory amino acid receptors, induces a number of changes in the functional activity of nerve cells and, in particular, their capacity for excitability or inhibition in the presence of an addictive substance via an increase in intracellular Ca+ + concentration. The major consequences of NMDA receptor activation include the following sequences, or cascades, of events occurring within nerve cells: a) translocation and activation of protein kinases such as protein kinase C → phosphorylation of substrate proteins such as cytosolic enzymes, channel proteins, receptor proteins, etc. → changes in functional activity; b) initiation of early gene (c-fos, c-jun, ztf-268, etc.) expression by either increased intracellular Ca+ + or Ca+ + -activated protein kinases -> expression of functional genes responsible for production of cellular enzymes (such as protein kinases), receptor proteins (such as the NMDA receptor), ion channel proteins (such as K+, Na+, Ca+ + channels), neuropeptides (such as dynorphin), etc. → changes in functional activity; c) Ca+ +/calmodulin (or other C&+ + binding proteins) induced activation of enzymes and other cellular components → activation of Ca+ +/calmodulin-protein kinase systems such as Ca+ +/calmodulin kinase II → autophosphorylation of enzymes (e.g., Ca+ +/calmodulin kinase II) or other functional proteins → changes in functional activity; d) Ca-t- +/calmodulin induced activation of constitutive nitric oxide synthase as well as induction of inducible nitric oxide synthase - production of nitric oxide → i) production of cyclic guanosine monophosphate via activation of guanosine cyclase resulting in activation of protein kinases and early gene expression; ii) direct protein modification such as enzymes, receptor and/or channel proteins; iii) lipid membrane modification and/or nucleic acid modification via scavenge of free radicals; iv) induction of neurotoxicity at higher nitric oxide levels; v) retrograde actions in adjacent neurons or glial cells such as facilitation of glutamate release/NMD A receptor activation and/or inhibition of post-synaptic NMDA receptors → changes in functional activity; e) interactions with the cyclic adenosine monophosphate/protein kinase A system, the phospholipase C-inositol triphQsphate-Ca+ +/diacylglycerol- protein kinase system, the phospholipase A2-arachidonic acid/prostanoids/ leukotrienes system → changes in functional activity induced by second messenger systems other than NMDA receptor/_lCa⁺⁺/Ca⁺⁺-calmodulin/protein kinase systems; and, f) interactions with other excitatory amino acid receptor subtypes including non-NMDA receptors and metabotropic receptors as well as intracellular events subsequent to the activation of these excitatory amino acid receptor subtypes → changes in functional activity induced by the non-NMDA and metabotropic receptor activation. A substance that blocks the NMDA receptor will effectively prevent all of the foregoing major intracellular sequences of events from taking place. However, even with activation of the NMDA receptor, it is still possible to treat neuropathic pain in accordance with this invention by administering the cyclooxygenase-2-i-ohibitor and a nontoxic substance that blocks at least one of the foregoing major intra-cellular sequences of events brought about by activation of the NMDA receptor. Thus, e.g., a substance that interferes with translocation and activation of protein kinase C or with calmodulin induced activation of constitutive nitric oxide synthase as well as induction of inducible nitric oxide synthase is also useful for the practice of this invention.

Nontoxic substances that block a major intracellular consequence of NMDA receptor activation and are therefore useful in the practice of the invention include inhibitors of protein kinase C, e.g., gangliosides such as ganglioside GM_t (monosialoganglioside) and ganglioside GT_lb (trisialoganglioside); amphipathic long chain bases such as sphingosine, N,N,N-trimethylsphingosine, sphinganine and psychosine; quinolyloxazole-2-ones such as 4-methyl-5-(3-quinolinyl)-2-(3H)- oxazolone and phenyl-5-(2-quinolinyl)-2-3(3H)-oxazolone; l,4-bis-(amino- hydroxyalkylamino)-anthraquinones such as l,4-bis-(3-propylamino-2- hydroxypropylamino)-9J0 anthracenedione and 1 ,4-bis-(3-benzylamino-2- hydroxypropylamino)-9J0 anthracenedione; and, mixtures and pharmaceutically acceptable salts of any of the .foregoing.

