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IIIUS00532102A United States Patent (19) 11 Patent Number: 5,321,012 Mayer et al. 45) Date of Patent: Jun. 14, 1994

(54) INHIBITING THE DEVELOPMENT OF 4,924,008 5/1990 Abou-Gharbia et al...... 54/812 TOLERANCE TO AND/OR DEPENDENCE 4,937,232 6/1990 Bell et al...... 514/26 ON ANARCOTC AODCTIVE SUBSTANCE 4,942,182 7/1990 Weiss et al...... 54/812 4,959,493 9/1990 Ohfume et al...... 562/506 75) Inventors: David J. Mayer; Donald D. Price; 4,975,430 12/1990 Jahr et al...... 54/255 Jianren Mao, all of Richmond, Va.; 4,990,519 2/1991 Jones et al...... 5.4/314 John W. Lyle, Belnar, N.J. 4,994,446 2/1991 Sokolovsky et al...... 514/75 s 4,994,467 2/1991 Zimmerman ...... 514/284 73) Assignee: Virginia Commonwealth University 4,996,047 2/1991 Kelleher et al. ... 424/79 Medical College, Richmond, Va. 5,013,540 5/1991 Redburn ...... 424/10 5,028,611 7/1991 Halikas ...... 514/277 (21) Appl. No.: 43,280 5,028,707 7/1991 Nichols et al...... 54.6/156 5,034,395 7/1991 Tamada et al...... 514/277 (22 Filed: Apr. 6, 1993 5,034,400 7/199 Olney ...... 514/315 5,041,446 8/1991 Silvestrini ...... 514/255 Related U.S. Application Data 5,047,229 9/1991 Nahas et al...... 424/0 63 Continuation-in-part of Ser. No. 10,583, Jan. 28, 1993, (List continued on next page.) abandoned. OTHER PUBLICATIONS 51 Int. Cl...... A61K 31/70; A61K 31/55; o a- a A61K 31/54; A61K 31/44 Koyunchoglu et al., International Journal of Clinical 52 U.S. Cl...... 514/25; 514/216; , Therapy and Toxicology, vol. 28, No. 4 514/223.5; 514/225.5; 514/224.5; 514/282; 1990 (147-152), The treatment of addicts with 514/231.2; 514/289; 514/812; 536/53; 536/55.1 : A double-bine comparison of dex 58 Field of Search...... 31/25,282.812,2235, tromethorphan with . 514/225.5, 224.5, 216,536/53, 55.1 Marek et al. Abstract No. 92034071, Brain-Res., Aug. (56) References Cited 30, 1991 558(1), pp. 163-165. U.S. PATENT DOCUMENTS (List continued on next page.) 2,770,569 11/1956 Fromherz et al...... A Primary Examiner-Frederick E. Waddell 4,126,684 11/1978 Robson et al...... 424/254 Assistant Examiner-T. J. Criares 4,316,888 2/1982 Nelson ...... 424/27 Att Agent Fi w w Dilworth & Barrese 4,362,870 12/1982 Portoghese ...... 542/403 orney, Agent, or firm-Lullw 4,46,871 1/1983 Walter et al. . ... 424/177 (57 ABSTRACT 4,446,140 5/1984 Nelson ...... 424/260 4,464,378 8/1984 Hussain .. ... 424/260 Nontoxic substances that block the N-methyl-D-aspar 4,476,141 10/1984 Cormier ..... r 424/32 tate (NMDA) , e.g., a such as dex 4,758,559 7/1988 Wasley et al. . ... 514/21 tromethorphan or , or that block a major 4,788,055 1 1/1988 Fischer et al...... 424/79 intracellular consequence of NMDA receptor activa 4,806,543 2/1989 Choi...... 54/464 4,816,264 5/1989 Phillips et al. ... 424/468 tion, e.g., a ganglioside such as GM 1 or GT1b, a pheno 4,816,450 3/1989 Bell et al...... 514/25 thiazine such as or a naphthalenesulfona 4,828,836 5/1989 Elger et al...... 424/464 mide such as N-(6-aminohexyl)-5-chloro-1-naph 4,834,965 5/1989 Martani et al...... 424/488 thalenesulfonamide, inhibit the development of toler 4,834,985 5/1989 Eiger et al...... 424/488 ance to and/or dependence on addictive drugs, e.g., 4,888,347 12/1989 Woodruff et al. ... 514/289 such as , , etc. 4,906,779 5/1990 Weber et al...... 564/238 4,912,114 3/1990 Revesz ...... 514/282 4,919,916 4/1990 Golwyn ...... 424/10 9 Claims, 10 Drawing Sheets 5,321,012 Page 2

U.S. PATENT DOCUMENTS 5,137,919 8/1992 Igarashi et al...... 564/642 5,051,426 9/1991 Parnell ...... 54/263 E. SE Era. m is 5,051,442 9/1991 Salituro et al. ... 514/419 5,151,360s 9/1992 Handa et al...... 435/240.2 5,057,519 10/1991 Suberg ...... 514/282 5,171,752 12/1992 Caldirola- et al...... 514/648

5,071,646 12/1991 Malkowska et al. . ... 424/497 5, 183,807 2/1993 della Valle et al. 514/25 5,075,341 12/1991 Mendelson et al...... 514/282 5,y 185,329a was 2/1993 Gawin et al...... - - 514/159 5,091,391 2/1992 Aizenman et al...... 514/31 5, 190,925 3/1993 della Valle et al...... 514/25 5,093,129 3/1992 Horivitz et al...... 424/451 a W. 5,093,525 3/1992 Weber et al...... 564/238 5,095,009 3/1992 Whitten et al...... 514/85 OTHER PUBLICATIONS 5,109,0175,106,847 4/1992 SchmesingSalituro et al.et al...... 549/77(::: Marek et al. Abstract No. 91316632, Brain-Res., Apr. 5,118,675 6/1992. Jirkovsky et al...... 514/80 26, 1991 547(1), pp. 77-81. 5,124,319 6/1992 Baudy et al...... is Tanganelliet al. Abstract No.91226742, Neurosci-Lett, 5,124,340 6/1992 Jaffe et al...... 514/279 Jan. 28, 1991 122(2), pp. 270-272, 5,133,974 7/1992 Paradissis et al. . 424/480 Trujillo et al. Abstract No. 91095981, Science, Jan. 4, 5,137,889 8/1992 Tamada et al...... 514/252 1991 251(4989), pp. 85-87. U.S. Patent June 14, 1994 Sheet 1 of 10 5,321,012

