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US 20020035105A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0035105 A1 Caruso (43) Pub. Date: Mar. 21, 2002

(54) COMPOSITION AND METHOD COMBINING PCT/US98/09253, filed on May 6, 1998 and which is AN WITH AN NMDA a non-provisional of provisional application No. , FOR TREATING 60/045,900, filed on May 7, 1997. NEUROPATHIC PAN Publication Classification (76) Inventor: Frank S. Caruso, Colts Neck, NJ (US) Correspondence Address: (51) Int. Cl." ...... A61K 31/5513; A61K 31/496; Peter G. Dilworth, Esq. A61K 31/135 DILWORTH & BARRESE, LLP (52) U.S. Cl...... 514/220; 514/253.04; 514/649; 333 Earle Ovington Blvd. 514/657 Uniondale, NY 11553 (US) (21) Appl. No.: 09/966,975 (57) ABSTRACT (22) Filed: Sep. 28, 2001 The neuropathic pain alleviating effectiveness of an antide Related U.S. Application Data preSSant is significantly potentiated by administering the (60) Division of application No. 09/434,907, filed on Nov. antidepressant prior to, with or following the administration 5, 1999, which is a continuation of application No. of a nontoxic NMDA receptor antagonist. US 2002/0035105 A1 Mar. 21, 2002

COMPOSITION AND METHOD COMBINING AN asSociated with the NMDA receptor, e.g., the glycine-bind ANTDEPRESSANT WITH AN NMDA RECEPTOR ing site, the phenylcyclidine (PCP)-binding site, etc., as well ANTAGONIST, FOR TREATING NEUROPATHIC as the NMDA channel. Thus, the invention herein contem PAN plates the use of nontoxic substances that block an NMDA receptor binding Site, e.g., , or block the BACKGROUND OF THE INVENTION NMDA channel, e.g., a Source of magnesium Such as magnesium Sulfate. 0001. This invention relates to a composition and method for alleviating neuropathic pain. More particularly, this 0007. The term “nontoxic” as used herein shall be under invention is directed to Such a composition and method in stood in a relative Sense and is intended to designate any which an antidepressant is combined with a nontoxic substance that has been approved by the United States Food antagonist, or blocker, for the N-methyl-D-aspartate and Drug Administration (“FDA") for administration to (NMDA) receptor. humans or, in keeping with established regulatory criteria and practice, is Susceptible to approval by the FDA for 0002 Neuropathic pain is pain that is due to functional administration to humans. The term "nontoxic' is also used abnormalities of the nervous system. Fields, “Pain', herein to distinguish the NMDA receptor antagonists, or McGraw-Hill, Inc. (1987), pp. 133 et seq. There are a variety blockers, that are useful in the practice of the present of possible mechanisms by which nerve dysfunction can invention from NMDA receptor antagonists such as MK 801 cause neuropathic pain: hyperactivity in primary afferent or (the compound 5-methyl-10,11-dihydro-SH-dibenzea,d) central nervous System (CNS) nociceptive neurons, loss of cyclohepten-5,10-imine), CPP (the compound 3-2-carbox central inhibitory connections, and increased activity in ypiperazin4-yl) propyl-1-phosphonic acid) and PCP (the Sympathetic efferents. Neuropathic pain typically occurs compound 1-(1-phenylcyclohexyl)piperidine) whose toxici following injury to elements of the nervous System involved ties effectively preclude their therapeutic use. in nociception, Such as peripheral nerve injury, in which the lesions deafferent the nociceptive pathway, the resultant pain 0008. The terms “potentiate' and “potentiating” are used Sometimes being referred to deafferentation pain. Neuro herein in their art-recognized Sense, i.e., as referring to a pathic pain is much more likely to occur with peripheral than Significant increase in the level of neuropathic pain-allevi with central nervous System damage. Examples of causes of ating activity for the combination of antidepressant and painful nerve injury are: accidental trauma, tumors, cerval