Additional nontoxic substances that block a major intracellular consequence of NMDA receptor activation and as such are useful in the practice of the invention include inhibitors of calmodulin such as the phenothiazines, in particular, chlorpromazine, chlorpromazine sulfoxide, prochlorperazine dimaleate, perphenazine, trifluoperazine, fluphenazine, fluphenazine enanthate, fluphenazine decanoate, thioridazine, mesoridazine besylate, piperacetazine, acetophenazine dimaleate, carphenazine dimaleate, butaperazine dimaleate and phenothiazine sulfoxide; naphthalenesulfonamides such as N-(6-aminohexyl)-5-chloro-l- naphthalenesulfonamide, N-(6-aminohexyl)-5-chloro-2-naphthalenesulfonamide and N- (6-aminohexyl)-5-bromo-2-naphthalenesulfonamide ; 4-substituted-4H,6H-pyrrolo[l ,2- a][4,l] benzoxazepines such as l,3-dihydro-l-{l-[(4-methyl-4H,6H-pyrrolo[l,2-a][4,l] benzoxazepin-4-yl)methyl]-4-piperidi-nyl}-2H-benzimidazol-2-one; benzhydryls such as N-[2](diphenylmethylthioethyl]-2-(trifluoromethyl)-benzeneethanamine, N-[2-(bis(4- fluorophenyl)methylthio)- et-hyl]-2-(trifluorome yl)be---zeneetha----amine and N-[2- (bis(4-fluorophenyl)memyllMo)ethyl]-3-(trifluoromethyl)benzene-et-hanamine; tricyclic antidepressant drugs such as imipramine, 2-cWoroimipramine and amitriptyline; penfluridol; haloperidol; pimozide; clozapine; calmidazolin; and, mixtures and pharmaceutically acceptable salts of any of the foregoing.

Of the two groups of analgesia-enhancers, the nontoxic NMDA receptor antagonists are preferred and of these, dextromethorphan is preferred for the reasons previously stated.

With regard to dosage levels, the cyclooxygenase-2 inhibitor must be present in an analgesia-inducing amount, e.g., at a level corresponding to the generally recommended adult human dosages for a particular cyclooxygenase-2 inhibitor, and the nontoxic NMDA receptor antagonist or substance that blocks a major intracellular consequence of NMDA activation must be present at a level that potentiates the analgesia-inducing effectiveness of the cyclooxygenase-2 inhibitor. Given the wide variations in dosage level of the cyclooxygenase-2 inhibitor which depends to a large extent on the specific cyclooxygenase-2 inhibitor being administered, there can similarly be a wide variation in the dosage level of the nontoxic NMDA receptor antagonist or substance that blocks a major intracellular consequence of NMDA receptor activation. These amounts can be determined for a particular drug combination in accordance with this invention employing routine experimental testing.

While the cyclooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation need not be administered together, they must both be present in the patient at effective levels at the same time. While it is within the scope of the invention to administer the cyclooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/ or substance that blocks a major intracellular consequence of NMDA receptor activation separately, as a matter of convenience, it is preferred that they be coadministered as a single therapeutic composition. All modes of administrations are contemplated, e.g. , orally, rectally, parenterally, topically, or by intravenous, intramuscular, intrastemal or subcutaneous injection or in a form suitable by inhalation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy.

A therapeutic composition containing the cyclooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation will ordinarily be formulated with one or more pharmaceutically acceptable ingredients in accordance with known and established practice. Thus, the composition can be formulated as a liquid, powder, elixir, injectable solution, etc. Formulations for oral use can be provided as tablets or hard capsules wherein the pharmacologically active ingredients are mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are mixed with water or miscible solvents such as propylene glycol; PEG's and ethanol, or an oleaginous medium, e.g., peanut oil, liquid paraffin or olive oil. For topical administration in the mouth, the pharmaceutical compositions may take the form of buccal or sublingual tablet, drops or lozenges formulated in conventional manner.

For topical administration to the epidermis the compounds of the invention may be formulated as creams, gels, ointments or lotions or as transdermal patches. Such compositions may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening, gelling, emulsifying, stabilizing, dispersing, suspending, and/or coloring agents. The compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be. administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example as a sparingly soluble salt.