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MAXIMAL POSSIBLE EFFECT (%) 5,321,012 1 2 or blocker, in reducing morphine dependence in labora NHIBITING THE DEVELOPMENT OF tory animals. However, MK-801 has been found to be TOLERANCE TO AND/OR DEPENDENCE ON A toxic and is therefore unsuitable for pharmaceutical use. NARCOTIC ADDCIVE SUBSTANCE SUMMARY OF THE INVENTION CROSS REFERENCE TO RELATED In accordance with the present invention, a composi APPLICATION tion is provided which comprises an addictive substance This application is a continuation-in-part of copend and at least one nontoxic substance that blocks the N ing U.S. patent application Ser. No. 08/010,583, filed methyl-D-aspartate receptor or at least one major intra Jan. 28, 1993, now abandoned. 10 cellular consequence of N-methyl-D-aspartate receptor activation. BACKGROUND OF THE INVENTION Further in accordance with the present invention, a This invention relates to a composition containing an method of inhibiting the development of tolerance to addictive substance and a component which inhibits the and/or dependence on an addictive substance adminis development of tolerance to and/or dependence on the 15 tered to a mammal which is liable to addiction thereto is addictive substance. More particularly, the invention provided which comprises administering the addictive relates to a composition containing an addictive sub substance to the mammal before, with or following stance such as morphine or codeine and at least one nontoxic substance that blocks the N-methyl-D-aspar administration to the mammal of a tolerance-reducing tate (NMDA) receptor, e.g., a morphinan such as dex 20 and/or dependence-reducing amount of at least one tromethorphan or dextrorphan, or that blocks at least nontoxic substance that blocks the N-methyl-D-aspar one major intracellular consequence of NMDA recep tate receptor or at least one major intracellular conse tor activation, e.g., a ganglioside such as ganglioside quence of N-methyl-D-aspartate receptor activation. GM1 or GT1b, a such as trifluoperazine Still further in accordance with this invention, a or a naphthalenesulfonamide such as N-(6-aminohexyl)- 25 method of alleviating withdrawal symptoms in a man 5-chloro-1-naphthalenesulfonamide. mal addicted to an addictive substance is provided Morphine is a rapid and effective drug for the treat which comprises administering to the addicted mammal Inent of severe pain but its long term administration has the addictive substance before, with or following ad been limited due to its negative side effects, principally ministration to the mammal of a dependence-reducing tolerance and dependence, which develop rapidly after 30 amount of at least one nontoxic substance that blocks administration. In an effort to make morphine of greater the N-methyl-D-aspartate receptor or the intracellular use in the treatment of pain, it has been combined with consequences of N-methyl-D-aspartate receptor activa a variety of substances intended to inhibit one or more tion thereby alleviating withdrawal symptoms when the of its undesirable side effects. U.S. Pat. No. 2,770,569 addictive substance is withdrawn from the mammal. describes the combination of morphine with the com 35 The term "nontoxic' as used herein shall be under pound levo-d-hydroxy-N-allyl-morphinan which is said stood in a relative sense and is intended to designate any to suppress or eliminate such undesirable side reactions substance that has been approved by the United States of morphine as depression, nausea and vomiting. U.S. Food and Drug Administration ("FDA") for adminis Pat. No. 4,126,684 discloses reducing either the addic tration to humans or, in keeping with established crite tion liability of an addictive substance such as a narcotic ria, is susceptible to approval by the FDA for adminis or a or the withdrawal symptoms tration to humans. caused by deprivation of such a substance in an addicted Subject by administering the addictive substance, e.g., BRIEF DESCRIPTION OF THE DRAWINGS: morphine, with a 4-amino-3-p-halophenylbutyric acid. FIGS. 1-10 are graphical representations of experi U.S. Pat. No. 4,415,871 describes the prevention of 45 mental data demonstrating the effectiveness of specific treatment tolerance and physical dependence in chronic nontoxic substances that block the N-methyl-D-aspar morphine treatment by combining the morphine with tate receptor or a major consequence of N-methyl-D- any of the specific dipeptides indicated