or nontoxic NMDA receptor antagonist compared with that lumbar Spine disease, and Surgical procedures. These inju which could have been expected based on the neuropathic ries usually involve one or two peripheral nerves or nerve pain-alleviating activities of the antidepressant and nontoxic roots, and the pain is felt in the body region normally NMDA receptor antagonist administered alone. innervated by the damaged nerves. Additionally, there are 0009. The expression “neuropathic pain-alleviating” also toxic, metabolic, and hereditary causes of painful shall be understood herein to include the expressions “neu polyneuropathies, erg., abuse, diabetes mellitus and ropathic pain-Suppressing and “neuropathic pain-inhibit toxicity due to cancer chemotherapy. These tend to be ing” as the invention is applicable to the alleviation of Symmetrical and are most Severe on the distal limbs. existing neuropathic pain as well as the Suppression or 0003 U.S. Pat. No. 5,352,683 discloses a method for the inhibition of neuropathic pain which would otherwise ensue treatment of chronic pain, inclusive of neuropathic pain, by from an imminent neuropathic pain-causing event. administration of a nontoxic N-methyl-D-aspartate receptor 0010. The expression “neuropathic pain-alleviating antagonist Such as dextromethorphan. However, there is no amount as applied to the antidepressant employed in the mention in this patent of combining a nontoxic NMDA therapeutic composition and method of this invention shall receptor antagonist with an antidepressant for the treatment be understood to mean an amount of antidepressant which of neuropathic pain. when administered by itself or in combination with the nontoxic NMDA receptor antagonist provides significant SUMMARY OF THE INVENTION neuropathic pain-alleviating activity. 0004. In accordance with the present invention, a thera peutic composition for alleviating neuropathic pain is pro DESCRIPTION OF THE PREFERRED Vided which comprises at least one antidepressant in an EMBODIMENTS amount Sufficient to alleviate neuropathic pain and at least 0011) Any of the known and conventional neuropathic one nontoxic N-methyl-D-aspartate receptor antagonist in pain-alleviating can be used herein. For an amount Sufficient to potentiate the neuropathic pain extensive listings of antidepressants, See, e.g., Goodman and alleviating activity of the antidepressant. Gilman’s “The Pharmaceutical Basis Of Therapeutics”, 8th ed., McGraw-Hill, Inc. (1990), pp. 405-414, and “Reming 0005 Further in accordance with the present invention, a ton's Pharmaceutical Sciences”, 17th ed., Mack Publishing method of alleviating neuropathic pain is provided which Company (1985), pp. 1093-1098. Specific neuropathic pain comprises coadministering to a mammal exhibiting neuro alleviating antidepressants that can be used herein include pathic pain at least one antidepressant in an amount Suffi antidepressants Such as hydrochloride, cient to alleviate neuropathic pain and at least one nontoxic imipramine pamoate, 2-chloroimipramiine, N-methyl-D-aspartate receptor antagonist in an amount Suf hydrochloride, , hydrochloride, ficient to potentiate the neuropathic pain-alleviating activity epin hydrochloride, hydrochloride, trimi of the antidepressant. pramine maleate, hydrochloride, 0006. The term “N-methyl-D-aspartate receptor” shall be hydrochloride, and the like, antidepressants Such understood to include all of the binding site Subcategories as hydrochloride, and the like; monoamine US 2002/0035105 A1 Mar. 21, 2002 oxidase (MAO) inhibitors such as phenelzine sulfate, iso nist need not be administered together, they must both be carboxazid, tranylcypromine Sulfate, and the like, present in the patient at effective levels at the same time. uptake inhibitorS Such as hydrochloride, fluox While it is within the scope of the invention to separately