The compounds of the invention may be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion. For- mulations for injection may be presented in unit dosage from e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glyceride.

For intranasal administration, the compounds of the invention may be used, for example, as a liquid spray, as a powder or in the form of drops.

For administration by inhalation, the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlo- rodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insulator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.

Aqueous suspensions can include pharmaceutically acceptable excipients such as suspending agents, e.g., sodium carboxymethyl cellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as naturally occurring phosphatide, e.g. , lecithin, or condensation products of an alkylene oxide with fatty acids, e.g., polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, e.g, heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with. partial esters derived from fatty acids and a hexitol, e.g., polyoxyethylene sorbitol monoleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, e.g., polyoxyethylene sorbitan monoleate. The aqueous suspensions can also contain one or more preservatives, e.g., ethyl-or-n-propyl-p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or sodium or calcium cyclamate.

In addition to the cyclooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation, the therapeutic composition herein can contain at least one other pharmacologically active substance, e.g. , a non-narcotic analgesic such as tramadol, acetaminophen, aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, zomepirac, and the like, or a narcotic analgesic such as codeine, oxycodone, dihydrocodeine, hydrocodone, levorphanol, morphine, and the like. EXAMPLES 1-35 The following unit dosage forms are illustrative of the pain-alleviating drug combinations in accordance with the present invention:

Nontoxic NMDA Receptor Additional Active

Example Cyclooxygenase-2 Inhibitor (mg) Blocker (mg) Component (mg)

1 5-(4-fluorophenyl)-6-[4-(methyl- dextromethorphan sulfonyl)phenyl]spiro[2.4]hept-5-ene (25) hydrobromide (30)

5-(4-fluorophenyl)-6-[4-(methyl- dextromethorphan acetaminophen (325) sulfonyl)phenyl]spiro[2.4]hept-5-ene (25) hydrobromide (30)

5-(4-fluorophenyl)-6-[4-(methyl- dextrorphan sulfonyl)phenyl]spiro[2.4]hept-5-ene (25) hydrobromide (30)

5-med-anesulfonamido-6- dextromethorphan (2-thienylthio)-l-indanone(25) hydrobromide (30)

5-methanesulfonamido-6- dextromethorphan acetaminophen (325) (2-thienylthio)- 1 -indanone(25) hydrobromide (30)

5-methanesulfonamido-6- dextrorphan (2-thienylthio)-l-indanone(25) hydrobromide (30)

5-methanesuifonamido-6- amantadine (30) (2-thienylthio)-l-indanone(25)

5-methanesulfonamido-6- me antine (30) (2-thienylthio)-l-indanone(25) methyl 3,5-bis(l,l-dimethylethyl) dextromethorphan benzoate (25) hydrobromide (30) ιo methyl 3,5-bis(l,l-dimethylethyl) dextromethorphan acetaminophen (325) benzoate (25) hydrobromide (30)

11 methyl 3,5-bis(l,l-dimethylethyl) dextrorphan benzoate (25) hydrobromide (30)

12 methyl 3,5-bis(l,l-dimethylethyl) amantadine (30) benzoate (25)

13 methyl 3,5-bis(l,l-dimethylethyl) memantine (30) benzoate (25)

14 l-(2,4,6-trichlorobenzoyl)-5- dextromethorphan methoxy-2-methyl-3-indolyl acetic acid (25) hydrobromide (30) 15 l-(2,4,6-trichlorobenzoyl)-5- dextromethorphan ibuprofen (325) methoxy-2-methyl-3-indolyl acetic acid (25) hydrobromide (30) Nontoxic NMDA Receptor Additional Active

Example Cyclooxygenase-2 Inhibitor (mg) Blocker (mg) Component (mg)

5 16 l-(2,4,6-trichlorobenzoyl)-5- dextrorphan methoxy-2-methyl-3-indolyl acetic acid (25) hydrobromide (30)

17 l-(2,4,6-trichlorobenzoyl)-5- amantadine (30) methoxy-2-methyl-3-indolyl acetic acid (25)

10

18 l-(2,4,6-trichlorobenzoyl)-5- memantine (30) methoxy-2-methyl-3-indolyl acetic acid (25)