therein. U.S. Pat. No. 5,041,446 discloses inhibiting the development aspartate receptor activation for inhibiting morphine of tolerance to morphine by combining the morphine SO tolerance and dependence in rats. with dapiprazole. U.S. Pat. No. 5,057,519 achieves a FIG. 1 shows the effects of systemic doses of dextror reduction in morphine tolerance by combining the nor phan (DEX) in inhibiting the development of tolerance phine with a benzamide antagonist for a subtype of the to morphine analgesia in rats; serotonin receptor, 5-HT3. Trujillo et al., "Inhibition of FIG. 2 shows the effects of systemic doses of dextror morphine tolerance and dependence by the NMDA 55 phan on jumping, a withdrawal symptom produced by MK-301’, Science, 251 (4989), pp. subcutaneous in rats previously injected with 85-87, Jan. 4, 1991; Tanganelli et al., “Glutamate antag morphine; onists prevent morphine withdrawal in mice and guinea FIG.3 shows the effect of ganglioside GM in inhibit pigs', Neuroscience Letters, 122(2), pp. 270-272, Jan. 28, ing the development of morphine tolerance in rats; 1991; Marek et al., "Excitatory amino acid antagonists FIG. 4 shows the effects of systemic doses of ganglio ( and MK-801) attenuate the develop side GM 1 on jumping rats; ment of morphine tolerance in the rat', Brain Research, FIG. 5 shows the effects of intrathecal doses of gan 547(1), pp. 77-81, Apr. 26, 1991; and, Marek et al., “De glioside GM on inhibiting the development of toler layed application of MK-801 attenuates development of ance to morphine analgesia in rats; morphine tolerance in rats, Brain Research, 558(1), pp. 65 FIG. 6 shows the effects of ganglioside GM in inhib 163-165, Aug. 30, 1991 discuss the role of MK-801 (the iting the development of morphine tolerance to a de compound 5-methyl-10,11-dihydro-SH-dibenzoa,d)cy gree which is equivalent to that of the neurologically clohepten-5,10-innine), an NMDA receptor antagonist toxic NMDA receptor antagonist MK-801; 5,322,012 3 4. FIG. 7 and 8 show the effects of the calmodulin an By way of inhibiting the development of tolerance to tagonist trifluoperazine (TFP) in inhibiting the develop and/or dependence on any of the foregoing and simi ment of morphine tolerance in rats; and, larly addictive substances, the addictive substance is FIGS. 9 and 10 show the effects of the calmodulin administered before, with or following the administra antagonist N-(6-aminohexyl)-5-chloro-1-naphthalene tion of at least one nontoxic substance that blocks the sulfonamide hydrochloride (W-7) in inhibiting the de N-methyl-D-aspartate (NMDA) receptor or the intra velopment of morphine tolerance in rats. cellular consequences of N-methyl-D-aspartate recep tor activation. Activation of the NMDA receptor, a DESCRIPTION OF THE PREFERRED subtype of excitatory amino acid receptors, induces a EMBODIMENTS 10 number of changes in the functional activity of nerve A particularly important category of addictive sub cells, and in particular, their capacity for excitability or stances with which the present invention is concerned inhibition in the presence of an addictive substance, via are the narcotic analgesics, e.g., , deriva an increase in intracellular Ca++ concentration. The tives, and their pharmaceutically acceptable major consequences of NMDA receptor activation salts. Specific examples of narcotic analgesics include 5 include the following sequences, or cascades, of events alfentanyl, alphaprodine, , , co occurring within nerve cells: deine, , , , a) translocation and activation of protein kinases such , heroin, , , isome as protein kinase C-- phosphorylation of substrate pro thadone, , , , teins such as cytosolic enzymes, channel proteins, re 20 ceptor proteins, etc.--changes in functional activity; , , morphine, extracts, opium b) initiation of early gene (c-fos, c-jun, zif-268, etc.) fluid extracts, powdered opium, granulated opium, raw expression by either increased intracellular Ca-|--|- or opium, tincture of opium, , , Ca++-activated protein kinases-expression of func , , , racemethorphan, tional genes responsible for production of cellular en , and pharmaceutically accept 25 zymes (such as protein kinases), receptor proteins (such able salts thereof. For a detailed discussion of these and as the NMDA receptor), ion channel proteins (such as other narcotic analgesics, reference may be made to K--, Na+, Ca++ channels), neuropeptides (such as Jaffe et al., " Analgesics and Antagonists' in ), etc.