etine hydrochloride, hydrochloride, citalopram, administer the antidepressant and the nontoxic NMDA cis-isomeric derivative of 4-phenyl-1,2,3,4-tetrahydro-1- receptor antagonist, as a matter of convenience, it is pre naphthalenamine Such as Sertraline hydrochloride, trans ferred that these drugs be coadministered in a Single dosage isomeric derivative of 4-phenyl-1,2,3,4-tetrahydro-1-naph form. All modes of administrations are contemplated, e.g., thalenamine, aryloxy indanarnine, and the like, and, other orally, rectally, parenterally, nasally, topically or by intrave antidepressants Such as hydrochloride and ben actyzine hydrochloride. nous or intramuscular injection. 0012 Among the nontoxic substances that block the 0016 A therapeutic composition containing the antide NMDA receptor and as such are useful for potentiating the preSSant and nontoxic NMDA receptor antagonist will ordi neuropathic pain-alieviating activity of the antidepressant in narily be formulated with one or more pharmaceutically accordance with this invention are dextromethorphan ((+)- acceptable ingredients in accordance with known and estab 3-hydroxy-N-methylmorphinan), its metabolite lished practice. Thus, the composition can be formulated as ((+)-3-hydroxy-N-methylmorphinan), (1-amino a liquid, powder, elixir, injectable Solution, etc. Formula adamantine), (3.5 dimethylaminoadamantone), tions for oral use can be provided as tablets or hard capsules their mixtures and their pharmaceutically acceptable Salts. wherein the pharmacologically active ingredients are mixed Other useful nontoxic Substances that block the NMDA with an inert Solid diluent Such as calcium carbonate, receptor include pyrroloquinoline quinone, 4-hydroxy calcium phosphate or kaolin, or as Soft gelatin capsules 2(1H)-quinolone derivatives and cis-4-(phosphono-methyl)- wherein the active ingredients are mixed with an oleaginous 2-piperidinecarboxylic acid. Of the foregoing nontoxic Sub medium, e.g., liquid paraffin or olive oil. stances that block the NMDA receptor, dextromethorphan is 0017 Aqueous Suspensions can include pharmaceuti preferred due to its ready availablilty and its established use cally acceptable excipients Such as Suspending agents, e.g., in over-the-counter where it functions as a Sodium carboxymethyl cellulose, methylcellulose, hydrox cough SuppreSSant. ypropylmethylcellulose, Sodium alginate, polyvinylpyrroli 0013 The antidepressant must be present in a neuro done, gum tragacanth and gum acacia, dispersing or Wetting pathic pain-alleviating amount. Such an amount can corre agents Such as naturally occurring phosphatide, e.g., leci spond to the recommended adult human dosage level for a thin, or condensation products of an alkylene oxide with particular antidepressant when administered by itself or it fatty acids, e.g., polyoxyethylene Stearate, or condensation can be less than this amount provided that in combination products of ethylene oxide with long chain aliphatic alco with the nontoxic NMDA receptor antagonist, Significant hols, e.g., heptadecaethylene-oxycetanol, or condensation neuropathic pain-alleviating activity is achieved. The products of ethylene oxide with partial esters derived from NMDA receptor antagonist must be present at a level fatty acids and a hexitol, e.g., polyoxyethylene Sorbitol Sufficient to potentiate the neuropathic pain-alleviating monoleate or condensation products of ethylene oxide with effectiveness of the antidepressant. Specific dosage levels partial esters derived from fatty acids and hexitol anhy for the antidepressants that can be used herein are given, drides, e.g., polyoxyethylene Sorbitan monoleate. The aque interalia, in the “Physicians Desk Reference”, 1996 Edition ouS Suspensions can also contain one or more preservatives, (Medical Economics Data Production Company, Montvale, e.g., ethyl-or-n-propyl-p-hydroxy