15 19 3-(4-(aminosulfonyl)phenyl)-2- dextromethorphan (4-fluorophenyl)thiophene (30) hydrobromide (30)

20 3-(4-(aminosulfonyl)phenyl)-2- dextromethorphan aspirin (325) (4-fluorophenyl)thiophene (30) hydrobromide (30) 0

21 3-(4-(aminosulfonyl)phenyl)-2- dextrorphan (4-fluorophenyl)thiophene (30) hydrobromide (30)

22 3-(4-(aminosulfonyI)phenyl)-2- amantadine (30) (4-fluorophenyl)thiophene (30) 5

23 3-(4-(aminosulfonyl)phenyl)-2- memantine (30) (4-fluorophenyl)thiophene (30) 24 3,5-bis(l ,l-dimethylethyl)benzenethiol (25) dextromethorphan

30 hydrobromide (30)

25 3 ,5-bis(l , 1 -dimethylethy l)benzenethiol (25) dextromethorphan acetaminophen (325) hydrobromide (30)

35 26 3,5-bis(l,l-dimethylethyl)benzenethiol (25) dextrorphan hydrobromide (30)

27 3,5-bis(l,l-dimethylethyl)benzenethiol (25) amantadine (30)

40 28 3,5-bis(l,l-dimethylethyl)benzenethiol (25) memantine (30)

29 3-(4-(methylsulfonyl)phenyl)-2-phenylbenzo dextromethorphan [b]furan (25) hydrobromide (30)

45 30 3-(4-(methylsulfonyl)phenyl)-2-phenylbenzo dextromethorphan ibuprofen (325) [bjftiran (25) hydrobromide (30)

31 3-(4-(methylsulfonyl)phenyl)-2-phenylbenzo dextrorphan [b]furan (25) hydrobromide (30)

50

32 4-[l,4-dihydro-3-(trifluoromethyl)-[l] dextromethorphan benzopyrano[4,3-c]pyrazol-l-yl] hydrobromide (30) benzenesulfonamide (25) Nontoxic NMDA Receptor Additional Active

Example Cvclooxygenase-2 Inhibitor (mg) Blocker (mg) Component (mg) 33 5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo dextromethorphan

[2,l-b]thiazol (25) hydrobromide (30)

34 4-[l ,5-dihydro-6-fluoro-7-methoxy-3- dextromethorphan (trifluoromethyl)-[2]benzothiopyrano[4,3-c] hydrobromide (30) pyrazol-l-yl]benzenesulfonamide (25)

35 l-methylsulfonyl-4-[l,l-dimethyl-4- dextromethorphan (4-fluoroρhenyl)cyclopenta-2,4-diene-3-yl] hydrobromide (30) benzene (25)

In each of these dosage units, the nontoxic NMDA receptor antagonist dextromethorphan hydrobromide significantly potentiates the pain-alleviating activity of the cyclooxygenase-2 inhibitor.

Claims

WHAT IS CLAIMED IS:

1. A method of alleviating pain which comprises admi stering to a mammal exhibiting pain (a) an analgesia-inducing amount of at least one cyclooxygenase-2 inhibitor and (b) an analgesia-potentiating amount of at least one analgesia-potentiator selected from the group consisting of nontoxic N-methyl-D- aspartate receptor antagonist and nontoxic substance that blocks a major intracellular consequence of N-methyl-D-aspartate receptor activation.

2. The method of Claim 1 wherein the cyclooxygenase-2 inhibitor is selected from the group consisting of substituted spiro compound, sulfonamide 2,3- substituted cyclopentadienyl compound, aromatic cycloether, 1-aroyl acid, phenyl heterocycle, cyclic phenolic thioether derivative, 3,4-substituted pyrazole, N-benzyl-3- indoleacetic acid, diaryl bicyclic heterocyclic, benzopyranopyrazolyl derivative, aryl substituted 5,5 fused aromatic nitrogen compound, heteroarylpyranopyrazolyl derivative, pyridyl substituted cyclopentadiene, substituted pyrazole, lactone, ortho substituted phenyl compound and 3,4-diaryl substituted pyridine.