--changes in functional activity; "Goodman and Gillman's Pharmacological Basis of c) Ca+ +/calmodulin (or other Ca-|--|- binding pro Therapeutics', Goodman et al., eds. 7th ed., 1985, Mac 30 teins) induced activation of enzymes and other cellular Millan and Company, New York pp. 491-531. components-activation of Ca+ +/calmodulin-protein Other addictive substances that can be utilized herein kinase systems such as Ca+ +/calmodulin kinase include , , acetylme H--autophosphorylation of enzymes (e.g., Ca----/cal thadol, , , alphamepro modulin kinase II) or other functional proteins-- dine, , , , 35 changes in functional activity; , betameprodine, , beta d) Ca+ --/calmodulin induced activation of constitu , , , codeine methylbromide, tive synthase as well as induction of induc codeine-N-oxide, , , dex ible nitric oxide synthase-production of nitric oxide tromoramide, , , dihy i) production of cyclic guanosine monophosphate via dromorphine, , , dimethyl 40 activation of guanosine cyclase resulting in activation of thiamubutene, , , protein kinases and early gene expression; ii) direct , ethanol, , etonita protein modification such as enzymes, receptor and/or Zene, , , , hydromor channel proteins; iii) lipid membrane modification and phinol, , , levomora /or nucleic acid modification via scavenge of free radi mide, , , me 45 cals; iv) induction of neurotoxicity at higher nitric oxide thyldihydromorphine, , morphine methyl levels; v) retrograde actions in adjacent neurons or glial promide, morphine methylsulfonate, morphine-N- cells such as facilitation of glutamate release/NMDA oxide, myrophin, , , , receptor activation and/or inhibition of post-synaptic , , , nor NMDA receptors-- changes in functional activity; morphine, , , phenampro SO e) interactions with the cyclic adenosine monophos mide, , , , phol phate/protein kinase A system, the phospholipase C codine, proheptazoine, , propiran, inositol triphosphate-Ca++/diacylglycerol-protein , , and the phar kinase system, the phospholipase A2-/. maceutically acceptable salts thereof. prostanoids/leukotrienes system-changes in functional Still other addictive substances that can be utilized in 55 activity induced by second messenger systems other the practice of the invention include the sedatives and than NMDA receptor/Ca++/Cat-calmodulin/protein hypnotics, e.g., such as chlordiazepox kinase systems; and, ide, clorazepate, , , halazepam, f) interactions with other excitatory amino acid re ketazolan, borazepam, oxazepam, prazepam, temaze ceptor subtypes including non-NMDA receptors and pam, triazolam and the pharmaceutically acceptable 60 metabotropic receptors as well as intracellular events salts thereof, such as amobarbital, ambobar subsequent to the activation of these excitatory amino bital, barbital, butabartital, mephobarbital, methohexi acid receptor subtypes--changes in functional activity tal, , , secobarbital, talbutal, induced by the non-NMDA and metabotropic receptor thiannylal and thiopental and the pharmaceutically ac activation. ceptable salts thereof and other sedatives and hypnotics 65 A substance that blocks the NMDA receptor will Such as , , methaqualone, effectively prevent all of the foregoing major intracellu Inethyprylon and the pharmaceutically acceptable salts lar sequences of events from taking place. However, thereof. even with activation of the NMDA receptor, it is still 5,321,012 5 6 possible to inhibit the development of tolerance to and consequence of NMDA receptor activation or the two vor dependence on an addictive substance by combin substances can be administered separately provided ing the addictive substance with a substance that blocks both are ultimately present in effective amounts in the at least one of the foregoing major intracellular sequen patient. Introduction of the composition into the patient ces of events. Thus, e.g., a substance that interferes with can be by way of oral administration or by intravenous, translocation and activation of protein kinase C or with intramuscular, subcutanous, intrathecal, epidural or calmodulin induced activation of constitutive nitric intracerebroventrilcular injection. oxide synthase as well as induction of inducible nitric The preferred dosage of addictive substance and the oxide synthase is also useful for the practice of this nontoxic substance that blocks the NMDA receptor or invention. O a major intracellular consequence of NMDA receptor Among the nontoxic substances that block the activation can vary widely, e.g., from about 0.25 to NMDA receptor and as such are useful in the practice about 250 mg/day, but actual amounts will vary accord of the present invention are such as dextro ing to the particular active substances being used, the ((+)-3-hydroxy-N-methylmorphinan) and particular formulation containing the active