benzoate, one or more N.J.) as well as in other reference works including Goodman coloring agents, one or more flavoring agents and one or and Gilman’s “The Pharmaceutical Basis of Therapeutics” more Sweetening agents, Such as Sucrose, Saccharin or and “Remington's Pharmaceutical Sciences' both of which Sodium or calcium cyclamate. as referred to above. Given the wide variation in dosage 0018. In addition to the antidepressant and nontoxic level of the antidepressant which depends to a large extent NMDA receptor antagonist, the therapeutic composition on the Specific antidepressant being administered, there can herein can optionally contain at least one other pharmaco Similarly be a wide variation in the dosage level of the logically active Substance e.g., an antianxiety agent Such as NMDA receptor antagonist. These amounts can be deter meprobamate and , e.g., chlordiazepoxide, mined for a particular drug combination employing routine diazepam, oxazepam, cloraZepate, lorazepam, prazepam, experimental testing. For example, in the case of the tricy alprazolam, halazepam, clonazepam and the like; an antip clic antidepressant imipramine hydrochloride and the non Sychotic agent Such as , e.g., , toxic NMDA receptor blocker dextromethorphan, dosages hydrochloride, triflu hydrochlo of from about 50 to about 360 mg/day of the former ride, beSylate, hydrochloride, coadministered with from about 30 to about 120 mg/day of acetophenazine maleate, hydrochloride, the latter will usually provide acceptable results. fluphenazine enanthate, fluphenazine decanoate, trifluopera 0.014 When the nontoxic NMDA receptor antagonist Zine hydrochloride and the like; a non-narcotic analgesic Selected for use herein is dextromethorphan, dextrorphan or Such as , acetaminophen, aspirin, diclofenac, diflu Sale thereof, the antidepressant drug must be other than a Sinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbipro monoamine oxidase inhibitor Since antidepressants of this fen, ibuprofen, indomethacin, ketoprofen, ketorolac, type are contraindicated for these NMDA receptor antago meclofenamic acid, mefenamic acid, nabumetone, nists. naproxen, oxaprozin, phenylbutaZone, piroXicam, Sulindac, tolmetin, Zomepirac and the like; or a narcotic analgesic 0.015 While the neuropathic pain-alleviating antidepres Such as codeine, dihydrocodeine, hydrocodone, levorphanol, Sant and the potentiating nontoxic NMDA receptor antago morphine, oxycodone, and the like. US 2002/0035105 A1 Mar. 21, 2002

EXAMPLES 1-46 -continued 0019. The following unit dosage forms are illustrative of the neuropathic pain-alleviating therapeutic combinations in Ex- Nontoxic Active Additional accordance with the present invention: am- Dosage Antidepressant NMDA Receptor Component(s) ple Form Drug (mg) Blocker (mg) (mg) 23 ablet imipramine dextrorphan hydrochloride hydrobromide Ex- Nontoxic Active Additional (25) (30) al- Dosage Antidepressant NMDA Receptor Component(s) 24 ale dextrorphan ple Form Drug (mg) Blocker (mg) (mg) hydrochloride hydrobromide (10) (30) 1. capsule chlomipramine dextromethorphan 25 ablet imipramine amantadine (30) hydrochloride hydrobromide hydrochloride (25) (30) (25) 2 capsule chlomipramine dextromethorphan 26 ale fluoxetine amantadine (30) hydrochloride hydrobromide hydrochloride (50) (30) (20) 3 capsule imipramine CeXOleOa. 27 ablet imipramine memantine (30) pamoate (75) hydrobromide hydrochloride (30) (25) 4 capsule imipramine CeXOleOa. 28 ale fluoxetine memantine (30) pamoate (125) hydrobromide hydrochloride (30) (25) 5 tablet imipramine CeXOleOa. 29 ablet imipramine dextromethorphan acetaminophen hydrochloride hydrobromide hydrochloride hydrobromide (325) (50) (30) (25) (30) 6 intra- imipramine CeXOleOa. 