3. The method of Claim 2 wherein the substituted spiro compound is selected from the group consisting of 5-(4-fluorophenyl)-6-[4- (methylsulfonyl)phenyl]spiro[2.4]hept-5-ene, 4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en- 5-yl]benzenesulf onamide and 6-(4-fluorophenyl)-7- [4-(methylsulfonyl)phenyl] spiro[3.4]oct-6-ene, sulfonamides is selected form the group consisting of 5- methanesulfonamido-6-(2-thienylthio)- 1-indanone and 5-methanesulfonamido-6-(2-(4- methyl-l,3-diazinylthio))-l-indanone, 5-methanesulfonamido-6-(2-thiazolylthio)-l- indanone, the 2,3-s╧ìbstituted cyclopentadienyl compound is selected from the group consisting of l-methylsulfonyl-4-[l , l-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien- 3-yl]benzene, 4-t4-(4-fluorophenyl)-l , l-dimethylcyclopenta-2,4-dien-3- yljbenzenesulfonamide and l-methylsulfonyl-4-{4-(4-trifluoromethylphenyl)-l- trifluoromethylcyclopenta-2,4-dien-3-yl]benzene, the aromatic cycloether is selected from the group consisting of methyl 3,5-bis(l,l-dimethylethyl)benzoate, 3,5-bis(l,l- dimethylethyl) benzenemethanol and l,3-bis(lJ-dimethylethyl)-5-(2- chloroethyl)benzene, the 1-aroyl acid is selected from the group consisting of l-(2,4,6- trichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid and l-(2,6- dichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid, the phenyl heterocycle is selected from the group consisting of 3-(4-(aminosulfonyl)phenyl)-2-(4- fluorophenyl)thiophene, 2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2- cyclopentenone and 4-(4-methylsulfonyl)phenyl)-5-(4-fluorophenyl)isothiazole, the cyclic phenolic thioether derivative is selected from the group consisting of 3,5- bis(l , l-dimethylethyl)benzenethiol, trans-2-[[3 ,5-bis(l , l-dimethylethyl)henyl] hiojcyclohexanol and 3,6-dioxabicyclo-[3J.0]hexane, the 3,4-substituted pyrazole is selected from the group consisting of 4-(4-fluorophenyl)-l-methyl-3-[4- (methy lsulf ony l)phenyl] -5 -trifluoromethy l)pyrazole , 1 -benzy l-4-(4-fluorophenyl)-3- [4- (methylsulfonyl)phenyl]-5-(trifluoromethyl)pyrazole and l-allyl-4(4-fluorophenyl)-3-[4- methylsulfonyl)phenyl]-5-(trifluoromethyl)-lH-pyrazole, the N-benzyl-3-indoleacetic acid is selected from the group consisting of 2-(5-bromo-l-(4-bromobenzyl)-2-methyl- lH-indol-3-yl)propionic acid, (S)-( +)-2-(5-bromo-lr(4-bromophenyl)-2-methyl-lH- indol-3-yl)acetyl acid and (R)-(-)-2-(5-bromo-l-(4-bromobenzyl)-2-methyl-lH-indol-3- yl)propionic acid, the diaryl bicyclic >heterocyclic is selected from the group consisting of 3-(4-(methylsulfonyl)phenyl)-2-phenylbenzo[b]furan, 3-(4-(methanesulfonyl)phenyl)- 2-phenylbenzo[b]thiophene and 2-(4-fluorophenyl)-3-(4-aminosulfonyl)phenyl)-4H- thieno[2,3-c]furan-6-one, the benzopyranopyrazolyl derivative is selected from the group consisting of 4-[l,4-dihydro-3-(trifluoromethyl)-[l]benzopyrano[4,3-c]pyr---zol-l- yljbenzenesulforiamide, methyl[l-[4-(aminosulfonyl)phenyl]-l ,4-dihydro- [l]benzopyrano[4,3-c]pyrazol-3-yl] carboxylate and 4-[3-(trifluoromethyl)-lH- benzofuro[3,2-c]pyrazol-l-yl] benzenesulfonamide, the aryl substituted 5,5 fused aromatic nitrogen compound is selected from the group consisting of 5-(4- methylsulfonyl)phenyl)-6-phenylimidazo[2, l-b]thiazole, 2-methyl-5- (methylsulfonyl)phenyl)-6-phenylimidazo[2, l-b]thiazole and 3-methyl-5-(4- methylsulfonyl)phenyl)-6-phenylimidazo[2, l-b]thiazole, the heteroarylpyranopyrazolyl derivative is selected from the group consisting of 4-[l,5-dihydro-6-fluoro-7-methoxy- 3-(trifluoromethyl)-[2]benzothiopyrano[4,3-c]pyrazol, 4-[l,4-dihydro-3- (trifluoromemyl)-[l]benzopyrano-[4,3-c]pyrazol-l-yl]ber--zenesulfonamide and 1 ,5- dihydro-6-fluoro-7-methoxy-l-[(4-methylsulfonyl)phenyl]-3-(trifluoromethyl)-