substances dextrorphan ((+)-3-hydroxy-N-methylmorphinan), 15 and the state and circumstances of the host being their mixtures and the pharmaceutically acceptable salts treated. As those skilled in the art recognize, many thereof. Other useful nontoxic substances that block the factors that modify the action of the active substances NMDA receptor include (2-(2-chlorophenyl)- herein will be taken into account by the treating physi 2-(methylamino)cyclohexanone), pyrroloquinoline qui cian such as the age, body weight, sex, diet and condi none and cis-4-(phosphonomethyl)-2piperidinecarboxy 20 tion of the subject, the time of administration, the rate lic acid. and route of administration, and so forth. Optimal dos Nontoxic substances that block a major intracellular ages for a given set of conditions can be ascertained by consequence of NMDA receptor activation and are those skilled in the art using conventional dosage deter therefore useful in the practice of the invention include mination tests in view of the experimental data provided inhibitors of protein kinase C such as the gangliosides, 25 herein. in particular, ganglioside GM (monosialoganglioside) In alleviating withdrawal symptoms in addicted sub and ganglioside GT1b (trisialoganglioside); amphipathic jects deprived of the addictive substance, the substance long chain bases such as sphingosine, N,N,N-trime that blocks the NMDA receptor or a major intracellular thylsphingosine, sphinganine and psychosine; quinoly consequence of NMDA receptor activation can be ad loxazole-2-ones such as 4-methyl-5-(3-quinolinyl)-2- 30 ministered to the subject, together with the addictive (3H)-oxazolone and phenyl-5-(2-quinolinyl)-2-3(3H)- substance, at a dosage rate of about 0.25 to about 250 oxazolone; 1,4-bis-(amino-hydroxyalkylamino)an mg/day, again, specific dosage levels and routes of thraquinones such as 1,4-bis-(3-propylamino-2-hydrox administration being selected in accordance with the ypropylamino)-9,10 anthracenedione and 1,4-bis-(3-ben subject's circumstances. As a result of this treatment, zylamino-2-hydroxypropylamino)-9,10 anthracened 35 the subject will experience a reduced level of depen ione; and, mixtures and pharmaceutically acceptable dence on the addictive substance eventually reaching salts of any of the foregoing. the point where total withdrawal of the substance will Additional nontoxic substances that block a major result in at most mild withdrawal symptoms. intracellular consequence of NMDA receptor activa The composition herein can be formulated as a liquid, tion and as such are useful in the practice of the inven powder, elixir, injectable solution, etc. Formulations for tion include inhibitors of calmodulin such as the pheno oral use can be provided as hard gelatin capsules thiazines, in particular, chlorpromazine, chlorproma wherein the composition is mixed with an inert solid zine sulfoxide, prochlorperazine dimaleate, perphena diluent such as calcium carbonate, calcium phosphate zine, trifluoperazine, , fluphenazine enanth or kaolin, or as soft gelatin capsules wherein the compo ate, fluphenazine decanoate, , mesoridazine 45 sition is mixed with an oleaginous medium, e.g., liquid besylate, piperacetazine, dinaleate, car paraffin or olive oil. phenazine dinaleate, dimaleate and phe Aqueous suspensions can contain the composition in nothiazine sulfoxide; naphthalenesulfonamides such as admixture with pharmaceutically acceptable excipients N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, such as suspending agents, e.g., sodium carboxymethyl N-(6-aminohexyl)-5-chloro-2-naphthalenesulfonamide 50 cellulose, methylcellulose, hydroxypropylmethylcel and N-(6-aminohexyl)-5-bromo-2-naphthalenesulfona lulose, sodium alginate, polyvinylpyrrolidone, gun mide, 4-substituted-4H,6H-pyrrolo1,2-a)4,1) benzox tragacanth and gum acacia; dispersing or wetting agents azepines such as 1,3-dihydro-1-(1-(4-methyl-4-H,6H such as naturally occurring phosphatide, e.g., , pyrrolol,2-a4, 1) benzoxazepin-4-yl)methyl)-4- or condensation products of an alkylene oxide with piperidinyl)-2H-benzimidazol-2-one; benzhydryls such 55 fatty acids, e.g., polyoxyethylene stearate, or condensa as N-2(diphenylmethylthioehtyl)-2-(trifluoromethyl)- tion products of ethylene oxide with long chain ali benzeneethanamine, N-(2-(bis(4-fluorophenyl)methyl phatic , e.g., heptadecaethyleneoxycetanol, or thio)ethyl-2-(trifluoromethyl)benzeneethanamine and condensation products of ethylene exide with partial N-2-(bis(4-fluorophenyl)methylthio)ethyl)-3-(tri esters derived from fatty acids and a hexitol, e.g., poly fluoromethyl)benzeneethanamine; tricyclic