3O ablet imipramine dextromethorphan aspirin (325) muscular hydrochloride hydrobromide hydrochloride hydrobromide injection (100) (30) (25) (30) 7 tablet amoxapine (50) dextromethorphan 31 ablet imipramine dextromethorphan ibuprofen (325) hydrobromide hydrochloride hydrobromide (30) (25) (30) 8 tablet desipramine CeXOleOa. 32 ale fluoxetine dextromethorphan acetaminophen hydrochloride hydrobromide hydrochloride hydrobromide (325) (100) (30) (10) (30) 9 tablet amitriptyline dextromethorphan perphenazine 33 ablet fluoxetine dextromethorphan aspirin (325) hydrochloride hydrobromide (2) hydrochloride hydrobromide (25) (30) (10) (30) O tablet amitriptyline dextromethorphan chlordiazepoxide 34 ale fluoxetine dextromethorphan ibuprofen (325) hydrochloride hydrobromide (10) hydrochloride hydrobromide (25) (30) (10) (30) 1. capsule CeXOleOa. 35 ablet imipramine dextrorphan acetaminophen hydrochloride hydrobromide hydrochloride hydrobromide (325) (25) (30) (25) (30) 2 capsule nortriptyline CeXOleOa. 36 ablet imipramine dextrorphan aspirin (325) hydrochloride hydrobromide hydrochloride hydrobromide (25) (30) (25) (30) 3 tablet amitriptyline CeXOleOa. 37 ablet imipramine amantadine (30) acetaminophen hydrochloride hydrobromide hydrochloride (325) (75) (30) (25) 4 intra- amitriptyline dextromethorphan 38 ablet fluoxetine amantadine (30) aspirin (325) muscular hydrochloride hydrobromide hydrochloride injection (20) (30) (70) 5 capsule dextromethorphan 39 ablet imipramine memantine (30) acetaminophen maleate (25) hydrobromide hydrochloride (325) (30) (25) 6 ablet fluoxetine CeXOleOa. 40 ablet imipramine memantine (30) ibuprofen (325) hydrochloride hydrobromide hydrochloride (10) (30) (25) 7 ablet sertraline CeXOleOa. 41 ablet phenelzine amantadine (30) hydrochloride hydrobromide sulfate (15) (50) (30) 42 ablet phenelzine memantine (30) 8 ablet paroxetine CeXOleOa. sulfate (15) hydrochloride hydrobromide 43 ablet isocarboxazid amantadine (30) (20) (30) (30) 9 ablet maprotiline CeXOleOa. 44 ablet isocarboxazid memantine (30) hydrochloride hydrobromide (30) (50) (30) 45 ablet tranylcypro- amantadine (30) 2O ale razodone CeXOleOa. mine sulfate hydrochloride hydrobromide (30) (50) (30) 46 ablet tranylcypro- memantine (30) 21 ablet bupropion CeXOleOa. mine sulfate hydrochloride hydrobromide (30) (100) (30) 22 ablet dextromethorphan meprobamate hydrochloride hydrobromide (400) (1) (30) 0020. In each of these dosage units, the nontoxic NMDA receptor antagonist dextromethorphan hydrobromide Sig US 2002/0035105 A1 Mar. 21, 2002 nificantly potentiates the neuropathic pain-alleviating activ 12. The therapeutic composition of claim 8 wherein the ity of the antidepressant component(s). narcotic analgesic is Selected from the group consisting of What is claimed is: codeine, dihydrocodeine, hydrocodone, levorphanol, mor 1. A therapeutic composition comprising at least one phine, and oxycodone. antidepressant, in an amount Sufficient to alleviate neuro 13. The therapeutic composition of claim 1 wherein the pathic pain and at least one nontoxic N-methyl-D-aspartate nontoxic NMDA receptor blocker is at least one member receptor antagonist in an amount Sufficient to potentiate the Selected from the group consisting of dextromethorphan, neuropathic pain-alleviating activity of the antidepressant. dextrorphan, amantadine, memantine and pharmaceutically 2. The therapeutic composition of claim 1 wherein the acceptable Salt thereof, except that in the case of dextrorphan antidepressant is at least one member Selected from the or Salt thereof, the antidepressant is other than of the group consisting of tricyclic antidepressants, tetracyclic monoamine oxidase inhibitor type. antidepressants, monoamine oxidase inhibitors, Serotonin uptake inhibitors, bupropion hydrochloride and benactyzine 14. A method of alleviating neuropathic pain which com hydrochloride. prises administering to a mammal exhibiting neuropathic 3. The therapeutic composition of claim 2 wherein the pain at least one antidepressant in an amount Sufficient