[2]benzothiopyrano-[4,3-c]pyrazol-l-yl]benzenesulfonamide, the pyridyl substituted cyclopentadienes is selected from the group consisting of l-methylsulfonyl-4-[l,l- dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl]benzene and 4-[4-(4- fluoropyhenyl)-l , l-dimethylcyclopenta-2,4-dien-3-yl]benzenesulfonamide, the substituted pyrazole is selected from the group consisting of l-ethyl-4-(4- fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-lH-pyrazole, 3-amino- 4,4, 4-trifluoro-2(4-fluoropheny 1)- 1 - [4-(methylthio)pheny 1] -2-buten- 1 -one and 1 -benzy 1- 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)pyrazole, the lactone is selected from the group consisting of 3-phenyl-4-(4-methylsulfonyl)phenyl- 2-(5H)-furanone and 3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)- furanone, the ortho substimted phenyl compound is selected from the group consisting of 2-[(4-methylthio)phenyl]-l-biphenylJ-cyclohexene-2-(4'-methylsulfonylphenyl) benzene, and 3-(4'-methylsulfonylphenyl)-4-phenylphenol, and the 3,4-diaryl substituted pyridine is selected from the group consisting of 5-(4-fluorophenyl)-2- methoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine, 2-ethoxy-5-(4- fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine and 5-(4- fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6- (trifluoromethyl)pyridine.

4. The method of Claim 1 containing a therapeutically effective amount of at least one other pharmacologically active substance (c).

5. The method of Claim 4 wherein the pharmacologically active substance (c) is selected from the group consisting of non-narcotic analgesics and narcotic analgesics.

6. The method of Claim 5 wherein the non-narcotic analgesic is selected from the group consisting of tramadol, acetaminophen, aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin and zomepirac.

7. The method of Claim 5 wherein the narcotic analgesic is selected from the group consisting of codeine, dihydrocodeine, hydrocodone, levorphanol, morphine and oxycodone.

8. The method of Claim 1 wherein the nontoxic N-methyl-D- aspartate receptor antagonist is at least one member selected from the group consisting of dextromethorphan, dextrorphan, amantadine, memantine and pharmaceutically acceptable salts thereof.

9. The method of Claim 3 wherein the nontoxic N-methyl-D- aspartate receptor antagonist is at least one member selected from the group consisting of dextromethorphan, dextrorphan, amantadine, memantine and pharmaceutically acceptable salts thereof.

10. The method of, Claim 1 wherein (a) and (b) are coadministered.

11. The method of Claim 8 wherein (a) and (b) are coadministered as a sustained release dosage form.

12. A therapeutic composition comprising (a) an analgesia-inducing amount of at least one cyclooxygenase-2 inhibitor and (b) an analgesia-potentiating amount of at least one analgesia-potentiator selected^' from the group consisting of N- methyl-D-aspartate receptor nontoxic antagonist and nontoxic substance that blocks a major intracellular consequence of N-methyl-D-aspartate receptor activation.