antidepres oxyethylene sorbitol monoleate or condensation prod sant drugs such as , 2-chloroimipramine and ucts of ethylene oxide with partial esters derived from ; ; ; pinozide; cloza fatty acids and hexitol anhydrides, e.g., polyoxyethyl pine; calmidazolin; and, mixtures and pharmaceutically ene sorbitan monooleate. Such aqueous suspensions can acceptable salts of any of the foregoing. also contain one or more preservatives, e.g., ethyl- or Administration of the composition of this invention 65 n-propyl-p-hydroxy benzoate, one or more coloring can be in the form of a single dosage unit containing agents, one or more flavoring agents and one or more both the addictive substance and the nontoxic substance sweetening agents, such as sucrose, saccharin or sodium that blocks the NMDA receptor or a major intracellular or calcium cyclamate. 5,321,012 7 8 Dispersible powders and granules suitable for prepa (MOR--SAL). Vertical bars refer to the range of the ration of an aqueous suspension by the addition of water numbers of jumps. Thus, 3.13 and 6.25 mg/kg dextror provide the composition in admixture with a dispersing phan (but not 1.56 mg/kg) significantly reduced the or wetting agent, suspending agent and one or more incidence of jumping in morphine tolerant rats, a behav preservatives. Suitable dispersing or wetting agents and 5 ioral manifestation of morphine dependence, brought suspending agents are exemplified by those already about following subcutaneous injection with 2 mg/kg mentioned above. Additional excipients, e.g., sweeten naloxone. Thus, coadministration of dextrorphan with ing, flavoring and coloring agents, can also be present. morphine greatly inhibits the development of both tol Syrups and elixirs can be formulated with sweetening erance to and dependence on morphine while the anal agents, for example glycerol, sorbitol or sucrose. Such O gesic effect of the morphine remains substantially unaf formulations can also contain a demulcent, a preserva fected. tive and flavoring and coloring agents. The composition of this invention or either of its EXAMPLE 2 principal active ingredients can be provided in sustained The effects of ganglioside GM in inhibiting mor release dosage form of which many kinds are known, 15 phine tolerance and dependence utilizing both systemic e.g., as described in U.S. Pat. Nos. 4,788,055; 4,816,264; and intrathecal treatment were evaluated. The systemic 4,828,836; 4,834,965; 4,834,985; 4,996,047; 5,071,646; treatment procedure, including both morphine and gan and, 5,133,974, the contents of which are incorporated glioside GM 1 administration, was exactly the same as by reference herein. that used in the experimental work presented in Exam The examples that follow are illustrative of the inven 20 ple 1 except that ganglioside GM1 was given 1 hour tion. before each morphine administration. As shown in FIG. 3, the tail flick latency in ganglio EXAMPLE side GM -treated (10, 30, 60 mg/kg, n = 6/group) rats The effect of systemic dextrorphan on prevention of remained significantly longer than that of saline-treated the development of morphine tolerance and depen 25 rats on days 5, 7, 9 and 10 of repeated morphine admin dence was examined in Sprague-Dawley rats weighing istration, indicating the prevention of the development 350-400gm. Morphine tolerance was developed in the of morphine tolerance by ganglioside GM1. Although rats by twice daily subcutaneous injection of 10 mg/kg all 3 doses of ganglioside GM were effective, 30 and 60 morphine sulfate. The analgesic effect of the morphine mg/kg were more effective at days 9 and 10 than 10 was examined by using the well known tail-flick test 30 Ing/kg. which measures the latency of tail-flick upon radiant FIG. 4 shows the effects of systemic doses of ganglio heat stimulation. The latency of tail-flick test is defined side GM 1 on jumping, a withdrawal symptom produced as the time elapsed from the onset of radiant heat to the by subcutaneous naloxone (2 mg/kg) in rats previously flick of the rat's tail. In order to examine the effect of injected with morphine (10 mg/kg) twice daily for 9 dextrorphan on the development of morphine toler 35 days. Asterisks indicate median number of jumps in ance, each morphine-treated rat also received intraperi GM treatment groups (M--G) that were significantly toneal administration of either dextrorphan (1.56, 3.13, less than that of the control group (MOR--SAL). Ver 6.25, 12.5 mg/kg, n=5/group) or saline (n = 6) given 30 tical bars refer to the range of the numbers of jumps. All minutes prior to each morphine administration. three doses 10 mg/kg (10); 30 mg/kg (30); 60 mg/kg FIG. 1 shows the effects of systemic doses of dextror 40 (60) of GM were effective with 60 mg/kg GM 1 being phan (DEX) on tolerance to morphine analgesia pro the most effective dose tested. duced by twice daily subcutaneous administration of 10 ng/kg morphine. Each symbol represents mean tail EXAMPLE 3 flick latency scores (those above 4.5 seconds reflect This example demonstrates the effectiveness of gan analgesia) for each group of rats (N=5-6) and vertical 45 glioside GM1 in preventing the development of mor bars are standard errors in this and the other figures. phine tolerance at the site of the spinal cord. Morphine Baseline scores were between 4 and 5 seconds (at Day sulfate 10 ug was delivered once daily through an intra O) and post-drug scores measured 1 hour after drug thecal (spinal) canula implanted 5 days before the first administration were close to 10 seconds for the first 5 morphine injection. Ganglioside GM or saline also was days of daily drug administration. The control group 50 delivered intrathecally 30 minutes before each nor (open triangles) show marked reduction in response to phine injection. morphine (i.e., tolerance) at 7 and 9 days. In contrast, FIG. 5 shows the effects of the intrathecal doses of dextrorphan potently prevented the development of ganglioside GM 1 on tolerance to morphine analgesia morphine tolerance as shown by no significant de produced by once daily intrathecal administration of 10 creases in tail flick latencies, i.e., remaining analgesic 55 ug morphine. Intrathecal ganglioside GM was given 30 during the whole course of repeated morphine adminis min before each morphine administration. Each symbol tration. Asterisks indicate mean scores that were signifi represents mean scores for maximal possible effects (and cantly different from those of the control group. All hence analgesia) for each group of rats (n = 5-6) nea tested doses of dextrorphan were effective in prevent sured at 15, 30, 60, 90, 120, 180, and 240 minutes after ing development of morphine tolerance with optimal 60 morphine injection on Day 8, i.e., 24 hours following 6 doses ranging from 3.13 mg/kg to 12.5 mg/kg. consecutive daily intrathecal morphine injections. Ver FIG. 2 shows the effects of systemic doses of dextror tical bars are standard errors. Maximal possible effects phan on jumping, a withdrawal symptom produced by (MPE) were calculated by the formula % subcutaneous naloxone (2 mg/kg) in rats previously MPE=(TL-BL)/(10.- BL)x 100. TL: actual tail injected with morphine (10 mg/kg) twice daily for 9 65 flick latency; BL: baseline latency obtained before the days. Asterisks indicate median number of jumps in first morphine injection; 10: cut-off time for radiant heat dextrorphan treatment groups (MOR. --DEX) that were stimulation. The control group (open circle) showed significantly less than that of the control group marked reduction in response to inorphine (i.e., toler 5,321,012 9 10 ance) at each tested time point. In contrast, treatment phan, trifluoperazine, N-(6-aminohexyl)-5-chloro-1- with ganglioside GM effectively prevented the devel naphthalene sulfonamide, their mixtures and their phar opment of morphine tolerance as indicated by signifi maceutically acceptable salts. cantly higher maximal possible analgesia effects of mor 2. The composition of claim 1 wherein the narcotic phine (160 nmolis 80=40 nmol) as compared to those of 5 analgesic is selected from the group consisting of alfen saline-treated rats. Asterisks indicate mean scores that tanyl, alphaprodine, anileridine, bezitramide, codeine, were significantly different from those of other groups. dihydrocodeine, diphenoxylate, ethylmorphine, fenta nyl, heroin, hydrocodone, hydromorphone, isometha EXAMPLE 4 done, levomethorphan, levorphanol, metazocine, meth The effects of ganglioside GM and the toxic NMDA O adone, metopon, morphine, opium extracts, opium fluid receptor antagonist MK 801 on morphine tolerance extracts, powdered opium, granulated opium, raw were evaluated. opium, tincture of opium, oxycodone, oxymorphone, As shown in FIG. 6, treatment with ganglioside pethidine, phenazocine, piminodine, racemethorphan, GM1 (60 mg/kg) inhibited the development of mor racemorphan, thebaine, their mixtures and their phar phine tolerance to the degree equivalent to that induced 15 maceutically acceptable salts thereof. by 0.3 mg/kg MK 801. However, 50% (3 out of 6) of 3. The composition of claim 1 in sustained release the rats treated with 0.3 mg/kg MK 801 died before the dosage form. completion of the experiment and the remaining rats in 4. The composition of claim 1 wherein the