to is Selected from the group consisting alleviate neuropathic pain and at least one nontoxic N-me of imipramine hydrochloride, uinipramine pamoate, 2-chlor thyl-D-aspartate receptor antagonist in an amount Sufficient oimipramine, amitriptyline hydrochloride, amoxapine, to potentiate the neuropathic pain-alleviating activity of the desipramine hydrochloride, doxepin hydrochloride, protrip antidepressant. tyline hydrochloride, trimipramine maleate, nortriptyline 15. The method of claim 14 wherein the antidepressant is hydrochloride and clomipramine hydrochloride. at least one member Selected from the group consisting of 4. The therapeutic composition of claim 2 wherein the tricyclic antidepressants, tetracyclic antidepressants, tetracyclic antidepressant is maprotiline hydrochloride. monoamine oxidase inhibitors, Serotonin uptake inhibitors, 5. The therapeutic composition of claim 2 wherein the bupropion hydrochloride and benactyzine hydrochloride. monoamine oxidase inhibitor is Selected from the group 16. The method of claim 15 wherein the tricyclic antide consisting of phenelZine Sulfate, isocarboxazid and tranyl preSSant is Selected from the group consisting of imipramine cypromine Sulfate. hydrochloride, imipramine pamoate, 2-chloroimipramine, 6. The therapeutic composition of claim 2 wherein the amitriptyline hydrochloride, amoxapine, desipramine Serotonin uptake inhibitor is Selected from the group con hydrochloride, doxepin hydrochloride, protriptyline hydro sisting of paroxetine hydrochloride, fluoxetine hydrochlo chloride, trimipramine maleate, nortriptyline hydrochloride ride, traZOdone hydrochloride, citalopram, cis-isomeric and clomipramine hydrochloride. derivative of 4-phenyl-1,2,3,4-tetrahydro-1-naphthalena 17. The method of claim 15 wherein the tetracyclic mine, trans-isomeric derivative of 4-phenyl-1,2,3,4-tetrahy antidepressant is maprotiline hydrochloride. dro-1-naphthalenamine and aryloxy indananline. 7. The therapeutic composition of claim 1 containing a 18. The method of claim 15 wherein the monoamine therapeutically effective amount of at least one other phar oxidase inhibitor is Selected from the group consisting of macologically active Substance. phenelZine Sulfate, isocarboxazid and tranylcypromine Sul 8. The therapeutic composition of claim 7 wherein the fate. other pharmacologically active Substance is Selected from 19. The method of claim 15 wherein the serotonin uptake the group consisting of antianxiety agents, inhibitor is Selected from the group consisting of paroxetine agents, non-narcotic analgesics and narcotic analgesics. hydrochloride, fluoxetine hydrochloride, trazodone hydro 9. The therapeutic composition of claim 8 wherein the chloride, citalopram, cis-isomeric derivative of 4-phenyl-1, antianxiety agent is Selected from the group consisting of 2,3,4-tetrahydro-1-naphthalenamine trans-isomeric deriva meprobamate and chlordiazepoxide. tive of 4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine, and 10. The therapeutic composition of claim 8 wherein the aryloxy indanamine. antipsychotic agent is perphenazine. 20. The method of claim 14 wherein the nontoxic NMDA 11. The therapeutic composition of claim 8 wherein the receptor blocker is at least one member Selected from the non-narcotic analgesic is Selected from the group consisting group consisting of dextromethorphan, dextrorphan, aman of tramadol, acetaminophen, aspirin, diclofenac, difluSinal, tadine, memantine and pharmaceutically acceptable Salt etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibu thereof, except that in the case of dextromethorphan, dex profen, indomethacin, ketoprofen, ketorolac, meclofenamic trorphan or Salt thereof, the antidepressant is other than of acid, mefenamic acid, nabumetone, naproxen, Oxaprozin, the monoamine oxidase inhibitor type. phenylbutaZone, piroXicam, Sulindac, tolmetin and Zomepi C.