13. The therapeutic composition of Claim 12 wherein the cyclooxygenase-2 inhibitor is selected from the group consisting of substituted spiro compound, sulfonamide, 2, 3 -substituted cyclopentadienyl compound, aromatic cycloether, 1-aroyl acid, phenyl heterocycle, cyclic phenolic thioether derivative, 3,4- substituted pyrazole, N-benzyl-3-indoleacetic acid, diaryl bicyclic heterocyclic, benzopyranopyrazolyl derivative, aryl substituted 5,5 fused aromatic nitrogen compound, heteroarylpyranopyrazolyl derivative, pyridyl substituted cyclopentadiene, substituted pyrazole, lactone, ortho substituted phenyl compound and 3,4-diaryl substituted pyridine.

14. The therapeutic composition of Claim 13 wherein the substituted spiro compound is selected from the group consisting of 5-(4-fluorophenyl)-6-[4- (methy lsulf ony l)phenyl] spiro [2.4] hept-5-ene , 4- [6-(4-fluorophenyl) spiro [2.4]hept-5-en- 5-yl]benzenesulfonamide and 6-(4-fluorophenyl)-7-[4-(methylsulfonyl)phenyl] spiro[3.4]oct-6-ene, sulfonamides is selected form the group consisting of 5- methanesulfonamido-6-(2-thienylthio)-l-indanone and 5-methanesulfonamido-6-(2-(4- methyl-l,3-diazinylthio))-l-indanone, 5-methanesulfonamido-6-(2-thiazolylthio)-l- indanone, the 2,3-substituted cyclopentadienyl compound is selected from the group consisting of l-methylsulfonyl-4-[l, l-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien- 3-yl]benzene, 4-[4-(4-fluorophenyl)-l , l-dimethylcyclopenta-2,4-dien-3- yljbenzenesulfonamide and l-methylsulfonyl-4-{4-(4-trifluoromethylphenyl)-l- trifluoromethylcyclopenta-2,4-dien-3-yl]benzene, the aromatic cycloether is selected from the group consisting of methyl 3,5-bis(lJ-dimethylethyl)benzoate, 3,5-bis(l,l- dimethylethyl) benzenemethanol and l,3-bis(l,l-dimethylethyl)-5-(2- chloroethyl)benzene, the 1-aroyl acid is selected from the group consisting of l-(2,4,6- trichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid and l-(2,6- dichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid, the phenyl heterocycle is selected from the group consisting of 3-(4-(am--nosulfonyl)phenyl)-2-(4- fluorophenyl)thiophene, 2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2- cyclopentenone and 4-(4-methylsulfonyl)phenyl)-5-(4-fluorophenyl)isothiazole, the cyclic phenolic thioether derivative is selected from the group consisting of 3,5- bis(l , l-d-jnethylethyl)be-nzenethiol, trans-2-[[3 ,5-bis(l , l-dimethylethyl)henyl] hiojcyclohexanol and 3,6-dioxabicyclo-[3.L0]hexane, the 3,4-substituted pyrazole is selected from the group consisting of 4-(4-fluorophenyl)-l-methyl-3-[4-

(methylsulfonyl)phenyl]-5-trifluoromethyl)pyrazole, l-benzyl-4-(4-fluorophenyl)-3-[4- (methylsulfonyl)phenyl]-5-(trifluoromethyl)pyrazole and l-allyl-4(4-fluorophenyl)-3-[4- methylsulfonyl)phenyl]-5-(trifluoromethyl)-lH-pyrazole, the N-benzyl-3-indoleacetic acid is selected from the group consisting of 2-(5-bromo-l-(4-bromobenzyl)-2-methyl- lH-indol-3-yl)propionic acid, (S)-(+)-2-(5-bromo-l-(4-bromophenyl)-2-methyl-lH- indol-3-yl)acetyl acid and (R)-(-)-2-(5-bromo-l-(4-bromobenzyl)-2-methyl-lH-indol-3- yl)propionic acid, the diaryl bicyclic heterocyclic is selected from the group consisting of 3-(4-(methylsulfonyl)phenyl)-2-phenylbenzo[b]furan, 3-(4-(methanesulfonyl)phenyl)- 2-phenylbenzo[b]thiophene and 2-(4-fluorophenyl)-3-(4-aminosulfonyl)phenyl)-4H- thieno[2,3-c]furan-6-one, the benzopyranopyrazolyl derivative is selected from the group consisting of 4-[l,4-dihydro-3-(trifluoromethyl)-[l]benzopyrano[4,3-c]pyrazol-l- yljbenzenesulfonamide, methyl[l-[4-(aminosulfonyl)phenyl]-l,4-dihydro- [l]benzopyrano[4,3-c]pyrazol-3-yl] oarboxylate and 4-[3-(trifluoromethyl)-lH- benzofuro[3,2-c]pyrazol-l-yl] benzenesulfonamide, the aryl substituted 5,5 fused aromatic nitrogen compound is selected from the group consisting of 5-(4- methylsulfonyl)phenyl)-6-phenylimidazo [2 , 1 -bjthiazole , 2-methyl-5- (methylsulfonyl)phenyl)-6-phenylimidazo[2, l-b]thiazole and 3-methyl-5-(4- methylsulfonyl)phenyl)-6-phenylimidazo[2, l-b]thiazole, the heteroarylpyranopyrazolyl derivative is selected from the group consisting of 4-[l,5-dihydro-6-fluoro-7-methoxy- 3-(trifluoromethyl)-[2]benzothiopyrano[4,3-c]pyrazol, 4-[l ,4-dihydro-3-