nontoxic the group showed apparently poor grooming and substance that inhibits the development of tolerance to weight loss indicating adverse effects of MK 801 on 20 and/or dependence on the narcotic analgesic is selected health. The rats treated with ganglioside GM or dex from the group consisting of dextromethorphan, dex trorphan continued to appear well groomed and did not trorphan, their mixtures and their pharmaceutically show weight loss. None of the rats in the GM1 or dex acceptable salts. trorphan treatment groups died due to drug administra 5. The composition of claim 4 wherein the narcotic tion. Thus, dextrorphan and GM 1 are nontoxic in con 25 analgesic is selected from the group consisting of co trast to MK 801 which exhibits severe cytotoxic effects deine, fentanyl, heroin, hydrocodone, morphine, oxyco and as such, is unlikely to be approved by the FDA for done, their mixtures and their pharmaceutically accept administration to humans. able salts. EXAMPLES 5 AND 6 6. The composition of claim 5 wherein the narcotic 30 analgesic is selected from the group consisting of co These examples illustrate the effects of the phenothi deine, fentanyl, heroin, hydrocodone, morphine, oxyco azine trifluoperazine (Example 5) and the na done, their mixtures and their pharmaceutically accept phthalenesulfonamide N-(6-aminohexyl)-5-chloro-1- able salts. naphthalenesulfonamide hydrochloride (Example 6) in 7. A method of inhibiting the development of toler preventing the development of morphine tolerance in 35 ance to and/or dependence on a narcotic analgesic ratS. administered to a mammal which is liable to addiction Calmodulin is an intracellular cofactor necessary for thereto which comprises administering the narcotic the nitric oxide pathway that can be initiated upon analgesic to the mammal before, with or following ad NMDA receptor activation. FIGS. 7-10 demonstrate ministration to the mammal of a tolerance-reducing that trifluoperazine (TFP) and N-(6-aminohexyl)-5- and/or dependence-reducing amount of at least one chloro-1-naphthalenesulfonamide hydrochloride (W-7), nontoxic substance that inhibits the development of both of which are calmodulin antagonists, effectively tolerance to and/or dependence on the narcotic analge prevent the development of morphine tolerance in rats sic, said nontoxic substance being selected from the following intrathecal administration. In both cases, rats group consisting of dextromethorphan, dextrorphan, receiving once daily morphine sulfate (10 ug) and saline 45 trifluoperazine, N-(6-aminohexyl)-5-chloro-1-naphtha injection given intrathecally for 7 consecutive days lene sulfonamide, their mixtures and their pharmaceuti developed tolerance to the analgesic effect of morphine cally acceptable salts. as indicated by the reliable decrease in tail-flick laten 8. The method of claim 7 wherein the narcotic anal cies as compared to baseline latencies (day 1). In con gesic is selected from the group consisting of alfentanyl, trast, rats treated with TFP or W-7 (100 or 50 nmol) 50 alphaprodine, anileridine, bezitramide, codeine, dihy given immediately before each morphine administration drocodeine, diphenoxylate, ethylmorphine, fentanyl, showed a reliable analgesic effect of morphine (day 8) heroin, hydrocodone, hydromorphone, , employing the same dose regimen used in the saline levomethorphan, levorphanol, metazocine, methadone, treatment group. The prevention of the development of metopon, morphine, opium extracts, opium fluid ex morphine tolerance by TFP or W-7 is dose-related: 55 tracts, powdered opium, granulated opium, raw opium, 100 =50 nmold 25 = 12.5 nmol. Each data point in tincture of opium, oxycodone, oxymorphone, pethidine, FIGS. 7-10 represents the mean of a group of rats phenazocine, piminodine, racemethorphan, racemor (n = 6) and standard errors are shown by vertical lines. phan, thebaine, their mixtures and their pharmaceuti The asterisks refer to statistical differences (a = 0.05) cally acceptable salts thereof. between the saline group and each other group. 9. The method of claim 7 wherein the nontoxic sub What is claimed is: stance that inhibits the development of tolerance to 1. A composition comprising a narcotic analgesic and and/or dependence on the narcotic analgesic is selected at least one nontoxic substance that inhibits the develop from the group consisting of dextromethorphan, dex ment of tolerance to and/or dependence on the narcotic trorphan, their mixtures and their pharmaceutically analgesic, said nontoxic substance being selected from 65 acceptable salts. the group consisting of dextromethorphan, dextror s: six k sk