(frifluoromemyl)-[l]benzopyrano-[4,3-c]pyrazol-l-yl]be---^enesulfo----amide and 1 ,5- dihydro-6-fluoro-7-methoxy-l-[(4-methylsulfonyl)phenyl]-3-(trifluoromethyl)- [2]be-.-zol---╧ìopyrano-[4,3-c]pyrazol-l-yl]benzenesulfonamide, the pyridyl substituted cyclopentadienes is selected from the group consisting of l-methylsulfonyl-4-[l,l- dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl]be--╬╣zene and 4-[4-(4- fluoropyhenyl)-l , l-dimemylcyclopenta-2,4-dien-3-yl]benzenesulfo-╬▒amide, the substituted pyrazole is selected from the group consisting of l-ethyl-4-(4- fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-lH-pyrazole, 3-amino- 4,4,4-trifluoro-2(4-fluorophenyl)-l-[4-(methylthio)phenyl]-2-buten-l-one and l-benzyl- 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)pyrazole, the lactone is selected from the group consisting of 3-phenyl-4-(4-methylsulfonyl)phenyl- 2-(5H)-furanone and 3-(3 ,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)- furanone, the ortho substituted phenyl compound is selected from the group consisting of 2- [(4-methy lthio)phenyl] - 1 -biphenyl , 1 -cyclohexene-2-(4 ' -methylsulfonylpheny 1) benzene, and 3-(4'-methylsulfonylphenyl)-4-phenylphenol, and the 3,4-diaryl substituted pyridine is selected from the group consisting of 5-(4-fluorophenyl)-2- methoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine, 2-ethoxy-5-(4- fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine and 5-(4- fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6- (trifluoromethyl)pyridine.

15. The therapeutic composition of Claim 10 containing a therapeutically effective amount of at least one other pharmacologically active substance (c).

16. The therapeutic composition of Claim 15 wherein the pharmacologically active substance (c) is selected from the group consisting of non- narcotic analgesics and narcotic analgesics.

17. The therapeutic composition of Claim 16 wherein the non- narcotic analgesic is selected from the group consisting of acetaminophen, aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin and zomepirac.

18. The therapeutic composition of Claim 16 wherein the narcotic analgesic is selected from the group consisting of codeine, dihydrocodeine, heroin, hydrocodone, levorphanol, morphine and oxycodone.

19. The therapeutic composition of Claim 10 wherein the nontoxic

N-methyl-D-aspartate receptor antagomst is at least one member selected from the group consisting of dextromethorphan, dextrorphan, amantadine, memantine and pharmaceutically acceptable salts thereof.

20. The therapeutic composition of Claim 14 wherein the nontoxic N-methyl-D-aspartate receptor antagonist is at least one member selected from the group consisting of dextromethorphan, dextrorphan, amantadine, memantine and pharmaceutically acceptable salts thereof.

21. The therapeutic composition of Claim 12 wherein (a) and (b) are present in sustained release dosage form.